Antihypertensives

Question 1

Loop Diuretics

Answer 1

Furosemide, Torsemide, Ethacrynic acid.

MOA: Inhibit the Na/K/2Cl carrier in the thick ascending loop of henle

Question 2

Thiazide Duretics

Answer 2

Hydrochlorthiazide, Chlorthiazide, Chlorthalidone, Indapamide.

MOA: Inhibit the Na+/Cl- carier in the distal convoluted tubule.

Question 3

Adverse Effects of Thiazide and Loop

Answer 3

Hypokalemia

Appears in breast milk, so should be avoided in nursing mothers

Ischemic Ventricular Fibrillation and SCD. Caused by hypokalemia, hyponatremia, and calcium imbalance.

Question 4

K+ Sparing Diuretics

Answer 4

Amiloride, Triamterene, Spironolactone, Eplerenone

MOA: Inhibits ENAC channels, preventing sodium resorption in the collecting duct.

Adverse Effect: Hyperkalemia.

Question 5

Relevant Receptors

Answer 5

a1: vasoconstriction, tubular resorption of sodium

a2: Negative feedback inhibition for NE release

B1: Stimulation of renin release, Increased heart rate and force of contraction.

B2: Vasodilation (a1>B2)

Question 6

Cardioselective B1 Blockers

Answer 6

Atenolol and Metoprolol selectively block B1 receptors in the myocardium and kidneys, decreasing HR, force, cardiac output, and renin release. Mild decrease in peripheral resistance.

Question 7

Beta Blockers Adverse Effects

Answer 7

Rebound Hypertension due to upregulation of beta receptors, increasing tissue sensitivity to endogenous catecholamines.

Question 8

Beta Blocker Contraindications

Answer 8

Reactive Airway Disease
Myocardial conduction defects

DDI with Epinephrine and SA/AV conduction inhibitors, ie Verapamil and Diltiazem.

Question 9

a1 Antagonists

Answer 9

Prazosin, Terazosin, Doxazosin

MOA: a1 antagonists reduce arteriolar resistance and increase venous capacitance.

Adverse Effects:
-Postural Hypotension
-Retention of salt and water
-Peripheral edema.

Question 10

Combined Beta and a1 Receptor Antagonists

Answer 10

Labetalol is and equimolar mixture of stereoisomers that impact a1 and B receptors respectively. Labetolol can be used in hypertensive crisis because of its ability to block a1.

Carvedilol also has a1 antagonist activity in addition to its B antagonism, but is much weaker at a ratio of 1:10. Oxidation in the liver via CYP2D6 and is used adjunctively with diuretics and ACE inhibitors. Contraindicated in patients with decompensated HF dependent on sympathetic stim.

Decrease Preload and Afterload Simultaneously.

Question 11

Centrally Acting Adrenergic Agents

Answer 11

Clonidine, Guanabenz, Guanfacine stimulate a2A subtype receptors in the brain stem and reduce NE release.

Methyldopa is a prodrug, metabolized in adrenergic neruons to a-methylnorepinephrine, MNE acts on the presynaptic adrenergic neurons in the CNS by preventing further release of NE. Useful in pregnancy and renal insufficiency.

Adverse Effects Bradycardia, sinus arrest, and hepatotoxicity. 1-5% hemolytic anemia.

Question 12

Guanadrel

Answer 12

Guanadrel inhibits postganglionic adrenergic neuronal activation by acting as a false neurotransmitter.

Adverse Effects Hypotension and sexual dysfunction

DDI: Drugs that compete for catecholamine transporter on the presynaptic region reduce Guanadrel’s effects.

Contraindications: Pheochromocytoma

Question 13

Reserpine

Answer 13

Remains bound to CNS and peripheral neurons causing loss of function of VMAT which stores and accumulates catecholamines.

Adverse Effects: Psychotic depression

Contraindications: Depressive illness

Question 14

Calcium Channel Blockers

Answer 14

Block L type calcium channels, decrease intracellular calcium and calcium induced calcium release
Affect mostly cardiac and vascular smooth muscle. Slow HR and decrease TPR

Adverse Effects: Potential Baroreceptor reflex causing tachycardia.

DDI: Chronotropic effect with beta blockers. Not advised to use in combination when patient has a history of rhythm disease or MI.

Question 15

Dihydropyridines

Answer 15

Nifedipine, Isradipine, Nicardipine, Amlodipine, Felodipine.

Question 16

Phenylalkylamines

Answer 16

Verapimil

Question 17

Benzothiazepines

Answer 17

Diltiazem

Question 18

Clevidipine

Answer 18

3rd gen dihydropyridine. Ultra short acting (within 1-3 minutes) with high specificity to vasculature.

Question 19

Aliskiren

Answer 19

Direct Renin competitive inhibitor

Adverse Effects: Angioedema

Contraindicated in pregnant women

Question 20

ACE Inhibitors

Answer 20

Suffix -pril

MOA: Inhibition of ACE, preventing generation of Ang II.

Prevention of vasoconstriction due to ANG II binding to AT1R. Decreased formation of aldosterone decreases Na+ reuptake.

Adverse Effects: Angioedema, cough due to bradykinin accumulation.

Contraindications: Pregnancy, renal disease.

DDI: Hyperkalemia when used in high doses with K+ sparing diuretics.

Question 21

AT1 Receptor Antagonists

Answer 21

Suffix -sartan

Antagonists of AT1 receptors promoting relaxation of vascular smooth muscle. Also promote renal salt and water excretion. Leads to increased renin and Ang II in circulation due to decreased negative feedback.

Adverse Effects: Hypotension, Hyperkalemia, reduced renal function.

Question 22

Hydralazine

Answer 22

Arterial vasodilator causing a decrease in intracellular calcium by preventing IP3 mediated release of Ca.

Question 23

Minoxidil

Answer 23

Arterial Vasodilator

Prodrug that needs to by converted to minoxidil N-O sulfate.

MOA: Activates ATP modulated K+ channel, promoting efflux of K+ in smooth muscle causing relaxation

Adverse Effects: Hirsuitism, Pseudoacromegaly, Pericardial Effusion.

Question 24

Nitroprusside

Answer 24

Arterial and Venous vasodilator.

MOA: Releases NO which activates guanylyl cyclase-cGMP-PKG leading to vasodilation.

Contraindicated in patients with compromised renal or liver function.

Metabolism: Reacts with Hgb to form cyan-methemoglobin and cyanide. Thiosulfate breaks cyanide down to thiocyanate which is less toxic and eliminated. Remaining cyanide binds to mitochondrial cytochrome enzymes and prevents oxidative phosphorylation causing toxicity.

Adverse Effects: Rare cyanide toxicity causing toxic psychosis. Administration of thiosulfate preventatively can mitigate this. Treated with administration of hydroxocobalamin.

Question 25

Non Pharmacological Approaches

Answer 25

Reduction in weight in obese individuals
Restriction of excess sodium
Restriction of ethanol
Increase in physical activity
Avoid smoking