ANTIHYPERTENSIVE
DRUGS

ANTIHYPERTENSIVE DRUGS

Characteristics of the Ideal antihypertensive Drug

1. Efficacy
It should lower blood pressure (supine and standing) in all patients. This drug does not exist. When given as monotherapy (alone), the available antihypertensive drugs reduce the blood pressure in about 50% of patients. Age, race, level of blood pressure, pathophysiologic mechanisms and other undefined factors influence the hypotensive efficacy.

2. Safety
Drug should not produce any abnormal metabolic or hematologic effects and should not induce any organ (e.g., kideny, liver, central nervous system, skeletal muscle) dysfunction.
Majority of the available antihypertensive drugs are safe.

3. Freedom from Side-Effects
· Hypertensive patients are usually symptom-free.
· Many antihypertensive drugs produce some inconvenient symptoms such as flushing, impotence, drowsiness, fatigue, oedema, skin rash, cough, constipation and depression.

4. Long Duration of Action
Once a day administration will improve the patient compliance. This can be achieved by most of the available drugs.

Antihypertensive Drugs

5. Prevents or Induces Regression of Hypertensive Complications
· Most of hypertensive complications, i.e., target organ damage, are related to the severity and duration of hypertension.
· Other cardiovascular risk factors, e.g., dyslipidemia, impaired glucose tolerance, blood platelet and coagulation abnormalities, hyperinsulinemia are commonly present in hypertensive patients and contribute to a variable extent to the development of hypertensive complications.
· Antihypertensive drugs can prevent or retard the development of hypertensive complications.
· Antihypertensive drugs can induce regression of left ventricular hypertrophy.
· No clear evidence that any of the antihypertensive medications can induce regression of atherosclerotic complicaitons in man.
· Some antihypertensive drugs correct or improve associated metabolic and hemotologic abnormalities, e.g, impaired glucose tolerance, dyslipidemia while others worsen these abnormalities.

6. Correction of Hemodynamic Abnormality
The hemodynamic abnormality in hypertensive patients is an increase in systemic arterial resistance. Increased cardiac output is present in a very small subset of hypertensive patients. Majority of antihypertensives produce their hypotensive effect through arterial vasodilatation and decrease in systemic resistance.
7. Cost

· Drug treatment of hypertension has to continue for many years and in the majority of patients indefinitely, i.e., life long.

· Expensive drugs that patients can not afford will lead to interruption of treatment and failure of patients’ compliance.

Antihypertensive Drugs

Classification
1. Diuretics.
2. Beta Adrenergic Blockers.
3. Sympatholytics and Alpha Adrenergic Blockers.
4. Angiotensin – Converting Enzyme Inhibitors.
5. Angiotensin Receptor Blockers.
6. Calcium Antagonists.
7. Direct Arterial Vasodilators.
8. New Agents.

1. DIURETICS Types

1. Thiazides and related agents.
2. Loop diuretics.
3. Potassium sparing.

Mechanism of Hypotensive Action

Initial Effects
1. Decrease plasma volume.
2. Decrease extracellular fluid volume.
3. Decrease in cardiac output.

Intermediate and Long Term Effects
1. Decrease in total peripheral resistance.
2. Normalization of cardiac output.
3. Slight decrease in extracellular volume.

Antihypertensive Drugs

Advantages
1. Documented reduction in cardiovascular morbidity and mortality in hypertensive patients, particularly reduction in incidence of stroke.
2. Thiazides can be administered once daily or every other day.
3. Cheap: least expensive antihypertensive drugs.
4. Greater reduction in systolic compared with diastolic blood pressure. Best drugs for treatment of systolic hypertension and for hypertension in the elderly.
5. Can be combined with all other antihypertensives to produce synergistic effect.

Disadvantages

1. May require monitoring in some patients for adverse effects on serum potassium, glucose and uric acid.

2. Metabolic effects: (uncommon with small doses):
a. Hypokalemia
b. Hypomagnesemia
c. Hyperuricemia
d. Dyslipidemia: Increased total and LDL cholesterol.
e. Impaired glucose tolerance
f. Hyponatremia
g. Hypercalcemia (thiazides)
h. Increased serum lithium levels.

Side Effects
a. Impotence, loss of libido, sexual dysfunction in up to 22.0% of patients.
b. Postural hypotension, lightheadedness.
c. Palpitations.
d. Tiredness and weakness.
e. Arrhythmias secondry to hypokalemia. A serious complication in

Antihypertensive Drugs

patients receiving large doses and in those with left ventricular hypertrophy.

Limited Effectiveness
· Thiazides are not effective in patients with renal failure (serum creatinine > 2.5 mg%) because of reduced glomerular filtration rate.
· Nonsteroidal antiinflammatory drugs can antagonize diuretic effectiveness.

Potassium Supplementation
· Potassium supplements should not be routinely prescribed to patients receiving thiazide or loop diuretics.
· Potassium supplements are indicated in the following conditions:
a. Frank hypokalemia, i.e. serum potassium less than 3.3mEq/L.
b. Borderline hypokalemia (serum potassium 3.3-3.6mEq/L) in association with:
1. Concomitant digitalis therapy.
2. Premature beats in the resting ECG or
3. Left ventricular hypertrophy.

Special Indicatons for Diuretics
1. Hypertension complicated with heart failure.
2. Obese hypertensive: Hypervolemia is common in the obese.
3. Blacks: low – renin, volume dependent form of hypertention.
4. Elderly: Low-renin, salt sensitive form of hypertention.
5. Resistant hypertension: Loop diuretics in large doses are recommended while monitoring serum potassium. Common cause of resistance is salt and water retention secondry to drugs and reduction in renal blood flow.
6. Renal impairment: Loop diuretics are effective in patients with renal failure. 

Antihypertensive Drugs
7. Other sodium sensitive or low renin forms of hypertension, e.g.,primary aldosteronism.
8. Loop diuretics in hypercalcemia. Thiazides in calcium oxalate nephrolithiasis associated with normocalcemia.

Caution in Use
1. Diabetes mellitus.
2. Gout.
3. Hypokalemia – increase digitalis toxicity.
4. Potassium sparing diuretics are not recomended in renal failure.

Preparations and Dosage

A. Thiazides and Related Agents
1. Chlorthalidone (Hygroton): 12.5-50 mg/one-two days.
2. Hydrochlorothiazide (Hydrex): 12.5-50 mg/1-2 days.
3. Indapamide (Natrilix): 2.5-5.0 mg/day.

B. Loop Diuretics
1. Frusemide (Lasix): 20-600 mg/day (twice/day).
2. Ethacrinic acid (Edecrine): 25-100mg/day (twice/day).
3. Bumetanide (Burinex): 0.5-5.0 mg/day.

C. Potassium Sparing Diuretics
1. Spironolactone (Aldactone): 25-300 mg/day (twice-thrice/day
2. Amiloride: 5-10 mg/day (once or twice/day)
3. Triamterene: 50-150mg/day (once or twice/day)

D. Diuretic Combinations
1. Thiazide + amiloride (moduretic).
2. Thiazide + spironolactone (aldactazide).
3. Thiazide + ACE inhibitors: (capozide, zestoretic).
4. Thiazide + Beta-adrenergic blockers.

Antihypertensive Drugs

2. Beta-Adrenergic Blocking Agents

Types and Methods of Classification

1. Water vs lipid soluble: atenolol and nodolol are water soluble (do not cross blood-brain barrier), while metoprolol and propranolol are lipid soluble.

2. Cardio selective-acts mainly at B1 adrenergic receptors, e.g., atenolol, metoprelol, acebutolol, bisoprolol.

3. With intrinsic sympathomimetic activity (ISA), e.g., pindolol, acebutolol.

4. Combined alpha and beta blocker: Labetalol, carvedilol .

Mechanisms of Hypotensive Action

1. Decrease cardiac output (early).

2. Decrease peripheral vascular resistance (delayed effect).

3. Decrease plasma renin activity.

4. Resetting of baroreceptors.

5. Release of vasodilator prostaglandins.

6. Blockade of prejunctional beta-receptors (limit their facilitatory effect on norepinephrine release).

Advantages

1. Documented reduction in cardiovascular morbidity and mortality.
2. Cardioprotection-primary and secondry prevention of coronary artery events, i.e., ischemia, infarction, arrhythmias, death.
3. Relatively not expensive.
4. Can be given once daily.
5. Broad therapeutic spectrum, e.g., coronary artery disease, migrain, anxiety, arrhythmias.

Antihypertensive Drugs

Limitations and Side Effects

1. Bronchospasm and obstructive airway disease.
2. Aggravate peripheral arterial insufficiency.
3. Cold extremities.
4. Reduce exercise tolerance – fatigue.
5. Metabolic effects (absent in those with ISA) - raise triglyeride levels and decrease HDL cholesterol, may worsen insulin sensitivity and cause glucose intolerance.

6. Mask symptoms of hypoglycemia.
7. Impotence.

Contraindications and Precautions

1. Bronchial asthma, obstructive pulmonary disease.
2. Congestive heart failure.
3. Sick sinus syndrome. Heart block.

· Do not discontinue abruptly.

Special Indications

1. Hypertesnion associated with coronary artery disease.
2. Hyperkinetic circulation and high cardiac output hypertension.Young hypertensives.
3. Hypertrophic cardiomyopathy.
4. Supraventricular arrhythmias, sinus trchycardia.
5. Migrain.
6. Essential tremors.
7. Situational anxiety.
8. Combined with arterial vasodilators to prevent reflex sympathetic stimulation (tachycardia).

Antihypertensive Drugs

Preparations and Dosages

1. Propranolol (Inderal): 40-360 mg/day (twice/day).
2. Atenolol (Tenormin): 25-200 mg/day (once/day).
3. Metoprolol (Betalock, Blockadren): 50-200 mg/day (twice/day).
4. Nadolol (Corgard): 20-240 mg/day (once/day).
5. Pindolol (Visken): 10-60 mg/day (twice/day).
6. Carvedilol (Dilatrend): 25-50 mg/day.
7. Labetalol (Trandate): 200-1200 mg/day (twice/day).
8. Bisoprolol (Concor): 5-20 mg/day.

3. Sympatholytics And Alpha Adrenergic Blockers

Types

1. Alpha1-receptor blocks: e.g., prazosin.
2. Centrally acting a2 agonists, e.g., methyldopa, clonidine.
3. Peripheral acting adrenergic antagonists: e.g., guanethidine, rawolfia.
4. Imidazoline receptor agonists, e.g., rilmenidine, moxonidine.

Mechanism of Action (depends upon type)

1. Block alpha 1-postsynaptic adrenergic receptors and cause vasodilation (alpha adrenergic blockers).
2. Inhibit centeral efferent sympathetic activity (a2 - agonists).
3. Deplete tissue stores of catecholamines (rawolfia).
4. Inhibit catecholamines release from neuronal storage sites (guanethidine).
5. Imidazoline receptor agonists: Imidazoline receptors are present in the brain stem, the kidneys and other organs. They are directly involved in the regulation of the sympathetic outflow in the brain stem. Imidazoline receptor agonists lower blood pressure similar to

Antihypertensive Drugs

a2-agonists by inhibiting cenrtral efferent sympathetic activity.

Advantages

1. Alpha1– receptor blockers and imidazoline receptor agonists may improve lipid profile and insulin sensitivity.
2. Sedation (central sympatholytics).
3. Rapid onset of action.
4. Transdermal administration with clonidine patches (once/week).

Special Indications
1. Diabetes mellitus (alpha1-receptor blockers, imidazoline receptor agonists). The first choice, however, are ACE-Inhibitors.
2. Dyslipidemia (alpha1-receptor blockers, imidazoline receptor agonists).
3. Prostatic hypertrophy (alpha1-receptor blockers).
4. When there is a need for rapid reduction in blood pressure (clonidine).
5. When sedation is needed (sympatholytics).
6. Obesity with coexisting glucose intolerance or dyslipidemia (imidazoline receptor agonists).

Limitations and Side Effects (depend upon the type)

1. Postural hypotension.
2. Some require more than once daily administration.
3. Central nervous system effects: Drowsiness, lethargy, depression.
4. Dry mouth with central alpha-2 agonists.
5. Rebound hypertension when discontinued suddenly specially with clonidine.
6. First dose hypotension (alpha- receptor blockers).
7. Titration of dosage is sometimes required.
8. Combined diuretic therapy may be needed (methyldopa).
9. Nasal congestion, hyperacidity, activation of peptic ulcer (rawolfia).

Antihypertensive Drugs

Contraindications

1. Depression (rawolfia).
2. Acute hepatitis or active cirrhosis (methyldopa).
3. Active pepetic ulcer (rawolfia).

Preparations and Dosages

A. Alpha 1-Adrenergic Receptor Blockers
1. Prazosin (Minipress): 1-16 mg/day.
2. Doxazosin (Cardura): 1-20 mg/day.
3. Terazosin: 1-20 mg/day.

B. Centrally Acting Alpha 2-Agonists
1. Clonidine (Catapress): 0.1-1.2 mg/day (twice).
2. Clonidine TTS Patch: 0.1-0.3 mg once weekly.
3. Methyldopa (Aldomet): 1-3 gm/day.
4. Guanfacine (Estulic): 1-3 mg/day.

C. Peripheral Adrenergic Antagonists
1. Reserpine (Serpasil): 0.05- 0.25 mg/day.
2. Guanethidine (Ismelin): 10-100 mg/day.

D. Imidazoline Receptor Agonists
1. Rilmenidine (Hyperium): 1 mg/day.
2. Moxonidine (Cynt): 0.2, 0.3, 0.4 mg/day.

This group similar to a2 adrenergic receptor agonists (e.g., clonidine) inhibits central sympathetic outflow. They bind both a2 adrenergic receptors and imidazoline receptors, but they are more selective for imidazoline receptors i.e., more predominent action on imidazoline receptors.

Clonidine and other a2 adrenergic receptor agonists are accompained by adverse effects in particular sedation and dry mouth.

Antihypertensive Drugs

Imidazoline receptor agonists, rilmenidine (hyperium) and moxonidine (cynt) do not act at therapeutic doses on a2 receptors and are free from sedation. Furthermore, these agents acting on imidazoline receptors in the kidney, they decrease sodium and water reabsorption.

Possible Advantages of Imidazoline Receptor Agonists

1. Absence of contraindications, caution might be needed in presence of psychic depression.
2. No sedative effect at antihypertensive doses.
3. Do not impair the cardiovascular response to exercise.
4. Do not influence sexual function.
5. No important postural hypotension.
6. No rebound hypertension following abrupt withdrawal.
7. Improve insulin sensitivity in insulin- resistant hypertensives.
4. Angiotensin Converting Enzyme Inhibitors

Types

1. Sulfhydryl containing, e.g., captopril.
2. Non-sulfhydryl containing-prodrugs, e.g., benazalpril, ramipril,enalapril.
3. Non-sulfhydryl containing-not a prodrugs, e.g., lisinopril.
4. Phosphoryl containing, e.g., fosinopril.

Mechanism of Action

1. Inhibition of circulating angiotensin- converting enzyme (ACE).
2. Inhibition of tissue ACE.
3. Decreased release of norepinephrine from terminal adrenagic neurones.
4. Increased formation of bradykinin and vasodilatory prostaglandins.
5. Decrease secretion of aldosterone; help sodium excretion.

Antihypertensive Drugs

Advantages

1. Favorable metabolic profile.
2. Possible improvement in glucose tolerence and insulin resistance.
3. Renal glomerular protection effect specially in diabetes mellitus.
4. Cardioprotection: Prevention of cardiac dilatation, reversal of left ventricular hypertrophy, improvement of coronary flow, prevention and treatment of heart failure.
5. Does not adversely affect quality of life.

Special Indications

1. TypeII diabetes mellitues. Family history of diabetes, diabetic nephropathy.
2. Gout or family history of gout.
3. Hyperlipidemia, borderline lipid profile.
4. Congestive heart failure.
5. Follwing myocardial infraction.
6. Peripheral vascular disease.
7. High-renin hypertension.
8. Systolic hypertension: Increase large arteries compliance.
9. When optimal or peak physical and mental activities are required.

Limitation and Side Effects

1. Expensive.
2. Cough: commonest side effects. A dry irritant cough with tickling sensation in the throat (present in 10-30%).
3. Skin rash (6%).
4. Taste disturbances.
5. Limited efficacy in blacks or when receiving high salt diet.
6. Postural hypotension in salt depleted or blood volume depleted patients.
7. Allergic and sometimes anaphylactic reactions.
8.May cause hyperkalemia- monitor serum potassium specially when giving potassium supplements or potassium sparing diuretics.

Antihypertensive Drugs

9. Reduce the dose in renal failure when serum creatinine is more than 2.5 mg%.

Contraindications

1. Pregnancy.
2. History of allergy to ACE inhibitor.
3. Bilateral renal artery stenosis.
4. Unilateral renal artery stenosis in a single functioning or solitary kidney.

Preparations and Dosages

1. Benzapril (Cibacen): 10-20 mg/day.
2. Captopril (Capoten): 12.5-150 mg/day.
3. Enalapril (Renitec): 2.5-20 mg/day.
4. Lisinopril (Zestril): 5-40 mg/day.
5. Perindopril (Coversyl): 2-8 mg/day.
6. Ramipril (Tritace): 1.25-10 mg/day.
7. Fosinopril (Monopril): 10-40 mg/day.
5. Angiotensin Receptor Blockers (ARBS)

Mechanism of Action

There are two types of angiotensin-II receptors (A-II R):

Type 1: 
- Present in heart, blood vessels, kidneys,suprarenals, brain, nervous tissue.
- Mediates vasoconstriction, cellular proliferation, hypertrophy, migration, oxygen free radical production.

Type 2:
- Present in foetal tissue and reappears in inflammation and repair.

Antihypertensive Drugs
- Mediates vasodilatation, cell death (apoptosis).

· Currently available ARBS are selective and block only Type 1 A-II R.

Indications

Similar to ACE-inhibitors.

Rationale and Advantages over ACE-Inhibitors

- Angiotensin-converting enzyme inhibitors (ACE-I) proved effective in the treatment of hypertension and other conditions (e.g., heart failure). However, ACE-I have 2 important limitations:

1. Side effects namely cough and allergic reactions possibly due to excessive bradykinin.
2. Loss of their efficacy because of the generation of
A-II inspite of ACE inhibition by other enzymatic pathways.

- ARBS are free from side effects and their efficacy is maintained.

Special Indications

Patient who can not tolerate ACE-I because of side effects namely cough and allergy.

Preparations and Dosage

1. Valsartan (Tareg): 80-320 mg/day.
2. Valsartan + Thiazide diuretic (Co-Tareg).
3. Losartan (Cozaar): 25-100 mg/day.
4. Losartan + Thiazide diuretic (Hyzaar).
5. Irbesartan (Avapro): 150-300 mg/day.
6. Candesartan (Atacand): 16-32 mg/day.

6. Calcium Antagonists

Antihypertensive Drugs

Types and Methods of Classification

1. Selectivitiy for Ca channels (WHO classification):
a. Selective for Ca channels, e.g., verapamil, nifedipine, diltiazem.
b. Non-selective for Ca channels (not used in the treatment of hypertension), e.g., cinnerazine, prenylamine.

2. Chemical structure and binding site:
a. Dihydropyridine: Amlodipine, felodipine, isradipine, nifedipine, nicardipine, lacidipine.
b. Phenylalkylamine: Verapamil.
c. Benzothiazepine: Diltiazem.

3. Cardiac and vascular selectivity:
a. Prominent cardiac: Verapamil, diltiazem.
b. Prominent vascular: Dihydropyridines.

Mechanisms of Action

1. Decrease in the concentration of free intracellular Ca ions results in decreased contraction and vasodilation.
2. Diuretic effect through increase in renal blood flow and GFR.
3. Inhibit aldosterone secretion.
4. Restoration of baro reflex sensitivity.

Advantages

1. No metabolic distrubances: Glucose, potassium, uric acid and blood lipids do not change.
2. May improve renal function.
3. No central side effects: Maintain optimal physical mental and sexual activity.
4. Rapid onset of hypotensive effect with nifedipine, gradual effect with amlodipine.

Antihypertensive Drugs

Special Indications

1. Ischemic heart disease: Angina, specially vasospastic origin.
2. Elderly hypertensives.
3. Low renin hypertension, black hypertensives.
4. Supraventricular arrhythmias: Verapamil, diltiazem.
5. Peripheral vascular disease-Raynauld's phenomenon.
6. Hypertensive emergencies.
7. Hypertrophic cardiomyopathy.
8. Cerebral ischemia.
9. Diastolic LV failure.
10. Bronchial asthma.
11. Migrain.

Limitations and Side Effects
1. Expensive.
2. Cardiac depression: Verapamil and diltiazem.
3. Ankle edema, especially with amlodipine.
4. Some require more than once daily administration.
5. Headache: Nifedipine.
6. Facial flushing: Nifedipine.
7. Constipation: Sometimes with verapamil and diltiazem.
8. Palpitations.

Contraindications
1. Sick sinus syndrome and atrioventricular conduction defects (verapamil, diltiazem).
2. Congestive heart failure due to systolic dysfunction (verapamil, diltiazem).

Peparations and Dosages

Antihypertensive Drugs
1. Verapamil (Iosptin): 80-480 mg/day (twice).
2. Verapamil-long acting: 120-480 mg/day (once).
3. Diltiazem: 90-360 mg/day (twice).
4. Diltiazem-long acting: 120-360 mg/day (once).
5. Amlodipine (Norvasc): 2.5-10 mg/day (once).
6. Nifedipine (Adalat): 30-120 mg/day (thrice).
7. Nifedipine-long acting: 30-90 mg (once or twice).
8. Isradipine (Lomir): 2.5-10 mg/day (twice).
9. Isradipine-long acting: 5-10 mg/day (once).
10. Felodipine: 5-20 mg/day (once).
11. Lacidipine (Lacipil): 2-6 mg/day (once).

7. Direct Arterial Vasodilators

Types
1. Hydralazine.
2. Diazoxide.
3. Nitroprusside.
4. Minoxidil.

Mechanism of Action

- Relaxation of vascular smooth muscle cells leading to arterial dilation.
- Nitroprasside relaxation is through a mechanism similar to endothelium derived relaxing factor, (nitric oxide).
- Diazoxide and minoxidil act through potassium-channel opening (hyperpolarization) reducing calcium influx.

Advantages

Antihypertensive Drugs

Potent agents used in hypertensive emergencies.

Special Indications

1. Resistant hypertension.
2. Hypertensive emergencies.

Limitations, Side Effects and Contraindications
1. Some require intravenous administration (given only for a short period: diazoxide, nitroprusside).
2. Combination of diuretics and beta blockers are required.
3. Reflex tachycardia, excessive sympathetic stimulation, renin activation, salt and water retention.
4. Frequent daily administration.
5. Contraindicated in patients with ischemic heart disease.
6. Hirsutism (hypertrichosis) with minoxidil.
7. Lupus erythematosus with hydralazine.

Preparation and Dosages
1. Hydralazine: 50-200 mg/day (twice to four times).
2. Minoxidi: 2.5-80 mg/day (once or twice).
3. Diazoxide i.v. injection: Repeated boluses of 50 to150 mg (1-3 mg/kg) at 5 to 15 minute intervals.
4. Nitroprusside: i.v. infusion (pump)-initial doses 0.5 mg/kg/min, average dose 3 mg/kg/min.

- Maximum dose 10 mg/kg/min.
- Watch for thiocynate toxicity.
- Continuos monitoring of arterial pressure is essential during infusion. Immediate and severe drop in blood pressure can occur within seconds of infusion.

Antihypertensive Drugs

8. New Antihypertensive Drugs · Members of this group are not yet available in the market for clinical use.
1. Endothelin Antagonists

- Endothelins (ET), are potent vasoconstrictor peptides produced mainly by vascular endothelium.
- Endothetin receptors are of five types, the best characterized are types A and B:
· ETA and ETB receptors in smooth muscle cells, their stimulation induce contraction, proliferation and cell hypertrophy.
· ETB receptors in endothelial cells, their stimulation induce vasodilation.

- Endothelin is mainly involved in blood pressure elevation and vascular hypertrophy in moderate and severe. hypertension. Also endothelin plasma levels are elevated in heart failure.

- Administration of endothelin antagonists, e.g., Bosentan lowers blood pressure specially in the salt-sensetive patients.

2. Vasopeptidase Inhibitors
- Inhibit two key cardiovascular regulatory enzymes:
· Neutral endopeptidase (NEP).
· Angiotensin – converting enzyme (ACE).

- NEP inhibition blocks the inactivation of several peptides including natriuretic peptides, thus augmenting vasodilatation and natriuresis through increased levels of atrial natriuretic peptide and bradykinin.

- Example: Omapatrilat.

- Potentials advantages:
· Greater efficacy in lowering blood pressure.
· Better end-organ protection.

Antihypertensive Drugs

Reduced need for diuretics in some patients because of potential natriuretic effect.

- Potential drawbacks:

Allergic and anaphylactic reactions due to excess bradykinin production.