Antihypertensive Drugs

Dr. Karun KumarJR – II

Dept. of Pharmacology

Definition

• SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg• 95% (Primary HTN no specific cause) [obesity,

lack of exercise, metabolic syndrome (abdominal obesity, hyperlipidemia, and insulin resistance), ↑ Na & alcohol intake]• 5% (sec. HTN CKD/hyperald.) These include• Vascular endothelial cell dysfunction HTN

Role of endothelium

• Endothelium regulates vascular smooth muscle tone through the synthesis & release of relaxing factors such (NO & PGI2) & vasoconstr. factors (endothelin-1 & angiotensin II)• Angiotensin II Vascular injury (activating growth

factors that cause vascular smooth muscle proliferation and hypertrophy as well as fibrotic changes in the vascular wall)• Oxidative stress ↑ vasoconstr. F & ↓ relaxing

factors • Several antiHTN drugs, (carvedilol,ACE, AT1)

counteract endothelial cell dysfunction

Regulation of Blood Pressure• Short term SNS (Baroreceptor reflex)• Long term Kidneys (RAAS)• Blood-borne subst. (Vasopressin & Ang II v.c.) • Locally released adenosine, serotonin, endothelin,

and PGs also affect arteriolar smooth muscle toneCompensatory Rx 1. Reflex tachycardia, 2. fluid ret. By kidneys3. activation of RAAS

Diuretics

• ↑ renal Na excretion (anti-HTN activity) thiazide diuretics (DOC) foll. By loop• longer antiHTN effect than the loop diuretics • The thiazides tend to promote calcium retention• The loop diuretics enhance urinary calcium loss

Thiazide and Related Diuretics• 2 mechanisms1. Short term (↓ BV ↓ CO)2. Long term ↓ PVR (↓ Na content of arteriolar

smooth muscle cells ↓ muscle contraction in response to vasopressors (NE, angiotensin)

• Hydrochlorothiazide, Indapamide & Chlorthalidone• Indapamide Added benefit (vasodilation via CCB)

• Hydrochlorothiazide mild to moderate HTN (ACE i. or CCB may be preferable)• Thiazide diuretics are used in combination with

another class of antihypertensive agent, because the two drugs have additive or synergistic effects on blood pressure. • Using a low dosage of a thiazide diuretic (e.g., 12.5

to 50 mg of hydrochlorothiazide per day) usually produces a maximal antihypertensive effect with minimal hypokalemia.• Higher dose more hypokalemia but does not have

a greater effect on blood pressure.

Adverse Effects

• Thiazides elevate plasma levels of glucose, uric acid, and lipids in some patients. • Hematologic toxicity and aggravate hepatic disease.

(less common)• Evoke a compensatory increase in renin secretion,

(used with Ace i) least expensive agents available for treating hypertension.

Advantages of thiazides

1. Offer protection against osteoporosis (↓ Ca exc.)2. Least expensive agents available for HTN3. Effective and relatively safe when serum

potassium, glucose, uric acid, and lipid levels are monitored appropriately

Loop Diuretics

• Greater natriuretic effect & less effective than thiazide diuretics in the treatment of hypertensive patients with normal renal function.• For this reason, loop diuretics are usually reserved

for use in hypertensive patients who have poor renal function and a serum creatinine level greater than 2.3 mg/dL.

Potassium-Sparing Diuretics• Mild natriuretic effect, and they reduce renal

potassium excretion and thereby prevent hypokalemia caused by thiazide and loop-acting diuretics.• Eplerenone is similar to spironolactone but has

fewer endocrine side effects. • Eplerenone has been found to cause regression of

left ventricular hypertrophy in hypertensive patients and regression of microalbuminuria in patients with type 2 diabetes.

SYMPATHOLYTIC DRUGS

• The sympatholytic drugs used in the treatment of hypertension include adrenoceptor antagonists and the centrally acting α2-adrenoceptor agonists.

α-Adrenoceptor Antagonists• Not recommended bcoz Evoke reflex activation of

the SNS (↑ HR, ↑contractility ↑ O2 demand) • Because they activate the RAAS system & cause

fluid retention given with a diuretic. • Cause orthostatic hypotension, “first dose” syncope

(Prevented by beginning treatment with a low dose of the blocker at bedtime and withholding the diuretic for a day until the body adjusts to the lowered blood pressure)

β-Adrenoceptor Antagonists• Cardiac β1-receptors ↓ CO (↓HR & contractility• β1-receptors in renal JG cells inhibits renin sec.• Also, ↓ sympathetic outflow from CNS• Beneficial eff. in HTN persons with CVD • Coronary heart disease ↓ myocardial ischemia • MI Cardioprotective (↓ HR & vent. Arrhythmias) • Heart failure Improve symptoms & survival• Role of β-blockers in treating HTN without CVD

Less clear

• Most clinical guidelines ACEi,ARB,CCB/diuretic for HTN without preexisting heart disease.• The β-blockers are usually well tolerated and only

rarely cause orthostatic hypotension or produce hepatic, renal, or hematopoietic toxicity. Data from clinical trials suggest that β-blockers are only slightly more likely than a placebo to cause fatigue, sleep disturbances, and sexual dysfunction, but physically active persons may fid that β-blockers reduce exercise capacity as a result of a reduction in heart rate.• β-blockers ↓ insulin sensitivity (exc. 3rd gen.)• Also, nonsel. β-blockers delay recovery from

hypoglycemia by blocking β2-receptor–mediated glycogenolysis and hepatic glucose production

• Atenolol Less lipophilic (fewer CNS s/e)• Labetalol chr. HTN & HTN emergencies. Because

of its α-adrenoceptor–blocking activity, it can cause orthostatic hypotension. • Esmolol (i.v.) HTN in surgical patients & in persons

with HTN emergencies• Carvedilol has antioxidant properties that can

protect the vascular wall from free radicals that damage blood vessels and thereby contribute to the progression of cardiovascular disease. • Nebivolol (3rd gen.) selective β1-blocker with

antioxidant properties; ↑ endothelial NO rel. (vasodilating effect) Nebivolol provides another option for treating hypertension in patients with heart failure, diabetes, and cardiac arrhythmias

Centrally Acting Drugs

• Clonidine, guanfacine, and methyldopa. (↓ symp. outflow from VMC of medulla [α2-r] ) [↓ PVR]• Methyldopa converted to an active metabolite

(methylnorepinephrine) by central neurons, which then activates α2-receptors. • Clonidine HTN urgencies (↓ BP to a safe level)s

also ↓ SNS symptoms of alcohol, opioid, or nicotine withdrawal • Methyldopa HTN in pregnant women

side effects

• sedation, dry mouth, and impaired mental acuity. • Severe rebound hypertension can occur if they are

discontinued abruptly, and the dosage should be tapered gradually over 1 to 2 weeks if treatment is to be stopped.• Methyldopa is well known for its ability to cause

immunologic effects, including a Coombs-positive hemolytic anemia, autoimmune hepatitis, and other organ dysfunction. • TCAs block eff. of centr. acting sympatholytic drugs

Angiotensin inhibitors

1. Angiotensin converting enzyme (ACE) inhibitors, 2. Angiotensin receptor blockers (ARBs)3. Direct renin inhibitor called aliskiren. • ACEi & ARBs preferred drugs for the initial HTN

t/t. Also, reduce the risk of stroke & they are particularly useful in persons with diabetes or heart failure.

Angiotensin-Converting Enzyme Inhibitors

Stimuli to inc. renin

1. ↓ arterial pressure in renal afferent arterioles2. ↓ NaCl concentration in the distal renal tubule3. SNS activation of β1-receptors on renal JG cells• Renin protease enzyme• Angiotensin II activates AT1 and AT2.

AT1 receptors

• Coupled with enzymes that ↑ IP3 & ↓ cAMP • Effects activation of AT1 receptors 1. Contraction of vascular smooth muscle (v.c.)2. Sec. of aldosterone from adrenal cortex3. ↑ reabsorption of sodium from the PCT 4. ↑ release of NE from sympathetic nerves5. stimulation of cell growth in the arteries and

heart• AT2 receptors appear to have roles in

cardiovascular and metabolic functions

• ACE Inactiv. bradykinin, vasodilator peptide.• ↑ renal PG synthesis• Ang II ↑ toward pretreatment levels during long-

term ACE inhibitor therapy as a result of a compensatory increase in renin secretion. • This effect can be prevented by adding the direct

renin inhibitor aliskiren to the treatment regimen • ACE inhibitors primarily lower BP by ↓ PVR• ↓ arterial pressure (afterload) & venous pressure

(cardiac preload)

Adverse Effects

• Fetal & neonatal injury (Pregnant women)• RF in pts. with bilateral renal artery stenosis

(depend on Ang II to maintain RBF & GF)• Most common side effect Dry cough, angioedema

(bradykinin • Rash and an abnormal taste sensation may occur in

persons receiving captopril, which has a sulfhydryl group as the zinc-binding moiety.

Interactions

• Anti-HTN action augmented by diuretics and CCBs• interact with potassium-sparing diuretics and

potassium supplements to increase serum potassium levels and cause hyperkalemia.• They can also increase serum lithium levels and

provoke lithium toxicity in patients receiving lithium compounds for the treatment of bipolar disorder. • NSAIDs, such as ibuprofen, can impede the effects

of ACE inhibitors & other antihypertensive agents.

Indications

1. mild to severe HTN2. HTN with HF, MI, CKD, or DM3. HF & HF with MI & significant LVD (a cardiac

ejection fraction of less than 40%). 4. In diabetic patients who exhibit early signs of

renal impairment (e.g., albuminuria and ↑ serum creatinine levels), ACE inhibitors exert a renoprotective effect.

5. Stroke (cerebroprotective effect of acei/arb)

Specific Drugs

• In each class, a different chemical group binds the zinc ion in ACE

1. Sulfhydryl compound Captopril2. Phosphoryl agents fosinopril; and the 3. Carboxyl derivatives benazepril, enalapril,

lisinopril, quinapril, and ramipril. Enalaprilat (i.v.); others are oral

Angiotensin Receptor Blockers• Block AT1 receptors and reduce

1. Vasoconstriction2. Aldosterone secretion3. Sodium reabsorption by the proximal tubule 4. Norepinephrine release from SNS

• candesartan, irbesartan, losartan, telmisartan, valsartan, • Rarely cause the dry cough that occurs with ACE

inhibitors. • Losartan ↓ LVH, stroke risk & new onset DM

• Telmisartan 1. ↑ insulin sensitivity (PPAR γ)2. Protects patients at increased risk of CVD3. more powerful BP lowering ability than Ramipril• The ARBs may cause hyperkalemia, neutropenia,

and elevated serum levels of hepatic aminotransferase enzymes. • Not be used during pregnancy

CAPTOPRIL

C CoughA Allergies (Angioedema, urticarial, rashes)P Potassium level inc.T Taste alterationO On 1st dose hypotension (orthostatic)P Pregnancy, Pancreatitis (C/I)R Renal artery stenosisI Indomethacin & other NSAIDsL Lithium, Leukopenia, Liver toxicity

Direct Renin Inhibitor

• Aliskiren Protects against compensatory ↑ in Ang II

Vasodilators

• CCBs, hydralazine, minoxidil, and nitroprusside• CCBs HTN, angina, PVD & cardiac arrhythmias • Block Ca channels in plasma membranes of smooth

muscle relax vascular smooth muscle (v.d.)• Arteriolar smooth muscle > venous smooth muscle

(↓ PVR ; no eff. on CO); also have natriuretic effect • Diltiazem and verapamil also ↓ HR & CO• amlo, felo, isra, nicar,nife evoke reflex tachycardia.

• Initial t/t (HTN) & combined with diur/Acei/arb. • Protect against stroke, coronary heart disease, and

kidney disease. • verapamil and diltiazem reduce protein excretion in

patients with kidney disease and may be used with an ACE inhibitor or ARB for this purpose. • Used in HTN with asthma • Long-acting CCB (amlodipine or a SR formulation

such as the nifedipine gi system) for 24 hr BP dec.

Other Vasodilators

• Hydralazine and Minoxidil Used with other anti-HTN drugs to treat moderate to very severe HTN • When used alone, they often evoke reflex

tachycardia & cause fluid retention, & ppt. angina• Hydralazine Lupus-like syndrome, whereas

minoxidil hypertrichosis (excessive hair growth), particularly in women & is used for alopecia

Nitroprusside

• Sodium n (i.v.) HTN emergencies. • metabolized to CN in RBCs thiocyanate in the

presence of a sulfur donor. accumulate (dur. Of therapy with this drug is usually limited to a few days• Fenoldopam (i.v.) HTN emergencies (D1 rec. &

produces vd in systemic vascular beds (coronary, renal, & mesenteric vessels); kidney dilates both aff. & eff. Arterioles (↑RBF)

Management of Hypertension• Lifestyle Modifications exercise,wt. loss, mod. of

alcohol intake & diet low in Na & adeq. K Ca Mg. Fruits & vegetables & low sat. & total fat. • Selection of Drug Therapy• Stage I HTN A+B (<55) ; C + D (>55)• Stage II HTN 1 out of A/B + 1 out of C/D• Step 3 A/B + C + D• Step 4 (Resistant HTN) A + B + C + D

hypertensiveemergencies and urgencies.• Clonidine Less-severe HTN urgencies (slowly ↓

BP)• Ffenoldopam, nicardipine, labetalol, and sodium

nitroprusside. • Hydralazine HTN associated with eclampsia • Nitroglycerin HTN emergency in ac. cor. Ischemia• Enalaprilat Acute LVF• Esmolol Aortic dissection & periop. HTN

Pheochromocytoma

• Nonmalignant, catecholamine releasing tumors located in the medulla of the adrenal gland. (1/1000 of HTN)• Highly vascularized & contain ↑ NE & E (HTN crisis)• Treatment surgical removal• Pretreatment phenoxybenzamine & β-blockers• Metyrosine Inhibits tyrosine hydroxylase and

subsequent biosynthesis of catecholamines.