CVS Drugs 11 to 20
What are the cardiac effects of amiodarone at a cellular level?
- Prolongs AP duration (by blocking K+ channels)
- Blocks inactivated Na channels. The AP prolonging action reinforces this effect.
- Blocks depolarized cells > normal cells.
- Mild antisympathetic, noncompetitive inhibitor of beta receptors;
- Weak adrenergic blocker – slows HR and A-V node conduction.
- Weak Ca channel blocker. Inhibits abnormal automaticity; slows sinus rate; increases PR interval
- Potassium block
- PLUS 1 other
What are the mechanisms of pharmacokinetic drug interaction with Amiodarone and give two examples?
- Inhibits liver cytochrome metabolising enzymes
- Digoxin, Warfarin levels increase.
- Cimetidine increases amiod toxicity by decreasing hepatic clearance.
- Interacts with statins (artorvastatin and simvastatin; instead use pravastatin as not P450).
- Concentration and effects of Phenytoin, anaesthetics, cyclosporins, theophylline, procainamide, flecainide, quinidine are increased by amiodarone
- Enzyme induction/inhibition
- PLUS one example of either
Describe the pharmacokinetics of metoprolol?
Prompt: What’s the bioavailability? Why is this so?
- Oral or IV, Well absorbed
- Bioavailability 50% due to first-pass effect
- Large volume of distribution
- Half-life, 3-4 hours
- Metabolised in the liver
- Large Vd + first pass
How does metoprolol differ from propranolol in its action at beta receptors?
- B1 equipotent
- B2 50-100 fold less potent
- B1 selective
How do Beta Blockers control hypertension?
- Not fully understood
- Negative inotropic and chronotropic effects
- Slow a-v node conduction
- Antagonises release of renin caused by sympathetic nervous system
- Negative inotrope/chronotrope
Describe the pharmacokinetics of atropine?
- Oral or IV (usually), neb, topical; Well absorbed orally
- Widely distributed (including CNS)
- Half-life 2 hours
- Elimination: 60% excreted renally unchanged
- 40% phase I and phase II metabolism and renally excreted
- Wide distribution + short t1/2
At which receptors does atropine act?
- Muscarinic (equipotent at M1, M2 and M3)
- Nicotinic (minimal potency)
- Predominant Muscarinic
What are the effects of atropine on heart rate?
- Lower doses often an initial bradycardia (Blocks prejunctional M1 receptors)
- Dose dependant
What is the mechanism of action of Calcium Channel Blockers (CCB)?
- CCBs bind to receptors on alpha1,2, gamma and delta subunits of L-type Ca channel
- -> decreased frequency of opening of Ca channels in response to depolarisation
- -> decreased transmembrane Ca current
- -> decreased Ca influx ->
- Vascular smooth muscle relaxation
- Decreased Contractility in cardiac muscle
- Decreased SA node pacemaker rate
- Decreased AV node conduction velocity
- Need anti-arrhythmic and smooth muscle effects
What are the toxic effects of CCB’s?
- Cardiovascular: cardiac arrest; bradycardia; AV block; heart failure, hypotension
- Minor: flushing, dizziness, nausea, constipation, peripheral oedema
- 2 cardiovascular
What is the mechanism of action of atropine?
- Antimuscarinic at cholinergic receptors
What are the toxic effects of atropine?
- Tachycardia, flushing, dry skin mucous, mydriasis membranes, ileus, urinary retention, acute angle glaucoma, central anticholinergic syndrome (delirium with visual hallucinations)
- 3 to pass
What are the therapeutic uses for atropine?
- Symptomatic bradycardias, especially when vagally mediated.
- OGP poisoning/ Inocybe Mushroom poisoning, drying of secretions.
- Adjunct to reversal of non depolarising muscle relaxants and suxamethonium administration in young infants.
- 2 to pass
Regarding B agonists, by what cellular mechanism do they exert their effects?
- Bind to specific receptor.
- G-protein activation.
- Stimulate adenyl cyclase.
- Increased cyclic AMP.
- Increased free intracellular Ca.
- Activate protein kinase
Compare the cardiovascular of adrenaline and dobutamine.
- Adrenaline has B1, B2 and alpha effects.
- Increased inotrope and chronotrope.
- Peripheral vasoconstriction in most vascular beds.
- Vasodilatation in skeletal muscle beds (B2). May reduce TSVR.
- Dobutamine is a selective B1 agonist.
- Increases cardiac output with less reflex tachycardia as it has fewer B2 effects.
- Comes as racemic mixture of +ve and –ve isomers. One isomer has B agonist and alpha antagonist effects; the other has alpha agonist effects
What is flecainide’s mechanism of action?
- Na channel blockade (class effect). Predominant action is to inhibit the fast, or sodium, channel which is largely responsible for the rapid upstroke of the myocardial action potential in cardiac conducting tissue
- Class 1C action – – minimal effect on the Action Potential Duration and dissociates from the Na channel with slow kinetics. (no effect on QT interval)
- Decrease the rate of rise (Vmax, phase 0) of the action potential with little effect on duration
- Na channel block, class 1C
Describe flecainide’s pharmacokinetics.
- Well absorbed orally, half life ~ 20 hours
- Peak plasma drug levels at ~ 3 hours (range 1-6 hrs)
- Vd ranges from 5 to 13.4 L/kg (mean 8.7 L/kg)
- 30% of a single oral dose (range 10 to 50%) is excreted in urine as unchanged drug – remainder by hepatic metabolism.
- Usual dose 100- 200 mg daily
- SE: Hypotension, LV dysfunction
- 2 to pass
What are the effects of adrenaline on the blood vessels in different tissue? What receptors mediate these effects?
- Cutaneous (alpha)
- Mucous membranes (alpha)
- Skeletal muscle (ß2, (alpha)
- Renal (alpha), (delta)
- Splanchnic (alpha), ß
- Venous tone (alpha), ß
Pass: 3 tissues + receptors
Describe the effects of adrenaline on other organs besides the heart.
Eyes Pupillary dilation, Intraocular pressure — decreases, also decrease production of aqueous humor)
Relaxation of gastric smooth muscle
Genitourinary Uterine smooth muscle relaxation, Bladder relaxation, Bladder sphincter contraction, Ejaculation
Apocrine sweat glands — palm of hands
Salivary glands leading to dry mouth
Lipolysis — increased fatty acids and glycerol in circulation
Liver — enhanced glycogenolysis
Decreased extraceilular potassium
Insulin inhibits or stimulates insulin secretion
Pass: 3 organs
What are the actions of digoxin on the heart at therapeutic levels?
- Mechanical (Na-K ATPase)
- Direct — alters action potential
- Indirect (autonomic) – parasympathetic effects predominate
- Sensitisation of baroreceptors
- Central vagal stimulation
- Facilitation of muscarinic transmission
Pass: Mechanical and one other.
Are the parasympathetic effects uniform through-out the heart?
Affect atrial and A — V nodal function more than Purkinje or ventricular function
What are the sites of action of antihypertensive drugs (with examples)?
- Vasomotor centre – clonidine, methyldopa
- Sympathetic ganglia – trimethaphan
- Sympathetic nerve terminals – guanethidine, reserpine
- ß receptors of heart – ß blockers
- Angiotensin receptors of by – AT II receptor blockers
- a receptors of by – prazosin
- Vascular smooth muscle – hydrallazine, SNP, Ca blockers, GTN
- Kidney tubules – diuretics
- ß cells juxtaglomerular cells – ß blockers
Pass: 4 of bold.