ACE Inhibitors

Drugs
 Captopril
 Enalapril.
 Lisinopril.
 Perindopril.
 Fosinopril
 Trandolapril
 Ramipril
 Imidapril
 Benazepril
Captopril
 Sulfhydryl containing dipeptide of proline
 Abolishes the pressor action of AI but not that of AII.

Actions:
 Lowers BP, magnitude depends on Na status & level of RAS
 Produces hypotension as a result of decrease in total peripheral resistance.The
arterioles dilate & compliance of larger arteries is increased.
 Both systolic & Diastolic Pressure falls
 No effect on Cardiac Output.
 Renal Blood flow is not compromised even when BP falls substantially which
is due to greater dilatation of renal vessels.
 Cerebral & coronary blood flow is also not compromised.

Pharmacokinetics:
 70% of orally administered Captopril is absorbed.
 Presence of food reduces bioavailability
 Partly metabolised & partly excreted unchanged in urine.
 Cont..
Adverse Effects:Well tolerated by most patients if daily dose less than 150 mg.

1. Hypotension: specially in Diuretic treated & CHF patients; Troublesome in MI

2. Hyperkalemia: important risk in patients with impaired renal function& in those
taking K+ sparing diuretics,NSAIDs or ß blockers.
3. Cough: Persistent cough occurs in 4-16% patients within 1-8 weeks-often
requires discontinuation of drug. Caused by inhibition of breakdown of
Substance P/Bradykinin in the lungs of susceptible individuals
4. Rashes Urticaria:1-4% patients does not warrant drug discontinuation.
5. Angioedema: swelling of lips, mouth, nose, larynx – hours to few days
6. Dysgeusia:Reversible loss or alteration of taste sensation
7. Fetopathic:if given during later half of pregnancy but not teratogenic in the first
half.
8. Headache, Nausea, Vomitting & Bowel upset
9. Granulocytopenia & Proteinurea
10. Acute Renal failure =:contraindicated in patients due to dilatation of Efferent
Arterioles & fall in Glomerular filtration Pressure
2. Enalapril:
Enalapril Enalaprilat.
( Prodrug) (Active Moeity)
Advantages Over Captopril
 More Potent Captopril Dose is 25 mg BD.
Enalapril 5-20 mg OD or BD.
 Slower onset of action ,thus less liable to cause abrupt first dose hypotension.
 Longer duration of action.Single daily dose sufficient.
 Rashes & loss of taste are less frequent.

3.Lisinopril:
 Lysine derivative of Enalaprilat.
 Does not require hydrolysis.
 Decrease in venous return, cardiac contractility and cardiac output – in few
weeks

4. Perindopril:
 Slow onset of action. Converted into Perindoprilat.

5. Ramipril:
 Converted to Ramiprilat
 Distinctive Feature is extensive tissue distribution thus may inhibit local RAS
significantly
Uses Of ACE Inhibitors
1. Hypertension
 First line drug in all grades of hypertension
 50% patients respond to monotherapy & majority of the rest to their combination
with Diuretics or ß blockers.
 Reduce CVS morbidity & increase life expectancy of hypertensive patients due
to their specific effect on myocardial & vascular cell growth & remodelling
ADVANTAGES:
 Lack of postural hypotension,Electrolyte Disturbances, feeling of weakness or
CNS effects.
 Safety in Asthmatics Diabetes & peripheral Vascular disease patients
 Prevention of secondary Hyperaldosteronism & K+ loss due to diuretics.
 Renal Blood flow is well maintained.
 Reverse Left Ventricular Hypertrophy & increased wall-lumen ratio of blood
vessels that occurs in hypertensive patients.
 No Hyperuricemia & no deleterious effects on plasma lipid profile
 No rebound hypertension on withdrawal.
 Minimum worsening of quality of life parameters like general wellbeing.work
performance etc.
 Cont…
2. CHF:
 ACE Inhibitors cause both arteriolar & venodilatation in CHF patients by reducing preload as
well as afterload.
 Accumulated salt & water are lost due to improved renal perfusion & abolition of
mineralocorticoid mediated sodium retention.
 Unless contraindicated ACE Inhibitors are now advocated as First Line drugs in all patients with
Left Ventricular Inadequacy.

3. Myocardial Infarction:
 Reduce early as well as long term mortality in MI.

4. Prophylaxis in high CVS Risk Subjects

 Due to protective effect on Myocardium & vasculature.

5. Diabetic Nephropathy:
 Prolonged therapy prevent End Stage Renal Disease in Type I & II Diabetes
 Also retard diabetic Retinopathy.
 All patients with diabetic nephropathy whether Hypertensive or normotensive deserve ACE
Inhibitor therapy.
 Non-diabetic Nephropathy-chronic renal Failure improved – Reduce Proteinurea by decreasing
pressure gradient across glomerular capillaries

6. Scleroderma Crisis
 ACE Iinhibitors are life saving in this condition
AT1 Receptor Antagonists

 Losartan.
 Candesartan.
 Irbesartan.
 Valsartan.
 Telmisartan.
 Eprosartan
Losartan
Actions:
 Competitive antagonist of AII, devoid of partial agonistic activity & 10 000 times more
selective for AT1 than AT2 receptors.
 Does not block any other receptor or ion channel.
 It blocks all overt actions of AII like vasoconstriction, central & peripheral sympathetic
stimulation,release of Aldosterone Adr from Adrenals,renal action promoting salt &
water reabsorption,cetral action like thirst,vasopressin release & growth promoting
actions on heart & blood vessels.

Pharmacological Difference between ATI antagonists & ACE Inhibitors:

ATI Antagonists do not interfere with degradation of Bradykinin & other ACE Substrates:no
rise in level of Bradykinin.
 More complete inhibition of ATI receptor activation.
 They result in indirect ATII receptor activation whereas ACE Inhibitors result in
depression of both AT1 than AT2 activation.

Pharmacokinetics:
 Bioavailability is 33% due to first pass metabolism.

Losartan E3174 Excreted by kidney

In Liver (more potent
non competitive antagonist)
Excreted by kidney
 Cont…
Adverse Effects
 Well tolerated.
 Hypotension.
 Hyperkalemia.
 Fetopathic.
 Headache, dizziness, weakness & upper GI side effects.

Differences from ACE Inhibitors

 No first dose Hypotension.
 No Cough.
 No Dysguesia.
 Low incidence of Angioedema

USES:
1. Hypertension: First line Hypertensive drugs as alternatives to ACE Inhibitors
comparable in efficacy & other desirable features.
2. CHF found to be as efficacious as ACE Inhibitors.
3. MI & Diabetic Nephropathy.