Pharmacology Notes Medical Rotation - 2015

PHARMACOLGY NOTESROTATION BMEDICAL2015

Ron Castelino- 10-12 MCQs in end of year exams Question hint: What is used for HTN in pregnancy.

ContentsContents2Angina3Congestive Heart Failure6Acute Heart Failure8Acute Coronary Syndrome9Hypertension13Arrhythmias18Asthma23Antimicrobial Therapy26COPD31Dyslipidemia34Diabetes Mellitus36

Angina Presentation of Central Chest Tightness of Heaviness- brought on by exertion, alleviated by rest. Etiology Atherosclerosis > anaemia Stable vs Unstable Vs Variant (Prinzmetal) S w\ exertion - goes away with rest/GTN U at rest- not often relieved with GTN V Vasospasm of the Coronary Arteries. Relieved by Nitrate- random presentation (not rest/exertional) pattern... typical in AM- 1st line therapy blood supply.Principles of Mgmt Modify Risk Factors smoking, exercise, BMI, HTN, DMDrug therapy Rationale -Symptom relief and Prevent MI 1. Chest Pain relief- Short Acting Nitrate2. blocker or if contraindicated Ca2+-Channel Blockers, Long Acting Nitrates-Inotropic (O2 demand)-3. Statin- Independent of Cholesterol Profile to CVD risk4. Consider Other Antianginals- Ivabradine, Nicorandil, PerhexilineClassNameNotes

Short Acting NitratesGlyceryl Trinitrate - GTNSublingual (to bypass liver metabolism) 1 minute to effect lasts 1mm in two contaginous leads, or presumed new LBBB Anterior Wall Ischemia V2-4 Anteroseptal Ischemia V1-3 Apical or Lateral Ischemia V4-6 Inferior Wall Ischemia II, III, aVF Posterior Wall Ischemia, depression in V1-2 w\ upright T waves. Plus, ST elevation in posterior leads V7-9

Blood Tests Cardiac Enzymes Troponin Most cardiac specific marker, but NOT MI specific- initial reading asap. 8 hours detect most MI, 12 hours all. CK-MB- Normalises in 3-4 days therefore the preferred marker in re-infarction. LD lactate dehydrogenase Myoglobin FBC Serum Creatinine and Electrolytes Blood Glucose Levels UEC LFT

Interventions- Reperfusion therapy to restore blood flow to viable myocardium. Fibrinolytic therapy- pharmaceutical- within 30minutes of medical intervention (especially if known PCI unavailable). Dissolution of clot via Pharmacotherapy Fibrin selective- IV Tenecteplase, Alteplase, OR, Reteplase Non-fibrin selective - StreptokinaseAbsolute contraindications**- need transfer to appropriate facility for PCI Risk of bleeding active or diathesis, Suspected aortic dissection, INR>2-3 (on anticoagulant therapy) Risk of intercranial haemorrhage stroke w\in 3/12, known mets or 1, vascular lesion. Relative Contraindications Pregnancy Active Peptic Ulcer Adjuvant therapy antithrombin therapy risk of re-occlusion- DVT, PE Enoxaparin or unfractionated heparin

Percutaneous Coronary Intervention-transluminal coronary balloon angioplasty and stenting. - mechanical intervention- within 90-120 minutes of medical intervention Adjuvant therapy. Antiplatelet Heparin OR bivalirudin Optional additional platelet glycoprotein IIb/IIIa inhibitor (NSTEACS) Types of Stent Drug-eluting Stent - Used more in practice- is dependent on patient compliance with dual antiplatelet therapy. Bare Metal Stent Coronary Artery Bypass Grafting w\ CBP (cardiopulmonary by pass) & To operate on still heart- fibrillate, hypothermia or Cardioplegia (with K+ rich solution) Median Sternotomy, Conduit (saphenous vein, radial artery) anastomosed to coronary artery beyond lesion and ascending aorta. OR Left internal thoracic artery (LITA) to LAD (maintains original pathway from left subclavian). Risks death, stroke, sternotomy bleed or tamponade, infection, AF, renal failure. NOTES:PCI implies Stenting, angiography is imaging technique not interventionIf presentation of patient is >12 hours after onset of symptoms, MI may be complete. Reperfusion (fibrinolytic) should be considered w\ Continuing ischemia (persistent pain). Viable myocardium (preservation of R waves in infarct leads) Major complications (cardiogenic shock).

In addition + Nitrates blockers within 24hours for HR and BP stabilising Calcium Channel Blockers ACE-Is

Secondary Prevention Antiplatelet therapy Beta-blockers SL NTG ACE-I/ARB Warfarin Spironolactone Statin ? Fish Oils- we dont obtain therapeutic dose from current capsules. Lifestyle Changes

HypertensionIsolated systolic hypertension- from atherosclerosis of the large arteries. Accelerated Phase (malignant) Hypertension- rapid BP leading to vascular damage. Systolic >200mg, diastolic >130mg Bilateral retinal haemorrhage Papilledema (swelling of optic disc). ** marker of malignant HTN of ICPEssential Hypertension- unknown causeSecondary Hypertension Renal- intrinsic renal disease- Glomerulonephritis, polyarteritis nodosa, chronic pyelonephritis, systemic sclerosis, polycystic kidney. Renovascular disease- atheromatous Endocrine- Cushings, Conns Syndrome, pheochromocytoma, acromegaly, hyperparathyroidism Other- Pregnancy, Coarctation (congenital narrowing), Steroids.

Principles of MgmtTreat underlying cause- renal disease, alcoholismIdentify and Treat other CVD risk factors- dyslipidemia, obesity, smoking, alcohol, diabetes. Remove Secondary causes NSAIDs, Drugs therapy- rationale -Reduce Premature Cardiovascular morbidity and mortality. microvascular disease of the brain, kidney and retina. Attempt to reach recommended targets. For uncomplicated hypertension1. ACE Inhibitor (or ARB)2. Dihydropyridine CCB3. Thiazide Diuretic (low dose)With inadequate response add additional therapy instead of dose. dose will more likely cause adverse effects. Preferred combinations 1 + (2 or 3,) OR (2+3). If BP remains elevated consider Compliance High sodium diet (try lowering) Secondary hypertension (including drug induced) Volume overload- chronic kidney disease Sleep apnoea Alcohol/recreational drug use White coat 1. Ace inhibitors are first line, contraindicated in pregnancy Most ACE-Is have similar features, Exception Captopril: Short half-life- rarely used. S/E: Cough Hypokalaemia Hypotension Angioedema rare but serious Can occur at any time during treatment One occurrence is contraindication for future use of all ACE-Is and ARBs With Impaired Renal Function: First line drug for kidney disease with hypertension Dose may need to be adjusted GFR monitoring If it decreases more than 25% from baseline cease ACE-Is K+ should not exceed 6 Monitor: Kidney function, potassium, cough, angioedemaARBs Most ARBs have similar features, except losartan, which has risk of side effects and hepatotoxicity. 2. Calcium channel blockers Dihydropyridines act peripherally as vasodilators, and are used in uncomplicated HTN Nifidipine has a short half life, but a slow-release form can be used Nifidipines immediate release form has a high rate of reflex tachycardia as a side effect shouldnt be used in anyone who has angina (can worsen symptoms or precipitate MI). Amlodipine is most commonly used

Side effects: Peripheral oedema. This is diuretic resistant, as it is a result of fluid redistribution, rather than fluid overload, only goes away w\ treatment cessation. Hypotension Headache (especially early in treatment), goes away w\ time Reflex tachycardia Notes:Diltiazem and verapamil are centrally acting not used in uncomplicated HTNOnly Nifedipine can be used in pregnancy.

3. Thiazide Diuretics Only used as First line treatment in those over 65 It is associated with new onset diabetes Good evidence for treating Isolated systolic HTN Peripheral resistance, - at low dose cause vasodilation Hydrochlorothiazide 12.5-25mg is an anti HTN dose 25mg is diuretic dose Other diuretics are not used unless fluid overload issues. Use in impaired renal function- When creatinine clearance 1yr Thromboembolic risk Virchows Triad Disorganised Flow Hypercoagulability Endothelial DysfunctionPrinciples of Mgmt Treat underlying cause: HF, IHD, HTN, PE, Mitral Valve disease, Pneumonia, Hyperthyroidism, caffeine, alcohol, post op, K+, and Mg2+Non-pharmacological therapies: Carotid sinus massage- vagal stimulation - HR = Good for SVT Direct cardioversion (Af/Aflutter, VT/VF, highly successful - 80-90%) Cardiac pacing (permanent pacemakers, for bradycardia, AV block), Radiofrequency or surgical ablation (localised foci, SVT, AF, Aflutter) - Multiple ablations may be required.

CardioversionPharmacologicalElectrical

Advantages No need for sedation Potential to enhance subsequent electrical cardioversionAdvantages Success Rate >90%

Disadvantages Continuous medical supervision Proarrhythmia Thromboembolic Lo success rate for longstanding AFDisadvantages Needs sedation Skin burn Proarrhythmia Thromboembolic Potential interference of other medical devices

Rate Vs Rhythm Control

Rate ControlTarget Range HR 60-80bom resting, 90-115 w\ exercise Drug Therapy To obtain and maintain ventricular rate control: blockers- Atenolol, Metoprolol CCB Diltiazem/Verapamil (Non-dihydropyridines) Digitalis- Digoxin Class III antiarrhythmic Amiodarone When other methods ineffective.Rhythm Control Conversion the Sinus Rhythm More successful in recent onset AF, L atrium normal size. Avoid in elderly asymptomatic chronic AFDrug Therapy Amiodarone Flecainide

Thromboembolic Risk treatment Electroversion w\ no evidence of thrombus Subcutaneous Enoxaparin, risk of thrombus post stunningThree weeks of anticoagulant therapy in patient w\ Thrombus prior to electroversion Sub Cut- Dalteparin OR SC Enoxaparin IV Unfractionated HeparinLongterm Aspirin OR Warfarin (Valvular AF) OR Dabigatran

Post Cardioversion Rhythm maintenance Flecainide OR Sotalol OR AmiodaroneAcute AF w\ very ill patients / haemodynamically unstable O2 U&E Emergency Cardioversion within 48hrs (amiodarone if unavailable). Anti-coagulation therapy - LMWH Ventricular Rate control 1st line Verapamil OR Bisoprolol 2nd line Digoxin OR Amiodarone. Notes:Limitations of warfarin; slow onset of action, individual variability, food/drug interactions etc require regular monitoring and dosage adjustmentNewer anticoagulants (faster onset of action, fewer drug/food interactions, lower bleed risk etc) Xa inhibitors; rivaroxaban (direct/specific competitive Xa inhibitor, not inferior to warfarin with similar adverse events), apixiban (better than aspirin in AF who could not take warfarin with reduced stroke/embolism) IIa inhibitor; dabigatran (direct thrombin inhibitor) Ventricular arrhythmias; VT; Clinical features if >30secs (lignocaine/amiodarone/sotalol, cardioversion, radio frequency/ablation) VF; Sudden loss of consciousness, no BP, no pulse, cyanosis, death 3-5minutes Torsades de pointes; VT with QT prolongation, prolonged can lead to VT and death (lignocaine, Sinus bradycardia; caused by increased vagal tone, hypothermia, hypothyroidism, BB, CaCB, digoxin, amiodarone (treated with atropine)Reminder Class 1a- Na+ channel blocker- disopyramide Class 1b- Na+ channel blocker-lignocaine Class 1c- Na+ channel blocker-flecainide Class 2- sympathetic blockers- B-blockers Class 3- potassium channel blockers- amiodarone, sotalol Class 4- Ca channel blockers- verapamil, diltiazem Class 5- Other- adenosine, digoxinSecondary to Heart FailureAll arrhythmias are more frequent in patients with heart failure. Atrial Tachyarrhythmias Atrial Fibrillation Atrial Flutter Atrial enlargement = atrial stretch (proarrhythmic mechanism). Ventricular TachyarrhythmiasPrinciples of antiarrhythmic therapy in Heart Failure Avoid K+ depletion from diuretic therapy- Use K+ sparring agents. Avoid Mg+ depletion from diuretic therapy Use ACE-I in all patients at maximum dose tolerated. Use blockers Avoid long-term use of cardiac stimulants ( agonists, or Milrinone- PDE-I) because of their proven proarrhythmic quality. Avoid Class I arrhythmics (proarrhythmic quality).

AsthmaChronic Obstructive Respiratory Illness. Difficulties in exhaling air- resulting in wheeze and hyperinflation. Airway narrowing via Type 1 hypersensitivity (IgG): Remember has an acute phase and latent phase (2-24hr later). Bronchial muscle contraction w\ smooth muscle and basement membrane hypertrophy results in narrowed bronchial lumen. Mucosal swelling- mediated by mast cell and basophil degranulation-eosinophil mediated asthma, results in submucosal oedema and epithelial desquamation. Increased mucus production. goblet cell hyperplasia and mucous plugging. Status Asthmaticus- acute exacerbation of repetitive attacks of asthma. Remains unresponsive to initial treatment w\ bronchodilators. Diagnosis- observe obstructive respiratory pattern w\ spirometry. FEV1/FVC, (ratio) + RV w\ usually a 15% Fev1 following 2 agonists or steroid therapy. Principles of MgmtEncourage self-management to increase compliance Identify and Avoid Precipitant- Common = dust mite, pollen, moulds, domestic pets, drugs ( blockers, NSAIDs, Aspirin), exercise. Lifestyle factors smokingRe-enforce good inhaler techniqueConsider Influenza and pneumococcal vaccination. Consider desensitisation for allergens Drug Therapy- Rationale- Symptom control and relief, prevent exacerbation, improve and maintain lung function and QoL.Adults: 1. SABA for symptom relief SABA only if sympt. 2yrs 1. SABA symptom control2. Add montelukast for frequent intermittent or mild persistent asthma3. Add low dose ICS for persistent asthma stop after 3mths if control is good, esp. if >6yrsAt > 6yrs 4. Change montelukast to low dose ICS- or increase dose if already using.

Cromoglycate (cromone) 3-4 times a day Inhibits inflammatory mediator release from mast cells S/E- nasal congestionMontelukast Inhibits cysteinyl leukotriene receptor; antagonises airway smooth muscle contraction and inflammation caused by leukotrienes. S/E headache and nasal congestion. Potential hyperreactivity. Dermatologic and psychiatric rare by note worthy. REVIEW-REPEAT dispensing. C AND M can be used in patients with intolerable dysphonia induced by ICS

Antimicrobial TherapyConsider: Organisms Identity Organisms Susceptibility Bacteriostatic arrests growth and replication, limiting spread Bactericidal- kills the bacteria Site of infection Remember Lipid soluble to penetrate BBB, low molecular weight can penetrate BBB high Protein content will not pass into CSF Patient Factors Immune System Renal Dysfunction elimination Hepatic Dysfunction Poor perfusion- circulation to areas of infection effectiveness of therapy. Age Pregnancy- Cross Placenta, CONTRAINDICATION: Aminoglycosides Lactation Presence of foreign body Hx of Allergy/Adverse reactions Safety of the Agent Cost of the Therapy Route of Administation Oral- mild infections IV for seriousTypes of Antimicrobial TherapyPenicillinBactericidal- cell lysis and death- interfere w\ bacteria cell wall peptidoglycan synthesis when bound to penicillin-binding proteins. C/I- hx of allery. Amoxycillian Extended spectrum Rash- widespread erythematous maculopapular rash is common. Indication Exacerbation of chronic bronchitis, community-acquired pneumonia Acute bacterial otitis media, sinusitis Gonococcal infection Epididymo-orchitis, acute prostatitis, acute pyelonephritis, UTI Non-surgical prophylaxis of endocarditis Acute cholecystitis, peritonitis, eradication Amoxycillin w\ Clavulanic Acid = Augmentin Active against Beta-Lactamase Indication Hospital-acquired pneumonia Epididymo-orchitis (urinary tract source) PID (not sexually acquired) UTI Bites and clenched fist injuries Otitis media (unresponsive to amoxycillin) Acute bacterial sinusitis (unresponsive to amoxycillin) Acute cholecystitis (after IV treatment) Melioidosis Ampicillin Extended spectrum Indications Exacerbation of chronic bronchitis, community-acquired pneumonia Gonococcal infection, UTI Non-surgical prophylaxis of endocarditis Acute cholecystitis, peritonitis, epididymo-orchitis, acute pyelonephritis, acute prostatitis Benzathine penicillin Narrow Spectrum Prevention of Rheumatic fever Benzylpenicillin Narrow Spectrum Indication Bacterial endocarditis Meningitis Aspiration pneumonia, lung abscess Community-acquired pneumonia Syphilis Septicaemia in children Dicloxacillin Narrow Spectrum (stable to beta-lactamases) Indications Staphylococcal skin infections including folliculitis, boils, carbuncles, bullous impetigo, mastitis, crush injuries, stab wounds, infected scabies Pneumonia Osteomyelitis, septic arthritis Flucloxacillin Narrow Spectrum (stable to beta-lactamases) Indications Staphylococcal skin infections including folliculitis, boils, carbuncles, bullous impetigo, mastitis, crush injuries, stab wounds, infected scabies Pneumonia Osteomyelitis, septic arthritis Septicaemia Empirical treatment for endocarditis Surgical prophylaxisNote C/I for flucloxacillin and Dicloxacillin= Cholestatic hepatitis, risk >55yrs, female and course > 2 weeks. Phenoxymethylpenicillin (Penicilllin V) 60-70% absorbed orally. Limited to Staph and Strep Indications S. pyogenes tonsillitis, pharyngitis or skin infections Prevention of rheumatic fever Moderate-to-severe gingivitis (with metronidazole) Ticarcillin w\ Clavulanic Acid Toxicity Impaired platelet function/ Indications Mixed (aerobic and anaerobic) infections, especially if P. aeruginosa is involved Febrile neutropeniaNotes:Jarisch-Herxheimer reactionFever, chills, headache, hypotension and flare-up of lesions lasting for 1224 hours (due to release of pyrogens from the organisms) can occur shortly after starting to treat syphilis and other spirochete infections; prednisolone may be used to minimise likelihood of reaction in cardiovascular syphilis or neurosyphilis where this can be dangerousAminoglycosidesFor treatment of serious gram-negative intestinal infections and sepsisInhibit protein synthesis by irreversibly binding to the 30S ribosomal subunit and causing cell membrane damage. Concentration-dependent bactericidal effect.Adverse Effect- Serious and dose-related Ototoxicity Nephrotoxicity Transient Myasthenic SyndromeMay result in respiratory depression; can usually be reversed with prompt administration of IV calcium gluconate; the effect of neostigmine is variable. Amikacin Indications Treatment of infections caused by organisms resistant to other aminoglycosides Mycobacterial infections Gentamicin IM/IV Indications Empirical treatment for 35yr smoker or exposed to air pollutants. Chronic Dyspnoea and Sputum Production. Minimal diurnal variation. Pink Puffer- alveolar ventilation, near normal PaO2 and low PaCO2, breathless but not cyanosed, can progress to type 1 respiratory failure Blue Bloater- alveolar ventilation with a low PaO2 and high PaCO2. Cyanosed, not breathless, can develop cor pulmonale. Respiratory centre not sensitive to CO2- dependent on hypoxic drive to maintain resp *** caution should be taken with O2 therapy. Common clinical presentations: Chronic Cough, Dyspnoea, SOBOE, Sputum, Cyanosis of mucus membranes, Barrel chest (hyperinflation), RR at rest, shallow breathing, pursed lips, use of accessory respiratory muscles, tripod brace position. Complications: Acute exacerbations Polycythaemia Respiratory Failure Cor Pulmonale w\ Oedema and JVP Pneumothorax (ruptured bullae) Lung Ca.Principles of Mgmt - COPDXConfirm Diagnosis FEV1: FVC ratio post bronchodilator