HTN Drugs

What antihypertensive drug classes are considered first-line according to Dr. Hasan's lecture?

Calcium channel blockers (CCBs), ACE inhibitors or ARBs, and thiazide/thiazide-like diuretics. Chlorthalidone is specifically highlighted as a first-line thiazide-like diuretic.

Are beta-blockers first-line antihypertensive drugs?

No. Beta-blockers are considered alternative antihypertensive agents. They lower BP mainly through cardioinhibition and decreased renin release.

What antihypertensive drug classes are considered less commonly used?

Alpha agonists/antagonists, direct renin inhibitors, endothelin-1 receptor antagonists, NO donors, and direct vasodilators/K+ channel openers.

What is the major equation relating cardiac function and vascular resistance to blood pressure?

BP = HR × SV × TPR. Therefore, decreasing HR, stroke volume, or total peripheral resistance can decrease blood pressure.

What receptors do first-generation nonselective beta-blockers inhibit?

β1 and β2 receptors.

What receptors do second-generation cardioselective beta-blockers preferentially inhibit?

β1 receptors. However, selectivity can be lost at high doses, so drugs such as metoprolol can begin blocking β2 receptors.

What is the normal β1 receptor signaling pathway in cardiac muscle?

Epinephrine activates β1 → Gs → ↑ adenylyl cyclase → ↑ cAMP → ↑ PKA → ↑ L-type Ca2+ channel activity and intracellular Ca2+ → stronger cardiac contraction (positive inotropy).

How do beta-blockers decrease cardiac contractility?

β1 blockade inhibits the Gs → cAMP → PKA pathway → ↓ Ca2+ entry through L-type Ca2+ channels and ↓ intracellular Ca2+ → ↓ cardiac contraction = negative inotropy.

How do beta-blockers decrease heart rate?

β1 blockade in the SA node decreases Gs → cAMP → PKA signaling and reduces funny-channel and Ca2+ channel activity → slower SA node firing → negative chronotropy.

How do beta-blockers affect AV node conduction?

β1 blockade decreases AV nodal firing/conduction through reduced cAMP and Ca2+ channel activity → negative dromotropy.

What are the overall cardiac effects of beta-blockers?

↓ inotropy → ↓ contraction strength; ↓ chronotropy → ↓ HR; ↓ dromotropy → ↓ AV conduction. Overall, ↓ HR and ↓ stroke volume → ↓ BP.

Why can nonselective beta-blockers cause vasoconstriction?

β2 activation normally increases Gs → cAMP → PKA in vascular smooth muscle, which inhibits MLCK and promotes relaxation. Blocking β2 removes this vasodilatory effect and can promote vasoconstriction.

Why can nonselective beta-blockers cause bronchoconstriction?

β2 receptors normally mediate bronchodilation. Blocking β2 receptors prevents bronchodilation and can cause bronchoconstriction, which is especially concerning in asthma or COPD.

Why can beta-blockers mask hypoglycemia?

Hypoglycemia normally produces sympathetic warning symptoms such as tachycardia and tremor. Beta-blockers suppress these adrenergic symptoms, making hypoglycemia harder to recognize.

Why should beta-blockers not be abruptly discontinued?

Chronic beta-blocker use causes upregulation of β receptors. Abrupt discontinuation exposes these increased receptors to catecholamines → excessive sympathetic activity, tachycardia, hypertension, and potentially ischemia.

What are the major side effects of beta-blockers emphasized in lecture?

Bradycardia, hypotension, masking of hypoglycemia, pulmonary effects/bronchoconstriction, erectile dysfunction, and rebound sympathetic activity if abruptly discontinued.

Propranolol (Inderal) — Class, MOA, and side effects

1st-generation nonselective β1/β2 blocker. Blocks Gs-coupled β receptors → ↓ cAMP/PKA. β1 blockade causes ↓ HR, contractility, AV conduction, and renin; β2 blockade may cause vasoconstriction and bronchoconstriction. Side effects: bradycardia, hypotension, bronchoconstriction, masking hypoglycemia, erectile dysfunction; do not abruptly discontinue.

Nadolol (Corgard) — Class, MOA, and side effects

1st-generation nonselective β1/β2 blocker. Blocks β-mediated Gs → cAMP signaling → ↓ cardiac rate/contractility and renin. β2 blockade can cause bronchoconstriction and vasoconstriction. Side effects: bradycardia, hypotension, pulmonary effects, masking hypoglycemia; do not abruptly discontinue.

Timolol (Blocadren) — Class, MOA, and side effects

1st-generation nonselective β1/β2 blocker. Inhibits Gs → cAMP signaling → ↓ HR, contractility, AV conduction, and renin. β2 blockade may cause bronchoconstriction. Side effects: bradycardia, hypotension, pulmonary effects and masking hypoglycemia.

Atenolol (Tenormin) — Class, MOA, and side effects

2nd-generation cardioselective β1 blocker. Blocks β1 Gs → cAMP signaling → ↓ HR, contractility, AV conduction and renin release → ↓ BP. Side effects: bradycardia, hypotension and masking hypoglycemia. β1 selectivity decreases β2 effects but selectivity may be lost at high doses.

Metoprolol (Lopressor, Toprol XL) — Class, MOA, and side effects

2nd-generation cardioselective β1 blocker. ↓ Gs → cAMP/PKA signaling in the heart → ↓ chronotropy, inotropy, dromotropy and renin release. Side effects: bradycardia and hypotension. At high doses β1 selectivity can be lost and β2 receptors may also be blocked.

Bisoprolol (Zebeta) — Class, MOA, and side effects

2nd-generation β1-selective blocker. β1 blockade → ↓ Gs/cAMP → ↓ HR, contraction, conduction and renin → ↓ BP. Side effects: bradycardia, hypotension and masking hypoglycemic symptoms.

Esmolol (Brevibloc) — Class, MOA, and side effects

Short-acting 2nd-generation β1-selective blocker. Blocks β1-mediated Gs/cAMP signaling → rapid ↓ HR, AV conduction and contractility. Side effects: bradycardia and hypotension.

Labetalol (Trandate, Normodyne) — Class, MOA, and side effects

3rd-generation nonselective β1/β2 blocker with strong α1 blockade. β blockade produces cardioinhibition; α1 blockade prevents Gq → PLC → IP3 → Ca2+ signaling in vascular smooth muscle → vasodilation. Side effects: hypotension, orthostasis, bradycardia and possible bronchoconstriction.

Carvedilol (Coreg) — Class, MOA, and side effects

3rd-generation nonselective β1/β2 blocker + α1 antagonist. β blockade ↓ HR/contractility; α1 blockade ↓ PLC/IP3/Ca2+ → vasodilation. Also has cardioprotective, anti-ischemic and antioxidant properties. Side effects: bradycardia, hypotension, orthostasis and bronchoconstriction.

Nebivolol (Bystolic) — Class, MOA, and side effects

3rd-generation highly selective β1 blocker that also increases nitric oxide. β1 blockade decreases HR, contractility and renin; ↑ NO causes vasodilation. Side effects: bradycardia, hypotension and dizziness.

What is the normal α1 receptor signaling pathway in vascular smooth muscle?

α1 is Gq-coupled. α1 activation → PLC → IP3/DAG → ↑ intracellular Ca2+ → smooth muscle contraction → vasoconstriction.

How do α1 blockers lower blood pressure?

They prevent α1-mediated Gq → PLC → IP3 signaling → ↓ intracellular Ca2+ in vascular smooth muscle → vasodilation → ↓ TPR and BP.

Prazosin (Minipress) — Class, MOA, and side effects

Selective α1 antagonist. Blocks Gq → PLC → IP3 → Ca2+ signaling in vascular smooth muscle → vasodilation and ↓ BP. Side effects: orthostatic hypotension, dizziness and first-dose syncope.

Terazosin (Hytrin) — Class, MOA, and side effects

Selective α1 antagonist. Prevents α1-mediated ↑ intracellular Ca2+ → vascular smooth muscle relaxation and vasodilation. Side effects: orthostatic hypotension, dizziness and first-dose syncope.

Doxazosin (Cardura) — Class, MOA, and side effects

Selective α1 antagonist. Blocks Gq/PLC/IP3/Ca2+ pathway → vasodilation and ↓ BP. Side effects: orthostatic hypotension, dizziness and first-dose syncope.

Alfuzosin (Uroxatral) — Class, MOA, and side effects

α1 antagonist used primarily for BPH. Blocks α1-mediated contraction in prostate/bladder smooth muscle. Side effects: dizziness and orthostatic hypotension.

Tamsulosin (Flomax) — Class, MOA, and side effects

Preferential α1A antagonist used primarily for BPH. Relaxes prostate/bladder neck smooth muscle with less vascular effect. Side effects: dizziness, orthostatic hypotension and abnormal ejaculation.

Where are central α2 receptors involved in blood pressure regulation located?

Presynaptically in the brain's vasomotor center. α2 receptors function as negative-feedback receptors that decrease norepinephrine release.

What is the normal signaling pathway of central α2 receptors?

α2 receptors are Gi-coupled → ↓ cAMP and ↓ presynaptic Ca2+ entry → ↓ norepinephrine release → ↓ sympathetic activity.

How do central α2 agonists lower blood pressure?

They stimulate presynaptic α2 receptors in the vasomotor center → ↓ NE release → ↓ sympathetic outflow → negative chronotropic/inotropic effects plus vasodilation → ↓ BP.

What are the major side effects of central α2 agonists?

Bradycardia, dry mouth, sedation and withdrawal/rebound symptoms if abruptly discontinued.

Clonidine (Catapres) — Class, MOA, and side effects

Central α2 agonist. Stimulates presynaptic Gi-coupled α2 receptors → ↓ NE release and sympathetic activity → ↓ HR, contractility and vascular tone. Side effects: bradycardia, dry mouth, sedation and severe rebound hypertension if abruptly stopped.

Methyldopa (Aldomet) — Class, MOA, and side effects

Central α2 agonist/prodrug. Converted to an α2-acting metabolite that reduces central NE release and sympathetic activity → ↓ BP. Side effects emphasized for this class: bradycardia, dry mouth and sedation.

Guanfacine (Tenex) — Class, MOA, and side effects

Central α2 agonist. Activates presynaptic Gi-coupled α2 receptors → ↓ NE release → ↓ sympathetic activity. Side effects: bradycardia, dry mouth, sedation and withdrawal effects if abruptly discontinued.

What type of calcium channel is targeted by antihypertensive calcium channel blockers?

L-type voltage-gated Ca2+ channels.

What happens when L-type Ca2+ channels open normally?

Ca2+ enters the cell and stimulates ryanodine receptors in the sarcoplasmic reticulum → further intracellular Ca2+ release → increased contraction.

What is the major difference between non-DHP and DHP calcium channel blockers?

Non-DHPs (verapamil, diltiazem) act more strongly on the myocardium/SA and AV nodes. DHPs (-dipines) act predominantly on peripheral vascular smooth muscle and cause vasodilation.

How do non-DHP calcium channel blockers affect the heart?

Block L-type Ca2+ channels in SA/AV nodes and cardiomyocytes → ↓ chronotropy, ↓ dromotropy and ↓ inotropy.

How do DHP calcium channel blockers lower blood pressure?

Block L-type Ca2+ channels in vascular smooth muscle → ↓ intracellular Ca2+ → ↓ Ca2+-calmodulin activation of MLCK → ↓ contraction → vasodilation → ↓ TPR/BP.

What are the major side effects of calcium channel blockers?

Hypotension, peripheral edema (especially DHPs), exacerbation of GERD, and drug interactions. Non-DHPs can additionally cause bradycardia and constipation.

What important drug interaction is associated with verapamil?

Verapamil inhibits P-glycoprotein and can decrease elimination of P-gp substrates such as digoxin → increased drug concentrations.

Verapamil (Isoptin, Calan, Verelan) — Class, MOA, and side effects

Non-DHP CCB. Blocks cardiac L-type Ca2+ channels → ↓ SA/AV nodal firing, ↓ HR/conduction and ↓ contractility. Side effects: bradycardia, hypotension, constipation, GERD exacerbation; inhibits P-gp and can increase digoxin levels.

Diltiazem (Cardizem) — Class, MOA, and side effects

Non-DHP CCB. Blocks L-type Ca2+ channels in heart and vessels → ↓ chronotropy, dromotropy and inotropy plus vasodilation. Side effects: bradycardia, hypotension, constipation and peripheral edema.

Nifedipine (Procardia, Adalat) — Class, MOA, and side effects

DHP CCB. Blocks L-type Ca2+ channels primarily in vascular smooth muscle → ↓ intracellular Ca2+ → vasodilation → ↓ TPR/BP. Side effects: hypotension, peripheral edema, headache/flushing and possible reflex tachycardia.

Nicardipine (Cardene) — Class, MOA, and side effects

DHP CCB. Predominantly blocks vascular L-type Ca2+ channels → arterial vasodilation and ↓ BP. Side effects: hypotension, peripheral edema, headache and reflex tachycardia.

Amlodipine (Norvasc) — Class, MOA, and side effects

DHP CCB and first-line antihypertensive. Blocks vascular L-type Ca2+ channels → vasodilation and ↓ TPR. Side effects: peripheral edema, hypotension, flushing/headache and GERD exacerbation.

Clevidipine (Cleviprex) — Class, MOA, and side effects

DHP CCB. Blocks vascular L-type Ca2+ channels → arterial vasodilation and ↓ BP. Side effects: hypotension and reflex tachycardia.

Nimodipine (Nimotop) — Class, MOA, and side effects

DHP CCB with prominent effects on cerebral vascular smooth muscle. Blocks L-type Ca2+ channels → vasodilation. Side effects: hypotension and headache.

What are the major effects of angiotensin II at AT1 receptors?

AT1 receptors are Gq-coupled. Ang II → AT1 → ↑ IP3/DAG/Ca2+ → vasoconstriction. It also increases aldosterone, ADH, SNS activity and renal Na+/H2O reabsorption and inhibits renin release.

What are the major effects associated with AT2 receptor activation?

Generally oppose AT1: vasodilation, antiproliferative effects, K+ channel activation, Ca2+ channel inhibition, increased bradykinin and NO production.

How do ACE inhibitors affect the RAAS?

ACE inhibition → ↓ Ang II + ↑ bradykinin + ↑ Ang-(1-7). This produces vasodilation, ↓ SNS activity, ↓ aldosterone, ↓ ADH and ↓ Na+/water retention.

Why do ACE inhibitors cause a dry cough?

ACE normally breaks down bradykinin. ACE inhibition causes bradykinin accumulation → bronchial effects/bronchoconstriction → dry cough.

How do ACE inhibitors affect the renal efferent arteriole and GFR?

↓ Ang II causes dilation of the efferent arteriole → ↓ intraglomerular pressure → ↓ GFR.

Why can ACE inhibitors cause hyperkalemia?

↓ Ang II → ↓ aldosterone secretion → ↓ renal K+ excretion → potassium retention/hyperkalemia.

What happens to renin, Ang I and Ang II with ACE inhibitors?

↑ plasma renin concentration, ↑ renin activity, ↑ Ang I and ↓ Ang II. Bradykinin increases.

Captopril (Capoten) — Class, MOA, and side effects

ACE inhibitor. Inhibits ACE → ↓ Ang II and ↑ bradykinin/Ang-(1-7) → vasodilation, ↓ aldosterone/ADH and ↓ Na+/H2O retention. Side effects: hypotension, dry cough, hyperkalemia and ↓ GFR/renal dysfunction.

Enalapril (Vasotec; Enalaprilat IV) — Class, MOA, and side effects

ACE inhibitor. ↓ Ang II + ↑ bradykinin → vasodilation and ↓ aldosterone/ADH/SNS activity. Side effects: dry cough, hyperkalemia, hypotension and ↓ GFR.

Lisinopril (Prinivil, Zestril) — Class, MOA, and side effects

ACE inhibitor. ↓ Ang II and ↑ bradykinin → vasodilation, ↓ SNS activity and ↓ Na+/water retention. Side effects: cough, hyperkalemia, hypotension and renal dysfunction.

Ramipril (Altace) — Class, MOA, and side effects

ACE inhibitor. Blocks Ang I → Ang II conversion and bradykinin degradation → ↓ Ang II effects and vasodilation. Side effects: cough, hyperkalemia, hypotension and ↓ GFR.

Quinapril (Accupril) — Class, MOA, and side effects

ACE inhibitor. ↓ Ang II + ↑ bradykinin → vasodilation and ↓ aldosterone-mediated Na+/water retention. Side effects: cough, hyperkalemia, hypotension and renal dysfunction.

Benazepril (Lotensin) — Class, MOA, and side effects

ACE inhibitor. ↓ Ang II and ↑ bradykinin → vasodilation plus ↓ aldosterone/ADH. Side effects: dry cough, hyperkalemia, hypotension and ↓ GFR.

How do ARBs differ mechanistically from ACE inhibitors?

ARBs directly antagonize AT1 receptors. They do NOT inhibit ACE, so bradykinin does not accumulate. Ang II levels actually increase, but Ang II cannot activate AT1 and can instead stimulate beneficial AT2 effects.

What happens to Ang I and Ang II levels with ARBs?

Both Ang I and Ang II increase because AT1 blockade removes Ang II-mediated negative feedback on renin. Despite ↑ Ang II, AT1 effects are blocked.

Why are ARBs less likely than ACE inhibitors to cause cough?

ARBs do not inhibit ACE, so bradykinin continues to be degraded and does not significantly accumulate.

What happens to renin with ARBs?

Renin concentration and renin activity increase because blocking AT1 removes Ang II-mediated negative feedback on renin release.

Losartan (Cozaar) — Class, MOA, and side effects

ARB. Blocks Gq-coupled AT1 receptors → ↓ vasoconstriction, aldosterone, ADH, SNS activity and Na+/H2O retention. ↑ Ang II can stimulate AT2 receptors. Side effects: hyperkalemia, hypotension and renal dysfunction; much less cough than ACEIs.

Valsartan (Diovan) — Class, MOA, and side effects

ARB. Antagonizes AT1 receptors → blocks Ang II-mediated vasoconstriction and aldosterone/ADH effects while allowing AT2 signaling. Side effects: hyperkalemia, hypotension and renal dysfunction.

Irbesartan (Avapro) — Class, MOA, and side effects

ARB. Blocks AT1 → vasodilation, ↓ SNS activity and ↓ aldosterone-mediated Na+/water retention. Side effects: hyperkalemia, hypotension and renal dysfunction.

Candesartan cilexetil (Atacand) — Class, MOA, and side effects

ARB. Blocks Ang II binding to AT1 receptors → ↓ vasoconstriction and fluid retention. Side effects: hyperkalemia, hypotension and renal dysfunction.

Telmisartan (Micardis) — Class, MOA, and side effects

ARB. AT1 antagonism → ↓ Ang II-mediated vasoconstriction, SNS activity, aldosterone and ADH. Side effects: hyperkalemia, hypotension and renal dysfunction.

Olmesartan medoxomil (Benicar) — Class, MOA, and side effects

ARB. Blocks AT1 receptors → ↓ vasoconstriction and Na+/H2O retention while allowing Ang II to activate AT2. Side effects: hyperkalemia, hypotension and renal dysfunction.

How does aliskiren inhibit the RAAS?

Aliskiren directly inhibits renin activity → prevents angiotensinogen → Ang I → ultimately ↓ Ang II.

What happens to renin concentration versus renin activity with aliskiren?

Renin concentration ↑ because loss of Ang II negative feedback stimulates renin release, BUT plasma renin activity ↓ because aliskiren inhibits the released renin.

What happens to Ang I and Ang II with a direct renin inhibitor?

Both ultimately decrease because functional renin is inhibited.

Aliskiren (Tekturna) — Class, MOA, and side effects

Direct renin inhibitor (DRI). Inhibits renin activity → ↓ Ang I and Ang II. Loss of Ang II negative feedback causes ↑ renin concentration despite ↓ renin activity. Overall effects: ↓ SNS, vasodilation, ↓ aldosterone/ADH and diuresis. Side effects include hyperkalemia and hypotension.

Which antihypertensive classes increase plasma renin concentration?

Direct renin inhibitors, ACE inhibitors, ARBs, diuretics and calcium channel blockers increase plasma renin concentration. Beta-blockers decrease renin.

Which antihypertensive drug class increases renin concentration but decreases renin activity?

Direct renin inhibitors such as aliskiren.

How do beta-blockers affect renin?

β1 blockade on juxtaglomerular cells decreases renin release → ↓ plasma renin concentration/activity and ↓ Ang I/Ang II.

Why do diuretics increase RAAS activity?

Diuretics decrease blood volume. The body compensates for the perceived low-volume state by increasing renin release → ↑ Ang I and ↑ Ang II.

Where do thiazide diuretics act?

Early distal convoluted tubule (site 3).

What transporter do thiazide and thiazide-like diuretics inhibit?

Na+/Cl− cotransporter (NCC) in the distal convoluted tubule.

What are the major effects of thiazide diuretics?

↑ Na+ and Cl− excretion → natriuresis/diuresis and initial ↓ blood volume. They also increase Ca2+ reabsorption. Long-term antihypertensive effect includes vasodilation by an incompletely understood mechanism.

How do thiazides affect calcium?

They increase Ca2+ reabsorption → hypercalcemia risk but may help prevent calcium-containing kidney stones and increase bone density.

Why do thiazides cause hypokalemia?

More Na+ reaches the collecting tubule. Na+ is reabsorbed by principal cells in exchange for increased K+ secretion → hypokalemia. Increased H+ secretion also contributes to metabolic alkalosis.

What acid-base disturbance can thiazides cause?

Metabolic alkalosis.

What are the major side effects of thiazide diuretics emphasized in lecture?

Volume depletion, hypotension, hypokalemia, hyponatremia, hypochloremia, metabolic alkalosis, hypomagnesemia, hypercalcemia, hyperuricemia, decreased glucose tolerance, lipid changes and erectile dysfunction.

Chlorothiazide (Diuril) — Class, MOA, and side effects

Thiazide diuretic. Blocks Na+/Cl− cotransporter in DCT → ↑ NaCl excretion/diuresis and ↑ Ca2+ reabsorption. Side effects: hypokalemia, hyponatremia, metabolic alkalosis, hypomagnesemia, hypercalcemia, hyperuricemia and hypotension.

Hydrochlorothiazide (HydroDIURIL, Esidrix, Oretic) — Class, MOA, and side effects

Thiazide diuretic. Inhibits NCC in DCT → natriuresis/diuresis and ↑ Ca2+ reabsorption. Side effects: hypokalemia, hyponatremia, metabolic alkalosis, hypercalcemia, hyperuricemia and hypotension.

Chlorthalidone (Hygroton) — Class, MOA, and side effects

Thiazide-like diuretic and specifically highlighted first-line antihypertensive. Blocks NCC in DCT → ↑ NaCl excretion and ↓ blood volume initially; chronic vasodilation contributes later. Side effects: hypokalemia, hyponatremia, metabolic alkalosis, hypercalcemia and hyperuricemia.

Metolazone (Zaroxolyn) — Class, MOA, and side effects

Thiazide-like diuretic. Blocks Na+/Cl− cotransporter in DCT → natriuresis/diuresis. Side effects: hypokalemia, hyponatremia, volume depletion, metabolic alkalosis and hyperuricemia.

Indapamide (Lozol) — Class, MOA, and side effects

Thiazide-like diuretic. Inhibits NCC in DCT → NaCl excretion plus chronic BP-lowering vasodilation. Side effects: hypokalemia, hyponatremia, metabolic alkalosis and hyperuricemia.

Where do ENaC inhibitors act?

Late distal tubule/collecting tubule and collecting duct, primarily in principal cells.

How do ENaC inhibitors work?

Block epithelial Na+ channels → ↓ Na+ reabsorption → natriuresis while decreasing K+ and H+ secretion → potassium-sparing effect, hyperkalemia and metabolic acidosis.

What are the major side effects of ENaC inhibitors?

Hyperkalemia and metabolic acidosis.