block 3 - medico...

BLOCK 3 GASTROINTESTINAL, CARDIOVASCULAR &

RESPIRATORY SYSTEMS

COPYRIGHT MBBS NOTES © DATO FARID FADZILAH

First Edition

GASTROINTESTINAL SYSTEM

A. Drugs for Peptic Ulcer 1. Classify drugs used in acid peptic disease based on their mechanism of action. *** 2. Explain the role of following drugs in acid peptic disease: H2 blockers, proton pump

inhibitors (PPIs) and antacids. *** 3. List the uses of H2 blockers and proton pump inhibitors (PPIs).*** 4. Describe the role of the following drugs in acid peptic disease: sucralfate, colloidal

bismuth subcitrate (CBS), prostaglandin analogues and anticholinergics. ** 5. Describe the pharmacokinetic features of PPIs. *** 6. Explain the drug interaction between antacid/ H2 blocker/PPI and sucralfate. ***

(Tripathi) 7. List the adverse effects of the following: H2 blockers, PPIs and antacids. *** 8. List the adverse effects of the following: sucralfate and prostaglandin analogues. ** 9. Explain the rationale for using antacid combinations in acid peptic disease. *** 10. List the drugs used to eradicate H. pylori. *** 11. Explain the rationale for using US-FDA approved triple drug regimen for H. pylori

eradication. *** 12. Explain the role of each drug used in quadruple therapy for H. pylori eradication. **

B. Anti-emetics (Tripathi)

1. Classify antiemetics based on their mechanism of action. *** 2. Describe the mechanism of antiemetic action of the following: anticholinergics,

(Tripathi) 5HT3 antagonists,(tripathi) prokinetics and antihistaminics. *** 3. Describe the differences between metoclopramide and domperidone. *** 4. Explain how prokinetics are useful in gastroesophageal reflux disease. *** 5. List the adverse effects of the following: hyoscine, promethazine, metoclopramide and

ondansetron. *** 6. Explain the drug interaction between the following: metoclopramide and levodopa,

cisapride and CYP3A4 inhibitors.*** 7. Mention antiemetics of choice in the following: motion sickness, morning sickness,

cancer chemotherapy induced vomiting, drug induced vomiting, vertigo and gastric stasis in diabetes. ***

C. Anti-amoebic Drugs

1. Classify antiamoebic drugs based on their site of action. *** 2. Describe the mechanism of action of metronidazole. *** 3. Describe the therapeutic uses of metronidazole. *** 4. Describe the adverse effects of metronidazole. *** 5. Explain the drug interaction of metronidazole with alcohol. *** 6. Describe the advantages of tinidazole and secnidazole over metronidazole. *** 7. Explain the mechanism of action of diloxanide furoate. *** 8. Describe the therapeutic uses of diloxanide furoate. *** 9. Outline the treatment for the following: asymptomatic intestinal amoebiasis, invasive

intestinal amoebiasis and amoebic liver abscess. *** (Katzung)

D. Anti-helminthic Drugs 1. Describe the mechanism of action of the following: mebendazole/albendazole,

diethylcarbamazine citrate (DEC) and praziquantel. *** 2. List the therapeutic uses of the following: mebendazole, albendazole and DEC. *** 3. Describe the adverse effects of the following: mebendazole,albendazole and DEC. *** 4. Describe the advantages of albendazole over mebendazole. *** 5. Describe the advantages of using albendazole over praziquantel in the treatment of

neurocysticercosis. ** (Tripathi)

E. Drugs for Constipation 1. Classify laxatives and purgatives based on their mechanism of action. *** 2. Describe the mechanism of action of the following: bulk laxatives, lubricant laxatives,

surfactant laxatives,stimulant/irritant purgatives and osmotic purgatives. *** 3. List adverse effects of various classes of laxatives and purgatives. *** 4. Explain the therapeutic uses of lactulose. ** 5. List various indications for each class of laxatives and purgatives. *** 6. Describe purgative habit. **

F. Drugs for Diarrhoea

1. Describe the composition of WHO-ORS. *** 2. Describe the importance of each ingredient in ORS. *** (Tripathi) 3. List non-diarrheal uses of oral rehydration therapy. *** (Tripathi) 4. Describe cereal based ORS. ** 5. Classify non-specific antidiarrheal agents based on their actions.*** 6. List the drugs used in inflammatory bowel disease (IBD). ** 7. Discuss the role of sulfasalazine in IBD. ** 8. Describe the advantages of meselamine (mesalazine) over sulfasalazine. * 9. Explain the rationale for combining diphenoxylate with atropine in the treatment of

diarrhoea. *** 10. Explain the mechanism of action of antimotility and antisecretorydrugs. *** 11. Describe the advantages of loperamide over codeine as an antidiarrhoeal agent. ** 12. Describe adverse effects and contraindications of antimotility and antisecretorydrugs.

***

G. Drugs for Irritable Bowel Syndrome (IBS) 1. List various classes of drugs used in IBS with examples. * 2. Describe the role of alosetron in IBS. *

RENAL AND CARDIOVASCULAR SYSTEMS

A. Diuretics 1. Define diuretics. *** 2. Classify diuretics based on their site of action. *** 3. Explain the mechanism of action of following: loop diuretics, thiazides, potassium

sparing diuretics (amiloride/triamterene and spironolactone) and carbonic anhydrase inhibitors. ***

4. Describe the therapeutic uses of frusemide. *** 5. Describe the adverse effects of loop diuretics. *** 6. Explain the drug interactions of frusemide with digoxin, NSAIDs, aminoglycosides and

lithium. *** 7. Describe the therapeutic uses of thiazides. *** 8. Describe the adverse effects of thiazides. *** 9. Explain the drug interactions of thiazides with digoxin and lithium.*** 10. Describe the therapeutic uses of potassium sparing diuretics.*** 11. Describe the adverse effects of potassium sparing diuretics. ** 12. Explain the drug interaction of potassium sparing diuretics with angiotensin converting

enzyme inhibitors and thiazides/loop diuretics. *** 13. Describe the characteristic features of osmotic diuretics. *** 14. Explain the role of mannitol in cerebral edema and glaucoma.*** 15. List the other therapeutic uses of osmotic diuretics. *** 16. List the adverse effects and contraindications of osmotic diuretics. *** 17. Describe the therapeutic uses of carbonic anhydrase inhibitors.** 18. Describe the adverse effects of carbonic anhydrase inhibitors.**

B. Vasopressin analogues

1. List ADH receptor agonists (vasopressin analogues).** 2. Describe the therapeutic uses of vasopressin and its analogues based on V1 & V2

receptor-mediated actions.** 3. Describe the adverse effects of vasopressin and its analogs. *

C. Drugs Affecting Renin Angiotensin Aldosterone System (RAAS)

1. Draw RAAS cascade and indicate sites of action of groups of drugs with examples that inhibit the cascade. ***

2. Describe the advantages of enalapril over captopril. ** 3. Explain the therapeutic uses of ACE inhibitors. *** 4. Describe the adverse effects of ACE inhibitors. *** 5. Explain the drug interactions of ACE inhibitors with NSAIDs and potassium sparing

diuretics. *** 6. Describe the differences between ARBs and ACE inhibitors. ***

D. Drug therapy of hypertension 1. Depict physiological mechanisms that control blood pressure and indicate the sites of

action of various classes of antihypertensive drugs. *** 2. Explain the antihypertensive action of the following: thiazides, beta blockers, ACE

inhibitors, ARBs, calcium channel blockers (CCBs), clonidine, methyldopa, hydralazine, minoxidil, diazoxide and fenoldopam. ***

3. List the indications of frusemide in hypertension. *** 4. Explain why frusemide is a weaker antihypertensive than thiazides. *** 5. Describe advantages of CCBs over other vasodilators as antihypertensive drugs.*** 6. Describe the differences between verapamil/diltiazem and dihydropyridines. *** 7. Describe the pharmacokinetic features of amlodipine. *** 8. Describe the adverse effects of the following: verapamil, diltiazem and nifedipine. *** 9. List other uses of CCBs 10. List the adverse effects of clonidine and methyldopa. *** 11. Explain the rationale for using the following drug combinations in the treatment of

hypertension:***

Vasodilator and beta blocker

ACE inhibitor/ARB and diuretic

ACE inhibitor/ARB and beta blocker 12. Describe the antihypertensive action of prazosin. *** 13. Describe the therapeutic uses of minoxidil. ** 14. List the adverse effects of hydralazine and minoxidil. ** 15. Discuss the role of sodium nitroprusside in the treatment of hypertension. *** 16. Describe the treatment of hypertensive emergencies. *** 17. Choose the appropriate drug(s) to treat hypertension in the following: diabetes,

pregnancy, elderly patients, peripheral vascular disease, migraine, benign prostatic hypertrophy, coronary artery disease, CCF, supraventricular tachycardia, thyrotoxicosis, hyperlipidemia and bronchial asthma/COPD. ***

18. List the antihypertensive drugs to be avoided in the following: diabetes, pregnancy, peripheral vascular disease, benign prostatic hypertrophy, coronary artery disease, CCF, thyrotoxicosis, hyperlipidemia and bronchial asthma/COPD***

E. Anti-arrhythmic Drugs

1. Describe various types of arrhythmias. ** 2. Classify antiarrhythmic drugs as proposed by Vaughan Williams and Singh. *** 3. Describe the mechanism of action of class I, class II, class III and class IV antiarrhythmic

drugs. *** 4. Explain the role of lignocaine in arrhythmias. *** 5. List the adverse effects of lignocaine. *** 6. List the adverse effects of amiodarone. *** 7. Discuss the role of adenosine in arrhythmias. *** 8. List the other drugs used in paroxysmal supraventricular tachycardia. ***

F. Drugs used in angina pectoris and myocardial infarction 1. Classify antianginal drugs based on their mechanism of action.*** 2. List the drugs used for chronic prophylaxis of angina. *** 3. List the drugs used to terminate an attack of angina. *** 4. Describe the mechanism of action of nitrates. *** 5. Explain the mechanism of relief of chest pain with nitrates in classical angina. *** 6. Describe the mechanism of relief of chest pain with nitrates in variant angina. *** 7. Describe the important pharmacokinetic features of the following: nitroglycerine,

isosorbide dinitrate and isosorbide mononitrate.*** 8. Describe the therapeutic uses of nitrates with route of administration. *** 9. Explain the management of acute attack of angina. *** 10. Explain the role of nitrites in cyanide poisoning. *** 11. Describe the adverse effects of nitrates. *** 12. Describe the drug interaction of nitrates with sildenafil and other vasodilators. *** 13. Explain how CCBs are effective in classical, variant and unstable angina. *** 14. Explain the rationale for using beta blockers in angina. *** 15. Explain why beta blockers are contraindicated in variant angina.*** 16. Explain the rationale for using various drug combinations in angina. *** 17. Explain the role of following drugs in angina: K+ channel openers, trimetazidine,

ranolazine, ivabradine, antiplatelet drugs and statins. ** 18. Outline the drug therapy of myocardial infarction. ***

G. Drug therapy of Heart Failure

1. Classify drugs used in the treatment of heart failure based on their mechanism of action. ***

2. Explain the mechanism of action of digitalis. *** 3. Explain the pharmacological actions of digitalis on the following: heart, blood vessels

and kidney. *** 4. Describe the role of digitalis in the treatment of acute heart failure. *** 5. List the other therapeutic uses of digitalis. *** 6. Describe the adverse effects of digitalis. *** 7. Explain the management of digitalis toxicity. *** 8. Describe the contraindications of digitalis. *** 9. Explain the important drug interactions of digitalis. *** 10. Explain the role of phosphodiesterase III inhibitors in the treatment of heart failure. ** 11. Explain the role of the following drugs in the treatment of heart failure: diuretics, ACE

inhibitors/ARBs, beta blockers, vasodilators, dopamine and dobutamine. ***\Describe the role of furosemide in the treatment of acute pulmonary edema. ***

12. Describe the role of vasopeptidase inhibitors, natriuretic peptides and vasopressin receptor antagonist in the treatment of heart failure. **

13. List the drugs used for the relief of congestive symptoms of heart failure. *** 14. List the drugs that arrest/ reverse disease progression in heart failure. ***

RESPIRATORY SYSTEM

A. Drugs for Bronchial Asthma 1. Classify drugs used in the treatment of bronchial asthma based on their mechanism of

action. *** 2. Explain the role of following drugs in bronchial asthma: beta-2 agonists,

anticholinergics and mast cell stabilisers. *** 3. Describe the adverse effects of beta-2 agonists. *** 4. Describe the mechanism of action of methylxanthines. ** 5. Describe the important pharmacokinetic features of theophylline. ** (Tripathi) 6. Describe the therapeutic uses of methylxanthines. ** 7. Describe the adverse effects of methylxanthines. ** 8. Discuss the role of glucocorticoids in bronchial asthma. *** 9. Describe the role of following drugs in asthma: leukotriene receptor antagonists and

omalizumab. ** 10. Describe the other therapeutic uses of mast cell stabilisers. *** 11. List the adverse effects of the following: mast cell stabilisers and leukotriene receptor

antagonists. ** 12. Describe the advantages of using MDI with spacer.[Tripathi] 13. Describe the other devices used to administer inhalational drugs in asthma.

***[Tripathi] 14. Describe the management of different types of asthma. ***[Tripathi]

B. Drugs for Cough

1. Describe the mechanism of action of the following: expectorants and antitussives. *** 2. List the adverse effects of the following: expectorants and antitussives. *** 3. Describe the advantages of dextromethorphan and noscapine over codeine in the

treatment of cough. *** 4. Describe the role of following drugs in the treatment of cough: antihistamines and

bronchodilators. ** [Tripathi] 5. List the drugs used in the treatment of productive cough and non-productive cough.

***

C. Anti-tubercular Drugs 1. Enumerate first line essential, first line supplemental and second line antitubercular

drugs. *** 2. Describe the mechanism of action of the following: isoniazid (INH), rifampicin,

pyrazinamide and ethambutol. *** 3. Describe the pharmacokinetic features of INH. *** 4. Describe the adverse effects of the following: INH, rifampicin, pyrazinamide and

ethambutol. *** 5. Explain the rationale for using pyridoxine with INH. *** 6. Describe the important drug interactions of rifampicin. *** 7. List the other therapeutic uses of rifampicin. ** 8. Describe the goals of antitubercular chemotherapy. *** [Tripathi] 9. Discuss short course chemotherapy of new sputum positive pulmonary tuberculosis

(category I TB). ***

D. Anti-leprotic Drugs 1. Enumerate drugs used in leprosy. ** 2. Describe the mechanism of action of dapsone and clofazimine.** 3. Describe the adverse effects of dapsone. ** 4. Explain WHO regimens for multibacillary and paucibacillary leprosy. ** 5. List the drugs used in treatment of lepra reaction. **

GASTROINTESTINAL SYSTEM

DRUGS FOR PEPTIC ULCER

PEPTIC ULCER

NORMAL MECHANISM OF ACID SECRETION

The basolateral membrane of parietal cell contains receptors for Gastrin (CCK2 receptor) released from G cells in pyloric glands Histamine (H2 receptor) released from enterochromaffin-like cells (ECL cells) Acetylcholine (M3 receptor) released from vagal efferents

H2 receptors result in an increase in cAMP levels but M3 and CCK2 receptors act by stimulating phospholipase C mobilizes intracellular Ca2+

Gastrin is secreted in response to: Increase in antral pH Food constituents Vagally mediated reflexes involving ENS ganglion cells release gastrin releasing

peptide (GRP) and Acetylcholine

Surface epithelial cells secrete HCO3- which gets trapped in the mucous layer over the mucosal

surface, offering protection against harsh acid condition (stabilized by trefoil peptide) Prostaglandins augment mucous and HCO3

- secretion gives cytoprotective effect PGE2 also inhibits acid secretion by opposing cAMP generation via EP3 receptors (in

parietal cells) and gastrin release (from antral G cells)

The chief cells/peptic cells release pepsinogen which in on acidic medium (pH<2) is cleaved to form pepsin, a proteolytic enzyme

PEPTIC ULCER DISEASE

A localized defect extending at least into the submucosa as a result of acid and pepsin attacks

Usually develops on a background of chronic gastritis, as a result of the imbalance between mucosal defences and damaging forces

Major sites: 1st part of duodenum Junction of antral and body mucosa Distal oesophagus (as a result of GERD or ectopic gastric mucosa) Gastro-enterostomy sites

Defensive forces: Surface mucous secretion Bicarbonate secretion Mucosal blood flow Apical surface membrane transport Epithelial regenerative capacity Elaboration of prostaglandins

AETIOPATHOGENESIS

Helicobacter pylori infection Flagella for motility in viscous mucous Urease generates NH3 from urea elevates pH Adhesins increased bacterial adherence to surface epithelial cells Toxins eg. CagA in ulcer and cancer development

NSAIDs Interfere with cytoprotection provided by prostaglandins Reduces HCO3

- secretion

Alcohol direct cellular injury

Gastric hyperacidity eg. in parietal cell hyperplasia, excessive secretory responses, Helicobacter pylori infection, Zollinger-Ellison syndrome (excess gastin release)

Chronic renal failure and hyperparathyroidism results in hypercalcaemia stimulates gastrin production increases acid secretion

Self-imposed/exogenous psychological stress directly increases gastrin acid secretion

Smoking increases nervous stimulation of stomach secretory glands CLINICAL FEATURES & COMPLICATIONS

Epigastric burning and aching pain

Perforation into adjacent cavity peritonitis

Penetration into adjacent organ eg. liver, pancreas

Haemorrhage from eroded vessels in the ulcer base

Anaemia

Obstruction due to fibrous strictures

Malignant transformation (rare)

CLASSIFICATION OF DRUGS USED IN PEPTIC ULCER

Mechanism of action Drugs

Neutralize gastic acid (antacids)

Systemic antacids: Sodium bicarbonate

Non-systemic antacids: Buffer type: Aluminium hydroxide, Magnesium trisilicate,

Magaldrate Non-buffer type: Magnesium hydroxide, Calcium carbonate Miscellaneous: Alginates, Simethicone

Reduce gastric acid secretion

H2 receptor antagonists: Cimetidine, Ranitidine, Famotidine, Nizatidine, Roxatidine, Loxatidine

Proton pump inhibitors: Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole, Esomeprazole

Anti-cholinergics: Propantheline, Oxyphenonium, Pirenzepine, Telenzepine

Prostaglandin analogues: Misoprostol, Enprostil, Rioprostil

Mucosal protective drugs

Sucralfate, Colloidal bismuth subcitrate, Ranitidine bismuth citrate

Ulcer healing drugs Carbenoxolone

Anti-Helicobacter pylori drugs

Amoxicillin, Clarithromycin, Tetracycline, Metronidazole, Ranitidine bismuth citrate, Bismuth subsalicylate and proton pump inhibitors (in combination)

ANTACIDS

THERAPEUTIC USES

Antacids are weak bases that neutralize gastric HCl, thereby raising the pH of stomach contents, decreasing the acid load delivered to duodenum and reducing activity of pepsin

Minor contributions: Stimulation of PGE2 and PGI2 production by gastric mucosa Also enhances mucosal blood flow, stimulate secretion of mucous and HCO3

- Partly from a protective layer over gastric mucosa

ADVERSE EFFECTS

Distension and belching (bloating) Due to production of CO2 Belching occurs only on using CaCO2 and NaHCO3 No belching occurs on using Mg(OH)2 or no CO2 produces

Hypercalcaemia, renal insufficiency and metabolic alkalosis Excessive dose of CaCO3, given along with milk These are called “milk-alkali syndrome”

Metabolic alkalosis Increased pH of blood and urine Unreacted alkali such as NaHCO3 get readily adsorbed from gastrointestinal lumen

Exacerbation of fluid retention in patients with hypertension, congestive heart failure and renal insufficiency Due to ↑ Na+ load, as it is highly water soluble and rapidly absorbed from the gut

Acid rebound or “rebound acidity” Due to ↑pH (>4.0) Cause reflux secretion of gastrin which stimulates acid production

RATIONALE FOR USING ANTACID COMBINATION IN PEPTIC ULCER DISEASE Advantages of combination of Magnesium salts and Aluminium salts

1. A prompt and sustained effects produced, because

Mg hydroxide fast acting

Al hydroxide slow acting 2. Bowel movement is least affected, because

Mg salts cause diarrhoea

Al salts cause constipation

Hence, both are used together to minimize the impact of bowel movement 3. Gastric emptying is least affected, because

Mg salts enhances the gastric emptying

Al salts delays the gastric emptying 4. Drug combination reduces the dose of the drug, thus reduces their toxicity

H2 RECEPTOR ANTAGONISTS

DRUGS Cimetidine, Ranitidine, Famotidine, Nizatidine, Roxatidine, Loxatidine MECHANISM OF ACTION

Competitively inhibits H2 receptors on parietal cells and suppress basal and food stimulated acid secretion

Block actions of histamine released from ECL cells

Also inhibits direct stimulation on parietal cells by gastrin or Acetylcholine

Results in marked decrease in gastric secretion (long duration) and pepsin production (short duration)

Rank order of potency of the drugs: Nizatidine > Famotidine > Ranitidine > Cimetidine

Nizatidine, Famotidine and Ranitidine are newer drugs, while Cimetidine is the earliest drug THERAPEUTIC USES

Gastroesophageal reflux disease (GERD)

Duodenal and gastric ulcers

NSAIDs induced ulcers

Prevention of stress related gastric bleeding

Prevention of ulcer recurrence

Zollinger-Ellison syndrome (widespread severe peptic ulceration)

Chronic urticarial ADVERSE EFFECTS

Extremely safe drugs

Headache, fatigue, myalgia and constipation may occur, but rarely

Mental status changes may occur with I.V. Cimetidine only

Endocrinal effects are seen in Cimetidine only It inhibits the binding of dihydrotestosterone to androgen receptors causing

impotence in males) It inhibits metabolism of estradiol and increases serum prolactin level causing

gynaecomastia in males and galactorrhoea in females (on long term use)

H2 blockers reduce the secretion of intrinsic factor but no vitamin B12 deficiency occurs even after prolonged use

They cross placental barrier but have no harmful effects on foetus

They are secreted into breast milk, hence should be provided during pregnancy and lactation

PROTON PUMP INHIBITORS

DRUGS Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole, Esomeprazole PHARMACOKINETICS

Absorption occur in intestine

Drug is given orally as enteric coated formulation

Pantoprazole can be both oral and I.V.

Bioavailability of respective drugs:

Food decreases their bioavailability: Drugs should be administered on an empty stomach However, in fasting state, only 10% proton pumps are active, rest are in dormant state Therefore, drugs must be administered in the morning before taking breakfast This is because peak serum concentration coincides with the maximum activity of

proton pumps Optimal binding of proton pumps to PPIs occurs when pumps are in active state

They require acid for activation therefore, other acid suppressing agents are not co-administered

The drugs are highly protein bound

Short serum half-life: 1-2 hours However, duration of acid inhibition lasts upto 24 hours It is because PPIs are irreversible inactivator, so at least 18 hours is needed for the

synthesis of new H+/K+–ATPase pump

Rapid first pass metabolism

Metabolized by liver

In case of liver impairment, dose reduction is needed

Excretion is through urine and faeces ROLES OF PPIs

Mainly decrease acid secretion

Also inhibit gastric mucosal carbonic anhydrase

Hence decrease HCO3- secretion in mucous

Features of PPIs Prodrug Active form is sulfonamide cation Weak base Irreversible binding

MECHANISM OF ACTION

PPIs enter parietal cell from blood by passive diffusion across lipid membrane ↓

In canaliculi of parietal cells, PPIs (weak base) which are exposed to acidic environment get concentrated by ion trapping mechanism, where they are activated

↓ Formation of sulfonamide cation (activated form)

↓ They bind covalently with sulfhydryl group of cysteines from extracellular domain H+/K+–ATPase

pump ↓

Inactivating it irreversibly and shutting off acid secretion

Acid secretion will only resume after newly synthesized pumps are inserted into luminal membrane of parietal cells

THERAPEUTIC USES

Duodenal and gastric ulcer disease

Gastroesophageal reflux disease (GERD)

NSAIDs induced ulceration

Prevention of ulcer recurrence

Zollinger-Ellison syndrome

Helicobacter pylori associated ulcers PPIs promote eradication of Helicobacter pylori by raising the intragastric PH which

helps in lowering the minimal inhibitory concentration (MIC) of antibiotics used against Helicobacter pylori

Most effective regimen of Helicobacter pylori eradication is a combination of two antibiotics and one PPI given twice daily

ADVERSE EFFECTS

PPIs are quite safe, yet diarrhoea, headache and abdominal pain may occur

They cross BBB, but not teratogenic

However, their safety during pregnancy and lactation has not been established

PPIs inhibit absorption of vitamin B12 on prolonged use

PPIs cause hypochlorhydria, theoretically, should increase the risk of enteric infections due to Shigella and Salmonella and by bacterial strains that have the potential to convert ingested nitrates into carcinogenic nitrites and nitrosamines

Increased risk of gastric neoplasia on prolonged use Suppressed gastric HCl secretion Feedback inhibitory role of stomastatin over gastrin release is endangered Gastrin level rise 2-4 fold in patients taking PPIs Gastrin causes hyperplasia of ECL cells which may transform into carcinoid tumour

Increased risk of chronic inflammation of gastric body with prolonged use of PPIs, in patients with Helicobacter pylori associated peptic ulcers which culminate into atrophic gastritis and intestinal metaplasia

SUCRALFATE

It is an aluminium salt of sulfated sucrose

Unabsorbed, hence devoid of side effects

However, as it also binds phosphate ions in intestine, hypophosphataemia may occur

Antacids lower its efficacy as polymerization only occurs in acidic media

Sucralfate adsorbs Tetracyclines, Fluoroquinolones, H2 blockers, Phenytoin and Digoxin hence decrease their absorption

MECHANISM OF ACTION

1. In acidic environment (pH<4), it polymerizes by cross-linking of molecules forms a sticky-like gel over ulcer crater which acts as acid-resistant barrier

2. Dietary as well as mucosal proteins also get adsorbed over this coat, forming another layer to provide further resistance

3. There is evidence that suggest it also stimulates mucosal PGE2 synthesis and HCO3- secretion

4. It is also believed to bind epithelial as well as fibroblast growth factors which promotes mucosal repair

5. Promotes ulcer healing (but it has no acid neutralizing action and delays gastric emptying), but not effective against NSAIDs-induced ulcers

ADVERSE EFFECTS

Hypophosphataemia

Constipation

Dry mouth

Nausea DRUG INTERACTION WITH ANTACIDS

Antacids should not be taken with Sucralfate because its polymerization is dependent on the pH of the acid Sucralfate polymerizes at pH <4 by cross-linking of molecules Antacids neutralize gastric acid and raise pH of gastric contents Hence, this combination is not synergistic

Antacids given concurrently reduce the efficacy of Sucralfate

COLLOIDAL BISMUTH SUBCITRATE

In gastric acidic media, it forms an acid-protective coating over ulcer base

Reported to stimulate PGE2, mucous and HCO3- secretion

It dislodges Helicobacter pylori from the surface of gastric mucosa and has direct antimicrobial activity against this organism

Many duodenal ulcer cases which did not heal after H2 blocker treatment, get healed after 4 subsequent weeks treatment with Colloidal bismuth

Heals peptic ulcer within 4-8 weeks of treatment

Given orally, excellent safety profile (but can cause blackening of stool & darkening of tongue)

On prolonged use, Bismuth toxicity can occur (osteodystrophy, encephalopathy and albeit)

Antacids reduce its efficacy

Another bismuth salt used in clinical practice is Ranitidine bismuth citrate, which upon hydrolysis by gastric acid releases Bismuth as well as Ranitidine

Currently used as one of the agents in an anti-Helicobacter pylori treatment regimen

PROSTAGLANDIN ANALOGUES

DRUGS Misoprostol, Enprostil, Rioprostil MECHANISM OF ACTION They mimic the protective role of PGE2 and PGI2 on gastric mucosa by:

Inhibiting acid secretion by inhibiting CAMP in parietal cells

Inhibiting gastrin release from antral cells (G cells) ↓ intracellular Ca2+ and histamine release ↓ acid secretion

Stimulating the secretion of mucous and HCO3-

Acts as a buffer to neutralize the acid secreted Reinforce the protective effects of mucous layer covering gastric and duodenal mucosa

Enhances mucosal blood flow MISOPROSTOL

Used to heal peptic ulcer in patients using NSAIDs and in chronic heavy smokers

But not widely accepted due to its adverse effects and a need for multiple daily dosing due to short plasma half-life of 25-30 minutes

PPIs are equally effective and better tolerated for this indication ADVERSE EFFECTS

Diarrhoea and colicky pain (because it increases water and electrolyte secretion in intestine)

Other GIT side effects include nausea, vomiting and flatulence

Headache and dizziness can occur

It causes uterine contraction and uterine bleeding (hence should not be given to pregnant or women that may become pregnant)

ANTI-CHOLINERGICS

SELECTIVE M1 RECEPTOR BLOCKERS

Examples: Pirenzepine, Telenzepine

They block M1 receptor of paracrine cells in gastric mucosa ↓ histamine release ↓ acid secretion

Effectively heals and prevent recurrence of duodenal ulcers

Side effects: Dry mouth Blurred vision Constipation Urinary retention

No CNS side effects as they do not cross BBB NON-SELECTIVE ANTI-MUSCARINICS

Examples: Propantheline, Oxyphenonium

They are not used to treat peptic ulcer anymore because of: Peripheral side effects: dry mouth, blurred vision, constipation, urinary retention Increase gastric emptying time prolong exposure of ulcer bed to gastric acid Increase gastric emptying time and relax lower oesophageal sphincter exacerbate

GERD by allowing food reflux into oesophagus

DRUG REGIMEN

DRUG COMBINATIONS

a) Triple therapy (14 days)

Omeprazole (or Lansoprazole) + Clarithromycin + Amoxicillin (or Metronidazole)

Ranitidine bismuth citrate + Tetracycline + Metronidazole (or Clarithromycin) b) Quadruple therapy (14 days)

Omeprazole (or Lansoprazole) + Bismuth subsalicylates + Metronidazole + Tetracycline c) Sequential therapy (10 days)

For first 1-5 days, Omeprazole (or Lansoprazole) + Amoxicillin

For next 6-10 days, Omeprazole (or Lansoprazole) + Clarithromycin + Tinidazole TRIPLE THERAPY REGIMEN

Has comparable success rates that are desired

Combination therapy for 14 days provides greatest efficacy compared to 7-10 days short term regimen

Efficacious combination should provide eradication rate of >90% ROLE OF EACH DRUG IN QUADRUPLE THERAPY REGIMEN

Omeprazole Inactivate proton pump irreversibly and shutting off acid secretion

Inhibits gastric mucosal carbonic anhydrase and reduces HCO3- secretion

to mucous

Bismuth subsalicylate

Dislodges Helicobacter pylori from surface of gastric mucosa

Direct antimicrobial activity against this organism

Gets converted to Bismuth oxychloride and Bismuth citrate with chelate glycoproteins and amino acids at ulcer base to form acid resistant protective coating

Metronidazole

Metronidazole enters the microorganism

Nitro group in Metronidazole acts as electron acceptor

Nitro group is reduced by ferredoxins

Binds to microorganism protein

Disrupts replication, transcription and repair process of DNA

Causes cell death (bactericidal activity)

Tetracycline

Broad spectrum antibiotics

The drug passes through outer membrane of Gram negative bacteria by diffusing through porin channel

Binds reversibly to 30S ribosomal subunit

Prevents binding of aminoacyl tRNA to mRNA ribosomal complex

Prevents the addition of amino acid to the growing peptide chain

Inhibits bacterial protein synthesis (bacteriostatic activity)

ANTI-EMETICS

ANTI-EMETICS BASED ON THEIR MECHANISM OF ACTION

Anti-cholinergics (M1 blocker) Hyoscine (Scopolamine)

Dicyclomine

H1 anti-histaminics (Anti-cholinergic + anti-serotonin +

Ca2+ channel blocker)

Promethazine

Diphenhydramine

Dimenhydrinate

Doxylamine

Cyclizine

Meclizine

Cinnarizine

Neuroleptics (D2 blocker)

Chlorpromazine

Triflupromazine

Prochlorperazine

Haloperidol

Prokinetic drugs

Metoclopramide

Domperidone

Cisapride

Mesapride

Itopride

5-HT3 antagonist

Ondansetron

Granisetron

Palonosetron

Ramosetron

NK1 receptor antagonist Aprepitant

Foxaprepitant

Adjuvant emetics

Dexamethasone

Benzodiazepines

Dronabinol

Nabilone

DRUGS MECHANISM OF ACTION

Anticholinergics Hyoscine Dicyclomine

Blocking conduction of nerve impulse across a cholinergic pathway from vestibular apparatus to the vomiting centre

Has poor efficacy of vomiting of other aetiology

H1 anti-histaminics

Promethazine Diphenhydramine Dimenhydrinate

Effects are based on anti-cholinergic, anti-histaminic, weak anti-dopaminergic, and sedative properties

Central anti-cholinergic action block the extrapyrimidal side effect of metoclopramide while supplementing its anti-emetic effect

Promethazine has weak anti-dopaminergic action

Cinnarizine Inhibits influx of Ca2+ from endolymph into the vestibular sensory cell which mediates labyrinthine reflexes

Neuroleptics Prochlorperazine

Act by blocking D2 receptor in the CTZ

Antagonize apomorphine induced vomiting

Additional anti-muscarinic, M1 as well as H1 anti-histaminic properties

Prochlorperazine is a labyrinthine suppressant

Prokinetics drug Metoclopramide D2 antagonist: It inhibits the dopamine receptor thus causing increase in acetylcholine release at primary cholinergic neuron

5-HT4 agonist: Activation of 5-HT4 receptor at excitatory interneuron, thus enhance acetylcholine release by myenteric motor neuron

5-HT3 antagonist: At high concentration, it block 5-HT3 receptor at inhibitory interneuron, thus suppress NO release, thus enhance acetylcholine release by myenteric motor neuron

All of this then lead to increase in LES tone, facilitate gastric peristalsis and speed up gastric emptying

Domperidone Similar to metoclopramide

Peripheral D2 receptor blocker

Cisapride 5-HT4 agonist action which promote acetylcholine release form myenteric plexus aided by 5-HT3 antagonism

5-HT3 antagonist Ondansetron Granisetron Palonosetron

Block the depolarizing action of 5-HT exerted through 5-HT3 receptor on vagal afferent in the GIT as well as NTS and CTZ

Blocks emertogenic impulses arised in GIT

METOCLOPRAMIDE

MECHANISM OF ACTION

It is a D2 receptor antagonist, 5-HT3 receptor antagonist and 5-HT4 receptor agonist

Central actions (anti-emetic effect): Mainly due to blockade of D2 receptor in CTZ At high concentration, it also blocks 5-HT3 receptor in CTZ It also blocks D2 receptor in basal ganglia causes extrapyramidal symptoms

Peripheral action (prokinetic effect): Activation of 5-HT4 receptor present in excitatory interneurons enhance Acetylcholine

release from primary cholinergic neuron in myenteric plexus (major mechanism) Due to blockade of D2 receptor, Dopamine loss its inhibitory control over Acetylcholine

release from primary cholinergic neuron in myenteric plexus Blockade of 5-HT3 receptor on inhibitory interneurons (in high doses only) suppress the

release of NO, which indirectly facilitates Acetylcholine release in myenteric plexus

Metoclopramide

D2 receptor antagonist ↓

Acts on myenteric neuron ↓

↓ inhibitory action on myenteric motor neuron

5-HT3 receptor antagonist ↓

Acts on inhibitory ENS interneuron (IEI)

↓ ↓ release of NO from IEI

5-HT4 receptor agonist ↓

Acts on excitatory ENS interneuron (EEI)

↓ ↑ release of Acetylcholine from

EEI

↑ Acetylcholine release from myenteric motor neuron ↓

↑ smooth muscle contraction ↓

Effects

Increases LES tone

Facilitates gastric peristalsis

Speeds up gastric emptying

PROKINETIC AGENTS Drugs that enhance the co-ordinated activity among various segments of the gut to propel luminal content

1. Stimulate GIT motility 2. Increase lower oesophageal sphincter pressure (hence useful for GERD) 3. Speed up gastric emptying (hence useful in gastroparesis) 4. Stimulate small intestine (hence beneficial for post-operative paralytic ileus and

colonic pseudo-obstruction) 5. Enhance colonic transit time (hence useful for treating constipation)

ADVERSE EFFECTS As Metoclopramide being a central and peripheral D2 blocker, it produces:

Drowsiness

Dizziness

Diarrhoea

Sedation

Muscle dystonias can be treated with centrally acting anti-cholinergics (Benzhexol) or anti-histaminics with anti-cholinergic action (Promethazine)

Extrapyramidal side effects (in high doses) like tremor and rigidity – due to blockade of D2 receptor in basal ganglia

Galactorrhoea in female

Gynaecomastia in male

Menstrual irregularities METOCLOPRAMIDE & LEVODOPA

Metoclopramide acts centrally and peripherally D2 receptor antagonist 5-HT3 receptor antagonist (only at high doses) 5-HT4 receptor agonist

By blocking Dopamine receptor in basal ganglia, it abolishes therapeutic effect of Levodopa

Hence, peripheral acting anti-emetic drug is more preferable to treat Levodopa-induced vomiting

Due to blockade of inhibitory effect of Dopamine on Prolactin release (on long term use)

DOMPERIDONE

MECHANISM OF ACTION

It is a prokinetic drug

Mechanism of action is similar to Metoclopramide

However, its anti-emetic efficacy is lower than Metoclopramide

Domperidone

D2 receptor antagonist ↓

Acts on myenteric neuron ↓

↓ inhibitory action on myenteric motor neuron







EEI



Effects

Increases LES tone


Speeds up gastric emptying DIFFERENCES BETWEEN METOCLOPRAMIDE & DOMPERIDONE

Metoclopramide Domperidone

Rapidly absorbed after oral administration

Usually oral but oral bio-availability is low (extensive first pass metabolism)

More potent and efficacious Less potent and less efficacious

Extrapyramidal side effect main Lack of extrapyramidal side effect

Penetrate/cross BBB Poorly cross BBB

CISAPRIDE

MECHANISM OF ACTION

No D2 receptor blocking properties

Hence, does not act on CTZ

Thus, facilitates GIT motility with no anti-emetic action

Cisapride







EEI



Effects

Increases LES tone


Speeds up gastric emptying CISAPRIDE & CYP3A4 INHIBITOR

Cisapride is primarily inactivated by CYP3A4

Administration of CYP3A4 inhibitor causes significant rise in Cisapride plasma level

At high concentration, Cisapride blocks delayed rectifying K+ channels in the heart

Thus, prolongs QT interval and predisposes to ventricular fibrillation

New congeners like Mosapride, Renzapride and Zacopride are preferred as they do not cause QT prolongation or arrhythmias

PROKINETICS IN GASTROESOPHAGEAL REFLUX DISEASE (GERD)

Metoclopramide, Cisapride and other prokinetics drug may relieve regurgitation and heartburn by: Increasing LES tone Improving esophageal clearance Facilitate gastric emptying Do not affect gastric acidity or promote healing of oesophagitis

Symptoms control afforded by prokinetics is much inferior compared to PPIs/H2 blockers. Their use in GERD has declined. It is now co-prescribed with PPIs/H2 blockers

ADVERSE EFFECTS

DRUGS ADVERSE EFFECTS

Hyoscine

(Scopolamine)

Sedation, dryness of mouth, blurred vision, cyclopegia, sedation, sleepiness and other anti-cholinergic side effects

Promethazine Sedation, dryness of mouth, nausea, vomiting

Metoclopramide

Usually-well tolerated Sedation, dizziness, loose stool, muscle dystonias (especially in

children) Long term effects: parkinsonism, galactorrhoea, gynaecomastia, no

teratogenic effect, but suckling infant may develop loose motion, dystonias, myoclonus

Ondansetron

Usually well-tolerated Most common: headache and dizziness Mild constipation, abdominal discomfort Hypotension, bradycardia, angina, and allergic reaction (especially

after I.V.)

ANTI-EMETICS OF CHOICE

CAUSE OF VOMITING PREFERRED DRUG

Motion sickness

Anti-cholinergics

Anti-histaminics

Anti-dopaminergic

Anti-HT3 drug

Morning sickness

Promethazine

Neuroleptics (Prochloperazine)

Metoclopramide (in low dose)

Dicyclamide

* Most cases of morning sickness can be managed by reassurance and dietary adjustment

Cancer chemotherapy induced vomiting

Ondansetron (prototype drug)

Aprepitant

Promethazine + Metoclopramide or Domperidone

Neuroleptics (Prochloperazine)

Drug-induced vomiting Neuroleptics (Prochloperazine)

Metoclopramide

Ondasetron

Vertigo Prochloperazine

Gastric stasis in diabetes Metoclopramide

first drug of choice

less effective

ANTI-AMOEBIC DRUGS

CLINICAL PRESENTATIONS OF AMOEBIASIS

Asymptomatic intestinal infection: carriers, passing cysts

Mild to moderate intestinal disease: non-dysenteric colitis

Severe intestinal infection

Hepatic abscess, amoeboma and other extra-intestinal disease CLASSIFICATION OF ANTI-AMOEBIC DRUGS

Luminal amoebicides Amides: Diloxanide furoate 8-Hydroxyquinolines: Iodoquinol Antibiotics: Paromomycin, Tetracyclines

Tissue amoebicides a) For intestinal and extra-intestinal amoebiasis

Nitroimidazoles: Metronidazole, Tinidazole, Ornidazole, Secnidazole, Satranidazole

Alkaloids: Emetine, Dehydroemetine b) For extra-intestinal amoebiasis only

Chloroquine

METRONIDAZOLE (PRODRUG)

MECHANISM OF ACTION

Drug of choice for intestinal and extra-intestinal amoebiasis

Acts on trophozoites

Has no effect on cysts

Nitro group of metronidazole is reduced by protozoan (ferredoxin) leading to cytotoxic reduced product that binds to DNA and proteins resulting into parasite death

THERAPEUTIC USES

Extra-luminal amoebiasis (combined with luminal amoebicide)

Trichomoniasis

Giardiasis

Broad spectrum of anaerobic bacteria eg. Helicobacter pylori infection, pseudomembranous colitis (Clostridium difficile), pelvic inflammatory disease and lung abscess

Amoebic brain abscess

Vincent’s angina

Prophylaxis after colorectal surgery

Helps in removal of guinea worm

ADVERSE EFFECTS

GIT: nausea, vomiting, dry mouth, metallic taste, diarrhoea

CNS: neurotoxicological effect Insomnia, dizziness Peripheral neuropathy, paresthesia Encephalopathy, convulsion (I.V. infusion, rare)

Dysuria, dark urine

Neutropenia

Disulfiram-like effect if taken with alcohol DRUG INTERACTIONS Metronidazole x Alcohol

When metronidazole is given with alcohol abdominal distress, nausea, vomiting, flushing or headache, tachycardia, hyperventilation

Metronidazole blocks aldehyde dehydrogenase enzyme

Ethanol Acetyldehyde Acetate OTHER DRUGS Tinidazole, ornidazole, secnidazole and satranidazole have longer duration, simpler dosing regimen, less toxicity compared to metronidazole, but are equally active

DILOXANIDE FUROATE

Split in the intestine (diloxanide + furoic acid), most of diloxanide is absorbed, conjugated to form a glucuronide which is excreted in urine (90%)

The unabsorbed diloxanide is the amoebicidal agent (10%) THERAPEUTIC USES

Drug of choice for asymptomatic intestinal infection

For eradication of infection and all forms of amoebiasis

Dose: 500 mg three times/day for 10 days

Alcohol dehydrogenase

Aldehyde dehydrogenase

Clinical setting Drug of choice

Asymptomatic intestinal infection

Luminal agent: Diloxanide furoate 500 mg TID for 10 days OR

Iodoquinol 650 mg TID for 21 days OR

Paromomycin 10 mg/kg TID for 7 days

Mild to moderate intestinal infection

Metronidazole 750 mg TID for 10 days OR

Tinidazole 2 g daily for 3 days + Luminal agent

Severe intestinal infection



Hepatic abscess, amoeboma, other extra-intestinal diseases



* Luminal agent and iodoquinol is contraindicated in pregnancy

ANTI-HELMINTHIC DRUGS

INTRODUCTION

The helminths are macroscopic, multicellular organisms having their own digestive, excretory, reproductive & nervous system

Anthelminthics are drugs that act either locally to expel worms from the GIT (vermifugal) or systemically to eradicate adult helminthes (vermicidal) or act on developmental forms that invade organs and tissues

Helminths harm the host by depriving him of food, causing blood loss, injury to organs, intestinal or lymphatic obstruction & by secreting toxins

Helminthiasis is rarely fatal, but is a major cause of ill health CLASSIFICATION

Nematodes Round worm (Ascaris lumbricoides) Hook worm (Necator americanus & Ancylostoma duodenale) Whip worm (Trichuris trichuria) Thread worm (Strongyloides stercoralis) Pin worm (Enterobius vermicularis) Filariasis (Wuchereria bancrofti or Brugia malayi) Elephantiasis (lymphatic filariasis of the lower extremity associated with Wuchereria bancrofti

infection) Onchocerciasis (Onchocerca volvulus) Guinea worm (Dracunculus medinensis)

Helminths

Platyhelminths (flat bodied

worms)

Trematodes (flukes)

Cestodes (tape worms)

Nemathelminths (round bodied

worms)

Trematodes Blood fluke (Schistosomiasis) Liver fluke (Fascioliasis) Intestinal fluke Lung fluke (Paragonimiasis)

Cestodes Beef tape worm (Taenia saginata) Pork tape worm (Taenia solium) Cysticercosis (pork tape worm larval stage) Fish tape worm Dwarf tape worm Dog tape worm (hydatid disease)

ANTHELMINTHICS

Kill helminths (vermicide)

Expel helminthes (vermifuge)

Drugs exert their anti-parasitic effects by interfering with: a) Neuromuscular functions b) Microtubular functions c) Calcium permeability d) Energy metabolism

BROAD SPECTRUM ANTHELMINTHICS

Benzimidazole group: Mebendazole, Albendazole, Thiabendazole, Triclabendazole

Mechanism of action of benzimidazoles:

Bind to β-tubulins & prevent their polymerization ↓

Breakdown of cytoplasmic microtubules ↓

Selective and irreversible inhibition of glucose uptake ↓

Depletion of glycogen stores, formation of ATP, disruption of metabolic pathways ↓

Parasitic death

ALBENDAZOLE

Pharmacokinetics

Administered orally

Fatty food increases its absorption

It is metabolized in the liver

It produces an active metabolite, albendazole sulfoxide which is widely distributed, including hydatid cyst. Hence preferred in the treatment of hydatid disease

Half-life is 8-12 hours

Clinical uses

Administered on an empty stomach when used against intraluminal parasites, but with a fatty meal when used against tissue parasites

Drug of choice for: Round worm (Ascaris lumbricoides) Hook worm (Necator americanus & Ancylostoma duodenale) Whip worm (Trichuris trichuria)

Recommended dose: Adults & children above 2 years 400 mg orally as a single dose at night For children of 1-2 years of age 200 mg OD

As an alternative for: Thread worm (Strongyloides stercoralis) Pin worm (Enterobius vermicularis) Liver fluke (Clonorchis sinensis) To treat or control lymphatic filariasis (Albendazole + Diethylcarbamazine/Ivermectin =

synergistic combination)

Preferred drug to treat: Cysticercosis (pork tape worm larval stage)

Albendazole + Corticosteroids to prevent inflammation caused by dying organism (toxins are released)

Cutaneous larval migrans Skin disease in human, caused by the larvae of various nematode parasites of

the hook worm family Visceral larval migrans

Caused by worms that are found in the intestines of dogs and cats. The dog parasite is called Toxocara canis & the cat parasite is called Toxocara cati

Hydatid disease (a cyst in the lung or liver containing larva of Taenia echinococcus) Treatment of choice for medical therapy & is useful adjunct to surgical removal

or aspiration of cysts Better results when albendazole is used along with praziquantel

Advantages of albendazole over mebendazole

Single dose administration in Ascaris, hook worm, Enterobius and Trichuris (3 day treatment with mebendazole)

Broader spectrum

Better tolerated

In strongyloidosis, albendazole is more effective than mebendazole

Also has weak microfilarial action, kills cysticerci, hydatid larvae, ova of Ascaris or hook worm & is effective in cutaneous larva migrans

Adverse effects

Short term therapy (up to 1 month): free of side effects

Long term use (for 3 months): epigastric distress, headache, alopecia, fatigue & lassitude, insomnia, transcient increase in aminotransferase enzyme (hepatotoxicity)

Teratogenic in animals, hence avoided during pregnancy

MEBENDAZOLE

Highly effective against gastrointestinal nematode infections

Particularly valuable for the treatment of mixed infections Pharmacokinetics

Administered orally (chewable tablets available)

Fatty food increases its absorption

Half-life is 2-6 hours Clinical uses

Drug of choice for Round worm (Ascaris lumbricoides) Hook worm (Necator americanus & Ancylostoma duodenale) Whip worm (Trichuris trichuria) Pin worm (Enterobius vermicularis) provides cure rate of 95-100%

As an alternative drug for Trichinella spiralis (trichinosis) Visceral larval migrans Capillaria philippinensis (intestinal capillariasis) Taenia saginata (beef tape worm)

Adverse effects

Short term therapy: free of side effects

Nausea, vomiting, diarrhoea and abdominal discomfort

Higher doses: rash, urticarial and elevation of liver enzymes such as aminotransferase (hepatotoxicity)

Contraindications

Pregnancy

Patients with liver cirrhosis

DIETHYL CARBAMAZINE (DEC)

Is a piperazine derivative available as citrate salt Mechanism of action The exact mode of action is unknown

i. DEC alters microfilarial surface structure, displace them from tissues phagocytosed by tissue fixed monocytes

ii. DEC hyperpolarizes worm’s musculature expelled iii. DEC blocks synthesis of prostaglandins capillary vasoconstriction blocks passage of

microfilariae through capillaries Clinical uses

Drug of choice for lymphatic filariasis due to Wuchereria bancrofti (bancroftian filariasis), Brugia malayi (brugian filariasis) & Loa loa (loiasis) Active against both microfilarial & adult worm Synergistic with albendazole Anti-histaminics & glucocorticoids may be required to control allergic reaction Also used for chemoprophylaxis of loiasis & filariasis

Visceral larva migrans (toxocariasis)

To treat tropical eosinophilia Tropical pulmonary eosinophilia (TPE) is a syndrome of wheezing, fever & eosinophilia Has been replaced by ivermectin for the treatment of onchocerciasis

Adverse effect

Pharmacological dose dependant effects: headache, weakness, malaise, anorexia, nausea, vomiting, dizziness and lethargy

Allergic side effects due to dying filariae: fever, lymphadenopathy, cutaneous swelling, leucocytosis, eosinophilia, oedema rashes, proteinuria, at times renal haemorrhage and encephalopathy

PRAZIQUANTEL

Effective against trematodes & cestodes, not nematodes Mechanism of action

a) In cestodes, Praziquantel causes influx of Ca2+ from endogenous stores intense contractions

expulsion of the worm from GIT b) In schistosomes (flukes),

Ca2+ influx damages tegument (outer body covering) vacuoles (holes) formed hidden parasite antigen is exposed

Host antibodies bind to these antigens & destroy them by phagocytosis Clinical uses

Schistosomiasis: drug of choice for all forms

Also effective against other flukes except F. hepatica

Tape worm infestations

Neurocysticercosis: albendazole is preferred Why albendazole is preferred over praziquantel in the treatment of neurocysticercosis? The course of treatment is shorter than praziquantel Cure rates in terms of resolutions of symptoms and disappearance of cysts are higher than

praziquantel Corticisteroids anhance absorption of albendazole, but lower the blood levels of praziquantel Albendazole is cheaper

DRUGS FOR CONSTIPATION

LAXATIVES

Laxatives are used to: 1. Treat constipation 2. To avoid undue straining at defaecation in cases having hernia, haemorrhoids or

cardiovascular disease 3. Before or after any anorectal surgery 4. In bed ridden patients

Result in elimination of soft semi-solid stool

Laxatives have mild activity and are usually faecal softeners

Type of laxatives Example

Bulk forming laxatives Wheat bran, Psyllium husk, Ispaghula husk, semisynthetic cellulose such as carboxyl-methyl cellulose and polycarbophils (synthetic fibers)

Osmotic laxatives Lactulose, Sorbitol

Lubricant laxatives Liquid paraffin

Surfactant laxatives Dioctyl sodium sulfosuccinate (Docusate sodium)

PURGATIVES

Purgatives are used to: 1. Complete colonic cleansing prior to gastrointestinal endoscopic procedures 2. For post-operative or post MI bed-ridden patients 3. To flush out worms after the use of an anti-helminthic drug 4. To prepare the bowel before surgery or abdominal X-ray 5. May be needed for neurologically impaired patients

Purgatives either provide semi-fluid stool or lead to watery evacuation. In low doses, these can be used as laxatives

Types of purgatives Examples

Osmotic purgatives (lead to watery evacuation)

a) Saline purgatives: Magnesium sulfate, Magnesium hydroxide (milk or magnesia), Sodium sulfate and Sodium phosphate

b) Polyethylene glycol (PEG): Electrolyte osmotic purgative

Irritant purgatives (provide soft semifluid stools)

a) Anthraquinone group: Senna, Cascara and Aloe b) Organic irritants: Phenolphthalein, Bisacodyl (and

its suppository), Sodium picosulfate c) Oils: Castor oil

MECHANISM OF ACTION

These are luminally active, hydrophilic, indigestible vegetable fibres

They stimulate peristalsis and defaecation reflexes by increasing faecal bulk due to their water absorbing and retaining capacity

Bulk Laxatives

It is also luminally active agent

It is pharmacologically inert mineral oil

It is a faecal lubricant and stool softener as it retards water absorption from the stool

Lubricant laxatives

It is again a luminally active agent and is anionic surfactant which softens the stool by decreasing the surface tension of fluids in the bowel

It also acts as a wetting agent for the bowel, because by emulsifying the colonic contents it facilitates the mixing of water into fatty substances of the faeces

Surfactant laxatives

They stimulate peristalsis by irritant action on intestinal mucosa

They also stimulate colonic electrolyte and fluid secretion by altering the absorptive and secretory activity of the mucosal cells

Aloe, senna and cascara occur naturally in plants. Senna is most commonly used. These plant purgatives contain anthraquinone glycosides

On reaching the colon, the bacteria degrade them to the active principle "anthrol" which either acts locally or it is absorbed into the circulation

After being excreted through bile, it then stimulates small intestine

Stimulant/irritant purgatives

They act on small as well as large intestine

Saline purgatives are soluble inorganic salts which increase the faecal bulk by retaining water by osmotic effect, thus increasing peristalsis indirectly

Magnesium salts also release cholecystokinin which further helps in increasing intestinal secretions and peristalsis. Polyethylene glycol (PEG) which is electrolyte osmotic purgative contains a non-absorbable (PEG) which is a sugar that retains water by virtue of its high osmotic nature

It is also used in a form of a balanced isotonic solution prepared by adding sodium chloride, sodium sulfate, sodium bicarbonate and potassium chloride

The isotonic solution of (PEG) is so designed that no electrolyte shift occurs across the intestinal wall. Therefore, the preparation is safe for all patients

Osmotic purgatives

ADVERSE EFFECTS OF LAXATIVES a) Bulk forming laxatives:

Not absorbed (quite safe)

May cause abdominal discomfort (bacterial digestion of vegetable fibers within the colon lead to bloating and flatus)

b) Osmotic laxatives:

Non-toxic (suitable for long term use)

Flatulence (common)

Cramps (may occur in few)

May feel nauseated due to its peculiar sweet taste

c) Lubricant laxatives:

Frequent use leads to deficiency of fat soluble vitamins as they are carried away with stool

Forcible administration can lead to aspiration lipid pneumonia

Delays the healing of enteric fistula

* Though used only occasionally, it is useful when straining at defecation is to be avoided

d) Surfactant laxatives

Not absorbed (non-toxic)

Being bitter in taste, it can cause nausea

Cramps and abdominal pain

Hepatotoxicity (prolonged use)

Increase the absorption of liquid paraffin, hence should not be given together ADVERSE EFFECTS OF PURGATIVES

a) Osmotic purgatives

May induce vomiting due to irritant effect

Hyperosmolar agents may lead to intravascular fluid depletion and electrolyte disturbance

Should not be given for long term use and to hypertensive and CHF patient

Magnesium salts should not be used for long period with renal insufficiency patient due to risk of hypermagnesaemia, as about 20% of ingested magnesium is normally absorbed

b) Irritant purgative

Senna glycosides are secreted through milk, so should be avoided in lactating mothers

These glycosides turn urine colour to yellowish brown (acidic urine) or to red (alkaline urine). Chronic use leads to brown pigmentation of the colon known as (melanosis coli)

Contraindicated in pregnancy to avoid pelvic congestion

All anthraquinone produce abdominal cramps and nausea

About 15-20% of phenolphthalein undergoes enterohepatic circulation and hence exhibits prolonged action. It may turn urine reddish pink

Skin rash (rare)

Uses are drastically decline because of the reports about its cardiac toxicity and carcinogenicity

THERAPEUTIC USES OF LACTULOSE

As osmotic laxatives

Used for the treatment of hepatic encephalopathy

For this purpose, a dose of 20g TDS orally is needed

In hepatoencephalopathy there is a severe hepatocellular damage because of which the portal blood is directly shunted to systemic circulation

Hence several toxic metabolites from the colon (eg. NH3) get accumulated in the blood leading to CNS toxicity

Lactulose is degraded to lactic acid and converts NH3 to ionized NH4+ salt which is then

excreted INDICATIONS OF LAXATIVES

Constipation

To avoid undue straining of defaecation in patient with hernia, haemorrhoids or CVS disease

Before and after any anorectal surgery

Bed ridden patients CONTRAINDICATIONS OF LAXATIVES

a) Bulk-forming laxatives

Not absorbed, and quite safe

May cause abdominal discomfort due to bloating and flatus (cause by bacterial digestion of vegetable fibre)

b) Osmotic laxatives

Non-toxic, suitable for long term use

Flatulence, abdominal cramps

Nausea (have peculiar sweet taste) c) Lubricant laxatives

Not palatable (can be given in emulsified form or juice)

Fat soluble vitamins (A,D,E,K) deficiency (carried away with stool in emulsified form)

Aspiration lipid pneumonia (forced administration)

Delay healing of enteric fistula d) Surfactant laxatives

Not absorbed, non-toxic

Nausea (bitter taste)

Abdominal cramps and pain

Prolonged use, cause hepatotoxicity

Increase absorption of liquid paraffin

PURGATIVE HABIT

Purgatives empty the entire colon

Hence, after successfully using one purgative, few days are needed at least before normal defaecation process restart

However, during this phase, patient may feel constipated and takes purgative again, leading to development of a vicious cycle

This is known as ‘purgative habit’

DRUGS FOR DIARRHOEA

COMPOSITION OF NEW FORMULA WHO-ORS

High sodium content ORS is use for adult diarrhoea

For children and infants, low sodium glucose-based formulation is preferred because losses of sodium are less

Can be used in cholera

May cause hyponatremia in adults with cholera

The composition of new 245 mmol/L formula:

Contents Concentrations

Sodium chloride – 2.6 g Potassium chloride – 1.5 g Sodium citrate – 2.9 g Glucose – 13.5 g Water – 1.0 L Total osmolarity = 245 mmol/L

Na+ – 75 mM K+ – 20 mM Cl- – 65 mM Citrate – 10 mM Glucose – 75 mM

IMPORTANCE OF EACH INGREDIENT IN ORS

1) Potassium: Important constituent; to replace substantial loss of K+ during acute diarrhoea 2) Base (citrate, lactate, bicarbonate): To correct acidosis which developed due to loss of alkali in

stools. May independently promote sodium and water absorption 3) Glucose: To capitalize on the intactness of glucose coupled Na+ absorption 4) Na+: Increase Na+ level will facilitate water retention to counter dehydration

NON-DIARRHOEAL USES OF ORAL REHYDRATION THERAPY

Post-surgical, post-burn and post-trauma maintenance of dehydration and nutrition (in place of I.V. infusion)

Heat stroke

During changeover from intravenous to enteral alimentation

SUPER ORS

ORS replaces the fluid or electrolytes what the body has lost due to diarrhoea

Glucose-based ORS can easily be made at home as per WHO standard formula: High sodium preparation

Sodium chloride 3.5 g

Potassium chloride 1.5 g

Sodium citrate 2.9 g

Glucose 20.0 g

Water 1.0 L

Total osmolarity : 311 mmol/L Preparation available:

1. RELYTE: one sachet dissolve in 200 ml water

2. PEDITRAL & GENLYTE: one sachet dissolve in 100 ml water

Cereal-based ORS (Super ORS) Has advantage of controlling diarrhoea much more effectively than the glucose-based

ORS Undigested starch is fermented in the colon to short chain fatty acid stimulate

sodium and water absorption back from the colon Rice powder also has protein which on hydrolysis, yields amino acid stimulate

colonic salt and water absorption Commonly used cereal-based ORS formula:

Super ORS

Pre-cooked rice flour 10.15 g



Potassium citrate 0.44 g

Water 200 ml


1. CERELYTE, RICETRAL: one sachet dissolve in 200 ml water


Potassium chloride 1.5 g


Glucose 13.5 g

Water 1.0 L


1. ELECTRAL MULTIDOSE, PUNARJAL, ELECTROKIND: one sachet dissolve in 1.0 L water

Low sodium preparation

NON-SPECIFIC ANTI-DIARRHOEAL AGENTS Anti-motility & anti-secretory agents:

1) Opiod agonists: Acts by stimulating peripheral µ and δ receptors on small intestine and large intestine. µ receptors decrease motility, while δ receptors decrease intestinal secretions Loperamide Diphenoxylate Difenoxin Racecadotril

2) Anti-cholinergic:

Decrease bowel motility Hyosyamine Dicyclomine

3) α₂-adrenergic receptor agonists:

Facilitates absorption, inhibits secretions of fluids and electrolytes & increase intestinal transit time Clonidine

4) Octreotide:

Action is similar to somatostatins. Inhibit the release of 5-HT3, gastrin, secretin, CCK, motilin, pancreatic polypeptide. Reduce GIT motility, intestinal fluids & electrolytes secretions, pancreatic secretion, gall bladder contraction

DRUGS USED IN INFLAMMATORY BOWEL DISEASE

Ulcerative Colitis Crohn’s Disease

1. Aminosalicylates: Sulfasalazine Olsalazine Balsalazine

2. Immunosupressant: Glucocorticoids: Prednisone

& Prednisolone Cyclosporine Azathioprine & 6-

Mercaptopurine

1. Anti-TNFα Drugs : Infliximab Adalimumab Certolizumab

2. Methotrexate 3. Antibiotics:

Metronidazole Ciprofloxacin

4. Anti-Integrin Monoclonal antibody : Natalizumab

Role Of Sulfalazine In Inflammatory Bowel Disease

Is a prodrug

An aminosalicylate

Commonly used in ulcerative colitis

Composed of sulfapyridine & 5-aminosalicylic acid (5-ASA)

On oral administration, sulfasalazine reach colon

Broken down by colonic bacteria (azoreductase enzyme) to sulfapyridine & 5-ASA

5-ASA acts locally by inhibiting the production of inflammatory mediators: Inhibits the synthesis of prostaglandins (by inhibiting

cyclo-oxygenase Inhibit the production of cytokinins Inhibit the activity of nuclear factor-kB Suppress the generation of superoxide free radicals

While sulfapyridine get absorbed and causes side effects: nausea, vomiting, headache Advantages Of Mesalazine Over Sulfalazine

Also 5-ASA

Well absorbed in the upper GIT, therefore has to be given as special formulations (delayed release capsule or pH-dependent tablets)

Have a lower incidence of side effects and more efficacious compared to sulfasalazine Rational For Combining Diphenoxylate With Atropine In The Treatment Of Diarrhoea

Most popular formulation – LOMOTIL contains diphenoxylate (2.5 mg) with small doses of atropine (0.025 mg) to discourage abuse potential

Atropine, besides providing anti-spasmodic effects, prevents the possible abuse of diphenoxylate

Undesirable effects of atropine would appear prior to the pleasurable effects of the opioid, if the dose is increased for abuse

MECHANISM OF ACTION OF ANTI-MOTILITY & ANTI-SECRETORY DRUGS 1) Opiod agonists

Drugs: Loperamide, Diphenoxylate, Difenoxine (an active metabolite of diphenoxylate), Racecadotril

Mechanism of action: Stimulate peripheral µ as well as δ receptors present on small and large intestine

Effects: Activation of µ receptor decreases motility, while activation of δ receptor decreases intestinal secretion

Racecadotril (enkephalinase inhibitor) increases local concentration of enkephalins in intestinal mucosa which then stimulate µ and δ receptors

2) Anti-cholinergics

Drugs: Hyoscyamine, Dicyclomine

Effects: decrease bowel motility which results in an increase of fluid absorption, back from the intestinal tract, and a decrease in abdominal cramps

3) α2 adrenergic receptor agonists

Drug: Clonidine

Effects: facilitates absorption, inhibits secretion of fluids and electrolytes as well as increases the intestinal transit time

4) Octreotide

Actions are similar to Somatostatin

Mechanism of action: Inhibition of the release of 5-HT, gastrin, secretin, CCK, motilin and pancreatic polypeptide

Effects: It reduces GIT motility, intestinal fluid and electrolyte secretion, pancreatic secretion and gall bladder contractions

Lactase digests lactose and prevents drawing of water into the GIT Advantage Of Loperamide Over Codeine As An Anti-Diarrhoeal Agent

CNS effects and dependence liability of codeine limit its usefulness

Loperamide does not cross BBB and has neither analgesic effects nor any addiction liability ADVERSE EFFECTS AND CONTRAINDICATIONS

1) Opiod agonists

Adverse effects: abdominal discomfort and dry mouth

Contraindications: patients with colitis, acute bacterial diarrhoea associated with high fever or blood in stool, and also for children below 2 years of age

2) Anti-cholinergics

Adverse effects: usual anti-cholinergic effects 3) α2 adrenergic receptor agonists

Adverse effects: blood pressure lowering effect 4) Octreotide

Short term adverse effects: nausea, abdominal discomfort, pain at the site of injection

Long term adverse effects: gall stone formation, hypothyroidism

DRUGS FOR IRRITABLE BOWEL SYNDROME (IBS)

INTRODUCTION

IBS includes Crohn’s disease and ulcerative colitis

Characterized by variety of GI symptoms such as disordered bowel habits (constipation, diarrhoea or both) in association of abdominal pain and bloating

Generally fall into two categories: Constipation-dominant-IBS or Diarrhoea-dominant-IBS DRUGS USED IN IBS

DRUGS EXAMPLES

Anti-diarhoeal-Anti-spasmodic drug Loperamide, Diphenoxylate, Fedotozine, Dicyclomine, Hyoscyamine, Mebeverine

Anti-depressant Amytriptyline, Desipramine

5-HT3 receptor antagonist Alosetron

5-HT4 receptor agonist Tegaserod

Chloride channel activator Lubiprostone

Miscellaneous agent Clonidine, Buspirone

Given to relieve abdominal pains and discomfort & also improving bowel disorder

Usually, for diarrhoea-dominant-IBS, anti-diarrhoeal agents are used

For constipation-dominant-IBS, fibre supplements are administered with enough water intake ROLE OF ALOSETRON IN IBS

A potent and selective 5-HT3 antagonist 5-HT3 is an inotropic receptor belonging to nicotinic-acetylcholine super family of

receptors which in GIT activate visceral afferent pain from the gut to CNS Blockade will also inhibit colonic motility by decreasing ion permeability besides

inhibiting unpleasant pain sensation

Previously used in women with diarrhoea-dominant abdominal pain associated with IBS who failed to respond to conventional therapy

Efficacy in man has not been established

In dosage 1 mg OD or BD, it reduces all IBS symptoms including pain and diarrhoea

Prolongs total colonic transit time by inhibiting colonic hypermotility but not used as anti-emetic (just like Ondansetron, yet Ondansetron is not used for treating IBS)

Side effects: constipation, sleep disorders and abdominal discomfort Constipation induced by it may results to Fatal Ischemic Colitis (FIC) Hence the drug has to be discontinued immediately if constipation or symptoms of FIC

occur Re-initiation of drug after treating FIC is also not advisable

From the year 2000, FDA has restricted its use in women with diarrhoea-dominant IBS not responding to other therapies

RENAL & CARDIOVASCULAR

SYSTEMS

DIURETICS

FUNCTIONS OF KIDNEY

Regulatory: fluid & electrolyte balance, acid-base balance

Excretory: excretion of nitrogenous waste products

Hormonal: production of renin, production of erythropoietin

Activation of vitamin D The mechanism of urine formation is by:

1) Glomerular filtration - Filtrate contains low molecular weight plasma components such as glucose, Na+, K+, Ca2+,

Cl- and HCO3- plus amino acids & organic solutes

- Most of the filtrate is reabsorbed from different segments of the renal tubule - Everyday, only 1.5 L of urine is produced

2) Tubular reabsorption DIURETICS

Diuretics are the drugs that promote the excretion of Na+ and water from the body by an action of the kidney

Most diuretics act from the luminal side of the membrane & must be present in the urine

Some directly act on different segments of the nephron

Some indirectly modify the contents of the urinary filtrate CLASSIFICATION

1) Diuretics acting directly on different segments of the nephron a) Drugs acting on the thick ascending limb of loop of Henle

Loop diuretics or high ceiling diuretics: Furosemide, Bumetanide, Torsemide, Piretanide, Ethacrynic acid, Indacrinone

b) Drugs acting on the proximal (early) part of the distal tubule Thiazide group: Chlorothiazide, Hydrochlorothiazide, Benzthiazide,

Polythiazide, Bendroflumithiazide, Clopamide Chlorthalidone, Xipamide, Indapamide, Metolazone, Quinethazone

c) Drugs acting on the collecting ducts and tubules K+ sparing diuretics: Amiloride, Triamterene

d) Aldosterone receptor antagonists at distal (later) part of the distal tubule & collecting tubule K+ sparing diuretics: Spironolactone, Eplerenone

2) Diuretics acting indirectly by modifying the contents of urinary filtrate Osmotic diuretics: Mannitol, Glycerol

3) Weak diuretics which mainly have non-diuretic use Carbonic anhydrase inhibitors: Acetazolamide, Dorzolamide, Ethoxzolamide,

Dichlorphenamide, Methazolamide

LOOP DIURETICS (HIGH-CEILING DIURETICS)

Site of action: thick ascending limb of loop of Henle

Most powerful of all diuretics

Capable of excreting 20-30% of Na+

Steep dose response curve, hence called high-ceiling diuretics

Administered by oral, I.M. and I.V. routes

Duration of effect for furosemide is usually 2-3 hours Mechanism of action

Enter proximal tubule via organic transporter

Blocks Na+, K+,2Cl- symporter in the thick ascending limb of loop of Henle

Increase Na+ concentration reaching the distal tubule promotes H+ and K+ secretion results in metabolic alkalosis (in high doses)

Inhibit Ca2+ and Mg2+ reabsorption

Inhibit uric acid secretion at proximal tubule hyperuricemia can lead to gout Therapeutic uses of furosemide

Oedematous states: congenital heart failure, cirrhosis of liver, renal disease

Hypertension associated with renal impairment

Acute pulmonary oedema: Furosemide induces renal prostaglandin synthesis ↑ renal blood flow & ↑ venous capacitance right ventricular filling pressure ↓ produces quick relief of left ventricular pressure & pulmonary oedema

Acute renal failure: enhance K+ excretion

Mild hyperkalemia

Anion overdose: bromide, fluoride & iodide, which are reabsorbed in the thick ascending limb

Non-diuretic uses: mild to moderate hypercalcemia Adverse effect

Hyperuricemia: may precipitate attacks of gout

Hypercalciuria and hypomagnesemia

Hypokalemia with hypokalemic alkalosis

Ototoxicity: due to extrusion of Na+ from endolymph to perilymph

Hyperglycemia: due to ↓ insulin release

Hypersensitivity reactions: in patients allergic to sulfonamides Drug interactions of furosemide

With digoxin: loop diuretics may enhance digitalis toxicity and can cause cardiac irregularities due to hypokalemia

With NSAIDS: NSAIDS inhibits PGE2 and PGI2 synthesis (they contribute to Na+ and K+ excretion to some extent), thus diminish the action of furosemide

With aminoglycosides: they exhibit additive ototoxicity and should not be used together

With lithium: serum lithium levels may rise with loop diuretic therapy as they increase the reabsorption of Li+ from the proximal tubule

THIAZIDES

Site of action: proximal (early) part of the distal tubule

Most widely used diuretics

Sulfonamide derivatives

All have equal maximal diuretic effect; differ in duration of action and potency

Inhibit the Na+,Cl- symporter

Moderately efficacious drug Mechanism of action

↑ Na+ concentration reaching the distal tubule promotes H+ and K+ excretion results in metabolic alkalosis

Enhance Ca2+ reabsorption

Also induce synthesis of prostaglandins

Also inhibit carbonic anhydrase in the proximal tubule Therapeutic uses Diuretic use (oedematous condition)

Pulmonary oedema due to congestive heart failure

Renal (nephrotic syndrome, chronic renal failure, acute glomerulonephritis)

Hypertension – 1st drug to be used Non-diuretic use (non-oedematous condition)

Idiopathic hypercalciurea calcium nephrolithiasis (renal calcium oxalate stone) Nephrogenic diabetes insipidus

Thiazide has paradoxical effect

Thiazides ↓ ECF volume hyponatremia enhance Na+ and water reabsorption from proximal tubule ↓ delivery of filtrate to distal tubule ↓ urinary output

Adverse effect

Hypokalemia – exchange of Na+ and K+ (more Na+ reabsorbed, more K+ excreted)

Metabolic alkalosis

Hyperuricemia

Hypercalcemia – rare, but they can unmask hypercalcemia due to other causes eg. hyperparathyroidism

Hyperglycaemia

Hyperlipidaemia on chronic use

Erectile dysfunction – idiosyncratic reaction

Hypersensitivity reactions – skin rashes, blood dyscrasias & rarely pancreatitis Drug interactions

With digoxin: thiazides may enhance digitalis toxicity and can cause cardiac irregularities due to hypokalemia

With lithium: serum lithium levels may rise with thiazide therapy as they increase the reabsorption of Li+ from the proximal tubule

Thiazides should be avoided or used with caution in patients having oedema due to liver cirrhosis because hypokalemia and hypochloraemic alkalosis may precipitate hepatic encephalopathy and generates more NH3 which a cirrhotic liver cannot convert to urea!!!

① INHIBITORS OF NA+ CHANNELS AT COLLECTING DUCTS

Example: Triamterene, Amiloride

Site of action: distal part of distal tubule and collecting tubules Mechanism of action

Block renal epithelial Na+ channel inhibit Na+ reabsorption and K+ excretion

↓ secretion of H+ results in metabolic acidosis

Mode of action of both are independent of aldosterone Therapeutic uses Major utility is in combination with other diuretics to prevent hypokalemia & to augment the

diuretic and hypertensive response Diuretic use

Liver cirrhosis: used with thiazides

Hypertension: used with thiazides/loop diuretics Non-diuretic use

Li+ induced polyuria: Amiloride blocks Li+ reabsorption through Na+ channels in the collecting duct

Cystic fibrosis: Amiloride aerosol ↑ fluidity of respiratory secretion

In conditions of hypokalemia Adverse effect

Hyperkalemia

Triamterene: ↑ blood urea, nausea, dizziness, muscle cramps, precipitate renal stones

Amiloride: diarrhoea and rarely skin rashes; IV or IM route ↓ blood pressure due to histamine release

K+ SPARING DIURETICS

② ALDOSTERONE RECEPTOR ANTAGONIST

Spironolactone: a synthetic steroid

Has limited diuretic action

Has long duration of action

Canrenone is the active metabolite of Spironolactone

Undergoes enterohepatic circulation Mechanism of action

Aldosterone binds to aldosterone receptor ↓

Attach to DNA ↓

Transcription, translation & production of aldosterone’s mediator proteins

↓ Na+ reabsorption & K+ excretion

Spironolactone blocks aldosterone receptor, therefore following steps cannot progress anymore. Hence, no Na+ reabsorption & K+ excretion

Therapeutic uses Diuretic use (oedematous conditions)

Primary hyperaldosteronism (Conn’s syndrome)

Secondary hyperaldosteronism caused by liver cirrhosis

In hypertension: with thiazides or loop diuretics Non-diuretic use

In congestive heart failure: retards disease progression and reduces mortality

In conditions of hypokalemia Adverse effects

Hyperkalemia

Delays healing of peptic ulcer

Gastrointestinal disturbances

Skin rashes

Gynaecomastia & menstrual irregularities (with use of higher doses on chronic basis) Drug interactions

With angiotensin converting enzyme inhibitors: this combination should be avoided to avoid exacerbation of hyperkalemia

With thiazides/loop diuretics: this combination is used to treat hypertension, because it checks hypokalemia, a side effect of these diuretics

Examples: Mannitol, Glycerol (hypertonic drugs)

Pharmacologically inert

Freely filtered at the glomerulus

Incompletely reabsorbed or not at all reabsorbed in the nephron

Non-metabolizable

Act indirectly by modifying the contents of urinary filtrate by increasing the osmolarity

Site of action: proximal tubule, descending limb of loop of Henle, collecting tubule Mechanism of action

Mannitol I.V. ↓

↑ osmolarity of ECF ↓

H2O shifts from ICF to ECF ↓

↑ filtration load at glomerulus; mannitol gets filtered ↓

Hypertonicity of fluid in the lumen ↑ ↓

↓ H2O reabsorption (from parts of the nephron that are freely permeable to H2O)

↓ Urine volume ↑ due to ↑ H2O excretion

Small ↑ in Na+ excretion Other electrolytes are also excreted

Therapeutic uses

To treat oliguria state (no urine formation) in shock or crush injury. In such conditions, GFR is decreased compensatory reabsorption of NaCl & H2O from proximal tubule distal part of nephron dries up urine flow ceases (osmotic diuretics retain fluid in the tubule & prevents onset of renal failure

To treat acutely raised intracranial pressure (cerebral oedema)

To treat acutely raised intraocular pressure (acute glaucoma): Mannitol I.V. increased plasma osmolarity ICF shifts from brain and eye into circulation decrease pressure

Adverse effect

Transcient expansion of ECF volume – may worsen congestive heart failure, pulmonary oedema or both (hyponatremia adds to this effect)

Orally osmotic diarrhoea. Hence used orally with activated charcoal to eliminate toxic substances/poisons from GIT

Contraindication

Anuria due to severe renal disease or acute tubular necrosis

Heart failure / acute left ventricular failure / pulmonary oedema

Active intracranial bleeding

OSMOTIC DIURETICS

Examples: Acetazolamide, Dorzolamide, Ethoxzolamide, Dichlorphenamide, Methazolamide

Rarely used as diuretics now; clinical applications involve sites other than kidney

They inhibit both the membrane-bound and cytoplasmic forms of carbonic anhydrase ↓

Complete abolition of NaHCO3 reabsorption in the proximal convoluted tubule ↓

↑ urinary excretion of HCO3- (alkaline urine containing NaHCO3, KHCO3 & H2O)

Mechanism of action

NaHCO3

- depletion, metabolic acidosis ↓

Compensatory reabsorption of Na+, Cl- from remaining segments of nephron ↓

The diuretic efficacy of Acetazolamide decreases significantly within 2-3 days (self-limiting action) Therapeutic uses

Glaucoma: Acetazolamide (oral), Brimzolamide & Borzolamide (eye drops)

To alkalinize the urine (to treat urate calculi and cystinuria)

Metabolic alkalosis

Petit mal epilepsy (absence seizure) Metabolic acidosis increase plasma CO2 decrease pH prevent convulsions ↑ Cl- in plasma stabilize neuronal membrane by causing hyperpolarisation

Acute mountain sickness: Acetazolamide ↓ CSF formation & ↓ its pH ↑ ventilation & ↓ symptoms of mountain sickness

Adverse effect

Refractoriness after repeated use

Hyperchloremic metabolic acidosis

Drowsiness and paraesthesia

Hypokalemia

CARBONIC ANHYDRASE INHIBITORS

VASOPRESSIN ANALOGUES

ADH RECEPTOR AGONIST

Drug Acts on

Vasopressin V1 & V2 receptor

Desmopressin V2 receptor action

Terlipressin Selective V1 with minimal V2 receptor

Felypressin Mainly vasoconstriction action of V1 receptor

Lypressin Vasopressor action of V1 receptor

THERAPEUTIC USES

Based on V1 receptor action

1. Bleeding oesophageal varices Preferred drug is Terlipressin V1 receptor mediated constriction of mesenteric blood vessels Results in reduction of blood flow through the liver to the varices Hence stops the bleeding of the oesophageal varices Simultaneous addition of Nitroglycerine with vasopressin (or Terlipressin) reduces the

cardiotoxic effects of vasopressin, while enhances the beneficial splanchnic effects of the drug

Terlipressin has lesser side effects than vasopressin

2. Post-operative paralytic ileus and to drive out intestinal gas before abdominal radiography Action of contraction of intestinal smooth muscle

3. Used during abdominal surgery in patients with portal hypertension

To reduce risk of haemorrhage

4. Prevent bleeding in acute haemorrhagic gastritis Vasoconstriction of gastric vascular bed

Based on V2 receptor action (preferred drug is Desmopressin)

1. Diabetes insipidus (DI) Only central DI (neurogenic or neurohypophyseal DI) response to the administration of

Desmopressin Nephrogenic DI does not response due to non-functional ADH receptors on collecting

duct Vasopressin is not used due to its short duration of action as treatment of DI needs long-

term therapy Desmopressin is also used to differentiate between neurogenic & nephrogenic DI

2. Primary nocturnal enuresis

Desmopressin is used intranasally with restricted fluid intake and behavioural conditioning

3. Relieve post-lumbar puncture headache

Due to its water retention property, it facilitates equilibration of fluid osmolarity in the CNS

4. Bleeding disorders in patients of haemophilia A and von Willebrand’s disease

Desmopressin elevates factor VIII and von Willebrand factor Shortens time of bleeding

5. Renal concentration test

ADVERSE EFFECT

1. V1 receptor mediated Adverse effects are more with vasopressin, Terlipressin and Lypressin than with Desmopressin Facial pallor – due to cutaneous vasoconstriction Nausea Abdominal cramps Urge to defecate – due to increased intestinal motility Precipitation of angina – due to constriction of coronary arteries Contraindicated in patients of hypertension & ischaemic heart disease

2. V2 receptor mediated

Fluid retention Hyponatremia

3. Common to vasopressin and Desmopressin

Irritation, ulceration and rhinitis (intranasal administration) Urticarial and pruritus Other form of allergy (rare)

DRUGS AFFECTING RAAS

RAAS CASCADE

Drugs Example

Renin release inhibitors Clonidine

Renin inhibitors Enalkiren, Remikiren, Aliskiren

Angiotensin-converting enzyme inhibitors

Captopril, Enalapril, Lisinopril, Ramipril, Benazepril, Perindopril, Quinapril, Trandolapril, Fosinopril, Moexipril, Imidapril

Angiotensin receptor antagonists Saralasin, Losartan, Valsartan, Telmisartan, Irbesartan, Eprosartan, Olmesartan, Candesartan

Advantages of Enalapril over Captopril

More potent effective dose 5-20 mg OD or BD

Its absorption is not affected by food

Onset of action is slower, less liable to cause abrupt first dose hypotension

Longer duration of action (treated hypertension with single dose)

Rashes and alteration of taste is less frequent THERAPEUTIC USES OF ACEIS ACEIs decrease systemic vascular resistance without increase the heart rate and promote natriuresis, thus it is used to:

Treat hypertension

Decrease morbidity and mortality in heart failure and left ventricular dysfunction after myocardial infarction

Treat patients with diabetic nephropathy as they decrease proteinuria and stabilize renal functions

Prevent the incidence of diabetic retinopathy in patient of type I diabetes

Produce dramatic improvement in otherwise prognostically grim condition of scleroderma renal crisis

ADVERSE EFFECTS

Adverse effect Reason

Hypotension

Hypotension after the first dose, particularly in sodium- depleted patients (those using loop diuretics, or on salt restriction or suffering with GIT fluid loss)

The treatment should be initiated with small doses of ACEIs

Dry cough Accumulation of bradykinin in the bronchial mucosa

Not dose related & occurs more frequently in women

Once ACEIs are stopped, the cough disappears within a week

Renal failure

In patient with bilateral renal artery stenosis or with stenosis of the artery to a single remaining kidney

Angiotensin II constricts the efferent arteriole, maintaining adequate GFR even when renal perfusion is low

Inhibition of ACE can induce acute renal insufficiency in such cases

Hyperkalemia In patients with renal failure or in patients taking K+ sparring

diuretics, owing to reduced, angiotensin II stimulated, aldosterone secretion

Teratogenic effect

ACEIs are not teratogenic during 1st trimester

Continued administration can cause foetal hypotension, anuria, renal failure, fetal malformations and even neonatal death

Angioneurotic oedema

Accumulation of bradykinin

Induction of tissue specific auto-antibodies

Minor adverse effect

Neutropenia, cholestatic type hepatotoxicity, glycosuria, proteinuria, altered sense of taste, allergic skin rashes

DRUG INTERACTION

With NSAIDS: Impair the hypotensive effect of ACEIs by blocking bradykinin-mediated vasodilation

With K+ sparring diuretics: Exacerbate ACEIs-induced hyperkalemia

Differences between ARBs and ACE inhibitors

ARBs have no effect on bradykinin metabolism, therefore it is more selective blockers of angiotensin-II effects than ACEIs

ARBs capable of blocking the effects of angiotensin II regardless any biochemical pathway for angiotensin II formation. ACEIs may not suffice for total elimination of angiotensin II

Both group stimulate renin release but ARBs cause circulating angiotensin II to raise but not with ACEIs. ACEIs stimulate AT2 receptors, causes vasodilation

ARBs do not cause cough or angioneurotic edema because they do not build up bradykinin levels

ARBs do not produce dysgeusia (distortion of taste perception) Similarities between ARBs and ACE inhibitors

Both can cause fetal toxicity and should be discontinued before second trimester of pregnancy

Both may precipitate renal failure in patients with bilateral renal artery stenosis

Both drugs can cause hyperkalemia in patients with renal failure or in patients taking K+ supplements or K+ sparring diuretics

First-dose hypotension, in rare cases, may occur

ANTI-HYPERTENSIVE DRUGS

HYPERTENSION

Arterial blood pressure >140/90 mmHg

Types of hypertension Primary or essential: no known cause, occurs in 95% of cases Secondary: hypertension results from the underlying disease present or drug

Stages of hypertension:

Stage Systolic range (mmHg) Diastolic range (mmHg)

Pre-hypertension <120-139 80-89

Stage I – Mild hypertension 140-159 90-99

Stage II – Moderate hypertension 160-179 100-109

Stage III – Severe hypertension >180 >110

Major risk of hypertension: Smoking Dyslipidaemia Diabetes mellitus Age >60 years Gender: men, post-menopausal women Family history

Usually no symptoms

The silent killer

May have headache, blurry of vision, fatigue and palpitation FACTORS THAT AFFECT BLOOD PRESSURE

Blood pressure

Cardiac output

Heart rate

Stroke volume

Contractility

Filling pressure

Blood volume

Venous tone

Peripheral resistance

Arterial diameter

Blood volume (viscosity)

TARGETS FOR ANTI-HYPERTENSIVE DRUGS

Heart rate

Contractility of heart

Blood volume

Venous tone

Arterial diameter ANTI-HYPERTENSIVE DRUGS

A: Aldosterone inhibitor, ACE inhibitor, α-blocker, ARBs

B: β-blocker

C: Calcium channel blocker

D: Diuretic, Directly acting vasodilator

Renin inhibitors

ACEI

ARB

Diuretic

Aldosterone antagonist

β-BLOCKERS

Mechanism of action:

β-blocker should be withdrawn gradually to prevent rebound hypertension

Indications: Mild to moderate hypertension along with diuretics give additive effect Used along with vasodilators

Reflexly mediated cardiac stimulation is a common feature of vasodilator treatment and may severely limit its anti-hypertensive effectiveness

A β-blocker prevents cardiac stimulation & thus preserves the effectiveness of the vasodilator

Further, vasodilator treatment initiates a reflex increase in plasma renin activity which is blunted by the use of a β-blocker

Contrarily, the vasodilator will prevent an increase in peripheral vascular resistance that results with the use of β-blockers

Used along with ACEI ACEI ↑ renin while β-blockers block renin release super additive effect

Contraindications: Concomitant insulin dependent diabetes Bronchial asthma or chronic obstructive pulmonary disease Raynaud’s phenomenon Variant angina Chronic congestive cardiac failure Peripheral vascular disease

β + α BLOCKERS

LABETALOL

Mixed (α + β) antagonist

It exhibits Selective blockade of α1 adrenoceptor Inhibition of neuronal uptake of norepinephrine Blockade of β1 receptors Partial agonist activity (ISA) at β2 receptors Some direct vasodilator properties

It is given orally to treat hypertension in elderly people where increased peripheral resistance is not desired

It is particularly useful in pheochromocytoma and for controlling rebound hypertension after clonidine withdrawal

It is also employed for the treatment of hypertensive patients because usually these patients are not adequately controlled by β-blockers

Side effects: postural hypotension, hepatotoxicity CARVEDILOL

It is a β1, β2 and α1 adrenoceptor blocker but its β1 and β2 blocking effects are greater than its α1 blocking effects

It inhibits free radical induced lipid peroxidation

It also prevents vascular smooth muscle mitogenesis (independent of α or β adrenoceptor blockade)

These effects may prove to be cardioprotective in patients of congestive heart failure

α-BLOCKER

Non-selective: Phenoxybenzamine

α1 selective: Prasozin, Terazosin, Doxazosin

Dilate arteries ↓ peripheral vascular resistance

Dilate veins ↓ venous return

Indications: Non-selective α-blocker is used in pheochromocytoma α1 selective blocker is used in hypertension with benign prostatic hyperplasia

CENTRAL SYMPATHOLYTICS

Also known as centrally acting anti-hypertensive drugs

Site of action: vasomotor centre in the brain METHYLDOPA

Mechanism of action: At adrenergic nerve ending

Methyldopa ↓

α-methyldopamine ↓

α-methylnorepinephrine ↓

Stored in vesicles ↓

Central α2 receptors at vasomotor centre ↓

↓ sympathetic outflow, hence ↓ blood pressure

Side effects of methyldopa: Mental related: sedative,

nightmares Tolerance Hepatotoxicity Psychological upset

Lactation in female Dry mouth Oedema Parkinsonism Anaemia (haemolytic)

Methyldopa is used to treat hypertension during pregnancy CLONIDINE

Mechanism of action: Partial agonist at α2A receptors in vasomotor centre in medulla

↓ ↓ sympathetic outflow

↓ ↓ heart rate, ↓ force of contraction

↓ ↓ venous capacitance, ↓ peripheral vascular resistance

↓ ↓ blood pressure

Activation of imidazoline receptor modulation of α2A receptor activity

Adverse effects: Mental related: sedation Dry mouth Nasal stuffiness Oedema

Impotence Rebound hypertension after

sudden withdrawal

DIRECT VASODILATORS

① ARTERIOLAR VASODILATORS Examples: Hydralazine, Minoxidil, Diazoxide, Fenoldopam HYDRALAZINE

Mechanism of action: Opens K+ channels Hyperpolarization of smooth muscle Vasodilation (↓

peripheral vascular resistance) ↓ blood pressure Release of NO (endothelial-derived relaxing factor) Vasodilation (↓ peripheral

vascular resistance) ↓ blood pressure

Arteriolar vasodilators

Adverse effects: activation of compensatory mechanisms Reflex tachycardia Renin release: ↑ aldosterone secretion Na+ and fluid retention

* How to prevent? Using: o β-blocker (Hydralazine + β-blocker) o Diuretics (Hydralazine + Thiazide)

Other adverse effects: Headache Nasal stuffiness

Used to treat hypertension during pregnancy MINOXIDIL

Mechanism of action: Minoxidil Active form Opens K+ channels Hyperpolarization of smooth muscle Vasodilation (↓ peripheral vascular resistance) ↓ blood pressure

Adverse effects: Tachycardia Palpitations Oedema Headache Nasal stuffiness Hirsuitism

Other use: male pattern baldness (when drug is applied topically) FENOLDOPAM

D1 agonist dilates peripheral arteries and cause natriuresis

Used in hypertensive emergencies DIAZOXIDE

Diazoxide Opens K+ channels Hyperpolarization of smooth muscle Vasodilation (↓ peripheral vascular resistance) ↓ blood pressure

Used in hypertensive emergencies

② ARTERIOLAR + VENOUS VASODILATOR Example: Sodium nitroprusside


Sodium nitroprusside causes arteriolar and venous dilatation

Decreases preload and afterload thus improve ventricular function

I.V. infusion: rapid onset of action (30 seconds), brief duration is 10 minutes

Uses: Hypertensive emergencies Acute congestive heart failure

Regular monitoring of blood pressure

Administer only fresh solution

Cover the infusion bottle with black paper

Adverse effects: Accumulation of cyanide hypoxia Accumulation of thiocyanate disorientation, convulsion Vasodilation Reflex tachycardia

Treatment of cyanide toxicity: Administration of sodium thiosulfate and hydroxycobalamine can be used to trap

cyanide ions Sodium thiosulfate acts as a sulfur donor & facilitates metabolism of cyanide to sodium

thiocyanate which is excreted in urine Hydroxycobalamine combines with cyanide ion to form non-toxic cyanocobalamine

ANGIOTENSIN CONVERTING ENZYME INHIBITORS (ACEI)

Examples: Enalapril, Lisinopril

Angiotensin-II: Release of norepinephrine from sympathetic neurons Absorption of Na+ from proximal tubule Cell growth in heart

Action of drugs: Inhibit ACE No angiotensin-II ↓ blood pressure

Adverse effects: Hypotension after first dose Dry cough Angioneurotic oedema Hyperkalemia Hyponatremia Foetal hypotension with a risk of foetal malformations if administered during II and III

trimester of pregnancy Altered sense of taste

Additional mechanism:

ACEI is one of the 1st choice of drugs in all grades of hypertension

Preferred in patients with: Diabetes – prevent diabetic

nephropathy Nephropathy

Left ventricular hypertrophy Congestive heart failure Post myocardial infarction

Adverse effects/limitations of captopril: Dry cough Hypotension Proteinuria Renal failure Hyperkalemia Teratogenic effect

Angioneurotic oedema Neutropenia Allergic skin rashes Altered sense of taste Glycosuria

Contraindication: Hypertension with bilateral renal artery stenosis

Explain the rationale for using ACEI with: β-blocker in hypertension: ACEI ↑ renin release, prevented by using β-blocker Diuretic in hypertension: ACEI ↑ renin release, diuretic ↓ renin release (synergistic

combination) NSAIDS in hypertension: NSAIDS ↓ prostaglandin synthesis

ANGIOTENSIN ANTAGONISTS

Also known as angiotensin receptor blockers

Examples: Losartan, Candesartan

They block AT1 receptors where angiotensin-II acts

Advantages over ACEIs: no cough and angioedema

Indicated in patients who develop cough with ACEI

DIURETICS

"COLT Pee” Carbonic anhydrase inhibitors (at the proximal tubule) Osmotic diuretics (at the Loop of Henle and other parts) Loop diuretics (at the ascending loop) Thiazides (at the distal tubule) Potassium-sparing diuretics (at the collecting tubules)

Diuretics used in hypertension: 1. Thiazides: Hydrochlorothiazide, Chlorthalidone, Indapamide 2. K+ sparing: Spironolactone, Amiloride 3. High ceiling diuretic: Furosemide

THIAZIDES


Role of thiazides: Cheaper Low dose, hence well tolerated Used with K+ sparing diuretics

Contraindications: Diabetes mellitus Gout Hyperlipidaemia Renal insufficiency Pregnancy

FUROSEMIDE

Strong diuretic

Weaker anti-hypertensive effect


Role of high ceiling diuretics: Severe hypertension with renal disease Hypertension with heart failure Hypertension with fluid retention

Not used for mild to moderate hypertension due to rapid diuresis and electrolyte imbalance

CALCIUM CHANNEL BLOCKERS (CCB)

Dihydropyridines (DHP): Nifedipine, Amlodipine, Nicardipine, Nimodipine

Non-dihydropyridines (Non-DHP): Verapamil, Diltiazem


Block use dependent L-type of calcium channels ↓

Stabilize them in inactivated state ↓

Decreased frequency of opening of channels Blood vessels: Relaxation of smooth muscle Vasodilation ↓ blood pressure Heart: No generation of action potential in automatic fibers

↓ heart rate, ↓ AV conduction, ↓ contractility Use: Supraventricular arrhythmias

Dihydropyridines (DHP) Non-Dihydropyridines (Non-DHP)

Therapeutic uses

Hypertension with neuropathy

Hypertension with diabetic nephropathy

To treat hypertension in patients with asthma, peripheral vascular disease and angina

Hypertension in pregnancy (safe)

Angina pectoris

Hypertension with neuropathy

Hypertension with diabetic nephropathy

To treat hypertension in patients with asthma, peripheral vascular disease and angina

Angina pectoris

Supraventricular arrhythmia

Not safe in pregnancy

Adverse effects & contraindications

Headache

Flushing

Oedema

Tachycardia

Gingival hyperplasia

Less vasodilatory adverse effect

No tachycardia

Constipation

Contraindication: conduction defects in heart and heart failure

Oedema with calcium channel blockers

Dihydropiridine

Nifedipine Amlodipine

Short acting

Frequent dosing or sustained release preparation

Low bioavailability

Fast oral absorption high vasodilatory adverse effect hence given with β blocker

Long acting (t1/2 : >35 hours)

Once daily, orally

Higher bioavailability

Slow oral absorption less vasodilatory adverse effect

Dilatation Increased

hydrostatic pressure

Oedema

HYPERTENSIVE EMERGENCIES

Hypertensive emergency is a situation in which blood pressure must be reduced by 25 mmHg within 1-2 hours to avoid risk of severe morbidity and death

These include patients with asymptomatic hypertension, with progressive target organ damage

It is the latter that determines the seriousness of the emergency and the selection of the drug

Emergencies include: Hypertensive encephalopathy (headache, irritability, confusion and altered mental

status due to cerebrovascular spasm) Hypertensive nephropathy (haematuria, proteinuria and progressive renal dysfunction

due to renal arteriolar necrosis) Intracranial haemorrhage Dissecting aneurysm Pre-eclampsia-eclampsia Pulmonary oedema Unstable angina Myocardial infarction Malignant hypertension

The initial goal in hypertensive emergency is to reduce blood pressure by no more than 25% (within few minutes to 1-2 hours) and then toward a level of 160/100 mmHg within next 2-6 hours

Subsequently, the blood pressure can be reduced to normal levels using oral medication over several weeks

Rapid and complete normalization of blood pressure should be avoided because chronic hypertension is always associated with autoregulatory changes in cerebral blood flow

Thus a rapid normalization of blood pressure would lead to cerebral, coronary or renal ischaemia

TREATMENT

Sodium nitroprusside Effective in treating hypertensive crisis associated with

encephalopathy, intracranial haemorrhage, myocardial infarction, aortic dissection

Glyceryl trinitrate I.V. infusion Action in 2-5 minutes Effective in acute left ventricular failure, myocardial infarction

Labetalol and hydralazine Effective in hypertensive crisis in pregnancy

Esmolol Effective in aortic dissection, myocardial infarction

Fenoldopam <5 minutes, I.V. infusion It also dilates renal blood vessels and promotes natriuresis Useful in hypertensive emergencies with impaired renal function

Enalapril and nicardipine

CONCOMITANT CONDITION DRUGS OF CHOICE DRUGS TO BE AVOIDED

Angina β-blockers; CCBs Vasodilators

Asthma & COPD CCBs; Diuretics; AT1 receptor antagonists

β-blockers; ACEIs

Benign prostatic hyperplasia α-blocker CCBs

Congestive heart failure Diuretics; ACEIs Verapamil and other CCBs

except Amlodipine; α-blokers

Diabetes (insulin-dependent) ACEIs; CCBs β-blockers; Diuretics

Hyperlipidaemia ACEIs; CCBs; α-blockers β-blockers (non-ISA); Diuretics

Isolated systolic hypertension in older patients

CCBs; Diuretics; α-blockers –

Post-myocardial infarction β-blockers (non-ISA); ACEIs β-blockers with ISA

Pregnancy Methyldopa; Dihydropyridine group of CCBs; Cardioselective β-blockers

ACEIs; AT1 receptor antagonists; Diuretics; Propranolol; Labetalol

Peripheral vascular disease CCBs; α-blockers β-blockers

Renal insufficiency CCBs; Diuretics K+ sparing diuretics

Supraventricular tachycardia Verapamil; Diltiazem –

Thyrotoxicosis β-blockers (without ISA) Drugs causing tachycardia

ANTI-ARRHYTHMICS

CARDIAC ELECTROPHYSIOLOGY

NORMAL CONDUCTION PATHWAY

ACTION POTENTIAL OF THE HEART

The slope of phase 0 = conduction velocity

Also the peak of phase 0 = Vmax

PACEMAKER ACTION POTENTIAL

EFFECTIVE REFRACTORY PERIOD (ERP)

It is also called as absolute refractory period (ARP) In this period the cell cannot be excited It takes place between phase 0 and 3

ARRHYTHMIA/DYSRHYTHMIA Abnormality in the site of origin of impulse, rate or conduction

Automaticity: ability of a cell to depolarize spontaneously

Fastest and steepest phase 4 in SA node

Conductance: phase 0 ARRHYTHMOGENIC MECHANISMS

Disorders in impulse formation or disorders in conduction

Disturbances of impulse formation a) Enhanced/ectopic pacemaker activity determined by ↑ slope of phase 4 b) Triggered activity: the next action potential (“after-depolarizations”) occurs before

phase 4 crosses the threshold potential

After potential in Phase 2 or 3 After potential in Phase 4

Disturbances of impulse conduction a) Re-entry: due to circus movement b) Wolff-Parkinson-White syndrome

ACTION OF DRUGS

Re-entry Wolff-Parkinson-White syndrome

IMPORTANT CARDIAC ARRHYTHMIAS

Extrasystoles (ES): AES, VES, nodal ES

Atrial flutter: Atrial rate: 200-350/min with 2:1 to 4:1 block

Atrial fibrillation: Atrial rate: 350-550/min Asynchronous activation of atrial fibers

Ventricular tachycardia: 4 or more consecutive extrasystoles

Ventricular fibrillation: irregular, rapid, uncoordinated contraction of ventricular fibers Loss of pumping function Leads to sudden cardiac death

Torsades de pointes: twisting of the points

Polymorphic ventricular tachycardia

Paroxysmal supraventricular tachycardia (PSVT): atrial tachycardia with 1:1 conduction (150-200) – due to re-entry or after depolarization

AV block: 1st, 2nd or 3rd degree (complete) TYPES OF ARRHYTHMIAS

Bradyarrhythmias

Tachyarrhythmias POSSIBLE MECHANISMS OF DRUG ACTION

Decrease conduction velocity (block Na+ or Ca+ channels)

Change the duration of the effective refractory period (block K+ channels)

Suppress abnormal automaticity (block Ca2+ channels or block β receptors) CLASSIFICATION Proposed by Vaughan Williams and Singh in 1969

Class Basic mechanism Drugs

I IA IB IC

Sodium channel blockers

Moderate

Weak

Strong

Quinidine, Procainamide

Lignocaine, Mexiletine

Propafenone, Flecainide

II Beta blockers Propranolol, Esmolol, Metoprolol

III Potassium channel blockers Amiodarone, Bretylium

IV Calcium channel blockers Verapamil, Diltiazem

* Biggest problem – anti-arrhythmics can cause arrhythmia!!!

CLASS I DRUGS – Na+ CHANNEL BLOCKERS

CLASS IA DRUGS

Effects on depolarization: Blockade Na+ channels: Activated (phase 0) > inactivated Slows the rate of rise of Phase 0 and decrease conduction of impulse

Effects on repolarization: prolonged repolarisation ↑ ERP

Slow the rate of rise of phase 0 of the action potential

Useful in atrial and ventricular arrhythmias CLASS IB DRUGS

Blockade Na+ channels: Inactivated (phase 2) > activated

Rapidly associate and dissociate from Na+ channels shorten the phase 3 repolarisation, hence decrease the ERP as well as APD

Effective in ventricle arrhythmias and in partially depolarised tissue (ischaemia) as in myocardial infarction more inactivated channels are available

Lignocaine is given I.V. as loading and maintenance dose I.V. due to high first pass metabolism LD and MD dose due to high volume of distribution and short duration of action

Indication: Acute ventricular arrhythmias following myocardial infarction and cardiac surgery

Pharmacokinetics of Lignocaine: Inactive orally Distributes rapidly Duration of action: 10-20 minutes Metabolism depends on hepatic blood flow

Adverse effects of Lignocaine: drowsiness, slurred speech, paresthesia, agitation, confusion, convulsion, least cardiotoxic (it has no effect on normal myocardium)

CLASS IC DRUGS Effects on depolarization:

Blockade Na+ channels: Activated (phase 0) > inactivated

Dissociates slowly

Have effect on normal myocardium (cause arrhythmias)

Markedly decrease the rate of phase 0 depolarisation in Purkinje and ventricular myocardial fibres

SUMMARY

Sodium channel blockade: IC > IA > IB

Increasing the ERP: IA > IC > IB (↓) ANS REGULATION OF HEART RATE

SNS: β1 receptors: ↑cAMP

PNS: M2 receptors: ↓ cAMP

↑cAMP: ↑ Ca2+ influx ↑ automaticity and conduction in pacemaker cells ↑ K+ efflux Shorten APD

CLASS II DRUGS – β BLOCKERS

SA node: ↓ automaticity Use: Exercise induced arrhythmias, arrhythmias in hyperthyroidism

AV node: ↑ERP Use: to control supraventricular arrhythmias

Prevent re-infarction and sudden cardiac death in post myocardial infarction patients

Uses of esmolol Short acting β blocker Used I.V. in acute arrhythmias

CLASS III DRUGS – K+ CHANNEL BLOCKERS

Block K+ channels

Prolong repolarization

Prolong duration of AP without altering phase 0

Prolong ERP Amiodarone is used commonly

Additional mechanism of action: Blocks inactivated Na+ channels Blocks Ca2+ channels and beta receptors

Hence has a broader spectrum of action

Used in supraventricular and ventricular arrhythmias Adverse effects of amiodarone:

↓BP, bradycardia

Nausea, GI upset

Photosensitization and skin pigmentation

Corneal deposits

Pulmonary alveolitis, fibrosis

Peripheral neuropathy

Liver damage

Abnormality in thyroid status (Amiodarone is an iodine containing drug hence causes altered thyroid function)

Less arrhythmogenic CLASS IV DRUGS – Ca2+ CHANNEL BLOCKERS

Inhibit L-type Ca2+ channels

Depress depolarization (phase 0) in automatic fibers decrease conduction in AV node

Decrease in phase 4 spontaneous depolarization decrease automaticity in SA node

Uses of Verapamil: Supraventricular arrhythmias PSVT (as first line drug) To control ventricular rate in AF and AFl

ADENOSINE

Naturally occurring nucleoside

Actions: Decreases conduction velocity Prolongs refractory period Mechanism of action: Stimulates adenosine receptors (A1 receptors) opens K+

channels hyperpolarisation in SA and AV nodes and atrium prolongs refractory period, ↓ conduction

Acute supraventricular arrhythmias and PSVT

Pharmacokinetics: t1/2 = 10 seconds taken by RBCs and endothelial cells

Adverse effects: flushing, bronchospasm

Drugs for PSVT Drugs for AV block

Diltiazem

Verapamil

Propranolol

Esmolol

Digoxin

Atropine

Adrenaline

Isoprenaline

Condition Drug Comments

Sinus tachycardia Class II, IV Other underlying causes may

need treatment

Atrial fibrillation/flutter Class IA, IC, II, III, IV, Digitalis Ventricular rate control is

important goal; anti-coagulation is required

Paroxysmal supraventricular tachycardia

Class IA, IC, II, III, IV, Adenosine –

AV block Atropine –

Ventricular tachycardia Class I, II, III –

Premature ventricular complexes

Class II, IV, Magnesium sulphate PVCs are often benign and do

not require treatment

Digitalis toxicity Class IB, Magnesium sulphate –

ANTI-ANGINAL & ANTI-ISCHAEMIC DRUGS

INTRODUCTION

Angina pectoris is caused by ischaemia, characterized by chest pain

There is an imbalance between oxygen supply & oxygen demand

Determinants of myocardial O2 consumption: O2 demand: heart rate, contractility, preload, afterload O2 supply: coronary blood flow, regional myocardial blood flow

Angina pectoris is a clinical manifestation of reversible myocardial ischaemia

Symptom: suffocating substernal pain in the chest

On exertion, angina pain mediates to neck, jaw, upper abdomen, shoulders and arms

It is relieved by rest

Hence, angina pectoris isreferred to chest pain due to an imbalance between the O2 requirement of the heart & O2 supplied to it via the coronary vessels

TYPES OF ANGINA

Classical/Stable angina Also called as angina of effort or exertional angina

There is increased myocardial O2 requirement

Cause: atherosclerosis of larger coronary arteries

Variant/Prinzmetal’s angina

The pain appears even during rest or sleep

There is recurrent localized coronary vasospasm – “vasospastic angina”

There is reduction in coronary blood flow

If it is untreated, it may deteriorate into unstable angina

Unstable angina

There are recurrent attacks of angina

Can occur during minimal exertion or during rest

Progressive occlusion of the coronary artery

Platelet aggregation at the ruptured plaque

CLASSIFICATION OF DRUGS 1) Nitrates

a. Rapid onset, short acting: Nitroglycerine (Glyceryl trinitrite), Isosorbide dinitrite (sublingual route)

b. Slow onset, long acting: Isosorbide dinitrite (oral route), Isosorbide mononitratre, erythrityl tetranitrate

2) β-blockers: Propranolol, Metoprolol, Atenolol, Bisoprolol, Celiprolol 3) Calcium channel blockers (CCBs)

a. Phenylakilamine: Verapamil b. Benzothiazepine: Diltiazem c. Dihydropyridines (DHPs)

Short acting: Nifedipine, Nicardipine Intermediate acting: Nitrendipine Long acting: Felodipine, Amlodipine

4) Miscellaneous a. Potassium channel openers: Nicorandil b. Cytoprotective drugs: Trimetazidine, Ranolazine c. Anti-platelet drugs: Aspirin, Ticlopidine, Clopidogrel, Dypiridamole d. Bradycardic drugs: Ivabradine e. HMG-coA reductase inhibitors: Statins

CLINICAL CLASSIFICATION Used to terminate an attack of angina: Nitroglycerine, Isosorbide dinitrate (sublingually) Used for chronic prophylaxis: All other drugs

NITRATES

Mechanism of action

Pharmacological actions 1) Vascular smooth muscle

Preload reduction (prominent action)

Afterload reduction

Redistribution of coronary blood flow

Dilatation of capacitance vessels ↓

Peripheral pooling of blood ↓

Decrease in venous return to heart ↓

Decrease in ventricular end-diastolic pressure

↓ Decrease in preload

↓ Decrease in cardiac workload &

O2 requirement

* Major beneficial effect in classical angina

Arteriolar dilatation ↓

Decrease in total peripheral resistance

↓ Decrease in afterload

↓ Decrease in cardiac workload &

O2 requirement

* Large doses of the drug ↓ peripheral vascular resistance ↓ blood pressure reflex sympathetic stimulation reflex tachycardia precipitates angina

Relaxation of bigger conducting

coronary arteries ↓

Redistribution of blood flow to ischaemic areas in angina

patients

* Nitrates cause dilatation of collateral vessels (secondary channel) allow blood that flow in primary blood flow to be distributed to ischaemic area, without an increase in blood volume

2) Dilatation of cutaneous, meningeal and retinal vessels 3) Action on other smooth muscles: relaxation of smooth muscles of the bronchi, biliary tract

and oesophagus

Pharmacokinetics

Nitrates are lipid soluble

Low oral bioavailability

Nitrates are inactivated in the liver – nitroglycerine has the highest inactivation in the liver

Thus, high first pass metabolism (except isosorbide mononitrate)

Through sublingual route: short acting

Through oral route: long acting

GTN (transdermal patch) – steady delivery of the drug in the circulation

GTN (volatile liquid) – stored in a tightly closed amber colored glass container Therapeutic uses

1) Angina pectoris

Nitrates in classical angina: reduction in cardiac workload by action on capacitance vessels

Nitrates in variant angina: dilatation of larger coronary vessels – relieves coronary artery spasm

Nitrates in unstable angina: dilatation of epicardial coronary arteries and reducing myocardial O2 demand

Hence, nitrates are only favourable to be used in classical and variant angina

Acute attack – GTN sublingual tablet/spray or isosorbide dinitrate sublingually

Can be repeated after 5 minutes

Not more than 3 tablets to be taken in 15 minutes

Prophylaxis of angina: longer acting nitrates (oral), GTN (transdermal)

Unstable angina: I.V. nitrates along with anti-platelet drugs 2) Myocardial infarction

GTN I.V./transdermal has protective effect against myocardial infarction

Relieves chest pain, pulmonary congestion & limits the area of necrosis

Post-infarction period – relieves angina pain 3) Congestive heart failure & acute left ventricular failure

I.V./Sublingual GTN or isosorbide dinitrate: reduces preload and afterload improvement in left ventricular function and pulmonary congestion

4) Oesophageal spasm

GTN sublingually

Cause relaxation of smooth muscles of the oesophagus 5) Biliary colic

GTN/Isosorbide dinitrate sublingually

Cause relaxation of smooth muscle of the gall bladder

Nitrites in cyanide poisoning Cyanide

↓ Chelates Fe3+ of cytochrome oxidase

↓ Tissue anoxia, seizures, coma

↓ Death

Haemoglobin

↓ Methemoglobin

↓ Cyanomethaemoglobin (unstable)

↓ Methemoglobin + sodium thiocyanate

↓ Excreted in urine

Adverse effects

Throbbing headache – because of dilatation of meningeal vessels

Flushing of face

Palpitation, dizziness, sweating

Postural hypotension

Tolerance

Dependence Tolerance Develops with all nitrates if there is continuous exposure It is dose-dependent It disappears within hours after stopping the drug Tolerance can be avoided:

By using the least effective dose Drug free interval

“Monday disease” is due to nitrate this is the evidence of development of tolerance Dependence Sudden withdrawal after prolonged exposure Precipitates coronary vasospasm and myocardial infarction

Drug interactions

1) Nitrates x Vasodilators Severe hypotension 2) Nitrates x Sildenafil

- Sildenafil is a phosphodiesterase-5 inhibitor results in ↑ cGMP - Hence, potentiates nitrate action - Results in severe hypotension, myocardial infarction, death

Sodium nitrite/Amyl nitrite I.V.

Cyanide

Sodium thiosulphate I.V.

CALCIUM CHANNEL BLOCKERS (CCBs)

Voltage-sensitive Ca2+ channels

Mediates entry of extracellular Ca2+ in response to depolarization

3 major types: L, N & T types

L-type Ca2+ channels: cardiac and smooth muscles, SA node & AV node

Composed of α1, α2, β, γ and δ subunits

Function: Smooth muscle contraction Regulate E-C coupling Regulate pacemaker activity Regulate conduction velocity

Mechanism of action

Normal mechanism CCBs action

In cardiac muscles ↓

Ca2+ enters the cell ↓

Binds to the ryanodine receptors in the sarcoplasmic reticulum

↓ Release of Ca2+ from the sarcoplasmic reticulum

↓ Binds to troponin C on the actin filaments

↓ Muscle contraction

Calcium channel blockers ↓

Bind to α1 subunit of L-type Ca2+ channels ↓

Reduces the frequency of their opening in response to depolarisation

↓ Decrease in transmembrane Ca2+ current

↓ Smooth muscle relaxation, decreased

contractility in cardiac muscle, decrease in pacemaker activity & conduction velocity

Actions

Verapamil Relatively cardio-selective Direct negative chronotrophic, dromotrophic and inotrophic effects

Nifedipine Relatively vascular smooth muscle selective Dilates arterial resistance vessels

Diltiazem Intermediate selectivity

CCBs in angina

Classical angina Coronary dilatation Peripheral vascular disease: ↓ in peripheral vascular resistance, ↓ in afterload ↓ in

myocardial O2 demand Decrease in heart rate, contractility, conduction velocity (verapamil, diltiazem)

reduces myocardial O2 demand

Variant angina Relieves and prevents coronary artery spasm (Dihydropyridine)

Unstable angina CCB is used as an adjuvant, along with nitrates and β-blockers

β-BLOCKERS

Blockade of cardiac β1 receptors

↓ Decrease in heart rate & myocardial

contractility ↓

Decrease in cardiac workload ↓

Decrease in myocardial O2 requirement

Blockade of dilator β2 receptors ↓

Decreases total coronary blood flow

β-blockers also inhibit platelet aggregation

Blockade of dilator β2 receptors is not favourable in angina. Therefore, non-selective β-blockers are not used in angina

However, as β1-blocker ↓ heart rate, it increases diastolic perfusion time increases blood flow to ischaemic area

Cardioselective β-blockers are preferred over non-selective β-blockers

When there is abrupt withdrawal, there will be sudden increase in sympathetic tone of heart precipitate an angina attack and acute myocardial infarction

β-blocker is contraindicated in variant angina Blockade of β2 receptors unopposed α1 receptor mediated coronary constriction

accentuates coronary spasm in variant angina β2 action is dilatation, while α action is constriction

In classical angina It decreases frequency and severity of attacks It increases exercise tolerance

In unstable angina, it is used along with nitrates or CCBs DRUG INTERACTIONS

1) β-blockers + Long acting nitrates in classical angina Nitrates cause reflex tachycardia (blocked by β-blocker) β-blocker cause ↑ in end-diastolic volume, reduction in total coronary blood flow,

coronary spasm (counteracted by nitrates) 2) β-blockers + CCBs

Verapamil/Diltiazem should not be combined with β-blocker, due to addition of depressant effects on SA and AV nodes

No net effect as β-blocker causes bradycardia, while nifedipine causes reflex tachycardia

3) Nitrates + CCBs Nitrates decrease preload, while CCBs decrease afterload Hence, ↓ workload of the heart effectively rather than being used alone Useful in severe vasospastic angina

4) Nitrates + CCBs + β-blockers Nitrates ↓ preload CCBs ↓ afterload, ↑ coronary blood flow β-blocker ↓ cardiac workload Useful in severe and resistant cases of classical angina Verapamil/Diltiazem (Dihydropyridine) should be avoided

K+ CHANNEL BLOCKERS

They activate ATP sensitive K+ channels Hyperpolarization of vascular smooth muscle Vasodilation – decreases preload and afterload

They have nitrate like effect increases cGMP

Effective in classical and variant angina

Increases coronary blood flow

Does not produce tolerance like nitrates

Example of drugs: Nicorandil, Pinacidil, Cromakalim

TRIMETAZIDINE

It is a pFOX (partial fatty acid oxidation) inhibitor – partially inhibits fatty acid oxidation

It inhibits 3-ketoacyl coA thiolase (the key enzyme in fatty acid synthesis)

It prevents degradation of membrane unsaturated fatty acid, hence reduces myocardial O2 demand

Improves metabolic status of ischaemic tissue

Useful in stable angina

RANOLAZINE

Blockade of a late sodium current that facilitates calcium entry via the sodium-calcium exchanger – decreases contractility

Reduces angina frequency & increases exercise capacity

Prophylaxis of angina – adjuvant drug

IVABRADINE

Funny channels regulate pacemaker activity of SA node, which are activated upon hyperpolarization at voltages in the diastolic range

Funny current controls the rate of spontaneous activity of sinoatrial myocytes, hence the cardiac rate

Ivabradine blocks hyperpolarization-activated current (If) through Na+ channels in SA node

Hence, it decreases heart rate decreases myocardial O2 demand

ANTI-PLATELET DRUGS

They inhibit platelet aggregation

Cause coronary vasodilatation

Useful in unstable angina

STATINS

HMG-coA reductase inhibitor

Decreases in LDL levels

Improves endothelial function

Reduces platelet aggregation

Stabilization of atherosclerotic plaque

DRUG THERAPY OF MYOCARDIAL INFARCTION

Anti-platelet drugs (Aspirin, Clopidogrel)

Thrombolytic therapy (Streptokinase, Alteplase, Reteplase, Tenecteplase)

Nitroglycerine: relieves pulmonary congestion, limits infarct size

β-blockers (Metoprolol): Reduces infarct size & duration of ischaemia Prevents re-infarction Reduces incidence of ventricular fibrillation

ACE inhibitors (Ramipril, Lisinopril): prevents remodeling, decreases the chances of congestive heart failure

Opioid analgesics (Morphine, Phetidine): relieves pain

Diazepam/Alprazolam: relieves anxiety

Anti-coagulant (Heparin, Enoxaparin): prevention of thrombus extension, embolism, venous thrombosis

CARDIAC GLYCOSIDES & DRUGS FOR HEART FAILURE

It occurs when cardiac output is inadequate to provide the O2 needed by the body

Heart is Unable to pump sufficient amount of blood Unable to receive sufficient amount of blood

Causes: arteriosclerotic heart disease, myocardial infarction, ventricular tachycardia, anaemia

Types of heart failure: 1) Low output failure = Metabolic demands of the body is within normal limits but heart

is unable to meet them 2) High output failure = Due to co-existing conditions. Increased cardiac output is unable

to meet the excessive metabolic demands of the body

Left-sided heart failure is characterized by pulmonary congestion, oedema, shortness of breath, dyspnoea

Right-sided heart failure is characterized by peripheral oedema Compensatory mechanisms of a failing heart:

Increased sympathetic activity

Activation of RAAS

Ventricular remodeling Symptoms of heart failure

Pulmonary and peripheral oedema

Tachycardia

Dyspnoea with cyanosis and decreased exercise tolerance

Cardiomegaly and hepatomegaly Decompensated heart

Pulmonary and peripheral oedema

Dyspnoea with cyanosis

Hepatomegaly

Cardiomegaly

Reflex tachycardia

Decreased urine formation

Decreased exercise tolerance and fatigue Treatment goals

To provide symptomatic relief and restoration of cardiac performance

To slow disease progression

To improve survival

HEART FAILURE

DRUGS USED IN HYPERTENSION A) Positive inotropic drugs

1. Cardiac glycosides: Digoxin, Digitoxin 2. Phosphodiesterase III inhibitors: Amrinone, Milrinone, Levosimendan 3. β-adrenergic agonists: Dopamine, Dobutamine, Dopexamine

B) Drugs without positive inotropic effects 1. Diuretics: Thiazides, Furosemide, Spironolactone 2. Vasodilators: Hydralazine, Nitrates, Sodium nitroprusside 3. β-blockers: Metoprolol, Bisoprolol, Carvedilol 4. Angiotensin converting enzyme inhibitors: Enalapril, Lisinopril, Ramipril 5. Angiotensin receptor blockers: Losartan, Candesartan, Irbesartan 6. Vasopressin receptor antagonists: Conivaptan, Tolvaptan

NORMAL IONIC MOVEMENTS – CONTRACTION

1 – Na+-K+ ATPase 2 – Voltage sensitive L-type Ca2+ channel 3 – Na+-Ca2+ exchanger 6 – Sarcoplasmic reticulum calcium channel 9 – Sarcoplasmic reticulum Ca2+ ATPase

Digitalis is a major source of digoxin and Digitoxin

Mechanism of action: Digitalis

↓ Binds to and inhibits Na+-K+ ATPase on cardiac cell membrane

↓ Progressive accumulation of intracellular Na+ & loss of intracellular K+

↓ Reduction in calcium expulsion from the cell by Na+-Ca2+ exchanger

↓ Increase in cytoplasmic Ca2+ – sequestered by SERCA in the sarcoplasmic reticulum

↓ Increase in release of Ca2+ from sarcoplasmic reticulum

↓ Triggers contractile response of failing heart

↓ Increases cardiac output

PHARMACOLOGICAL ACTIONS

A) Heart – improves ventricular performance without affecting myocardial O2 demand

Heart failure – increases force of contraction and cardiac output

Shortens systole – more time for ventricular rest and filling

Reduces heart rate by vagal action on SA node, extravagal action – a direct depressant action on SA and AV nodes & also opposes compensatory sympathetic overactivity

Decreases conduction velocity – AV node and His-Purkinje fibres – prolongs effective refractory period (ERP)

Increased ERP and decreased A-V conduction – protects ventricle from atrial flutter or fibrillation

At smaller doses, ↑ conduction velocity ↓ ERP of atrial muscle

At higher doses, ↑ automaticity and contractility (shortens ERP of atrial muscles and ventricles – extrasystoles, pulsus bigeminus, ventricular fibrillation)

Cholinergic innervation is upto AV node – vagal effects of digitalis is more pronounced at AV node and atria

ECG shows: Prolongation of PR interval Shortening of QT interval Depression of ST segment Inversion or disappearance of T wave

B) Blood vessels

Opposes compensatory sympathetic overactivity in heart failure – decrease in peripheral vascular resistance, heart rate, venous return

Decreases preload

No prominent effect on blood pressure C) Kidneys

Diuresis in heart failure patients. Shifts oedematous fluid into circulation

CARDIAC GLYCOSIDES

THERAPEUTIC USES – CONGETIVE HEART FAILURE

Digitalis enhances contractility – increases ventricular ejection & shifts the ventricular function curve towards normal

Improves tissue perfusion – withdrawal of sympathetic overactivity – decrease in heart rate and central venous pressure

Diuresis – clearing of oedema

Subsides pulmonary congestion, relieves dyspnoea and cyanosis

Especially useful in patients with dilated heart and low ejection fraction

Cardiac arrhythmias – atrial flutter, atrial fibrillation and paroxysmal supraventricular tachycardia (PSVT) Depressant effect on AV conduction Increases ERP of AV node PSVT – increase vagal tone & depresses the pathway through SA and AV nodes

Dilated heart – restores cardiac compensation ADVERSE EFFECTS

Cardiac side effects Extracardiac side effects

Bigeminy Ectopic beats

Ventricular tachycardia Ventricular arrhythmias

Bradycardia AV block

Anorexia Nausea

Vomiting Fatigue

Headache Gynaecomastia

Neuralgia

TREATMENT OF DIGITALIS TOXICITY

Tachyarrhythmias: Caused by chronic use of digitalis – infuse KCl I.V.

Ventricular arrhythmias: Lidocaine I.V. suppresses the excessive automaticity

Supraventricular arrhythmias: Propanolol I.V. or orally

AV block and bradycardia: Atropine I.M. or cardiac pacing

Severe digitalis intoxication: Administer digoxin antibody eg. digibind Fab fragments PRECAUTIONS & CONTRAINDICATIONS

Hypokalaemia – enhances digitalis toxicity by increasing its binding to Na+-K+ ATPase

Elderly, renal or hepatic disease, children below 10 years

Myocardial infarction

Acute myocarditis

Hypothyroidism

Ventricular tachycardia, partial AV block – can cause complete AV block

Wolff-Parkinson-White syndrome – can cause ventricular fibrillation

DRUG INTERACTIONS

Diuretics – hypokalaemia – increased digitalis toxicity

Calcium salts – synergistic action – increased digitalis toxicity

Quinidine – reduces binding of digitalis to tissue proteins & also reduces its clearance – increased digitalis toxicity

Adrenergic drugs, Succinylcholine – induce arrhythmias in digitalized patients

Metoclopramide, Sucralfate, Antacids, Neomycin – decreases digitalis absorption

Propranolol, Verapamil, Diltiazem – additively depress AV conduction & oppose positive inotropic action of digitalis

Phenobarbitone, Phenytoin – enzyme inducers – increases metabolism of digitalis and decreases its effect

Positive inotropic and direct vasodilation Inhibits phosphodiesterase III that converts cAMP to AMP

↓ cAMP activates protein kinase that phosphorylates Ca2+ channel

↓ Increases Ca2+ flow into the cell – increases myocardial contractility

Short term I.V. use in severe and refractory congestive heart failure

Adverse effects: Inamrinone: thrombocytopenia, nausea, diarrhoea, arrhythmias Milrinone: can cause arrhythmias

DOPAMINE

D1 agonist action – renal vasodilation – improves renal perfusion and GFR

β1 agonist action – increases cardiac output

Low output heart failure with compromised renal function DOBUTAMINE

β1 agonist – inotropic action

Preferred drug (I.V. infusion) – acute heart failure accompanying myocardial infarction, advanced decompensated CHF

Prolonged use cause development of tolerance

PHOSPHODIESTERASE III INHIBITORS

Β-ADRENERGIC AGONISTS

Improve ventricular function & prolongs survival in CHF patients

Non-selective β and α blocking drug is favoured – Carvedilol

Carvedilol has β1, β2 and α blocking properties

Additional property: Inhibits free radical induced lipid peroxidation

Prevents cardiac and vascular smooth muscle mitogenesis

Attenuates adverse effects of high concentration of catecholamines

Mild to moderate cases of dilated cardiomyopathy with systolic dysfunction

Useful in mild cases and advanced CHF

Loop diuretics – reduces pulmonary oedema and cardiac size

They stimulate the release of prostaglandin

Loss of Na+ and water – increases excretion of H+ and K+ – arrhythmias and may enhance digitalis toxicity

Toxicity can be overcome by loop diuretics with K+ sparing diuretics SPIRONOLACTONE

Enhances diuresis by promoting Na+ and water excretion

Retains K+

Prevents cardiac remodeling by preventing myocardial and vascular fibrosis

Requires serum K+ monitoring

Arteriolar dilatation – reduces afterload – enhances ventricular stroke volume and improves ejection fraction

Venodilatation – reduces preload – improvement in left ventricular function

Prolong survival by preventing pathological remodeling of heart and blood vessels

Provides symptomatic as well as disease modifying benefits

Recommended in all grades of CHF

ARBs are used when patient is intolerant to ACE inhibitors with cough and angioedema, or pregnancy

β-BLOCKERS

DIURETICS

ACE INHIBITORS & ARBs

Reduce pulmonary congestion

Reduce preload and afterload – increases cardiac output

Prevent cardiac remodeling

Useful in acute heart failure

Heart failure + dyspnoea – venodilator like nitroglycerine or long action nitrates

Heart failure with low ventricular output – arteriolar dilator like hydralazine (↓ afterload)

Severe chronic heart failure – hydralazine with long acting nitrate (↓ preload and ↓ afterload)

Vasopressin through V1 receptor vasoconstriction

Vasopressin through V2 receptor anti-diuretic action

Conivaptan is V1 and V2 receptor antagonist – used in acute heart failure with hyponatremia

Tolvaptan is oral V2 receptor antagonist

Nesiritide – recombinant form of human B type natriuretic peptide

Secreted by ventricles – increases cGMP – reduces venous and arteriolar tone

Acute decompensated heart failure with dyspnoea at rest

Omapatrilat, Sampatrilat (drugs without positive inotropic effect)

Inhibits neutral endopeptidases and angiotensin converting enzymes

Decreases formation of angiotensin II – vasodilatation with Na+ and water excretion

Heart failure – improves cardiac function

VASODILATORS

VASOPRESSIN RECEPTOR ANTAGONISTS

NATRIURETIC PEPTIDES

VASOPEPTIDASE INHIBITORS

DRUGS USED IN HEART FAILURE

A) To provide symptomatic relief and restoration of cardiac performance

Inotropic drugs: Cardiac glycosides, Phosphodiesterase III inhibitors, β-adrenergic agonists

Diuretics

Vasodilators

β-blockers B) To slow disease progression and prolong survival

ACE inhibitors

ARBs

β blockers

Aldosterone antagonists

Combined hydralazine – nitrate therapy

RESPIRATORY SYSTEM

DRUGS FOR BRONCHIAL ASTHMA

DRUGS AFFECTING BRONCHIAL TONE

SITES OF ACTION OF ANTI-INFLAMMATORY DRUGS IN ASTHMA

CLASSIFICATION OF DRUGS FOR ASTHMA A) Bronchodilators

1. Selective β2 receptor agonists: Salbutamol, Torbutaline, Salmeterol, Formoterol, Bambuterol

2. Non-selective sympathomimetics: Epinephrine, Ephedrine, Isoprenaline

3. Anti-cholinergics: Ipratropium, Tiotropium, Oxitropium

4. Methylxanthines: Teophylline, Aminophylline

B) Anti-Inflammatory Drugs

1. Corticosteroids i. Oral: Prednisone, Prednisolone, Methylprednisolone

ii. Parenteral: Methylprednisolone, Hydrocortisone iii. Inhalational: Beclomethasone, Fluticasone, Budesonide, Triamcinolone, Flunisolide

2. Mast cell stabilisers: Sodium cromoglycate, Nedocromil 3. Leukotriene modulators

i. 5-lipoxygenase inhibitor: Zileuton ii. Cysteinyl leukotriene receptor antagonists: Montelukast

4. Monoclonal anti-IgE antibody: Omalizumab 5. Miscellaneous: Nitric oxide donors

SELECTIVE β2 RECEPTOR AGONISTS

Short acting (short term relievers): Salbutamol, Terbutaline

Long acting (long term prevention): Salmeterol, Formoterol, Bambuterol MOLECULAR MECHANISM OF AIRWAY SMOOTH MUSCLE RELAXATION Adrenergic drugs β2 receptors

Bronchial smooth Mast cells muscle cells ↑ CAMP production Bronchial relaxation ↓ mediators release ↓ inflammation

Adenylyl cyclase

stimulate

BENEFICIAL EFFECTS

Mainstay – reversible airway obstruction (asthma)

Caution – Blood pressure instability, ischaemic heart disease patients

Additional anti-inflammatory property (drawback desensitization due to down-regulation of β2 receptors)

Selectivity to β2 receptors minimal cardiac stimulation and minimal side effects

Inhaled medication targeted, more β2 selective and lessens systemic side effects

Improve mucociliary transport

Effective and fastest bronchodilator property SABA VS. LABA

SABA (Short acting β2 receptor agonists) LABA (Long acting β2 receptor agonists)

They bind to active site of β2 adrenoreceptor

Less lipid soluble

Early onset of action (<5 minutes), persists for 4-6 hours

Orally, inhalational (metered dose/dry powder/nebuliser), I.V. and I.M. route

Drug of choicefor acute attacks of asthma

Terbutaline is safe bronchodilator in pregnancy

They bind to active site and exo-site of β2 adrenoreceptor

Highly lipid soluble

Delayed onset

Inhalational and oral route

Indicated in nocturnal asthma and long-term prevention of asthma

ADVERSE EFFECTS

Minimal if inhaled (preferred)

Oral route Muscle tremors (direct + β2 in skeletal muscle) Tachycardia (chronotropic β2 and in high doses, β1 receptor is activated) Hyperglycaemia (↑ gluconeogenesis and ↑ glycogenolysis) Hypotension (peripheral vasodilatation)

Continued use Desensitization/down-regulation of receptors Diminished responsiveness to the previous dose Prevented by concurrent use of glucocorticoids (there is risk of ↓ K+)

Aerosol preparations – myocardial toxicity (fluorocarbons)

NON-SELECTIVE SYMPATHOMIMETICS

Epinephrine & Ephedrine (α & β)

Isoprenaline (β1 & β2)

Non-selective action cardiac side effects (↑ blood pressure, tachycardia, arrhythmia)

Epinephrine Can cause effective and rapid bronchodilatation Drug of choice for acute asthma till β1 agonists were available Rarely used due to cardiac side effects (tachycardia, hypertension, worsening of

angina, myocardial infarction and arrhythmias)

ANTI-CHOLINERGICS

Act as pharmacological antagonists of acetylcholine released from parasympathetic fibres

Ipratropium, Tiotropium & Oxitropium (aerosol) MOLECULAR MECHANISMS OF AIRWAY SMOOTH MUSCLE CONTRACTION

Acetylcholine acts on M3 receptor of airway smooth muscle cells and mucous glands ↓

Cause ↑in cGMP ↓

CGMP activates phospholipase C, PIP2 is converted into IP3 ↓

Release of Ca2+ from sarcoplasmic reticulum ↓

Bronchodilation ROLE IN ASTHMA

Less effective than selective β2 agonists

Also blocks M2 presynaptic autoreceptors (↑ acetylcholine release) ↓ Rx efficacy

Relieved by inhalational route (MDI, rotacaps, nebulizer)

Delayed onset of action (>30 minutes)

Poor absorption into systemic circulation (quartenary compounds)

Lacks classic anti-cholinergic side effects)

Additional to brochodilatory action, they also decrease mucous secretion (unlike atropine, lesser drying effect on mucous no mucous plugs)

No effect on late asthmatic response (inflammatory stage)

Second line drugs in moderate to severe asthma used as an adjuvant to β2 agonists/glucocorticoids (longer duration)

Action of acetylcholine is blocked by anti-

cholinergics, hence cause

bronchoconstriction

METHYLXANTHINES

Natural alkaloids: Caffeine, Theophylline, Theobromine

Beverages: coffee, tea, chocolate

Drugs: Theophylline, Aminophylline, Diprophylline

Mechanism of action: Inhibition of PDE-IV (eosinophils & mast cells) Inhibition of PDE-III (airway smooth muscle) Adenosine receptor inhibitor (bronchodilation)

Exhibits bronchodilatory + anti-inflammatory + immunomodulatory

Increase mucous clearance

Used in combination with β2 agonists – asthma and chronic obstructive pulmonary disease PHARMACOKINETICS OF THEOPHYLLINE

Absorption Well absorbed orally (sustained release preparation – SR)

Rectal absorption – suppositories (erratic)

Distribution

Distributed to all tissues

Crosses placenta

Secreted in milk

50% PPB (plasma protein binding)

Metabolism

Metabolized extensively in liver by CYP1A2 (>85%)

Metabolizing enzymes are saturable

At higher doses, first order kinetics (t1/2: 4-6 hours) zero order kinetics disproportionate ↑ plasma concentration

Prolongation of t1/2: 60 hours

Excretion Unchanged in urine (10%)

Elimination rate is variable

Varies according to age, comorbidities and concurrent medications

FACTORS AFFECTING ELIMINATION RATE (CLEARANCE) OF THEOPHYLLINE

Faster elimination Slower elimination

Children (t1/2: 3-5 hours)

Smoking

Cystic fibrosis

Hyperthyroidism

Adults (t1/2: 7-12 hours)

Elderly >60 years

Premature infants

Hypothyroidism

Cirrhosis

Congestive heart failure

Febrile viral illness, pneumonia

↓ breakdown of CAM ↑ cAMP

ADVERSE EFFECTS OF METHYLXANTHINES

Has a narrow safety margin (therapeutic window)

Therapeutic plasma range: 10-20 µg/ml

Dose dependent toxicity: >20 µg/ml

Systems affected: GIT, CNS and CVS Relationship between plasma concentration of

theophylline to its effects

Toxic effect

Therapeutic effect

Sub-therapeutic effect

>60 µg/ml: death

>40 µg/ml: seizures, diuresis, fever, arrhythmias

>30 µg/ml: tachypnoea, flush, hypotension

>20 µg/ml: nausea, vomiting

DRUG INTERACTIONS WITH THEOPHYLLINE 1) Agents which ↑ CYP1A2 (enzyme inducers) decrease theophylline concentration

Drugs: Phenytoin, Rifampicin, Phenobarbitone, Carbamazepine

Charcoal broiled meat

Smoking 2) Agents that inhibit theophylline metabolism

Drugs: Erythromycin, Ciprofloxacin, Cimetidine, Oral contraceptives, Allopurinol 3) Theophylline enhances the effects of sympathomimetics, digitalis, furosemide, hypoglycaemic

agents, oral anticoagulants THERAPEUTIC USES OF METHYLXANTHINES

Management of bronchial asthma

Treat chronic obstructive pulmonary disease (COPD)

Dyspnoea associated with pulmonary oedema that develops from congestive heart failure DRUGS FOR MANAGING “LATE ASTHMATIC RESPONSE” WITH ANTI-INFLAMMATORY PROPERTY Mainly a prophylactic role – “controllers of symptoms”

Corticosteroids: Systemic & Inhalational

Mast cell stabilizers : Inhalational

Leukotriene (LT) modulators : Oral

Anti-IgE antibody: S.C. / I.V.

20

10

0

Plasma conc.

(µg/ml)

CORTICOSTEROIDS

Inhaled/Systemic corticosteroids mainstay for Rx of moderate to severe asthma – “preventers” of attack

Anti-inflammatory and immunosuppressant

↓ mucosal oedema & bronchial hyper reactivity to allergens

Symptomatic reliefs, improve airflow, retard disease progression, reduce asthma exacerbations

Long term – adverse effects with oral CS are worse than asthma itself, tapering dose essential

Prophylaxis and treatment of seasonal and perennial allergy DRUGS

Oral: Prednisone, Prednisolone, Methylprednisolone

Parenteral: Methylprednisolone, Hydrocortisone

Inhalational: Beclomethasone, Fluticasone, Budesonide, Triamcinolone, Flunisolide, Ciclesonide

ROUTES OF ADMINISTRATION

Inhalation: ↑ topical action, ↓airway remodeling, ↓inflammation, long term treatment of asthma & COPD (combination with SABA/LABA)

Systemic: Severe chronic asthma when not controlled by other drugs – shift to inhaled steroid Following severe acute asthma (7-10 days) – oral corticosteroids Status asthmaticus – start with I.V., then switch to oral

Intranasal spray: Allergic rhinitis, nasal polyposis ADVERSE EFFECTS

Inhalational: dryness of mouth, voice changes & oral candidiasis

Ciclesonide: higher topical:systemic ratio

Oral: short courses (<2 weeks) – no HPA (hypothalamic-pituitary-adrenal) axis

Parenteral: used during status asthmaticus only for a brief period oral route (Hydrocortisone hemisuccinate)

MAST CELL STABILIZERS

Sodium cromoglycate & Nedocromil sodium (inhalation)

Inhibit degranulation of mast cells (all inflammatory cells)

Inhibit release of histamine, leukotrienes, platelet activating factor, interleukins

Prevent bronchospasm/asthma by allergens

Decrease frequency and severity of attacks

Effect over 4 weeks and lasts 2 weeks after discontinuation MECHANISM OF ACTION

THERAPEUTIC USES

Prophylaxis of chronic & seasonal asthma: long term in mild to moderate cases (not in acute)

Prophylaxis allergic rhinitis (nasal spray)

Allergic conjunctivitis (eye drops)

Preferred in patient having multiple allergic disorders ADVERSE EFFECTS

Inhalational: least systemic side effects

Cromoglycate inhalation: throat irritation, cough, arthralgia, headache

Mast cell degranulation

LEUKOTRIENE ANTAGONIST

Zileuton – blocks leukotriene receptor & leukotriene synthesis

Montelukast, Zafirlukast – leukotriene receptor blocker

Antagonise – leukotriene receptor mediated actions like bronchospasm, eosinophil accumulation in lung, bronchus inflammation, hyper reactivity

THERAPEUTIC USES

Prophylactic treatment of mild to moderate asthma as adjuvants with inhaled corticosteroids or selective β2 agonists

Prophylaxis in severe asthma: permit reduction in steroid dose, rescue β2 inhalation

Effective in aspirin induced asthma ADVERSE EFFECTS

Gastrointestinal distress, headache, rashes, eosinophilia

Churg-Strauss syndrome (vasculitis with eosinophilia)

Zileuton: hepatotoxic

MONOCLONAL ANTI-IGE ANTIBODY

The allergic cascade is interrupted by omalizumab

Omalizumab is a monoclonal antibody

It neutralizes free IgE in circulation

Little IgE available to bind mast cell to release mediators

Reserved for resistant asthma cases

Not useful for acute attacks or status asthmaticus

High cost limits its use as first line drug

DRUGS & DEVICES USED FOR ADMINISTRATION

INHALATIONAL DRUGS

β2 agonists: Salbutamol, Terbutaline, Salmeterol, Formoterol

Anti-cholinergics: Ipratropium, Tiotropium

Mast cell stabilizer: Cromoglycate

Glucocorticoids DRUG PARTICLE SIZE

Large particles – settle on oropharynx

1-5µm diameter – deposits on bronchioles

Very fine particles are exhaled out

Slow and deep inbreathing & hold the breath after inhalation * Inhalation devices: 10% drug reaches lung AEROSOLS

Drug in solution Metered dose inhaler (MDI) Nebulizer

Dry powder inhalers Rotahaler Spinhaler/Twisthaler

METERED DOSE INHALER (MDI)

Actuation – coordination with deep inspiration

Device – carried along, convenient

Improve drug delivery: spacer, face mask

Don’t require synchronized coordination with inspiration

Advantages of using a spacer

Improves drug delivery

Does not require synchronized coordination with inspiration

Increases inhaled to swallowed drug ratio

Decreases deposition of larger particles in the mouth (candidiasis) NEBULIZER

Produces mist of drug solution by pressurized air or O2

Inhaled through mouthpiece or face mask

Used at bed side

Severe episodes of asthma – kids and elderly

More drugs can be mixed simultaneously

ROTAHALER

Rotacap – capsule containing drug

Punctured while rotating the cap

Drug is aerosolized by inspiratory air flow

Requires high velocity of airflow (kids, elderly and sick patients)

Powder – irritate, cough, spasm SPINHALER/TWISTHALER

Keep drug

Use it

Reset to use again

STATUS ASTHMATICUS

Hydrocortisone hemisuccinate 100 mg I.V., followed by 100 mg 4th hourly infusion

Nebulized salbutamol (5 mg) + ipratropium (0.5 mg)

Salbutamol 4 mg I.M. (inhaled drug don’t reach smaller bronchi – severe narrowing/plugging)

High flow humidified oxygen inhalation

Intubation & mechanical ventilation

Sodium bicarbonate + saline – correct dehydration

Antibiotics – treat infection

ASTHMA SEVERITY CLASSIFICATION

Clinical course, severity

Daytime asthma symptoms

Night time awakenings

FEV1, PEF

Intermittent <1/week 2 and <2/month >80% predicted. Daily

variability <20%

Mild persistent ≥1/week but not daily >2/month >80% predicted. Daily variability is 20-30%

Moderate persistent Daily >1/week >60% but <80% predicted.

Variability >30%

Severe persistent Persistent, which limit

normal activity Daily

<60% predicted. Variability >30%

CHOICE OF DRUG FOR MANAGEMENT OF VARIOUS TYPES OF ASTHMA

Step-wise guidelines are recommended

After asthma control for 3-6 months, reduction of medication stepwise

Types Steps Drug therapy

Seasonal asthma – Regular inhaled: cromoglycates or low dose

steroids

Episodes: inhaled SABA

Mild episodic asthma Step 1

Inhaled SABA

Mild chronic asthma with occasional exacerbation

Step 2

Regular inhaled: cromoglycates or low dose steroids

Moderate asthma with frequent

Step 3

↑ dose inhaled corticosteroids + LABA

Additional: theophylline

Severe asthma Step 4 High doses inhalational corticosteroids + LABA

Additional: Leukotriene antagonist/oral theophylline/oral β2 agonist/inhaled ipratropium

Not controlled severe asthma

Step 5

High inhaled steroid + LABA

Add oral steroid

DRUGS FOR COUGH

ANTITUSSIVES

1. Centrally acting antitussive

Opioids (Codeine and Pholcodeine) Selectively block cough centre Suppress cough for 6 hours Administered orally Adverse effects: constipation, respiratory depression, drowsiness, convulsions,

postural hypotension, tachycardia

Non-opioids (Dextromethorphan, Noscapine, Pipazethate)

Drug Mechanism of action Adverse effect

Noscapine Block cough centre Headache, nausea, tremor

bronchoconstriction

Dextromethorphan Increase threshold of cough

centre Dizziness, nausea, drowsiness, ataxia

2. Central as well as peripheral action (Benzonatate)

Inhibits the afferent cough impulses to suppress the central cough centre

Inhibits the pulmonary stretch receptors

Possesses mild local anaesthetic action as well

Admistered orally

Adverse effects: drowsiness, nausea, headache, vertigo

3. Peripheral action (Prenoxdiazine)

Inhibits the pulmonary stretch receptors to relieve bronchospasm

Administered orally

Adverse effects: mild and infrequent EXPECTORANTS

1. Mucokinetics

Example: Essential oil, Ammonium chloride, Sodium citrate, Guaiacol, Guaifenesin

Stimulate the flow of respiratory tract secretions by stimulating the bronchial secretory cells (to increase the volume) and the ciliary movement (to facilitate their removal)

They also have reflex irritant effect on gastric mucosa that initiate the reflex secretions of respiratory tract fluid

Adverse effects: ammonium salt metabolic acidosis, nausea

DEMULCENTS: Honey, Liquorice, Syrup tolu, Syrup vasaka LOCAL ANAESTHETICS: Xylocaine, Bupivacaine

2. Mucolytics

Examples: Acetylcysteine, Carbocysteine, Bromhexine, Ambroxol, Dornase-alfa

Alter the chemical characteristics of mucus to decrease its viscosity and to facilitate its removal by ciliary action or coughing

Drug Mechanism of action Adverse effect

Acetylcysteine Decrease the mucosity of mucus by splitting the disulfide bond of mucoproteins

Gastrointestinal irritation, nausea, vomiting, rashes, bronchospasm, stomatitis

Carbocysteine Not clear -

Bromhexine Depolymerizes mucopolysaccharides of mucus directly and increase lysomal enzyme activity

Rhinorrhoea, lacrimation, gastric irritation, hypersensitivity

Dornase-alfa Cleaves the DNA -

Advantages of Dextromethorphan and Noscapine over codeine

Least addiction liability

No analgesic action

Least constipating effects

Minimal drowsiness Role of anti-histamines & bronchodilators

Anti-histamines Afford relief in cough due to sedative and anticholinergic actions Lack selectivity for cough centre No expectorant property Reduce secretion Example: Chlorpheniramine, Diphenhydramine, Promethazine

Bronchodilators Clearing secretion by increasing surface velocity of airflow during cough Used only when an element of bronchoconstriction is present and not routinely

Drugs used in the treatment of productive cough & non-productive cough

Productive cough (expectorants) Non-productive cough (antitussive)

Essential oil

Ammonium chloride

Sodium citrate

Guaiacol

Guaifenesin

Acetylcysteine

Carbocysteine

Bromhexine

Ambroxol

Dornase-alfa

Codeine

Pholcodeine

Dextromethorphan

Noscapine

Pipazethan

Benzonatate

Prenoxdiazine

ANTI-TUBERCULAR DRUGS

CLASSIFICATION

First line essential

Isoniazid (INH)

Rifampicin (Rifampin, RMP)

Pyrazinamide (PZA)

Ethambutol (ETB)

First line supplemental

Streptomycin (SM)

Rifabutin

Rifapentine

Second line anti-tuberculosis

Fluoroquinolones

Amikacin

Capreomycin

Ethionamide

Para-aminosalicylic acid (PAS)

Cycloserine

Thiacetazone

ISONIAZID

MECHANISM OF ACTION

Mycobacterial catalase peroxidase convert Isoniazid (prodrug) to biologically active form which inhibit mycolic acid synthesis

Bactericidal to actively growing tuberculous bacilli but not for dormant which only get inhibited

Active against Mycobacterium tuberculosis and Mycobacterium kansasi

It acts on both intracellular and extacellular tubercle bacilli

Equally active in acidic and alkali medium PHARMACOKINETIC FEATURES

Acetylator status influences the nature of INH toxicity but not anti-tubercular response because its plasma concentration normally above its inhibitory concentration

Rapid acetylator: Plasma half-life is 1 hour Seen in Eskimos, Japanese, 30% of Indian

Slow acetylator: Plasma half-life is 3 hours Seen in Egyptian, Mediterrinean jews, Swedes and 70% of Indian

It is absorbed well orally get distributed to pleural, peritoneal and synovial fluid

CSF concentration can reach upto 100% if there is meningitis

Metabolized by N-acetyltransferase to Acetylisoniazid in the liver

ADVERSE EFFECTS

Peripheral neuritis (paresthesias, numbness) More common with slow acetylators because of

↑ excretion of pyridoxine in urine Accumulated INH inhibits pyridoxine kinase which converts pyridoxine to

pyridoxine phosphate (active form) Prevented by prophylactic use of vitamin B6 (pyridoxine)

Hepatotoxicity Hepatitis ↑ risk in people aged 50-65 years, patients with liver disease, alcoholic or

in fast acetylators Fast metabolism of Isoniazid provides high concentrations of hepatotoxic metabolites

Acetylisoniazid and Acetylhydralazine

Nausea

Appetite loss

Abdominal pain

Rises in aminotransferases

Allergic reactions

Xerostomia

Haematological changes

Convulsion in seizure prone patients

Drug-induced systemic lupus erythematosus RATIONALE FOR USING ISONIAZID WITH PYRIDOXINE

INH is structurally similar to pyridoxine

In peripheral neuritis, accumulated Isoniazid inhibits pyridoxine kinase which converts pyridoxine to pyridoxine phosphate (active form) and ↑ excretion of pyridoxine in urine

Pyridoxine (vitamin B6) is given prophylactically to prevent the neurotoxicity even with the higher doses

Pyridoxine with Isoniazid will reduce the risk of peripheral neuritis

Prophylactic pyridoxine must be given to the diabetic, chronic alcoholics, malnourished, pregnant, lactating and HIV infected patients

Isoniazid neurotoxicity is treated by pyridoxine

Drug should be discontinued at the onset of these symptoms

RIFAMPICIN

MECHANISM OF ACTION

It binds to bacterial DNA-dependant RNA polymerase but does not bind to mammalian RNA polymerase, hence host cells are safe

Bactericidal for both intracellular and extracellular tubercle bacilli

Active against Mycobacterium tuberculosis, Staphylococcus aureus, Neisseria meningitidis, Haemophilus influenzae, Brucella sp. and Legionella sp.

OTHER THERAPEUTIC USES

Leprosy in combination of Dapsone

Prophylaxis of meningococcal and Haemophilus influenzae meningitis and carrier state

Second/third choice of drug for MRSA, diphtheria and Legionella infection

Combination of Doxycycline and Rifampicin is the first line therapy of brucellosis

For prosthetic valve endocarditis ADVERSE EFFECTS

Hepatitis Increased risk if used with Isoniazid or patients with liver disease Dose-dependent and reversible

Gastrointestinal disturbances

Rashes

Dizziness

Flu-like syndrome

Fever

Chills

Myalgias

Thrombocytopenia

Harmless red orange colour urine DRUG INTERACTIONS

Accelerates the metabolism of several other drugs such as oral contraceptives, anticoagulants and protease inhibitors used in HIV patients due to its enzyme inducing properties (induction of cytochrome P-450 isoforms) hence cause therapeutic failure of those drugs

It also enhances its own metabolism as well as corticosteroids, sulfonylureas, steroids, non-nucleoside reverse transcriptase inhibitors (NNRTIs), theophylline, metoprolol, fluconazole, ketoconazole, clarithromycin, phenytoin, etc.

PYRAZINAMIDE

MECHANISM OF ACTION

It enters Mycobacterium tuberculosis via passive diffusion

Bacterial pyrazinamidase convert Pyrazinamide to pyrazinoic acid (active metabolite) which inhibits mycobacterial fatty acid synthase-1

Hence mycolic acid synthesis as well as cell wall formation disrupted

Since it is active in low pH it is effective against intracellular bacilli ADVERSE EFFECTS

Hepatotoxicity

Hyperuricemia

Acute gouty arthritis

Nausea

Vomiting

Anorexia

Drug fever

Malaise

Avoided in pregnancy

ETHAMBUTOL

MECHANISM OF ACTION

It inhibits arabinosyl transferase

Hence polymerization of arabinoglycan is prevented

Arabinoglycan essential constituent of mycobacterial cell wall ADVERSE EFFECTS

Retrobulbar neuritis impairing visual acuity and red-green colour discrimination

Dose of 25 mg/kg/day for more than 9 months

Avoided in children

Decreases renal excretion of urates → precipitate gouty arthritis

Mild gastrointestinal intolerance

Rashes

Fever

Dizziness

GOALS OF ANTI-TUBERCULAR CHEMOTHERAPY 1) Kill dividing bacilli

Drugs with bactericidal action rapidly reduce bacillary load in the patient and achieve quick sputum negativity so that patient is non-contagious to the community

2) Kill persisting bacilli To cure tuberculosis and prevent relapse

3) Prevent emergence of resistance So that the bacilli remain susceptible to the drugs

SHORT COURSE CHEMOTHERAPY OF NEW SPUTUM POSITIVE PULMONARY TUBERCULOSIS (CATEGORY I TB)

Two phases involved: intensive phase, then followed by continuation phase

For both phases, all drugs are given thrice weekly under DOT scheme

Intensive phase: Lasts for 2 months Aimed to rapidly kill the bacteria, to minimize the chances for developing resistance

and to bring about sputum conversion and symptomatic relief Drug regimen: Isoniazid + Rifampicin + Pyrazinamide + Ethambutol

Continuation phase: Lasts for 4 months Aimed to eliminate the remaining bacilli to minimize the chances of relapse Drug regimen: Isoniazid + Rifampicin

ANTI-LEPROTIC DRUGS

LEPROSY

Leprosy is a chronic granulomatous infection caused by an Mycobacterium leprae

Cannot be grown on culture media, so drug sensitivity testing in vitro is not possible

Mycobacterium leprae lie within macrophages and remain dormant but alive

Large number of persons may be infected by the bacteria but only a few suffer clinically

Clinical leprosy is a consequences of deficient CMI in susceptible individuals

Transmission: person-to-person when bacilli are shed from the nose and skin lesions of the infected patients

Affects the peripheral nervous system, the skin and various tissues

Leprosy is classified based on its chemotherapy which are paucibacillary leprosy and multibacillary leprosy

PAUCIBACILLARY LEPROSY

Noninfectious leprosy with few bacilli

Also called tuberculoid leprosy

Important features: Less than 5 hypoaesthetic skin lesions Normally or only partially deficient cell mediated immunity Bacilli are rarely found in biopsies Lepromin test: positive There are prolonged remissions with periodic exacerbations

MULTIBACILLARY LEPROSY

Infectious leprosy with numerous bacilli

Mainly a lepromatous leprosy

Important features: More than 5 hypoasthetic but diffused skin lesions with mucous membrane

infiltrations Cellular immunity is largely deficient Skin and mucous membrane have numerous bacilli Lepromin test: negative Disease later progresses to anesthesia of distal parts and wounds

CLASSIFICATION OF ANTI-LEPROTIC DRUGS

Sulfones: Dapsone

Phenazine derivatives: Clofazimine

Anti-tubercular drug: Rifampicin

Antibiotics: Fluoroquinolones: Ofloxacin, Sparfloxacin, Pefloxacin Macrolides: Clarithromycin Tetracyclines: Minocycline

DAPSONE

Closely related to Sulfonamides and shares a common mechanism of action, ie. inhibition of bacterial folic acid synthesis

Thus, it is leprostatic

Mechanism of action: Dihydropteridine + PABA

Dihydropteroic acid

Dihydrofolic acid

Most widely used sulfone for long-term therapy of both types of leprosy

However, resistance emerges in some population of Mycobacterium leprae especially in lepromatous leprosy patients if it used as a monotherapy

Therefore, combination of Dapsone with Rifampicin and/or Clofazimine is recommended

Well absorbed after oral administration

Widely distributed throughout body fluids and tissues

Tends to remain in skin, muscle, kidney and liver upto 3 weeks after therapy is stopped

Skin which is heavily infected with Mycobacterium leprae may contain 10-15 times as much Dapsone as normal skin

CLOFAZIMINE

A phenazine dye which binds preferentially to mycobacterial DNA to inhibit mycobacterial growth

It is a leprostatic drug with anti-inflammatory properties

This is a major advantage of Clofamizine over other anti-leprotic drugs and therefore it has a valuable pace in the management of lepra reaction (erythema nodosum leprosum)

Is used for Dapsone-resistant leprosy or in patient intolerant to Dapsone

Anti-leprotic effect of Clofazimine has biological lag of 6-7 weeks

Oral absorption

Major elimination is through faeces

Plasma half-life is 60-70 hours

Widely distributed in tissues including phagocytes

Adverse effects: Usually well tolerated Non-haemolytic anaemia and methaemoglobinaemia in persons having G6PD

deficiency Mild side effects: nausea, loss of appetite, pruritis, drug fever, reversible neuropathy

and hepatotoxicity

Dihydropteroic acid synthase Dapsone

WHO REGIMEN A) Multibacillary (lepromatous) leprosy

Dapsone 100 mg daily + Clofazimine 50 mg daily for 29 days and 300 mg on 30th day + Rifampicin 600 mg once a month for 24 months

B) Paucibacillary (tuberculoid) leprosy

Dapsone 100 mg daily + Rifampicin 600 mg once a month (6 months)

If Dapsone is not tolerated, Clofazimine 50 mg daily for 29 days and 300 mg on 30th day

C) Alternative regimens for multibacillary leprosy

1. If Rifampicin is unsuitable because of resistance or intolerance:

Clofazimine 50 mg daily + Ofloxacin 400 mg daily + Minocycline 100 mg daily for first 6 months

And thereafter, Clofazimine 50 mg daily + Ofloxacin 400 mg daily (or Minocycline 100 mg daily) for further 18 months

2. If Clofazimine cannot be given because of unacceptable skin pigmentation or abdominal pain:

Dapsone 100 mg daily + Ofloxacin 400 mg daily (or Minocycline 100 mg daily) + Rifampicin 600 mg once a month for 24 months

DRUGS USED IN TREATMENT OF LEPRA REACTION

During Dapsone therapy, some reactive episodes might occur this is known as lepra reaction

There are two types namely type 1 lepra reactions and type 2 lepra reaction

Type 1 lepra reaction: Delayed hypersensitivity reactions against Mycobacterium leprae antigens (type IV

hypersensitivity) This is characterized by cutaneous ulceration and multiple nerve involvement It can be treated with Corticosteroids (Glucocorticoids and Mineralocorticoids drugs)

Type 2 lepra reaction: Also known as nodosum leprosum Humoral antibody response (type III hypersensitivity) This is characterized by enlarged lesions, become red, inflammed and painful It can be treated with Clofazimine, Thalidomide and Corticosteroids Clofazimine does not react as rapidly as Corticosteroids and Thalidomide

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