Antihypertensive Agents Classification

Antihypertensive Agents Introduction

Hypertension is defined as sustained or persistent elevation of arterial blood pressure in which systolic and/or diastolic blood pressure exceeds above 140/90 mm Hg. It is not a single disease; it results from defects in haemodynamic and biochemical function in the body. Arterial hypertension is directly proportional to the product of the cardiac output and total peripheral vascular resistance.

Hypertension has been divided into two major divisions according to the etiology.

Primary or essential hypertension: Where definite cause is unknown. This is the common form of hypertension.

Secondary hypertension: Due to renal, endocrine and vascular disorder.

Many mechanisms operate in equilibrium with each other in order to maintain a constant blood pressure. These include central mechanism, peripheral adrenergic activity, baro-chemo receptor, cardiac output, viscosity of blood, renin-angiotensin- aldosterone system, vascular factor, blood volume etc.

The vascular fluctuation in the circulation are communicated and controlled by baro and chemo receptor. Baro receptor is pressure sensitive receptor located in the walls of heart and blood vessels. When there is a fall in blood pressure in carotid sinus, it stimulates the sympathetic nervous system and result in vasoconstriction (ie. increase in blood pressure).

On the other hand, increase in the blood pressure activates the baro receptor, resulting in arterial dilatation thus opposing permanent hypertension. Loss of this inhibitor activity of baro receptor leads to hypertension.

Chemo receptors located in vessel walls are sensitive to the oxygen content in blood. Both these receptors are mediated through the release of renin, which activates angiotensin – aldosterone system.

Antihypertensive Agents Classification

Antihypertensive drugs are classified as:

Angiotensin-converting enzyme (ACE) inhibitors:

• Sulfhydryl-containing inhibitors : 
  • Example: Captopril
• Dicarboxylate-containing inhibitors :
  • Example: Enalapril, Lisinopril, Quinapril, Ramipril, Trandopril, Spirapril, Moxeipril, Benazepril
• Phosphonate-containing inhibitor :
  • Example:  Fosinopril
• Angiotensin antagonists : 
  • Example: Losartan, Irbesartan, Candesartan, Telmisartan, Valsartan.

Calcium channel blockers:

• 1, 4-Dihydro pyridine :
  • Example: Nifedipine, Nimodipine, Amlodipine,Nisoldipine, Felodipine, Nicardipine, Benidipine, Lacidipine.
• Phenyl alkyl amine :
  • Example: Verapamil
• Benzothiazepine :
  • Example: Diltiazem.
• Diamino propanol ether :
  • Example: Bepridil.
• Diuretics :
  • Example: Chlorthiazide, Hydrochlorthiazide, Furosemide, Spironolactone.
• ẞ – adrenergic blockers:
  • Examples: Propranolol, Atenolol, and Metoprolol.
• Mixed a and B – adrenergic blockers :
  • Example:  Labetolol, Carvedilol.
• a-adrenergic blockers :
  • Examples: Prazosin, Phenoxybenzamine, Phentolamine.
• Centrally acting sympatholytic agents :
  • Example:  Clonidine, Methyldopa.
• Vasodilators :
  • Examples:  Hydralazine, Minoxidil, Diazoxide, Sodium nitroprusside.
• Adrenergic neuron blockers : 
  • Example: Guanithidine, Reserpine, Pethanidine, Bretylium

Angiotensin-converting enzyme (ACE) inhibitors

The renin-angiotensin system is a normal system that plays an important role in the control of sodium excretion and body fluid volume. It interacts with sympathetic nervous system and aldosterone secretion in the regulation of blood pressure.

When the blood supply to kidney is reduced, kidney releases renin which is an aspartase protease endogenous enzyme that is secreted from the kidney due to the internal stimuli. Renin converts angiotensinogen to angiotensin-I (decapeptide). This in- turn converted into angiotensin-II (octapeptide) in the presence of ACE (angiotensin converting enzyme). Angiotensin-II is a potent vasoconstrictor, as well as it stimulates adrenal gland to produce aldosterone.

Aldosterone increases blood volume by increasing fluid and sodium retention. The net result is increase in blood pressure. Compounds which block ACE or bind to angiotensin-II receptor are more effective antihypertensive agents. ACE inhibitors are also used in the treatment of congestive heart failure as first-line therapy.

Sulfhydryl Containing Inhibitors

Captopril (Aceten, Capotril)

Synthesis

ADR: Hypotension, tachycardia, chest pain and palpitation.

Dose: 25mg orally 2 to 3 times a day one hr before a meal.

Use: It is used in condition such as post myocardial infarction, congestive heart failure and preservation of kidney function in diabetic nephropathy.

Enalapril (Invoril, Enamate)

It is a prodrug of Enalaprilate. It is devoid of side effects of rash and loss of taste seen in Captopril. It is hydrolyzed in the liver by esterase to active dicarboxylic acid enalaprilate.

Synthesis

ADR: Initial hypotension may be severe and prolonged. Dizziness, headache and fatigue.

Dose: 5mg at bed time. Increased up to 40mg in divided doses.

Use: A prodrug of Enalaprilate, longer acting ACE inhibitor used in the treatment of renovascular, essential and malignant hypertension and congestive heart failure.

Lisinopril (Zestril, Dilace, Linvas)

Lisinopril is a lysine analogue of Enalaprilate.

ADR: Dizziness, headache, fatigue and cough.

Dose: 5 to 10mg daily given at bed time.

Use: It is an ACE inhibitor used in the treatment of reno vascular essential and malignant hypertension and also for ventricular congestive heart failure.

Ramipril (Corpril, Ecator)

It is a prodrug converted into active metabolite Ramiprilate by hepatic bio- transformation.

ADR: Nausea, vomiting, diarrhea and dizziness.

Dose: 1.25mg once given at bed time may increase up to 10mg daily as needed.

Use: It is used as antihypertensive agent and also in the treatment of nephropathy.

Quinapril (Accupril)

Quinapril is a prodrug and its active metabolite is Quinaprilate.

ADR: Dizziness, cough, vomiting, upset stomach and fatigue.

Dose: 5 to 10mg twice daily.

Use: It is used as antihypertensive agent and also in the treatment of congestive heart failure.

Phosphonate Containing ACE inhibitors

Fosinopril (Fovas)

It serve as a prodrug, it is hydrolyzed to active di acid Fosinoprilate.

ADR: Dizziness, orthostatic hypotension, palpitation and headache.

Dose: Initially, 10mg once daily at bedtime. Maintenance dose of 10 to 40mg.

Use: It is used for the treatment of hypertension and some type of chronic heart failure.

Structure Activity Relationship

Angiotensin converting enzyme is a zinc containing glycoprotein. The important binding sites of ACE are cationic site to attract carboxylate ion. (Fig.20.2). Zinc ion that can polarize the carbonyl group of amide function to make it more susceptible to hydrolysis

Among the three zinc binding group, sulfhydryl group is superior, but they form disulfide which may result in shorter duration of action.

• N ring must contain a carboxylic acid group to mimic the C – terminal carboxylate of ACE substrate.
• Larger hydrophilic heterocyclic in the N ring increase the potency and alter pharmacokinetic properties.
• X – is usually a methyl group, which mimic the side chain alanine of the ACE substrate.
• When the stereochemistry of inhibitor is consistent optimum activity occurs with L-amino acid.

Angiotensin Antagonist

Angiotensin – II receptors antagonists overcome some disadvantage of ACE inhibitor which not only prevent conversion of angiotensin – I to angiotensin – II but also prevent ACE mediated degradation of bradykinin and cough an adverse effect of ACE inhibitor. These agents relax smooth muscles and there by promote vasodilation increased renal salt and water excretion.

Losartan (Resilo, Covance, Cosart)

It is the first non-peptide imidazole to be introduced as an orally active angiotensin-II antagonist. It inhibits competitively angiotensin-II to produce vasodilator effect.

ADR: Headache, dizziness, back pain and myalgia.

Dose: 50mg once daily, increased to 100mg daily as a single dose or in two divided doses if needed.

Use: It is used as antihypertensive agent and also in the treatment of heart failure.

Irbesartan (Irovel, Xarb)

ADR: Diarrhea, dizziness, fatigue and headache.

Dose: 150mg once daily, increased to 300mg once daily if necessary.

Use: It is an angiotensin II type – I receptor antagonist.

Candesartan (Candelong, Candesar)

ADR: Dizziness, headache, vertigo, depression and somnolence.

Dose: Initially, 8mg once daily adjusted according to response.

Use: It is an angiotensin II type – I receptor antagonist, used as antihypertensive agent.

Telmisartan (Telma, Tele, Telepres)

ADR: Dizziness and back pain.

Dose: Initially, 40mg once daily. Maximum dose is 80mg/day.

Use: It is used in the treatment of essential hypertension.

Valsartan (Valent, Starval)

ADR: Dizziness, headache and rash.

Dose: 80 to 320mg daily.

Use: It is a non-peptide angiotensin-II type – I receptor antagonist.

Calcium Channel Blockers

Calcium is necessary for the excitation, contraction coupling in both skeletal and smooth muscle. However in contrast to the contractile activity of the skeletal muscle, the contractility of the cardiac and vascular muscle is highly dependent on the extra cellular calcium concentration. Calcium transport in myocardial and vascular smooth muscle involves potential dependent channel, receptor operated channel, sodium calcium exchange and calcium ATPase.

Calcium channel blocker produces their effect through interaction with potential dependent channel. To date, six types of potential dependent channel have been identified – T, L, N, P, Q and R. The L-type channel is the site of action of calcium channel blockers and reduces Cat flux through the channel. This reduces the availability of intracellular calcium.

Potential depending channel can exists in one of the three conformations.

Resting state – It can be stimulated by membrane depolarization.

Open state – It allows the Ca* to enter.

Inactive state – It is refractory to further depolarization.

Calcium channel blockers act by prolonging depolarization which inhibits conduction velocity and contraction. As a result, calcium channel blockers are therapeutically used in angina, arrhythmias, hypertension and cardio vascular disorders.

Mechanism of Action

Calcium plays a critical role in many physiologic functions both intracellular and extracellular. The most important tissue in angina is myocardial and vascular smooth muscles. The depolarization and contraction of the myocardial cells are mediated, in a part by calcium influx. The calcium channel blockers produce a negative isotropic effect by interrupting the contractile response.

In vascular smooth muscles, calcium causes constriction by binding to a specific intracellular protein calmodulin to form a complex that initiates the process of vascular constriction. The calcium channel blockers inhibit vascular smooth muscle contraction by depriving the cell from the calcium ions.

1,4-Dihydro pyridine

• A phenyl ring substitution at 4th position optimizes activity. Substitution at para or unsubstituted phenyl ring decreases the activity.
• 1, 4 – Dihydro pyridine ring is essential for activity. Substitution at N or oxidation or reduction of the ring decreases or abolishes the activity.
• The 3rd and 5th position ester group optimizes activity. Any other electron withdrawing substitution results in agonist activity.
• When the ester at C3 and Cs are non- identical, the C4 become chiral and stereo selectivity is observed. S-enantiomer has proved to be more effective.

Amlodipine (Amlibon, Stamlo, Vamlo)

Synthesis

ADR: Headache, peripheral edema, fatigue and somnolence.

Dose: Initially, 5mg once daily increased to 10mg once daily if necessary.

Use: It is used as antianginal and antihypertensive agent.

Felodipine (Felogard, Plendil)

It is a dihydropyridine derivative. It is a slightly yellowish crystalline powder. It is insoluble in water and freely soluble in ethanol. It is a recemic mixture.

Synthesis

ADR: Chest pain, dizziness, jaundice, swelling of the lips, tongue or face, flushing, headache and peripheral oedema.

Dose: Initially 5mg once daily in the morning and can be taken up to 20mg if necessary.

Use: It is used in the treatment of angina and essential hypertension

Nifedipine (Nifedine, Angiblock)

Synthesis: (Hantzsch Synthesis)

Step 1: Preparation of Methyl – [2- acetyl – 3 – (2- nitrophenyl)] – 2-propenoate

Step 2: Preparation of Methyl-3-amino -2- butenoate

Step 3: Condensation of steps I and II products

ADR: Peripheral edema, hypotension, palpitations and tachycardia.

Dose: 10 to 40mg bid or 20 to 90mg once daily.

Use: It is used in the treatment of angina and hypertension.

Nimodipine (Nimodip, Modipin)

It is a dihydropyridine calcium channel blocker developed for the treatment of high blood pressure but it has shown good results in preventing a major complication of subarachnoid hemorrhage termed vasosapasm. It is a yellow crystalline substance practically insoluble in water.

ADR: Peripheral edema, hypotension, palpitation and tachycardia.

Dose: 60mg tablet for every 4 hrs.

Use: It is mainly used in the prevention of cerebral vasospasm and resultant ischemia.

Phenyl Alkylamine Derivative

Verapamil (Calaptin, Vasopten)

It is an almost white crystalline powder, free from odour with bitter taste. It is soluble in water, chloroform and methanol. It is available as HCl salt.

Synthesis

Step – 1: Preparation of 3, 4 – Dimethoxy-2- isopropyl valeronitrile

Step 2: Preparation of 3, 4 – Dimethoxy phenyl ethyl N-methyl 3 – chloro propyl amine

Step 3: Condensation of step I and step II products

ADR: Bradycardia, congestive heart failure, myocardial infarction and atrio-ventricular block.

Dose: 240mg daily in 2 to 3 divided dose.

Use: It is used in the treatment of angina pectoris, arrhythmias from ischemic myocardial syndromes and supraventricular arrhythmias.

Benzothiazepine derivatives

Diltiazem (Coriem XL, Dilgard)

Synthesis

It has two chiral centers (C2 and C1), the laevorotatory cis antipode is more active

ADR: Headache, ankle edema, hypotension, dizziness and fatigue.

Dose: 60 to 120mg bid, increased if necessary.

Use: It is used in the treatment of angina pectoris and also used as antiarrhythmic agent.

B- Adrenergic Blockers

All these agents block the effects of endogenous and exogenous catecholamine. These drugs slow the heart rate and decrease the force of contraction. B – Blockers are classified into two main types:

• Aryl ethanol amines:
  • Example:  Isoproterenol, Dichloro isoproterenol, Pronethalol.
• Aryloxy propanol amines:
  • Example:  Propranolol, Nodolol, Practolol, Metaprolol.

Therapeutic uses of B-blockers: Used in the treatment of hypertension, coronary artery disease, arrhythmias and open angle glaucoma.

Structure Activity Relationship

β – Blockers are structurally similar to ẞ agonist. The catechol ring can be replaced by a variety of ring system without loss of antagonistic activity.

• Replacement of catechol hydroxyl group with chlorine or phenyl ring system retains ẞ-blocking activity.
  • Example:  Pronethalol, Dichloro isoproterenol.
• N, N – disubstitution decreases ẞ-blocking activity. Activity is maintained when phenyl ethyl, hydroxy phenyl ethyl or methoxy phenyl ethyl groups are added to amine as a part of the molecule.
• The two carbon chain is essential for activity.
• Introduction of the – OCH2 – group into the molecule between the aromatic ring and the ethylamine side chain provides ẞ – blocking agents.
  • Example:  Propranolol.
• Nitrogen atom should be of 2° amine for optimum ẞ-blocking activity.
• B- Blockers exhibit a high degree of stereo selectivity in the production of their ẞ blocking effect. The carbon of side chain bearing hydroxyl group must be (S) configuration for optimal affinity to the ẞ – receptor.
• Example:  Levobunolol, Timolol.

Aryloxy Propanol amines

General method of preparation of Aryloxy propanol amine

The corresponding phenol reacts with epichlorohydrin and gives epoxide or chlorohydrin depending upon the reaction condition. The separation of both is not necessary because both can be converted into aryloxy propanolamine either through condensation or by aminolysis of the epoxy group with isopropyl amine or tert-butylamine.

Propranolol (Betacap, Ciplar)

The levo isomer is more active than dextro isomer.

Synthesis

ADR: Cold extremities, insomnia, fatigue and dizziness.

Dose: Initially, 40 to 80mg bid, usual range is 160 to 320mg daily.

Use: Effective antihypertensive agent. It is also used to treat arrhythmias, angina pectoris, post myocardial infarction and migraine prophylaxis.

Atenolol (Hipres, Manoten)

Synthesis

ADR: Bronchospasm, cold extremities, fatigue and dizziness.

Dose: 25 to 100mg daily as a single dose.

Use: It is a ẞ1 – selective drug with low lipid solubility. Mainly used in the treatment of essential hypertension.

Metoprolol (Meto, Betaloc)

Synthesis

ADR: Bradycardia, hypotension, chest pain and edema.

Dose: 50 to 100mg daily in single or divided dose. May be increased to 400mg daily.

Use: It is a selective ẞ1- adrenergic antagonist used in the treatment of hypertension.

Mixed a and ẞ – adrenergic blockers

Labetolol (Labesol, Normadate)

It is a competitive inhibitor of B1, B2 and a1 – adrenergic receptor. It is optically active because it has two optically active centers. 1R, 1’R isomer possess ẞ – antagonistic activity and 1S, 1’R isomer possess a – antagonistic activity

ADR: Orthostatic hypotension, dizziness and fatigue.

Dose: Initially 100mg bid, increase gradually according to patient response to 200 to 400mg bid.

Use: It is used to treat chronic hypertension of pheochromocytoma and hypertensive crisis.

Carvedilol (Carvil, Caslot)

Both ẞ and a- adrenergic blocking agent. Only S isomer is ẞ – blocking and both enantiomers have a- blocking activity.

Synthesis

ADR: Bradycardia, atrioventricular block, angina pectoris and hypervolaemia.

Dose: Initially, 12.5mg once daily increased to 25mg once daily after 2 days. If necessary may increase to 50mg once daily or in divided dose.

Use: It is used to treat hypertension and congestive heart failure.

a – Adrenergic Blockers

Prazosin (Minipress, Prazopress)

Synthesis

ADR: Postural hypotension, syncope, palpitations and lack of energy.

Dose: Initially, 500μg bid to tid for 3 to 7 days, increased to 1mg bid to tid for the next 3 to 7 days. Maximum dose is 20mg daily.

Use: It lowers blood pressure by blocking a1-adrenoreceptors.

Centrally acting Sympatholytic Agents

Clonidine (Arkamin, Catapres)

Clonidine is an example of phenyl imino imidazoline derivative that possesses selective a2 – adrenergic receptor activity.

Synthesis

ADR: Dry mouth, drowsiness, headache and constipation.

Dose: 50 to 100μg tid.

Use: Selective a2- adrenergic receptor. It is used as antihypertensive agent. It possess sedative property and used for withdrawal syndrome of opioid analgesic.

Methyl Dopa (Alphadopa, Sembrina)

Synthesis

ADR: Peripheral edema, mental depression, anxiety and nightmares.

Dose: 250mg bid to tid for 2 days. Maximum dose is 3gm daily.

Use: It is a drug of choice for treating hypertension during pregnancy.

Vasodilators

Introduction

These groups of drug act directly on the arteriolar smooth muscle and decrease vascular resistance and arterial blood pressure. Since these drugs causes salt and water retention, it should be used in conjugation with diuretics and B-blockers.

The impaired contractile function of the heart is due to increase in both preload and after load. Preload is the volume of blood that fills the ventricle during diastole. Elevated preload causes overfilling of the heart, which increases the workload. After-load is the pressure that must be overcome for the heart to pump blood into arterial system. Elevated after-load causes the heart to work harder to pump blood into arterial system. (

Vasodilators are useful in reducing excessive preload and after-load. Dilation of venous and arterial blood vessels leads to decrease in cardiac preload and after-load respectively.

Classification

The vasodilators may be classified as follows.

• Drugs with predominant venodilatory effect.
  • Example:  Nitrates which reduces preload.
• Drugs with predominant arteriolar dilating effect. eg: Hydralazine, Minoxidil which reduces after-load.
• Mixed arteriolar and venodilator: ACE inhibitors, Angiotensin antagonists, Sodium nitroprusside which reduces both preload and after-load.

Hydralazine (Apresoline)

Synthesis

ADR: Diarrhea, tachycardia, headache, loss of appetite, nausea, vomiting and depression.

Dose: 40 to 50mg in single or divided dose.

Use: It is used in the treatment of moderate to severe hypertension.

Minoxidil (Mintop, Gromane)

Minoxidil is a white crystalline powder, slightly soluble in water, chloroform and methanol. It is a piperidino pyrimidine derivative directly relaxes arteriolar smooth muscle.

It is directly acting vasodilator. It is inactive and bio-transformed in liver by sulfotransferase into active Minoxidil sulfate.

Minoxidil sulfate

Minoxidil contains nitric oxide moiety and may act as a nitric oxide agonist. It is also act as a potassium channel opener causing hyperpolarization of the cell membrane. They activate the ATP-sensitive potassium channel, which leads to a decrease in intercellular Ca * and reduces the excitability of smooth muscle. It reduces elevated BP accompanied by reflex tachycardia, increased cardiac output, and elevated plasma rennin. Applied topically it stimulates hair growth secondary to vasodilation. It increases cutaneous blood flow and stimulates resting hair follicles.

Synthesis

ADR: Reflex tachycardia, fluid retention, headache and nausea.

Dose: 2.5 to 5mg daily gradually increases at intervals at least 3 days to 40 or 50 mg daily depending on response.

Use: It is used for severe hypertension that is difficult to control with another hypertensive agent. Topically it is used to treat androgenetic alopecia (Male pattern baldness).

Diazoxide (Eudemine)

Synthesis

ADR: Hypotension, hyperglycemia, and edema.

Dose: Ito 3mg/kg within 30 second, repeated after 5 to 15 minutes if required.

Use: It is used in hypertensive emergency. It is also used as diuretics and vasodilator agent.

Adrenergic Neuron Blockers

Reserpine (Serpasil, Adelphane)

Reserpine is an alkaloid obtained from various species of Rauwolfia.

ADR: Nasal congestion, headache and CNS disorders.

Dose: Up to 500μg daily for about 2 weeks, subsequently reduced to lowest dose necessary to maintain response.

Use: It is effective orally and parenterally for the treatment of hypertension.