1 - Antihypertensive Agents - Jinn

Hypertension statistics?

~50 million Americans have BP ≥140/90

It is the most common CVD and a major risk factor for CAD, HF, stroke, and renal failure

About 30% don’t know they have it because it often has no symptoms

What are the causes of hypertension?

Primary (essential) → 90–95%, unknown cause

Secondary → ~10%, cause known → kidney abnormalities, congenital heart defects (e.g., aorta), or narrowed arteries

What causes secondary hypertension?

Kidney abnormalities

Congenital heart defects (e.g., aorta)

Narrowing of arteries

What is the short term treatment goal of hypertension?

Reduce blood pressure

What is the long term treatment goal of hypertension?

Reduce mortality → due to hypertension-induced disease stroke

• Congestive heart failure

• Coronary artery disease

• Nephropathy

• Retinopathy

What are the 3 ways of lowering blood pressure?

Reducing cardiac output

Reducing plasma volume

Reduce total peripheral resistance

Lowering blood pressure via reducing cardiac output?

Beta blockers

Ca2+ channel blockers

Lowering blood pressure via reducing plasma volume?

Diuretics

Lowering blood pressure via reducing total peripheral resistance?

Vasodilators

Alpha 1 — Adrenergic receptor antagonists

ACE inhibitors

Where do loop / high-ceiling diuretics act?

At the thick ascending limb of the loop of Henle

MOA of loop / high ceiling diuretics ?

Inhibit the Na⁺/K⁺/2Cl⁻ symporter in the → thick ascending limb of the loop of Henle

How does loop diuretics inhibiting the Na⁺/K⁺/2Cl⁻ symporter decrease BP?

Inhibiting the Na/K/2Cl symporter → decreases reabsorption of Na⁺, K⁺, and Cl⁻ → increase excretion of these ions and water → decrease blood volume → decrease BP

How are loop diuretics similar to thiazide diuretics?

Both are diuretics used to lower BP

Side effects of loop diuretics?

Hypokalemia → K+

Hyperuricemia → high level of uric acid

Hypersensitivity reactions

Examples of loop diuretics?

Furosemide

Bumetanide

Ethacrynic Acid

Where do thiazide diuretics act?

In the distal convoluted tubule

MOA of thiazide diuretics?

Inhibits Na+/Cl- symporter in the → distal convoluted tubule

How does thiazide diuretics inhibiting he Na/Cl symporter decrease BP?

Inhibiting the Na/Cl symporter → decreases Na⁺ reabsorption → increases water excretion → decrease blood volume AND direct vascular smooth muscle relaxation

Overall → decreasing BP

When are thiazide diuretics used?

For mild — moderate hypertension

For patients with normal kidney function

Well tolerated and cheap

Side effects of thiazide diuretics?

Hypersensitivity reaction

Hypokalemia → K+

What can be added to thiazide therapy to help prevent hypokalemia?

A K⁺— sparing diuretic

Example of a thiazide diuretic?

Chlorothiazide

When are Ca2+ channel blockers used?

For mild — moderate hypertension

All antagonists are equally effective for Stage 1 hypertension

MOA of Ca2+ channel blockers?

Bind to L-type Ca²⁺ channels → decreases intracellular Ca²⁺ → decrease cardiac contractility AND vasodilation → overall decreases BP

Side effects of Ca2+ channel blockers?

Edema

Hypotension

Tachycardia

Dizziness

Headache

What are the 3 classes of Ca2+ Channel blockers?

Dihydropyridines → Amlodipine, Nifedipine, Nicardipine

Phenylalkyl Amines → Verapamil

Benzothiazepine →Diltiazem

What does ACE inhibitor stand for?

Angiotensin-Converting Enzyme inhibitor

How do ACE inhibitors affect the renin-angiotensin system?

Inhibit Angiotensin II formation

Decreases Angiotensin II → less vasoconstriction and less aldosterone → increase Na⁺/water excretion → decrease blood volume → decrease BP

How do ARBs affect the renin-angiotensin system?

Block Angiotensin receptor activation

Block Angiotensin II receptor activation → less vasoconstriction and less aldosterone → increased Na⁺/water excretion → decreased blood volume → decreased BP

What does ARB stand for?

Angiotensin Receptor Blocker

ACE inhibitor vs ARBs?

ACE inhibitor → decrease Angiotensin II formation

ARB → blocks Angiotensin II receptor activation

Have the same overall downstream effects → but they block the pathway at different points

Systemic reduction of ACE inhibitors?

TPR → total peripheral resistance

Systolic and Diastolic pressure

Mean arterial pressure

Aldosterone secretion

Cardiac remodeling → physical heart changes

Systemic increases of ACE inhibitors?

Regional blood flow in vascular beds → more blood reaches tissues

Large artery compliance → arteries become more flexible

Examples of ACE inhibitors?

Captopril

Enalaprilat

Dicarboxylate-containing inhibitors

Lisinopril

Moexipril

Perindopril

Quinapril

Ramipril

Trandolapril

Are ACE inhibitors prodrugs?

Yes!

They must be biotransformed for activity by esterases

What is a common use for ACE inhibitors?

Initial choice for mild–moderate hypertension

What conditions are ACE inhibitors especially useful for?

Drug of choice for hypertension → due to diabetes mellitus

Also for hypertension caused by → CHF, arrhythmia, or kidney disease

What is ACE inhibitors most effective in?

High renin patients → enzyme by kidneys that help controls BP

More effective in Caucasian patients

What increases the efficacy of ACE inhibitors?

Diuretics!

Side effects of ACE inhibitors?

Hypotension

Cough

Hyperkalemia

Angioedema

Acute renal failure

Neutropenia

Proteinuria → protein in urine

Tetratogenic

Examples of ARBs?

Losartan

Valsartan

Irbesartan

Olmesartan medoxomil

Eprosartan

Azilsartan medoxomil

Telmisartan

Candesartan cilexetil

Therapeutic uses of ARBs?

Same uses as ACE inhibitors

First-line alone or with other agents

No bradykinin effects → no cough

Useful for HTN secondary to → CHF

Side effects of ARBs?

Hypotension

Hyperkalemia

Dyspepsia

Diarrhea

Abdominal pain

Headache, dizziness, fatigue

Upper respiratory tract infection

Back pain

Examples of non-selective Beta adrenergic blockers?

Propranolol

Bucindolol

Carteolol

Nadolol

(-)-S-Penbutolol

(S)-Timolol

Pindolol

Labetalol

Examples of Beta 1 selective adrenergic blockers?

Acebutolol

Atenolol

Bexaxolol

Bisoprolol

Esmolol

Metoprolol

(+)-SRRR-Nebivolol

What effects do beta blockers have?

Reduce cardiac output

Reduce renin release

Reduce sympathetic outflow → CNS effect

How effective are β-blockers for lowering BP?

Non-selective and cardioselective β-blockers are equally effective

Monotherapy

Cheap

When are β-blockers especially useful for hypertension?

High-renin hypertension

Hypertension with coronary insufficiency

Side effects of beta blockers?

Decreased exercise tolerance

Bradycardia

Sleep disturbance

Bronchospasm

Coldness of extremities

CNS effects → dizziness, confusion, or depression

Asthma

Peripheral vascular disease and diabetes

What are beta blockers contraindicated in?

Insulin-dependent diabetes

Examples of non-selective alpha adrenergic receptor antagonists?

Phentolamine

Phenoxybenzamine

Dibenamine

Examples of selective alpha-1 adrenergic receptor antagonists?

Prazosin

Doxazosin

Terazosin

MOA of alpha blockers?

Block vascular α₁ receptors → inhibit vasoconstriction → decrease total peripheral resistance → decrease BP

When are non-selective α-blockers used?

Hypertensive crisis caused by pheochromocytoma

How are selective α-blockers used?

As monotherapy or adjunct therapy

Side effects of alpha blockers?

Dizziness

Hypotension

Nasal congestion

Headache

Reflex tachycardia → especially with nonselective

Fluid retention → use with diuretic

Examples of centrally acting sympatholytics?

Methyldopa

Clonidine

Moxonidine

Rilmenidine

Guanabenz

Guanfacine

How do CNS sympatholytics lower BP?

α2 agonists act in the CNS → decrease sympathetic neuron firing → decrease sympathetic activity → decrease BP

What do CNS sympatholytics do to norepinephrine (NE) release?

Prevent it!

Act on prejunctional sympathetic neurons → prevent NE release → decrease sympathetic activity

Where do CNS sympatholytics act?

Nucleus of solitary tract + C1 neurons of the rostral ventrolateral medulla

brain areas that help control sympathetic nerve activity

Therapeutic uses of CNS sympatholytics?

Reduce BP by lowering TPR and cardiac output

Use with diuretic → to prevent fluid retention

Alpha 2 agonists → effective in ALL patients

Adverse effects of CNS sympatholytics?

Hypotension

Sedation: ~ 50% of all patients

Dry mouth

Vivid dreams

Depression

Withdrawal

Tachycardia

Nervousness, excitement

Autoimmune → Lupus, leukopenia

Hyperthermia

Reduced mental acuity

Peripheral sympatholytics?

Rarely used

Ex → Metyrosine (alpha-methyl-tyrosine), Guanethidine, and Reserpine

Metyrosine?

Inhibits tyrosine hydroxylase → rate limiting enzyme for NE synthesis

Peripheral Sympatholytic

Guanethidine?

Gets uptaken into NE vesicle → prevents NE release from the vesicle

Peripheral sympatholytic

Reserpine?

Inhibits accumulation of NE into vesicle

Peripheral Sympatholytic

Examples of direct acting vasodilators?

Hydralazine

Minoxidil

MOA of hydralazine?

Liberates NO from vascular endothelium → vasodilation → decreases total peripheral resistance → decreases BP

When is hydralazine used?

NOT a Monotherapy

Severe or refractory hypertension

Bioavailability → dependent on genetic factors

Adverse effects of hydralazine?

Tachycardia

Hypotension

Fluid retention

Lupus-like syndrome

How does minoxidil lower BP?

Opens K⁺ channels → reduces smooth muscle contractility → vasodilation → decreases BP

When is minoxidil used?

NOT a monotherapy

Severe or refractory hypertension

Long duration of action → 24 hours

Adverse effects of minoxidil?

Tachycardia

Fluid retention

Hypertrichosis → excessive hair growth anywhere on the body