Pharmacology - Hypertension Drugs

What are the three mechanisms of essential hypertension?

1. Disorder of sodium metabolism

2. Imbalance of the Renin-agiotensin system

3. Sympathetic overactivity

What are the five sites of action and the major drug classes that are active there?

Reduction of blood/ECF volume

-Diuretics

Inhibition of sympathetic tone

-Alpha and Beta blockers

-Central alpha 2 agonists

Renin-angiotensin-aldosterone system

-ACE inhibitors/ARBs

Vasodilators

Calcium channel blockers

MOA/Effects of thiazides as antihypertensives?

-1st line therapy for hypertension

-Reduces plasma volume and CO

-ARTERIOLAR VASODILATION

-MOST EFFECTIVE DIURETICS TO REDUCE BP IN PTS WITH NORMAL RENAL FUNCTION

CHLORTHALIDONE AND INDAPAMIDE

Adverse Effects of Chlorthalidone and Indapamide?

Orthostatic hypotension

Electrolyte disturbances

Dehydration

Rash (SULFA)

Gout, hyperglycemia, dyslipidemia

Which drugs are known as Alpha-Blockers and what are there additional uses?

Prazosin

• also used for PTSD nightmares

Doxazosin

• Longer half life. once daily

• Also used for BPH

Tamsulosin

• Used for BPH

-osin

What is the MOA of Prazosin, Doxazosin and Tamsulosin?

Blocks a1 adrenergic receptors in vascular smooth muscle

What are alpha blockers used for?

Inhibit NE mediated vasoconstriction

-leads to vasodilation and decreased BP

-MOD EFFICACY ANTIHYPERTENSIVE

What are the adverse effects of Prazosin, Doxazosin, and Tamsulosin?

Orthostatic Hypotension

-1ST DOSE EFFECT!!

Dizziness, fatigue

Peripheral edema

Reflex tachycardia

Nasal stuffiness

Sexual dysfunction - ejacualtion

Which drugs are known as Beta blockers and what are their targeted receptors?

Metoprolol

• B1 selective, most commonly used for HTN

Propranolol

• non-selective. used for migraine, performance anxiety

Carvedilol

• mixed a/B blocker, Also used for heart failure

What are the roles of the different beta receptors?

B1: Increase HR, contractility, stimulate renin release

B2: Bronchodilation, vasodilation in skeletal muscle, relax uterine smooth muscle, stimulate glycogenolysis, decrease GI motility

What is the MOA of metoprolol, propranolol, and carvedilol?

1. Decrease H, contractility and cardiac output

2. Inhibition of renin release

3. Inhibition of NE release from presynaptic adrenergic terminals

4. Reduction of central adrenergic tone

What are the adverse effects of metoprolol, propranolol, and carvedilol?

Bradycardia

Dyspnea - PROPRANOLOL

Fatigue, exercise intolerance

Dizziness, cold extremities

Blunted adrenergic symptoms - HYPOGLYCEMIA

Impotence

Hypotension - PH W/ CARVEDILOL

What are the common central alpha-2 agonists and additional uses?

Clonidine

• Most commonly used

Guanfacine

• less sedating than clonidine. Used for ADHD primarily; some HTN

Methyldopa

• Prodrug; preferred in pregnancy

What is the MOA and effect of clonidine, guanfacine, and methyldopa?

Stimulates alpha-2 adrenergic receptors in the CNS (brainstem)

• Inhibit sympathetic outflow

• Reduced systemic vascular resistance and cardiac output

• Lower BP

What are the adverse effects of clonidine, guanfacine, and methyldopa?

Sedation

Fatigue, drowsiness, depression (CNS)

Dry mouth

Bradycardia, orthostatic hypotension

Toxicity of Central sympathetic drugs:

Sedation

SEVERE REBOUND HYPERTENSION- CLONIDINE

Xerostomia

Sexual dysfunction

Hemolytic anemia - methyldopa

Hydrazaline, Minoxidil and Sodium nitroprusside are all part of what drug class?

Direct vasodilators

What is the MOA and use of Hydrazine?

MOA

• stimulation of NO release

Use

• Chronic HTN

• Post-stroke

• sometimes in pregnancy

What is the MOA and use of Minoxidil?

MOA

• K+ channel opening

Use

• Potent

• Reserved for resistant HTN or renal failure

What is the MOA and use of sodium nitroprusside?

MOA

• Production fo nitric oxide

Use

• Used in ICU for hypertensive emergencies (IV only)

What are the adverse effects of Sodium nitroprusside?

Box warning

• HYPOTENSION

Rebound hypertension

Substernal pain

Box warning

• CYANIDE TOXICITY

• CONCOMITANT USE WITH SLIDENAFIL IS NOT INDICATED

What are the adverse effects of Hydrazaline?

Compensatory tachycardia

Myocardial ischemia

LUPOID SYNDROME

Vasculitis

-Safe during pregnancy

What is the MOA and effect of calcium channel-blockers?

Bond to Ca++ channels from the inside of the membrane

Result

• Decrease in BP via arterial dilation and reduced CO

CAN BE REVERSED BY B-1 AGONISTS

• Physiological antagonism

What are the two types of CCBs?

Dihydropyridines

• Amlodipine, Nifedipine

Non-dihydropyridines

• Verapamil, Diltiazem

What’s the difference in Dihydropyridines and Non-dihydropyridines?

Dihydropyrodines

• Potent vasodilators, may cause edema and HAS AN EFFECT ON CO

Non-dihydropyridines

• Reduce HR and myocardial workload; watch for bradycardia

• HAS NO CHANGE TO CO AND DECREASES HEART RATE

What are other uses of CCBs?

ANGINA

ARRHYTHMIAS

RAYNAUD’S

What are the adverse effects of calcium channel blockers?

Peripheral edema

Orthostatic hypotension

Bradycardia

Dizziness, flushing, headache

Possible constipation with VERAPAMIL

What are the three pathways that are precursors to Renin?

1. Macula densa pathway

2. Intrarenal baroreceptor pathway

3. B-adrenergic receptor pathway

What drug class are Captopril and Lisinopril?

ACE Inhibitors

What’s the MOA of Captopril and Lisinopril?

1. Inhibition of Renin-angiotensin system

2. Increased plasma levels of bradykinin

What are the effects of Captopril and Lisinopril?

Relaxation of vascular smooth muscle

• Lowers BP and Naturesis

Reduces sympathetic tone and cardiac remodeling post-MI

What are the adverse effects of Captopril and Lisinopril?

Hypotension and postural hypotension

DRY COUGH, WHEEZING

Fatigue —> Aerobic capacity

CNS

• Alteration or loss of taste

• Headache, dizziness, fainting

Hyperkalemia

ANGIONEUROTIC EDEMA

CONTRAINDICATED IN 2ND AND 3RD TRIMESTERS OF PREGNANCY

What are the other uses of Captopril and Lisinopril?

Heart failure

Diabetic neuropathy

Post-myocardial infarction

Losartan and Valsartan are apart of what drug class?

Angiotensin II receptor blockers

What’s the MOA of Lasartan and Valsartan?

Competitive antagonism of AT1 receptors

What are the MAIN effects of Losartan and Valsartan?

Vasodilation

Increased salt and water secretion

NO EFFECT ON BRADYKININ METABOLISM

ADME: Losartan t1/2= 2 hours

What are the adverse effects of Losartan and Valsartan?

Hypotension - when associated with elevated ANG II levels

Hyperkalemia

LOWER INCIDENCE OF COUGH

Renal effect

TERATOGENIC, CATEGORY D

USED IN PTS WHO CAN’T TOLERATE ACE-INHIBITORS

What drug class are Sildenafil (Viagra), Vardenafil, and Tadalafil?

PDE5 Inhibitors

What is the MOA of Sildenafil, Vardenafil, and Tadalafil?

Inhibits cGMP PDE type 5

• These agents require INTACT INNERVATION

What are the adverse effects and CONTRAINDICATIONS of Sildenafil, Vardenafil, and Tadalafil?

Adverse effects

• Headache

• Flushing

• Effects on blue-green vision

CONTRAINDICATION

• Do NOT use in pts on nitrate vasodilators due to drug interaction

  • Severe refractory hypotension