anti-hypertensives

Question 1

Clonidine presentation and uses

Answer 1

Available as 25-300mcg tablets and as a colourless solution for injection containing 150mcg/mL.
Transdermal patch is also available but takes 48 hours to reach therapeutic levels.
Used in the treatment of HTN, chronic and acute pain, suppression of symptoms of opioid withdrawal and sedation

Question 2

Clonidine Mechanism of action

Answer 2

Stimulates alpha 2 receptors in the lateral reticular nucleus resulting in reduced central sympathetic outflow and alpha 2 receptors in the spinal cord where they augment endogenous opioid release and modulate noradrenergic pathways.
MAC is reduced (sedation increased) by stimulation of postsynaptic alpha 2 receptors centrally.

Question 3

Clonidine effects

Answer 3

CVS: Causes a prolonged fall in BP. CO is maintained despite bradycardia. PR interval is lengthened, AV node conduction depressed and BRR sensitised. Effects on vascular system complex as any vasoconstriction induced by alpha 2b receptors is offset by decreased SNS stimulation. Stablizes CVS response to surgical stimuli.
CNS - produces sedation and a reduction of up to 50% of MAC. Anxiolytic at low doses. Anxiogenic at high doses
Analgesia - provides analgesia with no respiratory depression. Acts synergistically with opioids.
Renal - causes diuresis
Endocrine - stress response to surgery is inhibited

Question 4

Clonidine kinetics

Answer 4

Clonidine is rapidly and almost completely absorbed orally.
Low protein binding. Vd 2.1L/Kg.
Elimination half life long at 9-18 hours. 50% excreted unchanged in urine therefore dose should be reduced in renal impairment

Question 5

Sodium Nitroprusside uses

Answer 5

Usually administered as a low dose infusion for hypertensive emergencies

Question 6

Sodium Nitroprusside mechanism of action

Answer 6

Vasodilates both arteries and veins by production of nitric oxide. Activates the enzyme guanylate cyclase leading to increased levels of intracellular cGMP. This causes vascular smooth muscle relaxation.

Question 7

Sodium Nitroprusside effects

Answer 7

CVS - Arterial vasodilation = decreased systemic vascular resistance. Venous vasodilation increases the venous capacitance and reduces preload. Cardiac output maintained by reflex tachycardia.
Resp - May inhibit HPV
CNS - ICP increased due to cerebral vasodilation and increased cerebral blood flow.

Question 8

Sodium Nitroprusside kinetics

Answer 8

Not absorbed orally. short t1/2. Duration of action less than 10 min.

Question 9

Sodium Nitroprusside toxicity

Answer 9

Metabolism is complication but causes cyanide ions to be formed. these can cause toxicity

Question 10

Nitric oxide MOA and use

Answer 10

Vasodilator. Synthesised in endothelial cells from amino acid L-arginine. Diffuses in to pre-capillary arterioles where it activates guanylyl cyclase and increases cGMP –> vascular smooth muscle relaxation.
Inhaled NO uses for severe pulmonary HTN and acute right heart dysfunction

Question 11

GTN presentation

Answer 11

Aerosol spray delivering 400mcg per metered dose
Tablets containing 300-600mcg - both used PRN sublingually.
Modified release tablets containing also available (either buccal or swallowed)
Transdermal patch (5-15mg/24 hours)

Question 12

GTN uses

Answer 12

used in the treatment and prophylaxis of angina, in LV failure associated with myocardial infarction and following cardiac surgery

Question 13

GTN mechanism of action

Answer 13

Vasodilates veins by the production of nitric oxide. Activates guanylate cyclase leading to increased cGMP. Causes vascular smooth muscle relaxation

Question 14

GTN effects

Answer 14

CVS - GTN produces vasodilation predominantly of the capacitance vessels (veins) - in contrast to SNP. This decreases venous return, preload and wall tension. Leads to decreased oxygen demand and increased coronary blood flow. Postural hypotension may occur. Coronary artery flow may be increased directly by coronary vasodilation. Tolerance occurs quickly however a daily drug free period of a few hours will prevent this
CNS - Increase in intracranial pressure and headache resulting from cerebral vasodilation may occur
GI - relaxes GI sphincters and sphincter of oddi

Question 15

GTN kinetics

Answer 15

Rapidly absorbed from sublingual mucosa and GI tract although latter is subject to extensive first pass metabolism resulting in oral bioavailability less than 5%.
Sublingual effects seen within 3 min and last 30-60min.

Question 16

Nifedipine presentation and uses

Answer 16

Capsules containing 5-10mg (sublingual) or oral 10-60mg. Onset of action 15-20min after oral .
Used in prophylaxis and treatment of angina, hypertension and raynauds syndrome

Question 17

Nifedipine effects

Answer 17

Reduces tone in peripheral and coronary arteries resulting in reduced systemic vascular resistance, decreased BP and increased coronary artery blood flow

Question 18

Nifedipine kinetics

Answer 18

Bioavailability of 60% due to first pass metabolism
Highly protein bound (95%) and elimination half life five hours.
Excreted inactive in urine

Question 19

Amlodipine

Answer 19

Dihydropryidine derivative that is available only for oral administration (5 to 10mg). Elimination half life is 30 to 40 hours.

Question 20

Hydralazine presentation and uses

Answer 20

Available as 25-50mg tablets and as 20mg powder for reconstitution.
Used orally in the control of chronic hypertension and chronic heart failure. Used IV in acute HTN associated with pre-eclampsia at 10-20mg

Question 21

Hydralazine MOA

Answer 21

Uncertain mechanism but involves activation of guanylate cyclase and an increase in cGMP. Decreases intracellular calcium and causes vasodilation

Question 22

Hydralazine effects

Answer 22

CVS - reduces arteriolar tone and SVR. Capacitance vessels (veins) are less affected. Reflex tachycardia and increase CO occur (can be antagonised by b blocker).
CNS - cerebral blood flow decreases due to vasodilation
GI - N + V common
Miscellaneous - peripheral neuropathy and blood dyscrasia. Long term therapy can cause lupus

Question 23

Cilazparil use

Answer 23

ACE inhibitor. Prodrug metabolized to active metabolite cilazaprilat.
Used for the treatment of hypertension and heart failure, especially in the presence of diabetic nephropathy

Question 24

Cilazapril MOA

Answer 24

ACE inhibitor. Competes with angiontensin 1 for binding at angiotensin converting enzyme. This leads to decreased angiotensin 2 and the effects of the drug lead from this. i.e decreased AT2 = decreased aldosterone, decreased vasoconstriction

Question 25

Cilazapril kinetics

Answer 25

Generally well absorbed 50-70%.
Metabolised by liver esterases to active drug. Eliminated by the kidneys.
Excreted renally therefore dose adjustment needed in renal failure

Question 26

Enalapril

Answer 26

Prodrug hydrolysed in the liver to active compound enalprilat. Half life 4-8 hours but increases in chronic use.

Question 27

Losartan presentation and uses

Answer 27

Angiotensin 2 receptor blocking agent.
Available as 25-50mg tablets and in combination with hydrochlorothiazide. Used in the treatment of HTN where dry cough is a side effect of ACEI.

Question 28

Losartan MOA

Answer 28

Specific AT2 receptor blocker at all sites within the body. Therefore inhibits all effects of AT2 including contraction of smooth muscle, thirst, ADH release, aldosterone secretion

Question 29

Losartan effects

Answer 29

Similar to ACEI except does not block the breakdown of bradykinin so don’t get the cough associated with ACEI.

Question 30

Losartan Kinetics

Answer 30

Bioavailability of 30% due to extensive first pass metabolism. Highly protein bound (99%).
Less than 10% excreted in inactive form in the urine