Hypertension(2nd part)Asmaa A.

Angiotensin Converting Enzyme Inhibitors

(ex: Enalapril, lisinopril, Ramipril, Captopril).

Angiotensin converting enzyme inhibitors (ACE inhibitors) are frequently used as the first-line antihypertensive drugs.

Mechanism of action

Angiotensin converting enzyme inhibitors:

a. Inhibit the generation of angiotensin II resulting in:

• Dilatation of arterioles Decrease peripheral vascular resistance (PVR) Decrease BP.

• Decrease in aldosterone production Decrease in Na+ and H2O retention Decrease BP.

• Decrease in sympathetic nervous system activity.

b. Inhibit the degradation of bradykinin, which is a potent vasodilator.

c. Stimulate synthesis of vasodilating prostaglandins through bradykinin.

All these actions contribute to their antihypertensive effect.

Pharmacokinetics

• ACE inhibitors are usually given orally. In hypertensive emergency, enalaprilat can be given intravenously.

• Food reduces the absorption of captopril; hence, it should be given 1 h before meals. They poorly cross the blood–brain barrier (BBB), are metabolized in liver and excreted in urine

Adverse effects* and contraindications

1. Cough (dry cough) is due to increased bradykinin levels in the lungs.Appearance of intractable cough is an indication to stop the drug.

2. Angioedema: Swelling in the nose, lips, mouth, throat, larynx, glottis.

There can be airway obstruction—patient’s airway should be protected. Ifrequired, adrenaline, glucocorticoids and antihistaminics should beadministered.

3. Proteinuria.

4. Teratogenic effect (growth retardation, fetal hypotension, renal failure andneonatal death)—hence contraindicated in pregnancy

5. Severe hypotension may occur 1–2 hour after taking the first dose.Hence, ACE inhibitors should be started with a small dose and thengradually increased.

6. Neutropenia.

7. Rashes.

8. Itching.

9. Loss of taste sensation (dysgeusia) and nausea.

In patients receiving ACE inhibitors, hyperkalaemia may occur in thepresence of renal insufficiency or when they are combined withpotassium-sparing diuretics.

ACE inhibitors are contraindicated in patients with bilateral renal arterystenosis. ACE inhibitors are also contraindicated in patients with singlekidney with renal artery stenosis, as they can precipitate renal failure.

Drug interactions

1. ACE inhibitors X potassium-sparing diuretics: Simultaneousadministration of these drugs can cause dangerous hyperkalaemia.

2. ACE inhibitors X lithium: ACE inhibitors retard the renalelimination of lithium and potentiate its toxicity.

3. ACE inhibitors X NSAIDs: NSAIDs by inhibitingprostaglandin (PG) synthesis, promote Na+ and water retentionon chronic use. Thus, they decrease the antihypertensive effect ofACE inhibitors.

Therapeutic uses of ACE inhibitors

1. Hypertension: (Mode of action: see above) ACE inhibitors are used inall grades of hypertension, especially in patients with diabetes andcongestive heart failure (CHF). They are preferred in patients with diabetesbecause they delay or prevent the progression of renal complications.

2. Congestive cardiac failure: ACE inhibitors should be prescribed to allpatients with impaired left ventricular function.

3. Acute myocardial infarction: ACE inhibitors should be started within24 h in patients with myocardial infarction (MI). They have shown bothshort-term and long-term improvement in survival.

4. Diabetic nephropathy: ACE inhibitors and angiotensin II receptorblockers (ARBs) are the preferred drugs in diabetic nephropathy.

Angiotensin Receptor Blockers (ARBs) or

Angiotensin Receptor Antagonists

ARBs are an appropriate choice for patients who are intolerant of ACEinhibitors because of cough ex: Losartan, Valsartan, Candesartan,Telmisartan)

The two types of angiotensin II-receptors are AT1 and AT2. Most of theeffects of angiotensin II are mediated by AT1 receptors. They arevasoconstriction, aldosterone secretion and the release of noradrenalinefrom sympathetic nerve endings. The role of AT2 receptors is notknown.

Angiotensin II

(Agonist)Angiotensin receptors (AT1)

(Competitive antagonism)ARBs

(Antagonists)

Angiotensin receptor blockers competitively inhibit the binding of angiotensin II

to AT1-receptor subtype and block its effects. ARBs produce effects similar to

those of ACE inhibitors.

ARBs do not affect bradykinin production.

Adverse effects

Angiotensin receptor blockers are better-tolerated as compared toACE inhibitors. They cause headache, hypotension, weakness,rashes, nausea, vomiting and teratogenic effects. They may causehyperkalaemia in patients with renal failure or in patients on K+sparing diuretics. They are less likely to produce cough orangioedema than ACE inhibitors.

Uses

Angiotensin receptor blockers are used in hypertension, congestive cardiacfailure (CCF), MI and diabetic nephropathy. The antihypertensive efficacyof ARBs is comparable with that of ACE inhibitors.

Like ACE inhibitors, ARBs prevent/delay the development of renalcomplications in diabetics. ARBs are mainly indicated in patients whodevelop cough with ACE inhibitors. ARBs also reduce the progression ofnephropathy in patients with diabetes. In CCF and MI, ARBs are used inpatients who are intolerant to ACE inhibitors.

Calcium Channel Blockers (CCBs)

Verapamil, diltiazem and dihydropyridines (nifedipine, amlodipine,felodipine, nicardipine, isradipine, etc.) are useful in all grades ofhypertension.

The antihypertensive effect is mainly due to peripheral vasodilatation.Dihydropyridines (DHPs) are more likely to cause headache, flushing,palpitation and reflex tachycardia.

The use of sustained-release preparations reduces the incidence of sideeffects. Β-Blockers can be used with nifedipine to counteract the reflextachycardia. Reflex tachycardia is minimal or absent with verapamil anddiltiazem because of their greater cardiac-depressant effect.

Verapamil and diltiazem should be avoided in patients with cardiacdysfunction because of their cardiac depressant effect. CCBs areparticularly useful in elderly patients and also in patients with angina,asthma, peripheral vascular diseases, migraine, hyperlipidaemia,diabetes and renal dysfunction.

α-Adrenergic Blockers

Nonselective α-blockers are not preferred for essential hypertension. They areused to treat hypertension in special conditions like pheochromocytoma,clonidine withdrawal and cheese reaction.

Selective α1-blockers: ends with the suffix “-osin”.The medications includealfuzosin, doxazosin, terazosin, tamuslosin and prazosin.

Prazosin causes first-dose phenomenon—postural hypotension that occursafter the first dose. Therefore, the initial dose should be small (1 mg) andusually given at bedtime so that the patient remains in bed for several hours,hence reduces the risk of fainting attacks. Terazosin and doxazosin are longeracting than prazosin, given once daily in the treatment of hypertension.

Centrally Acting Sympatholytics

• Clonidine

Clonidine is a centrally acting antihypertensive drug.

Mechanism of action

Clonidine is effective orally; highly lipid soluble and rapidly crosses BBB. It has a short duration of action, requires twice a day administration. Transdermal patch of clonidine controls BP for a week.

Adverse effects

Dryness of mouth and eyes, sedation, depression, bradycardia, impotence,nausea, dizziness, parotid gland swelling and pain are the adverse effectsof clonidine. Postural hypotension may occur.

Sudden stoppage of clonidine after prolonged use may cause withdrawalsyndrome—headache, nervousness, tachycardia, sweating, tremors,palpitation and rebound hypertension. This is due to:

• Supersensitivity of α-receptors.

• Precipitous release of large amount of stored catecholamines.

This is treated with intravenous sodium nitroprusside or labetalol.

Uses

Clonidine is used:

1. In hypertension.

2. To treat withdrawal symptoms in opioid and alcohol addicts.

3. As preanaesthetic agent.

4. As antidiarrhoeal in diabetic neuropathy.

• α-Methyldopa

It is a centrally acting sympatholytic agent.

α-Methyldopa, a prodrug, which enters the adrenergic neuron, is converted into an active form

and stored in the neurons. α-Methylnoradrenaline is a false transmitter that is released during nerve

stimulation instead of noradrenaline. α-Methylnoradrenaline acts by stimulating α2-receptors in vasomotor centre (VMC).

Adverse effects

These include nasal stuffiness, headache, sedation, mental depression,dryness of mouth, bradycardia, impotence, gynaecomastia, hepatitisand rarely haemolytic anaemia.

Clonidine and α-methyldopa are usually employed as the second- orthird-line agents in hypertension because of high incidence of sideeffects. α-Methyldopa is one of the preferred antihypertensive drugsduring pregnancy

Vasodilators

• Minoxidil

It is a powerful arteriolar dilator. It is effective orally. It causesreflex tachycardia, Na+ and water retention. Hence, minoxidil isused with a β-blocker and a diuretic. Topical minoxidil is used topromote hair growth in male type of baldness. (Minoxidil topicalsolutions and sprays are available.)

• Hydralazine

It is a directly acting arteriolar dilator. It is administered orally. Theside effects are reflex tachycardia, palpitation, sodium and waterretention, which can be countered by combining hydralazine with adiuretic and a β-blocker. Other side effects are headache,hypotension, flushing, angina, myocardial infarction, coronary stealphenomenon, etc. Immunological reactions such as lupus syndromemay occur.

• Sodium Nitroprusside

It is a powerful arteriolar and venodilator. It is unstable, rapidlydecomposes on exposure to light. So the solution should be preparedfresh; the infusion bottle and the entire drip-set should be covered withblack paper. It has a short duration of action, hence administered by i.v.infusion. It is rapid acting and dose is titrated according to response.Sodium nitroprusside is the drug of choice for hypertensive crisis; canalso be used to improve cardiac output in CCF. Nitroprusside cancause severe hypotension, hence close monitoring of BP is required.Prolonged administration may cause anorexia, nausea, vomiting,fatigue, disorientation, toxic psychosis due to accumulation of cyanide,which in turn may lead to severe lactic acidosis.

Hypertensive Crisis (Hypertensive Emergencies)

It is characterized by a very high blood pressure (systolic >220and/or diastolic >120 mm of Hg) with progressive end-organdamage such as retinopathy, renal dysfunction and/or hypertensiveencephalopathy.

It is a medical emergency. The BP should be reduced by not morethan 25% within minutes to 2 h, and then to 160/100 mm of Hgwithin 2–6 h. The preferred drug to treat the condition is sodiumnitroprusside (i.v. infusion). The other drugs that can be used in thiscondition are nitroglycerin(i.v.infusion), hydralazine (i.v.),phentolamine (intravenously), etc.

A= ACI inhibitors or ARBs C= Calcium channel blockerD= Diuretics

Drug sequencing in hypertension

Drug sequencing in hypertension

Primary prevention

First line therapyMonotherapy:•ACEI•ARB•CCB•Thiazide diuretic

Two-drug combination:•ACEI or ARB with CCB•ACEI or ARB with thiazide diuretic

Three-drug combination•Add CCB or thiazide diuretic ( the one not previously used)•Consider BB

Resistant hypertension• Four drug combination of ACEI or ARB with thiazide diuretic, dihydropyridineCCB, and BB•Consider an aldosterone antagonist•Consider alternative antihypertensives

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Indication for Hypertension and specific disease

Preferred Drugs for Hypertension Associated with the Following Conditions