Q1

Describe the mechanism of action of glyceryl trinitrate?

  • Taken up by vascular smooth muscle
  • Interacts with tissue sulfhydryl groups
  • Releases free radical nitric oxide
  • Activates cGMP
  • Dephosphorylates myosin light chains
  • Reduces intracellular Ca levels
  • Smooth muscle relaxation & vasodilation

Pass Criteria:

  • Vascular smooth muscle
  • Nitric oxide
  • Vasodilation

What are the clinical effects of nitrates?
(Prompt if needed: What other clinical effects may be seen?

  • Low doses – venodilation leads to  decreased preload & stroke volume
  • Higher doses – arterial dilation leads to decreased blood pressure as well as decreased cardiac output & decreased myocardial oxygen demand + dilation of coronary arteries/redistribution of perfusion
  • Improved oxygen delivery to myocardium & resolution of ischaemic pain
  • Adverse effects include:
  • Postural hypotension, tachycardia, dizziness, headache, flushing, blurred vision, dry mouth, rash

Pass Criteria:

  • Decreased BP
  • Decreased Myocardial oxygen demand
  • PLUS 2 listed other effects

Q2

Describe the mechanism of action of ACE inhibitors.

  • Competitive block conversion of angiotensin I to II
  • Decreased vascular tone from prevention of vasoconstrictor effects of Ang II (main effect)
  • Inhibition of aldosterone secretion caused by Ang II leading to reduced Na & H2 resorption resulting in decreased BP

Pass Criteria:

  • 3 in bold to pass

What are the adverse effects of ACE inhibitors?

  • Dizziness, hypotension
  • Headaches, weakness
  • Loss of taste, nausea, diarrhoea
  • Rash, fever, joint pain
  • Cough
  • Mild hyperkalaemia due to decrease in aldosterone secretion
  • Acute renal failure

Pass Criteria:

  • Hypotension or dizziness
  • Cough
  • PLUS 2 others

What are some drug interactions that occur with ACE inhibitors?

  • Diuretics Þ hypotension
  • General anaesthetics Þ hypotension
  • Lithium: lithium toxicity
  • NSAIDS: hyperkalaemia & reduced effects of ACE inhibitor
  • Potassium sparing diuretics / potassium supplements – hyperkalaemia

Pass Criteria:

  • 2 to pass

Q3

Describe the pharmacodynamics of therapeutic drugs that modulate the effect of angiotensin?

  • ACE inhibitors – bind ACE reversibly preventing conversion of AI to AII.
  • Inhibitory action on the renin-angiotensin system Stimulating action on the kallikrein-kinin system

What are the advantages of Angiotensin 2 receptor antagonists over ACE inhibitors?

  • Angiotensin II inhibitors – competitive antagonists at A II receptor
  • As AII inhibitors do not result in production of bradykinins, there is a decreased incidence of cough and angioedema.
  • Potentially greater effect as enzymes other than ACE can generate AII

Pass Criteria:

  • Able to describe actions and basic effects of ACE inhibitors
  • AND understanding that AII receptor antagonists and ACE inhibitors have different mechanisms

Q4

What is the cellular mechanism of action of GTN?

  • Denitration by glutathione S-transferase.
  • Free nitrite ions released and form NO.
  • NO activates guanylyl cyclise leading to increased cGMP and dephosphorylation of myosin and smooth muscle relaxation (precise mechanism unknown)

Pass Criteria:

  • Production of NO leading to smooth muscle relaxation

How does GTN relieve angina pain?

  • Venodilation leads to reduced venous return, reduce ventricular volume and reduced heart wall tension.
  • This reduces myocardial O2 requirement

Pass Criteria:

  • Know that venodilation and reduced venous is major factor reducing myocardial o2 requirement

Outline the pharmacokinetics of sublingual GTN

  • Oral bioavailability is low due to extensive first pass hepatic metabolism by high capacity organic nitrate reductase.
  • Rapid and efficient absorption by sublingual or intranasal routes but rapid elimination (t1/2 2-8 mins) and duration of action (15-30 mins) due to high capacity hepatic metabolism.
  • Denitrited metabolites conjugated to to glucuronide and excreted in urine.

Pass Criteria:

  • Poor oral bioavailability due extensive first pass metabolism and effective alternative routes of administration

Q5

How does GTN exert its effect on smooth muscle?

  • Nitrite -> NO -> increased cGMP -> relaxation.
  • Prostaglandins also involved

What are the clinical effects of GTN?

  • Venodilation -> reduced venous return -> reduced LVEDV -> reduced LV wall tension -> reduced myocardial oxygen consumption (-> reduced cardiac output in normal people, possibly increased in pathological conditions where pretreatment preload is abnormally high)
  • Other:
  • Arterial dilation -> throbbing headache (relatively ineffective on resistance vessels)
  • Other smooth muscle relaxation  (eg amyl nitrite + enhanced erection) less important
  • Decreased platelet aggregation, but no apparent beneficial therapeutic effect in this regard
  • Methaemoglobinaemia from nitrite but not from GTN

Pass Criteria:

  • Able to discuss pros and cons of at least two

Q6

What are the pharmacokinetic features of Beta Blockers?

  • Well absorbed
  • Low bioavailability
  • Large volume of distribution.
  • Most are metabolized in liver

Pass Criteria:

  • At least 2

What are the effects of beta blockers?

  • Decrease in hypertension, negative chronotrope and negative ionotrope, atrioventricular block, increased survival after AMI, Bronchospasm, decreased IO pressure

Pass Criteria:

  • At least 2

What are the effects of beta blocker in overdose?

  • Hypotension, bradycardia, cardiogenic shock, bronchospasm, seizures (cerebrotoxic),
  • NB Propanolol causes arrhythmias through Type 1 antiarrhythmic effects (Na channel block)

Pass Criteria:

  • At least 3

Q7

What is the mechanism of action of atropine?

  • Reversible block of cholinergic muscarinic receptors

Give examples of the organ effects of atropine?

  • CNS: decrease tremor and rigidity in Parkinson’s disease
  • Eye:– mydriasis and  cycloplegia
  • Cardiovascular: SA ( and AV) node; blocks vagal slowing -> rel tachycardia and incr conduction ( shorten PR )_, block coronary vasodilation
  • Respiratory:  blocks M receptors on smooth muscle and secretions
  • Gastrointestinal: Blocks motility and secretions
  • Genitourinary Relaxes smooth muscle in ureters and bladder wall ( spasm) and  slows voiding ( retention)
  • Skin: decreases sweating

Pass Criteria:

  • At least 3

What are the features of atropine poisoning?

  • Agitation and delerium
  • Raised temp
  • Blurred vision / mydriasis
  • Dry mouth / flushed skin
  • Tachycardia

Pass Criteria:

  • At least 4

Q8

At a cellular level, describe the action of calcium channel blockers.

  • Bind at intracellular L type calcium channel

What are the differences in pharmacodynamics between dihydropyridines and other Ca channel blockers?

  • Dihydropyridines are vascular smooth muscle selective
  • Verapamil / Diltiazem greater effect on cardiac/conducting tissue

How are these differing pharmacodynamics reflected in their side effect profile?

  • Dihydropyridines cause flushing, headache & tachycardia
  • Verapamil causes bradycardia
  • Both can cause hypotension

Q9

What is the mechanism of action of captopril?

  • Inhibit converting enzyme peptidyl dipeptidase which
  • Hydrolyzes AI to AII – get decreases peripheral vasc. resistance; CO and HR same
  • inactivates bradykinin – therefore get vasodilation, decreased Peripheral vascular resistance and decreased BP

What are the clinical uses of captopril?

  • CHF, after MI (better preservation of LVF – reduce post MI remodeling)
  • Diabetic nephropathy: diminish proteinuria, stabilize renal function – improved intrarenal hemodynamics
  • Hypertension

What are the adverse effects of captopril?

  • Hypotension after 1st dose if hypovolemic, diuretics, NaCl restriction, GI loss
  • ARF (bilateral renal a. stenosis)
  • Hyperkalemia – if renal insufficiency, DM
  • Dry cough, angioedema (bradykinin, substance P)
  • Fetal problems if 2nd, 3rd trimester
  • Neutropenia, proteinuria from high dose captopril
  • Minor – change taste, skin rash, drug fever

Q10

What is the mechanism of action of adenosine?

  • Enhanced K+ conductance – marked hyperpolarisation
  • Inhibition of cAMP induced Ca2+ influx – suppression of calcium dependant AP

What effect does this have on cardiac conduction?

  • Inhibits AV node conduction (at least )
  • Increases AV node refractory period
  • Lesser effect on SA node

GO ON TO
Questions 11 to 20