Q11

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

Pass Criteria:

  • 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

Pass Criteria:

  • Enzyme induction/inhibition
  • PLUS one example of either

Q12

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


Pass Criteria
:

  • Large Vd + first pass

How does metoprolol differ from propranolol in its action at beta receptors?

  • B1 equipotent
  • B2 50-100 fold less potent


Pass Criteria:

  • 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


Pass Criteria
:

  • Negative inotrope/chronotrope

Q13

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

Pass Criteria:

  • Wide distribution + short  t1/2

At which receptors does atropine act?

  • Muscarinic (equipotent at M1, M2 and M3)
  • Nicotinic (minimal potency)

Pass Criteria:

  • Predominant Muscarinic

What are the effects of atropine on heart rate?

  • Lower doses often an initial bradycardia (Blocks prejunctional M1 receptors)
  • Tachycardia

Pass Criteria:

  • Dose dependant

Q14

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

Pass Criteria:

  • 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

Pass Criteria:

  • 2 cardiovascular

Q15

What is the mechanism of action of atropine?

  • Antimuscarinic at cholinergic receptors

Pass Criteria:

  • Antimuscarinic

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)

Pass Criteria:

  • 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.
  • Antispasmodic
  • Mydriatic

Pass Criteria:

  • 2 to pass

Q16

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

Q17

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

Pass Criteria:

  • 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

Pass Criteria:

  • 2 to pass

Q18

What are the effects of adrenaline on the blood vessels in different tissue? What receptors mediate these effects?

Vascular resistance

  • 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.

Respiratory Bronchodilation

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

Metabolic acidosis

Decreased extraceilular potassium

Leucocytosis

Insulin inhibits or stimulates insulin secretion 


Pass: 3 organs


Q19

What are the actions of digoxin on the heart at therapeutic levels?

  • Mechanical (Na-K ATPase)
  • Electrical:
  • 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?

No

Affect atrial and A — V nodal function more than Purkinje or ventricular function


Q20

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
  • ACE

Pass: 4 of bold.


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