year 2 drug table - st

Class of Drug Name Pharmacokinetics MOA Clinical Use Major Effects Side Effects ST 1

Directly Acting Cholinomimetics

AcetylcholineDegraded by Ach-

esterase and recycled

Stimulates muscarinic and nicotinic receptors

None – stimulates all autonomic ganglia General Muscarinic:

Salivation,↑bronchial + GI secretions,

blurred vision,sweating,

hypotension,bradycardia.

Bethanecolt½=3-4hrs

limited access to brain

Muscarinic agonist, especially M3(glands)

↑Bladder emptying + GI motility

Pilocarpinet½=3-4hrs

not Ach-esterase substrate

Muscarinic partial agonist Glaucoma (local admin)Pupil

constriction aids fluid drainage

Indirectly acting Cholinomimetics

Anticholinesterase

Physostigminet½=30minsANS>NMJ

Reversible AChE inhibitor. Block active site with

carbamyl group.Reactivated by hydrolysis

Glaucoma (local), Atropine poisoning

Low: ↑Muscarinic

effectsModerate: ↑ANS

General MuscarinicHigher doses - ↑all ANS,

depolarising blockNeostigmine Myasthenia gravis

Ecothiopate (organo-

phosphorous compounds)

Irreversible AChE inhibitor. Phosphorylates enzyme

(stable)

Glaucoma (local)

[Insecticides]SLUDGE BBB

Excitation, convulsions, unconsciousness, resp

depression, death.Antidote: Pralidoxin BBB

Cholinoceptor Antagonists

Trimetaphan IV Nicotinic ion channel blockers (incomplete, use dependent)

[Ganglion Blocking]

To induce hypotension during surgery

Hypotension, vasodilation,

↓Renin secretion.

↓↓ ANS function. Death due to targeting skeletal muscle.↓ Secretions, pupil dilation, ↓GI tone, bronchodilationHexamethonium Anti-hypertensive

(not in use)

Atropine I.V. after MI Muscarinic antagonistParkinson’s disease,

IBS, MI (↓motility+secretions)

Cholinergic balance in basal

ganglia

Mild doses – agitation, ↓sweating, ↓secretions,

Cylopegia, CNS disturbance, drowsiness, mydriasis,

constipation at high dosesPoisoning: Hyperactivity ->

CNS depression.Hot, Dry, Blind, Mad:

Treat with anticholinesterase

Hyoscine(Anti-emetic)

Transdermal patch, oral, I.V.

Muscarinic antagonist. Acts at vestibular nucleus, NST,

vomiting centre.

Anaesthetic premedication,

prevents motion sickness (not during)

Sedation at mild doses,

bronchodilation

Tropicamide Local Muscarinic antagonist Examination of retina Pupil dilationIpratropium

bromide Inhalation Muscarinic antagonist Asthma, obstructive airway disease Bronchodilation

Neuromuscular blocking drugs

(non-depolarising)

Tubocurarine

I.V. (↑ charged) doesn’t cross BBB/

placenta. Not metabolised.

Excreted 70% urine, 30% bile.

Competitive AChR antagonist at NMJ.

70-80% block necessary.Graded block – greater block further away from endplate.

Relaxation of skeletal muscle during surgery. ↓ need for anaesthetic and permits artificial

ventilation.

Flaccid paralysis – eye muscles,

face, limbs, diaphragm

Hypotension (↓TPR, histamine release), reflex

tachycardia, bronchospasm, excessive secretions, apnoea – must assist respiration. Can

be reversed by anti AChE


(non-depolarising) Atracurium Duration – 15-60m

Spon Decompose See above See above Histamine: Bronchospasm, Excessive Secretion + HypoT

Depolarising Neuromuscular

BlockersSuxamethonium

Not broken down by AChE.

Hydrolysed by Pseudo-

cholinesterases. DOA – 3-7mins

AChR agonist. 2 ACh molecules.

Steady influx of Na+ means inactivation remains closed,

as potential cannot fall below threshold.

Brief procedures – tracheal intubation,

dislocations.Flaccid paralysis Muscle pain, loss of K+,

bradycardia

SNS Agonists(sympatho-mimetics)

Direct

Adrenaline

I.V., I.M., localPoor oral

absorption.DOA – mins –

quickly degraded

Non-selective (α<β)

Anaphylactic shock, COPD, heart block

management, spinal anaesthesia, prolong

DOA of local anaesthesia, glaucoma

Bronchodilation, suppression of mediators, ↑HR + contractility,

↑TPR, vasoconstriction

Secretions: ↓ mucus, thickerCVS: cold extremities

tachycardia, palpitations, arrhythmias, stroke &

pulmonary oedemaMuscle: Tremor

PhenylephrineResistant to

COMT, not MAO.Usually local admin

Selective α1 agonistVasoconstrictor, mydriatic, nasal decongestant

Pupil dilation, restricts blood to prevent mucus

production

CVS effects

Clonidine Oral, I.V.Selective α2 agonist

↓Sympathetic tone by pre-synaptic NA inhibition

Hypertension, migraine↓Sympathetic outflow from brainstem

IsoprenalineResistant to

Uptake 1 and MAO. t½=2hrs I.V.

Selective β1+β2 agonist

Heart block, cardiogeneic shock,

acute heart failure, MI (No longer for asthma)

Reflex tachycardia, dysrhythmias

Dobutaminet½=2min, rapid

COMT degradation. I.V.

Selective β1 agonistHeart block,

cardiogeneic shock, acute heart failure, MI

No reflex tachycardia

SalbutamolResistant to

COMT, MAO, Uptake 1. I.V., oral,

inhalation

Selective β2 agonist

AsthmaThreatened

uncomplicated premature labour

Bronchodilation, inhibition of mediators

Reflex tachycardia, tremor.Caution in cardiac patients,

hyperthyroidism and diabetics

SNS Agonists(sympatho-mimetics)Indirect

Tyramine

In cheese, wine, soy sauce.

Extensive 1st pass metabolism, short half life. No BBB

Weak non-selective agonistCompetitive Uptake1 inhibitorMAO Competitor. Displaces NA from vesicles into cytosol

causing NA leak from cell.

- -Hypertensive crisis

“Cheese Reaction” when taking MOA inhibiting drugs


Indirect sympatho-mimetic,

Drug of abuse,Local

Anaesthetic

Cocaine

Smoked – absorbed quickly,

slow orally, nasally. Well absorbed. Readily crosses

BBB. Degraded by plasma + hepatic esterases. 90% protein bound t½=30mins.

Excreted in urine.

Uptake 1 inhibitor.Prevents NA reuptake

therefore ↑ Synaptic Activity

Prevents re-uptake of Dopamine in NAcc.

Blocks voltage gated Na+

channels.

Local anaesthetic in ophthalmology.

Do not co-administer with Adrenaline

Euphoria, excitement, ↑motor activity, tachycardia,

vasoconstriction, ↑BP, HR, platelet activation, tremors,

convulsions, resp depression (medullary centres), death

SNS Antagonists

Propranolol β1+β2 antagonist Anxiety

Hypertension, Arrhythmias, Angina,

Glaucoma

↓CO, + BP during exercise Bronchoconstriction,

Cardiac Failure, Hypoglycaemia

Fatigue, Cold Extremities, Bad Dreams

Atenolol Not for Asthmatics β1 antagonist↓CO, effect on airways only in

high doses

Labetolol β1+α1 antagonist ↓TPR, no change in CO

Phentolamine α1+α2 antagonist Not used ↓BP, TPR, reflex ↑CO/HR

↑ NA release due to α2 blockade, reflex tachycardia,

↑ GI motility, diarrhoea

Prazosin Doxazosin α1 antagonist Hypertension

↓BP/, ↓CO, VD dramatic

hypotension, ↓LDL and ↑HDL

Postural hypotension

False Transmitters Methyldopa

Not degraded by MAO. Doesn’t cross placenta

Taken up by NA neurones, forms false transmitter. Less active on α1, more active on α2. Accumulates in neurone.

Hypertension(in pregnancy)

Renal blood flow well maintained – good in renal

failure.

Dry mouth, postural hypotension, sexual dysfunction, sedationHepatitis-like damage.

Drugs affecting rennin –

angiotensin – aldosterone

system

Enalapril, Captopril

Inhibit ACE, prevent conversion of angiotensin I to

angiotensin II

Hypertension, heart failure, post-MI,

diabetic nephropathy, renal insufficiency.

Prevent vasoconstriction→↓TPR→↓BP

Hypotension, dry cough, angioedema, hyperkalaemia,

renal failure

Losartan Non-competitive antagonist of Angiotensin 1 receptors.

Hypertension. Patients with heart failure that cannot tolerate ACEIs

Less extensive than ACE inhibitors

Aliskiren Inhibits Enzyme (Renin) Experimental

Calcium Verapamil Phenylakylamine Inhibit opening of L-type Angina, Hypertension, ↓ HR (AV) and AV block, bradycardia, heart


channel Antagonists

calcium channels. Causes arterial vasodilatation

SVT, atrial fibrillation contractility. failure, constipationDiltiazem Benzothiazepine Angina, Hypertension ↓ cardiac

workloadFlushing, headaches,

hypotension, ankle oedemaAmlodipine Dihydropyridines Hypertension

Βeta-Blocker Atenolol No longer 1st lineHypertensive β1 Antagonist

Angina, Cardiac dysrhthmias, HF, Thyrotoxicosis,

Glaucoma, Mirgane

-ve Chronotropic & inotropic

Control/Correct Dysrhythmia

Bronchoconstriction, heart block, bradycardia, fatigue,

cold extremities, nightmares, hypoglycaemia in diabetics

Organic Nitrates

Glyceryl Trinitrate

Extensive 1st pass metabolism. t½=30mins,

sublingual, oral.Latter 2 longer transdermally.

Release NO→venodilation ↓venous return. Weak

antiplatelet, coronary artery VDAngina

Improve myocardial

oxygen demand

Hypotension, headache, flushing,

Tolerance – Eccentric dosing.Nicorandil

Isosorbide Mononitrate

Opens K+ channels→ arterial dilation. Also NO donor.

Anti-arrhythmics

Adenosine t½ = 20-30sI.V.

Acts on A1 receptors to slow conduction through AV node

Terminate SVT, safer than verapamil

Chest pain, SoB, dizziness, nausea.

AmiodaroneDronedarone

t½ = 10-100daysD: Less toxic but

less effectiveComplex ion channel blocker SVTs and ventricular

tachyarrhythmias.

Accumulates in skin, lungs, thyroid. Photosensitive skin

rash, pulmonary fibrosis.

Digoxin

(Cardiac Glycosides)

t½=40hrs

Inhibit Na+/K+ pump. ↑intracellular Na+ →↑Ca2+ via

Na+/Ca Exchange → +ve inotropic effect.

Central Vagal Stimulation ->-ve chronotropic

Atrial fibrillation, relief of symptoms in heart

failure.

↓Ventricular rate,

↑contractility. Slows

conduction through AVn

Amiodarone and verapamil ↓digoxin excretion and tissue

binding. Immune antibody available for toxicity.AV block and ectopic

pacemaker.

IvabradineCI: post-MI, sick sinus syndrome;

cardiogenic shock;

Blocks If channel – Na/K channel in sinoatrial node

Angina (w/ normal sinus rhythm) Slows HR Bradycardia, 1 degree Heart

block, Ventricular & SVA

Cardiac IntropesDobutamine β1 selective agonist Positive Inotroic:

↑ Force of ContractionsMilrinone Phosphodiesterase Inhibitor:

Prevents cGMP breakdownDecrease chronic heart

failure survival rate

α-blockers + sympatholytics

DoxazosinPrazosin Competitive α1 antagonist Postural Hypotension

Phenoxybenzamine Irreversible α1 antagonist Pheochromocytoma (w/ β-blockers) Tachycardia


Centrally Acting Sympatholytics

Clonidine α2 adrenceptor agonist Hypertension ↓ Sym outflow from BrainMononidine Imadazoline agonist

Vasoconstrictor Sumitriptan5HT1D agonist.

Vasoconstriction of large arteries, inhibits trigeminal

nerve transmission.

Migraine AttacksCoronary vasoconstriction – do not use in patients with

coronary disease.

Drugs of abuse

Cannabis

Inhalation 50%Oral 10-15% ↑½-

2hr duration t½=7days (remains

in fat tissues). Metabolised in liver – active metabolite 11-hydroxy-THC.

Enterohepatic cycling. 25% urine,

65% Bile

Endogenous cannabinoid receptors (hippocampus, cerebellum, cortex, basal

ganglia CB1, immune cells CB2). Anandamide is endogenous agonist.

Inhibit GABA interneurones in VTA → disinhibition of

dopaminergic projection.

Abuse

Effects on perception,

depression of cognition, slow reaction times, defects in short term memory, ↑ satiety, motor incoordination

Tachycardia, vasodilation → reddening conjunctivae,

postural hypotension and fainting, immunosuppressant,

respiratory effects (tar, carcinogens), psychosis due to loss of anterior cingulated

cortex → loss of inhibition and more primitive actions

Cocaine

IV. Oral. Nasal. Inhalation

t½=20-90minPlasma/Liver

Choliensterase

Ecgonine Methyl Ester, Benzoylecgonine

Inhibits reuptake of dopamine in NAcc

VC, ↑ Sym, ↑ HR, ↓ Cerebral

Blood flow + hyper-pyrexia in CNS -> Epilsepy

Euphoria/Disphoria, Heightened Energy,

Insomnia, Restlessness, Talkative, Violence, Anorexia

Nicotine

Inhalation 20% absorbed.

Distributes rapidly in tissues.

Elimination t½=2-3hrs. Metabolised in liver to cotinine.

Nicotinic receptor agonist. Sympathetic activation via

peripheral receptors or directly on brain.

Binds to nicotinic receptors on dendrites of VTA

neurones →↑ firing rate.

-

CVS: ↑Sym : ↑ HR, BP, SV, vasoconstriction, blood coagulation, LDL, VLDL, FFA, risk of atherosclerosis, MI, CVD, stroke. ↓ oxygen

carrying capacity HDLMetabolic: ↑metabolic rate, ACTH, cortisol,

↓appetiteNeurological: ↓risk of Parkinson’s & Alzheimer’s

DisulfiramAcetaldehyde

dehydrogenase inhibitor. Causes build up of

acetaldehyde.

Aversion therapy for recovering alcoholics.

Acetaldehyde build up: flushing,

tachycardia, panic, distress.

None when alcohol not present.


Drugs of abuse Alcohol

Oral. 20% stomach, 80% SI.

Substantial 1stPM – saturation kinetics. 90% metabolised,

10% excreted unchanged by

lungs. 85% metabolised in liver, 15% Gut

↑ GABA mediated inhibition (sedative effects)

Inhibition on Ca2+ entry → ↓ NT release.

Inhibition of NMDA receptor function (memory loss?)

Major action on cortex, RAS, corpus callosum,

hypothalamus, hippocampus, cerebellum, basal ganglia.

CNS: Depressant, ↓sensory function, concentration, motor function, reaction time, coordination. ↑confidence, euphoria, memory loss. Coma,

resp failure. Dementia, degeneration of cerebellum, neuropathy, myopathy, Wernicke-Korsakoff syndrome.

CVS: Vasodilation, flushing, ↓Ca2+ entry, ↑prostaglandins, ↓thrombosis risk/ heart disease - ↑HDL, ↓plaque formation, ↓thromboxane, ↓platelet

aggregation.Chronic Liver: Fatty Liver -> Hepatitis -> Cirrhosis. Oesophageal Varice.

Endo: ↑ACTH, ↓Testosterone -> Feminisation. Foetal Development.

Anticoagulants

Warfarin

Oral, absorbed quickly. Delayed

Effect for 12-16hrs. t½=4-5days.

99.99% Plasma protein bound,

hepatic metabolism by CYP450.

Inhibits the activation of vitamin K → Prevents

synthesis of clotting factors II, VII, IX, X.

Prevention/ treatment of DVT, PE, prevent

clotting during haemodialysis/ bypass

surgery.

Anticoagulant

Haemorrhage, teratogenicity. Drug interactions with:

Drugs inhibiting/ inducing CYP450

Drugs which displace warfarin from albumin

Drugs inhibiting platelet function

Heparin

LMWH

Poor oral absorption. Given S.C./ I.V. short t½. Saturation kinetics. LMWH has longer

t½ and no saturation kinetics.

Activated antithrombin III which inhibits factor Xa and thrombin by active serine

binding.

LMWH has less action on thrombin

Bleeding, thrombocytopenia, osteoporosis,

hypersensitivity.Reversal by protamine I.V.,

binds to give inactive complex.

Antiplatelet agents

Aspirin(also NSAID)

Oral, highly plasma protein bound

Irreversible COX-1 (and slight COX-2) inhibitor. Acetylates active site. Prevents TXA2

and PGE2 production.

Prevention of high risk cardiovascular patients. Analgesic, antipyretic,

anti-inflammatory

Analgesic, antipyretic, anti-inflammatory, antiplatelet.

GI sensitivity (ulceration, bleeding, perforation). ↓Creatinine clearance,

↑bleeding time, BronchoC

ClopidogrelOral. Peak plasma conc at 4hrs, effect

delayed 4 days.

Pro-drug inhibits fibrinogen binding to GpIIb/IIIa

receptors.

Aspirin sensitive patients

Prevents platelet

aggregation

Bleeding, GI haemorrhage, diarrhoea, rash, rarely

neutropenia.

Abciximab

I.V. Binds rapidly to platelets and cleared with

platelets. t½=24-48hrs.

Antagonist of GpIIb/IIIa receptor (monoclonal

antibody)

Acute Coronary Syndromes, with

heparin and aspirin to prevent ischaemia in

unstable angina.

Bleeding, immunogenic.


Fibrinolytics

StreptokinaseI.V. 30-60 min

infusion

t½=12-18mins

Binds to plasminogen and activates - conformational Acute MI - ↓mortality

(additive with aspirin), acute thrombotic stroke (3hrs), DVT, PE arterial

thromboembolism

Break down clot

Bleeding, GI haemorrhage, stroke. Allergy

AlteplaseRecombinant tPA – works

better on plasminogen bound to fibrin than soluble → clot sensitive. Activates Plasmin

Bleeding, GI haemorrhage, stroke. Not antigenic

Statins SimvastatinPravastatin Oral

HMG-CoA reductase inhibitors. ↓cholesterol

production in the liver. ↑ LDL receptors on hepatocytes →

↓ LDL in blood.

Patients with high cholesterol, blood

pressure, diabetes or MI.

↓Total cholesterol,

LDL, TGs. ↑HDL

RARE: Myalgia, muscle cramps, myopathy,

rhabdomyolysis, acute renal failure

Not for Pregenant Women.

Fibrate BenzafibrateGemfibrozil

Ligand for PPAR-α -> ↑lipoprotein lipase activity First Line for high TG ↓10% LDL ↑10%

HDL ↓30%TG

MiscNicotinic Acid ↓VLDL release -> ↓ 30-50% TG. ↓ 10-20% Cholesterol + ↑HDL A number of UE

Ezetimibe Glucuronidation Activiated

Inhibits cholesterol absorption Combination Therapy

Diuretics

MannitolPharmacologically inert. Filtered by glomerulus, not

reabsorbed. ↑osmolarity of tubular fluid →↓water reabsorption

Prevent acute renal failure (given in clinical setting due to ↑osmol)

↑Urine volumeElectrolyte imbalance

(hypernatraemia: nausea, vomiting, Pul Oe) ↑ECF vol

AcetazolamineInhibit intra+extracellular carbonic anhydrase. ↓

HCO3 reabsorption →Na++H2O reabsorption ↓.↑Na+

delivery to DCT→↑K+ loss.

Used in glaucoma, metabolic alkalosis, &

renal stones.

↑Urine volume, and ↑K+,Na+ and HCO3 excretion.

K+ loss, metabolic acidosis.

Frusemide(Loop diuretic)

Oral, onset 1hr, DOA 4-6hrs.

Tubular secretion, ~50% metabolised.

Inhibitor of Na+/2Cl-/K+ pump.(Triple Transporter in Asc Limb). Dilutes interstitium →↓concentrating power of

collecting duct.

Acute pulmonary oedema, oedema due

to heart failure, renal or hepatic disease. Hypercalcaemia/ hyperkalaemia.

↑ Urine volume~15-

30%, ↑Na+, K+, Cl-, Ca2+, Mg2+

excretion.

Metabolic alkalosis, hypovolaemia, hypotension,

hypokalaemia.

Bendrofluazide(Thiazide)

Oral, onset 1-2hrs, DOA 8-12hrs.

Tubular secretion.

Inhibitors of Na+/Cl- pump at DCT, →↑Na+ delivery to collecting duct →↓water

reabsorption. ↑K+ loss due to compensation for Na+

Congestive heart failure, hypertension, nephrogenic diabetes

insipidus!?, severe resistant oedema.

↑Urine volume 5-10%.

↑Na+,K+,Cl-,Mg2+

excretion. ↓Ca2+

excretion.

K+ loss, diabetes mellitus (interferes with insulin secretion), metabolic

alkalosis.

Amiloride(Potassium

Sparing Diuretics)

Poor orally. Onset 6hrs. DOA 24hrs.

Excreted unchanged.

Blocks Na+ channel in Na+/K+

exchange mechanism. ↑Na+

and ↓K+ loss.

With other diuretics to prevent K+ loss

↑urine vol 5%. ↑Na+,H+, uric

acid loss.

Hyperkalaemia, metabolic acidosis.

Spironolactone Oral, onset/DOA – Aldosterone antagonist. Heart failure, ↑urine vol 5%. Hyperkalaemia,


days. Filtered by glomerulus.

Blocks Na+/K+ exchanger in DCT. ↑K+ retention.

hypertension to prevent K+ loss with diuretics.

↑Na+,H+, uric acid loss.

gynaecomastia, menstrual disorders, testicular atrophy.

Anti-emetics(see also anti-muscarinics:

Hyoscine)

PromethazineOral. Onset in 1-2hrs, peak effect 4hrs, DOA 24hrs.

Competitive antagonist of H1>muscarinic>D2 receptors.

Acts centrally at NST, vestibular nucleus and

vomiting centres

Motion sickness, normally

prophylactically. Disorders of labyrinth,

morning sickness, pre-/post-operatively.

Also relief of allergic

symptoms, anaphylaxis,

night sedation.

Dizziness, tinnitus, fatigue, sedation (excitation in

excess), convulsions, general anti-muscarinic.

Metoclopramide

Oral, rapid absorption,

Extensive 1stPM. I.V. Crosses BBB

and placenta.

Dopamine receptor antagonist (D2>>H1>>M).

Acts centrally at CTZ.

Nausea & vomiting associated with toxins, e.g. uraemia, radiation sickness, GI disorders,

chemotherapy.

↑ GI motility and gastric

emptying.

Drowsiness, dizziness, extrapyrimidal reactions

(children – Parkinsonian-like)Hyperprolactinaemia.

anxiety, ↓bioavailability when co-administered.

OndansetronOral, well

absorbed, excreted in urine.

5HT3 receptor antagonist. Blocks visceral afferents and

CTZ.

Chemotherapy (cisplatin), radiation sickness and post-

operatively.

Prevents nausea & vomiting

associated with toxins and pain

Headache, flushing and warmth, constipation.

Gastric and duodenal ulcers

Antibiotics e.g. Metronidazole

Targets anaerobic bacteria and protozoa Elimination of

Helicobacter pylori as part of triple therapy.

Metronidazole interferes with alcohol metabolism

Amoxycillin Broad spectrum

Clarithromycin Inhibits bacterial tRNA translocation

Gastric and duodenal ulcers:

PPIsOmeprazole

Oral. DOA 2-3days. Enteric coated for slow

release.

Irreversible inhibitor of H+/K+

pump. Weak base that accumulates in canaliculi and

is activated by acid.

Triple therapy for ulcers, GORD.

↓acid secretion by 90% Rare

H2 antagonists Cimetidine Oral, well absorbed.

Histamine receptor antagonists

Triple therapy for ulcers, GORD

↓acid secretion by 60%

Rare. Likely relapse after withdrawal. CYP450 inhibitorRanitidine

Gastric and duodenal ulcers:Cytoprotective

drugs

Bismuth chelate Strong negative charge in low pH. Binds to positive

charge groups to form gel-like complex. Limits H+

and pepsin getting to ulcer.

Triple therapy, resistant cases

↑PGs, mucus, HCO3 secretion. ↓ Helicobacter

pylori

Constipation↓Absorption of drugs and

nutrientsSucralfate

Misoprostal PG agonist (analogue of PGE1)

Co-prescribed with oral NSAIDs

Maintains mucus barrier, ↓acid secretion

Diarrhoea, abdominal cramps, uterine contractions.

Do not give in pregnancyAnt-Acids Ant-Acids Neutralises acid, ↑ gastric Non-ulcer dyspepsia


Al3+ & Mg2+ pH, ↓ Pepsin activity Reduce duodenal ulcer

Respiratory Drugs

(Salbutamol & ipratropium)

Aminophylline Oral, I.V.

Phosphodiesterase inhibitor. Prevents breakdown on

cAMP → prolonged smooth muscle relaxation.

AsthmaRelaxation of

airway smooth muscle.

Salmeterol Long-acting 12hrsPowder Inhalation β2 receptor agonist Asthma. COPD Longer than

Salbutamol

NSAIDs(Aspirin)

Ibuprofen Oral Reversible COX-1 and COX-2 inhibitor.

Analgesic, anti-inflammatory,

antipyretic

GI sensitivity (ulceration, bleeding, perforation). ↓Creatinine clearance,

bronchoconstriction (lower incidence than aspirin)

CelecoxibSelective reversible COX-2

inhibitor →↓ risk of ulceration (can still inhibit HCL secretion

with COX-1)

Patients at high risk of GI side effects, and asthmatics. Those

taking NSAIDs long-term.

Anti-inflammatory

↑ Risk cardiovascular events and MI.

Other analgesic ParacetamolOral. Conjugated with glutathione in

liver.

Not fully known. Restricted to nervous tissue. May inhibit

COX during conversion (peroxidation) of PGG2 to

PGH2

Mild-moderate pain relief

Analgesic, antipyretic

glutathione depletion → build up of N-acetyl-p-

benzoquinoneimine → oxidation of hepatic enzymes

→ liver failure. Treat with acetylcysteine or oral

methionine (oxidises their thiol groups instead)

Opiates

MorphineOral 40-50%

absorption~30minsMetabolised in

liver, excret urine.

Bind to μ, κ, δ G-protein receptors. ↑K+ loss & ↓Ca2+

entry. Analgesia: μ, κ receptors in

dorsal horn of spinal cord, ↓pain perception. μ, κ

receptors on PAG (actually inhibit GABA interneurones)

, ↑ pain tolerance. μ, δ receptors in NRPG to↑ pain

tolerance. Euphoria: μ receptors inhibit GABA neurones in

Pain relief, anti-tussive Analgesic

Respiratory depression nausea and vomiting ↓ GI motility pupil constriction histamine release

(itching, urticaria, rarely hypotension)

Dependence and withdrawal

CodeineOral. 5-10% converted to

morphine in liver.

Heroin

Oral 50-100% absorption, I.V. Metabolised by

plasma esterases. Excreted in urine.

Euphoria

More lipid soluble → brain faster. Quickly metabolised → more addictive

Fentanyl Oral, buccal, Very lipid


intranasal, dermal, 50-100%

absorption. Metabolised in liver

– oxidation. Excreted in urine.

VTA →↑ Dopamine in NAcc Cough: inhibit cough

centre, and afferents from larynx

Resp depression: μ2

receptors inhibit central chemoreceptors in medulla Nausea: μ receptors

soluble. Oxidised

metabolites may be active

Methadone t½=24hrs Wean heroin addicts

Most lipid soluble →

dissipates into fat very quickly.

Opioid antagonists Naloxone I.V. high dose,

short acting Opioid receptor antagonist Treatment of opiate overdose

Precipitates withdrawal symptoms

IBD

Glucocorticoids

Prednisolone Intracellular GC receptor agonist. Positive TFs for anti-

inflammatory proteins or negative TFs for

inflammatory proteins. ↓influx inflammatory cells. ↓antigen

presentation, cell proliferation

Reduces need for surgery. Treats severe

active disease

↓ vasodilation, swelling, cell recruitment +

tissue damage

Osteoporosis, ↑gastric ulceration, suppression HPA axis, diabetes, hypertension,

infection, Cushing’s syndrome

Fluticasone Tapered dose

BudesonideTopical admin –

fluid or foam enemas (high

1stPM)

IBD

Amino-salicylates

Sulfasalazine

Suppositories, enemas, pH

dependent release capsules (SI), slow release

microsphere (small and large bowel)

↓Eicosanoids, free radicals, cytokines, leukocyte

infiltration. Broken down to sulfapyridine and 5-ASA by

gut flora.

Maintenance of remission (no

immunosuppressive actions) Effective in

UC, not Crohn’s

Anti-inflammatory

Caused by sulfapyridine

Mesalazine 5-ASA molecule alone FewOlsalazine 2 5-ASA molecules linked

IBDImmuno-

suppressants

AzathioprinePro-drug, activated

by flora. Metabolised by

Xanthine oxidase

Active component is purine analogue →interferes with DNA synth →prevents cell

division.Enhances T-cell apoptosis

Maintenance of remission in Crohn’s.

Also somewhat effective in UC

↓Antibody + cell immune

responses, infiltration,

proliferation

Bone marrow suppression. Do not administer with

xanthine oxidase inhibitors (allopurinol) → blood

disordersInfliximab I.V. (now also S.C.)

t½=9daysMonoclonal anti-TNF

antibody. ↓activation of TNF Crohn’s disease –

people with refractory ↓cytokines, leukocyte

↑TB, infections, septicaemia, malignancy, demyelinating


receptors, inactivates TNF bound to receptors. Inhibits

inflammatory responses downstream

disease and fistulae. Most effect in young or

colonic CD

infiltration. ↑T-cell apoptosis, complement lysis of TNF-

expressing cells

disease, heart failure. Can be immunogenic – given with

azathioprine. Only in clinical setting due to anaphylaxis

GABA related drugs

(Sodium Valporate, VIgabatrin)

Muscinol GABAA agonist: Cl- hyperpolarisation -> IPSP

Baclofen

GABAB agonist. Mimics presyn action of GABA (Gs proteins) to 1.↓Ca2+ influx and ↓NT release from excitatory

neurones 2. ↑K+ conductance ->

Hyperpolarisation

Spinal cord muscle relaxant,

Spasmolytic for stroke, MS patients

↓Tone from upper motor

neurones

Bicuculline Competitive GABAA

antagonistNone, used

experimentally Convulsant

PhaclofenSaclofen

Competitive GABAB

Antagonists

Barbiturates

Phenobarbitone Bind to BARB subunit of GABAA receptor. Enhance

GABA linkage between GABA, GABA modulin and

BZ subunits. ↑GABA binding to GABA subunit (not

reciprocated). At high concs, direct opening of Cl- channel.

→ ↑Duration of channel openings.

Also ↓glutamate transmission

Anti-convulsant

Non-selective CNS

depressant, other membrane

effects also

Low margin of safety – resp depression, lethal overdose

(alkaline diuresis can be used to↑ excretion), ↓REM sleep

→hangover effects. Potentiate other CNS depressants, develop

tolerance (pharmacokinetic and tissue), dependence and

withdrawal (insomnia, anxiety, tremor, convulsions,

death)CYP450 inducers

Amobarbital t½=20-25hrsSedative/hypnotic, severe intractable

insomnia

Thiopentone General anaesthetic

Benzodiazepine Diazepam Oral, I.V. for status epilepticus. Protein

Bind to BZ subunit of GABAA

receptor. Enhance GABA Anti-convulsant, anti-

spastic, anxiolytic (long “Remove

anxiety without Sedation, confusion, ataxia.

Potentiate other CNS


bound. Wide distn. Metabolised in

liver. Excreted in urine

t½=32hrs. Metabolised to Temazepam

linkage between GABA, GABA modulin and BZ

subunits, ↑GABA binding to GABA subunit (reciprocated

effect).→ ↑Frequency of channel

openings

acting)Wide safety margin.

Don’t depress respiration or induce

liver enzymes.

impairing mental or physical

activity”

depressants. Tissue tolerance occurs.

Dependence and withdrawal less intense than BARBs.

↑In plasma if used with other highly protein bound drugs.

If overdose -> rousible sleep, give I.V. flumazenil

(competitive BZ antagonist)

Temazepamt½=8hrs.

Metabolised to Oxazepam

Sedatives, hypnotics (short acting)

Reduce mental/physical activity/ induce

sleepOxazepam t½=8hrs.

Other hypnotics Chloral HydrateMetabolised in liver to trichloroethanol

(active component)

Unknown. May be related to alcohol

Wide margin of safety with children and

elderly

In hospitals as hypnotic Few

Other anxiolytics

Propanolol Improves physical symptoms “Stage Fright”: Tachycardia β1, Tremor β2

Buspirone Slow onset (days/weeks) 5-HT1A receptor agonist. Anxiolytic

Fewer than benzodiazepines (especially sedative ones). Possible future alternative

Anti-parkinsonian

L-DOPABroken down by

DD, 95% in periphery

Precursor to dopamine. Dopa-decarboxylase

converts to Dopamine in nerve terminal

Treats hypokinesia, rigidity, tremor ↑ Dopamine

Acute: Nausea and vomiting, hypotension, psychological effects (schizophrenia-like)Chronic: Dyskinesias, on-off

effects. ↓ Effectiveness.

Carbidopa (w/ L-DOPA: Sinamet) Inhibitor of peripheral DD Given with L-DOPA to

prevent periphery bd↑half life of L-DOPA & ↓ UE

[[Madopar – L-DOPA + Benserazide]]

Domperidone Peripherally acting Dopamine receptor antagonist

Given with L-DOPA to prevent nausea

Prevents CTZ stimulation -

Bromocriptine(Pergolide, Ropinerol)

Doesn’t require conversion – used

when there are fewer neurones

Dopamine receptor agonists

Longer DOA than L-DOPA, more sustained,

fewer dyskinesias. Given with L-DOPA

↑ Stimulation of Dopamine receptors

Confusion, dizziness, nausea, vomiting,

hallucinations, constipation, headache, dyskinesias

Deprenyl (Selegiline)Resagiline

(R – promotes anti-apoptosis genes –

Early Trials)

Selective MAO-B inhibitor. Inhibits breakdown of

dopamine only in dopaminergic areas of CNS

Early stages of disease, or with L-

DOPA (↓required dose, ↓side effects)

↑DopamineNausea, vomiting,

hypotension, confusion, agitation

Entacapone Peripherally acting COMT inhibitors, prevent breakdown of dopamine. ↓Required dose of ↑Dopamine in

CNS.→


COMT in periphery converts L-DOPA→3-0-MD, which

compete for same mechanism to cross BBB.

L-DOPA. More potent than MAO inhibitors

↑bio-availability of L-DOPATolcapone CNS and

peripheral

Neuroleptics(typical)

Phenothiazine - Chlorpromazin

eDelayed effect, take weeks to work. Initially ↑dopamine

synthesis and receptors. ↓Over

time

D2 Dopamine-like receptor antagonists. Most block many

other receptor types (5-HT)Schizophrenia. Treat

positive but not negative symptoms

(due to D1 Dopamine deficit)

Anti-emetic (CTZ), anti-histamine (block H1

receptors), acute dyskinesias - reversible on withdrawal, controlled by anticholinergics

Tardive dyskinesias (20-30%) – made worse by withdrawal, only overcome by ↑neuroleptic

(months or years of treatment). Incidence ↓with atypical neuroleptics. Hyperprolactinaemia,

lactation. Anti-muscarinic

Haloperidol

Neuroleptics(atypical)

Sulpiride

ClozapineRelatively non-selective

between D1 and D2, but high affinity for D4

General Anaesthetics(inhalation)

Nitrous oxide Rapidly eliminated Brain ↔ Blood ↔ Alveoli. All very lipid soluble, so slow into blood, fast into brain

↓NMDA (glutamate) receptor function To maintain

anaesthesia(IV Propofol maintained

by Enflurane gas)

Loss of consciousness, suppression of

reflex responsesAmnesia, analgesia

Difficult to induce anaesthesia, less potent than

I.V. anaesthetics.

Halothane Potentiate GABAA and glycine receptor function. No

subunit selectivity. Inhibit nicotinic Ach receptors

Enflurane

General Anaesthetics(Intravenous)

EtomidateMetabolised in

liver. No excretion from lungs

Bind somewhere on GABAA

receptor and ↑activity. More effective on β subunits. β3 in spinal cord→ suppression of reflexes, α5 hippocampus→

amnesia

To induce anaesthesia. Suppress coughing,

airway excitation. More potent than inhalation

anaesthetics

Loss of consciousness, suppression of

reflex responsesAmnesia, analgesia

Difficult to control when in the bloodstream. Elimination slower than from lungsPropofol

Local Anaesthetics

(Cocaine)Lidocaine

t½= 2hrs Well absorbed from

mucous membranes (any

ROA) 70% protein bound. Hepatic

dealkylation

Voltage gated Na+ channel blocker. Weak base, crosses connective tissue into nerve,

into neurone. Becomes ionised with proton inside neurone, blocks open Na+

channel to prevent Na+ influx

Surface anaesthetic, minor surgery, limb

surgery, dental surgery, spinal anaesthesia,

epidural.

↓Generation and conduction of

a.p.s.Selective for small, non-myelinated

fibres

CNS: stimulation, restlessness, confusion, tremor (paradoxical, may block inhibitory systems)

CVS: myocardial depression, vasodilation, ↓BP


Cytotoxic Drugs1. AlkylatingAgents

2. Anti-metabolites

3. Cytotoxic antibiotics

4. Plant alkaloids

5. Misc

Cyclo-phosphamide

(mephalon, chloramibucil)

Pro-drug, hydroxylated by

CYP450 -> Phosphoramide

Mustard + Acrolein

Carbonium ion is reactive group, bind irreversibly to DNA, RNA, proteins. Main target is N7 of guanine, but

most have other targets

Cancer, immunosuppressants

at lower doses

Intra/inter-chain links interfere

with transcription/

replication

Myelotoxicity (↓leukocytes, ↑infections)

↓healing ↓growth in children Sterility Teratogenicity Hair loss Nausea and vomiting.

Methotrexate Folate antagonist. Prevents purine synthesis

Stops cells dividing

FluorouracilPyramidine Analogue –

interferes with 2’-deoxythymidylate synthesis

Azathioprine Purine AnalogueActinomycin D (Dactinomycin)

Interferes w/ topoisomerase II Transcription

Bleomycin I.V.Causes fragmentation of

DNA chains. Acts on non-dividing cells. Metal chelating

Kills cells

Doxorubicin Inhibits topoisomerase II, preventing DNA/ RNA synth

Stops cells dividing

Vincristine[Vinca Alkaloid] NOT I.T.

Bind to tubulin, prevents Spindle Formation. Arrests

mitosis at metaphase

Etoposide [A Podophyllotoxin]Inhibits topoisomerase II,

preventing DNA synthesis. Inhibits mitochondrial function

Hydroxyurea Inhibits ribonucleotides reductase

Cisplatin Causes guanine inter-strand links

Procarbazine Activated by CYP450

MAO inhibitor. Inhibits DNA/RNA synthesis and interferes with mitosis at

interphase. Alkylates N7 + O6 of Guanaine


Antibacterial Drugs affecting

Folate

Sulpha-methoxazole

Sulphonamides

Oral, readily absorbed.

Peak plasma conc 4-6hrs

Structural analogue of P-aminobenzoic acid.

Competitive inhibitor of dihydropteroate (enzyme of

folic acid synthesis)

Sequential BlockersCo-trimoxazole

UTI and Resp TISynergistic effects

Pneumocystis carinii in AIDS patients

Mild – nausea, vomiting, headache.

Severe – hepatitis, hypersensitivity, bone marrow suppression

TrimethoprimTetrahydrofolate

production inhibitor

Oral, fully absorbed. ↑concs

in lungs and kidney. ⅔ each

drug protein bound

Folate antagonist. Inhibits dihydrofolate reductase in

bacteria(See Methrotrexate –

Cancer)

Nausea, vomiting, skin rashes

Hypersensitivity to Sulphonamide

Antibacterial affecting

Peptidoglycan Synthesis

β-lactamPenicillin

Widely distributed in body fluids.

Crosses placenta. Only crosses BBB when meninges

inflamed. 90% renal tubular

secretion

Irreversible inhibitors of a trans-peptidation enzyme that cross-links peptide chains to form peptidoglycan cell wall

Resistance by β-lactamases (give with

inhibitors e.g. clavulanic acid)

Also ↓permeability of cell membrane and altered binding sites

BactericidalHypersensitivity – skin

rashes, fever, anaphylactic shock. GI disturbances.

Cephalosporins Cephalexin (O)Cefuroxine (P)Cefotaxime (P)

Some oral, most I.M./ I.V. Widely

distributed in body fluids. Cross

placenta + BBB. Mostly renal

tubular secretion

β-lactam antibioticInhibits transpeptidase

Resistance greater than penicillins. Altered

binding sites, ↓penetration

Bacterial meningitis

Bactericidal

Hypersensitivity, similar to penicillin.

Nephrotoxicity, alcohol intolerance.

Diarrhoea if oral.

Antibacterial affecting Protein

Synethesis

Tetracyclines Oral (sometimes parenterally).

Chelate metal irons → ↓absorption with

foods. Enter most body fluids. Excretion

from bile (Doxycycline all

bile) + renal filtration

Actively transported into bacteria. Interrupt protein synthesis. Compete with tRNA for A binding site ->

inhibits mRNA-tRNA

Gram+ and -, mycoplasma, rickettsia,

chamyldia, some spirochaetes and

protozoa. Resistance largely due to efflux

Bacteriostatic GI disturbances. Can cause bone deformities in children. Do not give when pregnant.

Some phototoxicity (Demeclocycline &

Minocycline) and vestibular disturbances.

High doses give anti-anabolic effect.

Do not give if renal function impaired - accumulation


Antibacterial affecting Protein

Synethesis

Chloram-phenicol

t½ = 2hrs Oral. Widely distributed

in tissues and fluids. Crosses BBB. 30-50% protein bound. Metabolised in

liver. 10% renally excreted

unchanged

Inhibits protein synthesis. Binds to 50S ribosome

subunit, inhibits transpeptidation.

Gram+ and -.Resistance due to

enzyme production. Plasmid mediated.

Bacteriostatic

Hypersensitivity. GI disturbances.

Pancytopenia (Bone marrow suppression),

Grey baby syndrome – vomiting, diarrhoea, flaccidity,

low temp + ash grey –>40% mortality.

GentamicinAminoglycoside

t½=2hrs. Polar, not absorbed orally. I.M./ I.V. minimal protein binding,

doesn’t enter cells, cross placenta or BBB. Excreted by

glomerular filtration

Inhibit protein synthesis. Bind to 30S subunit, alter codon:

anticodon recognition → production of defective

proteins

Gram+ and -.Resistance by enzyme inactivation (plasmid

mediated). Also failure of penetration, binding

site mutations.

Bactericidal (enhanced by

agents interfering with cell wall synth)

Requires active transport enter, which Chloramphenicol

can block.

Progressive Ototoxicity, Reversible nephrotoxicity

Loading Doses.

Anti-mycobacterial

agents

Isoniazid

Oral, readily absorbed. Widely

distributed, crosses BBB. Metabolism

involves acetylation

Not fully understood. Passes into mammalian cells –

effective against intracellular bacteria. Inhibits

mycolicacids (cell wall components)

Tuberculosis and leprosy. Penetrates to necrotic, tuberculous

lesions.

Bacteriostatic on resting cells,

bactericidal on dividing cells

Slow metabolisers have a better therapeutic response

(t ½ = 3hr vs 1.5hr)

Rifampicin

Oral, widely distributed.

Excreted in bile and urine. Undergoes

enterohepatic cycling.

Metabolites retain activity

DNA-dependent RNA polymerase inhibitor in

prokaryotes. Enters phagocytic cells

Mycobacteria and other Gram + and many gram

- species

Infrequent (<4%), skin eruptions,

fever, GI disturbances

PyrazinamideOral, widely

distributed, crosses BBB. Excreted by

glomerular filtration

Inactive at pH7, tuberculostatic at low pH.

Effective against intracellular organisms in acidic phagolysosomes

BacteriostaticArthralgia,

GI disturbances, Malaise + fever


Antifungal agents

Nystatin No absorption across mucus membranes

Binds to cell membrane, forms a pore →ion channel, interferes with permeability

and transport. Greater avidity for ergosterol(fungi, protozoa)

Infections of skin and GI tract

Rare. Nausea, vomiting,

rash

MiconazoleI.V. infusion if

systemic. Oral if GI. Short half life

Blocks ergosterol synthesis by enzyme inhibition →

altered fluidity, interfering with enzymes on membrane

Stops cell division,

prevents hyphae formation

Infrequent, GI disturbances,

pruritis, blood dyscrasias

Antiviral agents

Acyclovir

Oral, I.V., topical. 20% GI absorption. Widely distributed, ½ crosses BBB.

Excreted by filtration+ secretion

Converted to monophosphate by viral TK, then to

triphosphate by host TK. This is viral DNA pol substrate and

is a chain terminator

Herpes simplex, also CMV

Resistance due to change in viral TK

Minimal. Local inflammation in I.V.

infusion, nausea,

headache.

Zidovudine

Oral, 1stPM gives 60-80%

bioavailability. Also I.V. Crosses BBB. Metabolised with

glucuronide in liver. 20% excreted

unchanged in urine

Trhymidine analogue ->Reverse transcriptase

inhibitor. Similar to acyclovir.

Triphosphate form terminates chain.

Enters cells by passive diffusion

Patients with HIV/AIDSResistance due to

progressive accumulating mutations in reverse transcriptase

↓incidence of opportunistic

infection, ↓viral load, ↓risk of transmission

from mother to baby

Accidental Exposure

Common: Anaemia, Neutropenia

Uncommon: GI disturbance, skin rash, insomnia, fever, headache, abnormal liver

function,

Repeated: Confusion, anxiety, depression, flu-like

symptoms

Anti-convulsants

Phenytoin

t½=12-40hrs. Hepatic oxidation,

hydroxylation. Renal excretion.

Saturation kinetics. 70-90% protein

boundVoltage gated Na+ channel

blocker

Partial epilepsy and status epilepticus

Rash, vasculitis, fever, hepatitis, ataxia, sedation, gingival hypertrophy, folate deficiency,

depression, hirsutism, peripheral neuropathy.CYP450 inducer, easily displaced from proteins

Carbamazepine

t½=36hrs (↓with chronic treatment). Hepatic oxidation, conjugation. Can

auto-induce

Partial and secondary generalised seizures

Rash, hepatitis, nephritis, ataxia, dizziness, sedation, diplopia, Vit K def, depression, impotence, osteomalacia, hyponatraemia

Hepatic enzyme inducer


Anti-convulsants

Sodium Valporate

t½=4-12hrs. Hepatic oxidation,

conjugation

Enhance GABA mediated inhibition (possibly inhibits

GABA metabolism)

Wide spectrum, partial or generalised seizures

Hepatic toxicity (young), pancreatitis, drowsiness, encephalopathy, tremor,

blood dyscrasias, hair loss, weight gain, PCOS

Potent CYP450 inhibitor

Vigabatrin t½=6-8hrs, but longer DOA

GABA-T inhibitor – prolongs action of GABA inhibition

Little, some infantile spasms

Visual field defects (retinopathy) ~40%. No CYP450 involvement

Lamotrigine

t½=29hrs. Hepatic glucuronidation (no phase 1) t½= ↑by

valporate to 60hrs, ↓PHT/CBZ to 15hrs

Voltage gated Na+ channel blocker

Wide spectrum, partial or generalised seizures

Well tolerated, rash, headache, blood dyscrasia, ataxia, diplopia, dizziness, sedation, insomnia, mood disturbance. No CYP450

involvement

Anti-Convul Drug Effect on Anti-convulsants Drug Effect of Drug on X

Phenytoin

Amiodorone, Isoniazid Phenytoin Metabolism Inhibitor → ↑PHT Warfarin Induces CYP450 -> ↓ [warfin]. Monitor INR closely.

Aspirin Displaces phenytoin from protein bound -> only use near safn

AEDs (Lamotrigine) corticosteroids, cyclosporin Induces CYP450 -> ↓ [conc].

Valproate Displaces protein bound & inhibits metabolism → easy toxicity

Oral Conceptative w/ oestrogen ↓ Efficacy (50ug eostradiol req)

Carbamazepine

PHT, PB Induces metabolismAEDs (PHT, VPA, LTG) Reduce levels of othersVPA

LTGInhibits epoxide-hydrolase →

4x (VGA) ↑ CBZ-epoxideMacrolide antibiotics

(Erythomycin) Inhibits metabolism x2-3 CBZ OCP Inform patients

Ca2+ Channel blockers (Diltiazene / Verapamil) ↑ 2x CBZ (Nifedipine -> no effect) Warfarin ↓ [Warfarin]

Fluoxetine May ↑CBZ levels

Valproate

Hepatic Enzyme Inducerse.g. PHT, PB, CBZ ↓ [Valproate] AED ↑ [PHT, PB, LTG]

Antacids May impair absorptionCarbamzepine ↑ CBZ-epoxideSome NSAIDs, Aspirin,

phenylbutazone Displaces VPA from albumin -> Toxicity

year 2 drug table - st

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