DRUGS ACTING ON RAAS

DRUGS ACTING ON RAAS

Q. 1

Regarding ACE inhibitor which of the following is true –

 A

Inhibits conversion of angiotensinogen to angiotensin 1

 B

T1/2 of enalapril is more than lisinopril

 C

Omission of prior diuretic dose decreases the risk of postural hypotension

 D

It is effective only with left ventricular systolic dysfunction

Q. 1

Regarding ACE inhibitor which of the following is true –

 A

Inhibits conversion of angiotensinogen to angiotensin 1

 B

T1/2 of enalapril is more than lisinopril

 C

Omission of prior diuretic dose decreases the risk of postural hypotension

 D

It is effective only with left ventricular systolic dysfunction

Ans. C

Explanation:

The omission of prior diuretic dose decreases the risk of postural hypotension

Angiotensin-converting enzyme inhibitors (ACE inhibitors)

  • ACE inhibitors are drugs that exert their action by inhibiting the conversion of Angiotensin I to Angiotensin II. They inhibit the angiotensin-converting enzyme.

Example of ACE inhibitors:-

  • Captopril
  • Enalapril
  • Lisinopril
  • Ramipril
  • Trandolapril
  • Perindopril

Therapeutic uses of ACE inhibitors:

ACE inhibitors in hypertension

  • The inhibition of ACE lowers systemic vascular resistance.
  • ACE inhibitors lower mean, diastolic, and systolic blood pressure in various hypertensive states.
  • The initial change in blood pressure is directly related to plasma renin activity. Elevated plasma renin activity renders patients hyperresponsive to ACE inhibitor-induced hypotension and initial dosages of all ACE inhibitors should be reduced in patients with the high plasma levels of renin (e.g. patients with heart failure and salt depleted patients).

ACE inhibitors in left ventricular systolic dysfunction

  • ACE inhibitors should be given to all patients with impaired left ventricular systolic function. 
  • Inhibition of ACE commonly reduces afterload and systolic wall stress, and both cardiac output and cardiac index increases as do indices of stroke work and stroke volume.

Remember.

  • This important point about the use of ACE in heart failure.
  • Severe hypotension may result in a patient taking diuretics or who are hypovolemic, hyponatremic, elderly, have renal impairment or with systolic blood pressure <mmHg.
  • Therefore it may be necessary to reduce the dose of diuretic during the initiation of ACE inhibition to prevent symptomatic hypotension.
  • A test dose of captopril 6.25 mg by mouth may be given because its effect lasts only 4-6h. If tolerated, the preferred long-acting ACE inhibitor may then be initiated in a low dose.

ACE inhibitors in myocardial infarction

  • Several large prospective, randomized clinical studies involving thousands of patients provide convincing evidence that ACE inhibitors reduce overall mortality when treatment is begun during the peri-infarction period.

ACE inhibitors in chronic renal failure

  • Diabetes mellitus is the leading cause of renal disease. In patients with type I diabetes mellitus and diabetic nephropathy captopril prevent or delays the progression of renal disease. Specific reno-protection by ACE inhibitors is more difficult to demonstrate in type 2 diabetics.
  • Several mechanisms participate in renal protection afforded by ACE inhibitors. Increased glomerular capillary pressure induces glomerular injury and ACE inhibitors reduce this parameter both by decreasing arterial blood pressure and by dilating renal efferent arterioles.

Adverse effect of ACE inhibitors

Hypotension

  • A steep fall in blood pressure may occur following the first dose of an ACE inhibitor in patients with elevated PRA (plasma renin activity).
  • In this regard, care should be exercised in patients who are

Salt depleted

  • In patients being treated with multiple antihypertensive drugs,
  • In patients who have a congestive heart. failure
  • In patients who are on diuretics.
  • It may be necessary to reduce the dose of diuretics during the initiation of ACE inhibitors to prevent symptomatic hypotension.
  • The doses of ACE inhibitors should be initiated in low doses followed by gradual increment if the lower doses have been well tolerated.

Pharmacokinetics

  • All ACE inhibitors except captopril and lisinopril are prodrugs and are converted to the active agents by hydrolysis primarily in the liver.
  • Enalapril is an oral prodrug that is converted by hydrolysis in the liver to an active form Enalaprilat.
  • Enalaprilat itself is available only for intravenous use primarily for hypertensive emergencies.
  • Enalapril has a half-life of only 1.3 hours but enalaprilat because of tight binding to ACE has a plasma half-life of about 11 hours.
  • Lisinopril is the lysine analog of enalapril. Unlike enalapril, Lisinopril itself is active and its half-life in plasma is about 12 hours.
  • All ACE inhibitors are cleared as the intact compound by the kidney (except fosinopril and moexipril).

Q. 2

Regarding ACE inhibitor which of the following is true‑

 A

Inhibits conversion of angiotensinogen to arigiotensin I

 B

T 1/2 of enalapril is more than lisinoproil

 C

Omission of prior diuretic dose decreases the risk of postural hypotension

 D

It is effective only with left ventricular systolic dysfunction

Ans. C

Explanation:Omission of prior diuretic dose decreases the risk of postural hypotension [Ref KDT 6th/e p. 450]

Angiotensin converting enzyme inhibitors

  • Renin is an enzyme produced by the kidney in response to sodium depletion and increased adrenergic activity.
  • Renin converts a circulating glycoprotein (angiotensinogen) into the biologically inert angiotensin I, which is then converted by angiotensin converting enzyme (ACE or kininase II) into the highly potent vasoconstrictor Angiotensin II.
  • Angiotensin converting enzyme or (ACE) is located on the luminal surface of capillary endothelial cells, particularly in the lungs.
  • Angiotensin II exerts its effect by acting on two receptors i.e. ATi and AT2.

Main actions of Angiotensin II

a)Vasoconstriction

  • Angiotensin II is the most potent vasoconstrictor in the body. It increases total peripheral resistance by constricting precapillary arterioles and to a lesser extent postcapillary venules by activating ATi receptors.

Angiotensin II also produces peripheral vasoconstriction by enhancement of peripheral noradrenergic neurotransmission.

b) Release of Aldosterone from adrenal cortex

  • Angiotensin II stimulates the zona glomerulosa of the adrenal cortex to increase the synthesis and secretion of aldosterone.

c) Altered renal hemodynamics

  • Angiotensin II variably influences glomerular filtration rate via several mechanisms –

i) Constriction of the afferent arterioles which reduces intraglomerular pressure and tends to reduce GFR.

ii) Contraction of measangial cells which decreases the capillary surface area which reduces GFR.

iii) Constriction of efferent arterioles which increases intraglomerular pressure and tends to increase GFR.

The outcome of these opposing effects on GFR depends upon the physiological state :­- Normally G.F.R is slighthy reduced by angiotensin II.

d) Effect of Angiotensin II on cardiac structure :-

i)  Increased wall to lumen ratio in blood vessels

ii) Concentric cardiac hypertrophy

iii) Eccentric cardiac hypertrophy

iv) Thickening of intimal surface of blood vessels

ACE inhibitors

  • ACE inhibitors are drugs which exert their action by inhibiting the conversion of Angiotensin Ito Angiotensin R. They inhibit the angiotensin converting enzyme.

Example of ACE inhibitors:?

  • Captopril
  • Enalapril
  • Lisinopril
  • Ramipril
  • Trandolapril
  • Perindropil

Therapeutic uses of ACE inhibitors:?

ACE inhibitors in hypertension

  • Inhibition of ACE lowers systemic vascular resistance.
  • ACE inhibitors lower mean, diastolic and systolic blood pressure in various hypertensive states.
  • The initial change in blood pressure is directly related to plasma renin activity. Elevated plasma renin activity renders patients hyperre.sponsive to ACE inhibitor induced hypotension and initial dosages of all ACE inhibitors should he reduced in patients with high plasma level of renin (e.g. patients with heart failure and salt depleted patients).

ACE inhibitors in left ventricular systolic dysfunction

  • ACE inhibitors should be given to all patients with impaired left ventricular systolic .function. Although the mechanism by which ACE inhibitors improve outcome in patients with systolic dysfunction are not completely understood, the induction of a more favourable hemodynamic state most likely plays an important role.
  • Inhibition of ACE commonly reduces afterload and systolic wall stress, and both cardiac output and cardiac index increases as do indices of stroke work and stroke volume.
  • There is over whelming evidence that ACE inhibitors should be used in symptomatic and asymptomatic patients with a depressed Ejection fraction (< 40%).
  • Although the role of ACE inhibitors in left ventricular systolic dysfunction is firmly established whether these drugs improve diastolic dysfunction is an important open question. Infusion of enalaprilat into the left coronary arteries of patients with left ventricular hypertrophy significantly improves diastolic function.

Remember,

This important point about the use of ACE in heart failure.

  • Severe hypotension may result in patient taking diuretics or who are hypovolemic, hyponatremic, elderly, have renal impainnent or with systolic blood pressure < 100 minHg.
  • A test dose of captopril 6.25 mg by mouth may be given because its effect lasts only 4-61t. If tolerated, the preferred long acting ACE inhibitor may then be initiated in low dose.

ACE inhibitors in myocardial infarction

  • Several large prospective, randomized clinical studies involving thousands of patients provide convincing
    evidence that ACE inhibitors reduce overall mortality when treatment is begun during peri-infarction period.

ACE inhibitors in chronic renal failure

  • Diabetes mellitus is the leading cause of renal disease. In patients with type I diabetes mellitus and diabetic nephropathy captopril prevents or delays the progression of renal disease. Specific renoprotection by ACE inhibitors is more di’. ficult to demonstrate in type 2 diabetics.
  • Several mechanisms participate in renal protection afforded by ACE inhibitors. Increased glomerular capillary pressure induces glomerular injury and ACE inhibitors reduce this parameter both by decreasing arterial blood pressure and by dilating renal efferent arterioles.

Adverse effect of ACE inhibitors

Hypotension

  • A steep fall in blood pressure may occur following the first dose of an ACE inhibitor in patients with elevated PRA (plasma renin activity).
  • In this regard, care should he exercised in patients who are

– Salt depleted

– In patients being treated with multiple antihypertensive drugs,

– In patients who have congestive heart. failure

– In patients who are on diuretics.

  • The doses of ACE inhibitors should be initiated in low doses followed by gradual increment if the lower doses have been well tolerated.

Pharmacokinetics

  • All ACE inhibitors except captopril and lisinopril are prodrugs and are converted to the active agents by hydrolysis primarily in the liver.
  • Enalapril is an oral prodrug that is converted by hydrolysis in liver to an active form Enalaprilat.
  • Enalaprilat itself is available only for intravenous use primarily for hypertensive emergencies.
  • Enalapril has a half life of only 1.3 hours but enalaprilat because of tight binding to ACE has a plasma half life of about 11 hours.
  • Lisinopril is the lysine analogue of enalapril. Unlike enalapril, Lisinopril itself is active and its half life in plasma is about 12 hours.
  • All ACE inhibitors are cleared as the intact compound by the kidney (except fosinopril and moexipril).

Q. 3

Which of the following statements regarding aceinhibitors is true ?

 A

These convert angiotensinogen to angiotensin‑

 B

Omission of prior diuretic dose decreases the

risk of postural hypotension

 C

Lisinopril is shorter acting the enalapril

 D These are contra-indicated in diabetic patients
Ans. B

Explanation:Omission of prior diuretic dose decreases the risk of postural hypotension [Ref: Repeat AIIMS May 09]


Q. 4 Which of the following is a prodrug-

 A

Neostigmine

 B

Enalapril

 C

Captopril

 D

Esmolol

Ans. B

Explanation:

Ans. is ‘b’ i.e., Enalapril


Q. 5

Telmisartan lowers blood pressure by –

 A

Inhibiting formation of angiotensin I to angiotensin II

 B

Inhibiting conversion of renin to angiotensin I

 C

Blocking ATI receptors

 D

Interfering with degradation of bradykinin

Ans. C

Explanation:

Ans. is ‘c’ i.e., Blocking ATI receptors

ACE inhibitors : Captopril, enalapril, lisinopril, ramipril, perindopril, imidapril, trandopril, benazepril, fosinopril. Ren in inhibitors : Aliskiren, remikiren, enakiren.

ATI blockers : Losartan, candesartan, irbesartan, valsartan, telmisartan.


Q. 6 Drugs which is ACE inhibitor ?

 A Losartan

 B

Milrinone

 C

Candesartan

 D

Fosinopril

Ans. D

Explanation:

Ans. is ‘d’ i.e., Fosinopril

  • ACE inhibitors are captopril, lisinopril, ramipril, trandolopril, perindopril, enalapril, benazepril, fosinopril and imidapril.

Q. 7 Which of the following ACE inhibitor is not a prodrug –

 A

Captopril

 B

Enalapril

 C

Ramipril

 D

All

Ans. A

Explanation:

Ans. is ‘a’ i.e., Captopril

o All ACE inhibitors are prod rugs except captopril and Lisinopril.



Q. 8

All are true about losartan, except

 A

Angiotensin II antagonist

 B

Causes hyperuricemia

 C

Does not cause cough

 D

Long acting metabolites

Ans. B

Explanation:

Ans. is ‘b’ i.e., Causes hyperuricemia

Losartan is a mild uricosuric agent, Le causes hypouricemia

  • Losartan is a competitive antagonist of angiotensin II (10000 times more selective for AT! than AT2).
  • In liver it gets converted to long acting metabolite (E 3174) which is 10-30 times more potent non competitive antagonist of AT1
  • Plasma t ‘/2 of
  1. Losartan →   2hr
  2. E3174 →  6-9 hrs.
  • It has several advantages over ACE inhibitors
  • It does not cause cough and angiodema
  • It does not cause dysguesia (altered taste sensation)
  • It does not cause first dose hypotension
  • AT-11 antagonists are more effective than ACE inhibitors in blocking the vasopressor action of angiotension-IL

Similarities with ACE inhibitor

  • Hyperkalemia and, hypotension
  • Teratogenic  Contraindicated in pregnancy

Why do AT-II antagonists not cause cough and angiodema, while ACE inhibitors do ? Lets see

  • Bradykinin and sustance P are substrate for ACE.
  • ACE inhibitors increase level of these kinins by inhibiting ACE, which is responsible for cough and angiodema.
  • AT-II antagonists do not inhibit ACE (they block AT-II recepotors) –> No increase in the level of bradykinin and subustance P —> No cough & angiodema.

Q. 9 Aldosterone antagonist are –

 A Eplerenone

 B

Sprionolactone

 C

Amiloride

 D

a and b

Ans. D

Explanation:

Ans is ‘a’i.e., Eplerenone & b’i.e. Sprionolactone

o Aldosterone antagonists are spironolactone, eplerenone, canrenone, prorenone, mexrenone.


Q. 10

Aldosterone antagonists are NOT useful in the treatment of-

 A

Hypertension

 B

Congestive heart failure

 C

Gynaccomastia

 D

All

Ans. C

Explanation:

Ans. is ‘c’ i.e., Gynaecomastia

  • Spironolactone is a weak diuretic and can be used only in combinations with other more efficient diuretics‑

1)   Edema

o It is more useful in cirrhotic and neph retie edema because in these conditions aldosterone level is high.

o Spironolactone is the drug of choice for cirrhotic edema.

2)   To counteract K+ loss due to thiazide and loop diuretics –

3)   Hypertension

4) CHF


Q. 11 A hypertensive diabetic is having proteinuria, antihypertensive of choice is:

 A

Propanolol

 B

Clonidine

 C

Enalaprilat

 D

Alpha methyldopa

Ans. C

Explanation:

Answer is C (Enalaprilat)

The presence of proteinuria in this diabetic patient suggest a diagnosis of diabetic nephropathv.

The drugs of choice for management of hypertension in patients with diabetes are ACE inhibitors

Enalapril is an ACE inhibitor and the drug of choice for management of hypertension in patients with diabetic nephropathv.

ACE inhibitors or Angiotensin blockers should be the first line therapy in hypertensive individuals with type 2 Diabetes. They have no known adverse effect on glucose or lipid metabolism and minimize the development of diabetic nephropathy by reducing renal vascular resistance and renal perfusion pressure- Harrison

Indication                                                  –  Treatment of choice

Hypertensive patient with protenuriae                – ACE inhibitors or Angiolensin Blocker

Hypertensive patient with Diabetese                  – ACE inhibitors or Angiotensin Blocker

Hypertensive patient with diabetic Nephropathye – ACE inhibitor or Angiotensin Blocker

ACE inhibitors have become the drug of choice for chronic renal disease whether diabetic or non diabetic in origin.


Q. 12 Following is true regarding sulhydryl groups except‑

 A

They are present in coenzyme A and lipoic acid

 B

They are present in Captopril and penicillamine

 C

They are not involved in reduction of peroxides

 D

They are present in cysteine

Ans. C

Explanation:

Ans. is ‘c’ i.e., They are not involved in reduction of peroxides

  • Sulfhydryl Group (or thiol group)
  • It is an SH group of organic compounds.
  • Sulfhydryl groups have great and varied reactivity. They oxidize easily, with the formation of disulfides and
  • sulfenic, sulfinic, or sulfonic acids, and they readily undergo alkylation, acylation, and thiol-disulfide exchange.
  • They form mercaptides upon reacting with the ions of heavy metals, and they form mercaptals and mercaptols upon reacting with aldehydes and ketones, respectively.
  • Sulfhydryl groups play an important role in biochemical processes.
  • The sulfhydryl groups of coenzyme A, lipoic acid, and 4′-phosphopantotheine participate in enzymatic reactions for the formation and transfer of acyl residues that are related to lipid and carbohydrate metabolism.
  • The sulfhydryl groups of glutathione play an important role in the neutralization of foreign organic compounds and the reduction of peroxides; they are also of major importance in the fulfillment by glutathione of its function as a coenzyme.
  • In proteins, residues of the amino acid cysteine have sulfhydryl groups.
  • As components of the active centers of a number of enzymes, sulfhydryl groups participate in the catalytic effect of the enzymes and in the binding of substrates, coenzymes, and metal ions.
  • Drugs containing sulfhydryl groups are: captopril, zofenopril and penicillamine.

Q. 13 Which of the following is a pro drug is ‑

 A

Levodopa

 B

Poiglitazone

 C

Dexamethasone

 D

Captopril

Ans. A

Explanation:

Ans. is ‘a’ i.e., Levodopa

Prodru

  • Few drugs are inactive as such and need conversion in the body to one or more active metabolites.
  • Such a drug is called a prodrug.

Q. 14 Vasoconstrictor anong these ‑

 A NO

 B

PGI2

 C

Angiotensin-II

 D

ANP

Ans. C

Explanation:

Ans. is ‘c’ i.e., Angiotensin-II

Important chemical regulator of CVS are :

  1. Vasoconstrictors : Noradrenaline, Adrenaline, ADH (vasopressin), angiotension II, Endothelins, PGF2, thromboxane A2.
  2. Vasodilators : Kinins (Bradykinin, lysyl-bradykinin), PGE„ PGL (prostacyclin), VIP, ANP, Nitric oxide (NO)

Q. 15 Which of the following is a prodrug‑

 A Neostigmine

 B

Captopril

 C

Esmolol

 D

Enalapril

Ans. D

Explanation:

Ans. is ‘d’ i.e., Enalapril


Q. 16

Chronic cough is a side effect of‑

 A

Captopril

 B

Domperidone

 C

Cimetidine

 D

Celecoxib

Ans. A

Explanation:

Ans. is `a’ i.e., Captopril

Captopril is an ACE inhibitor and chronic cough is a known side effect of ACE inhibitors.

Adverse effects of ACE inhibitor

  • Hypotension
  • Cough
  • Angioedma 
  • Teratogenecity
  • Acute renal failure
  • Hyperkalemia
  • Rashes, Urticaria
  • Dysguesia
  • Gfanulocytopenia

Dysguesia is reversible loss or alteration of taste sensations.

Cough and angioedema are due to elevated bradykinin, caused by inhibition of bradykinin/substance P metabolism in lungs.


Q. 17 Which is correct of enalapril as compared to captopril

 A

Shorter action

 B

More potent

 C

Faster onset of action 

 D

More adverse reactions

Ans. B

Explanation:

Ans. is ‘b’ i.e., More potent

Enalapril

  • Enalapril is a prodrug converted in the body to Enalaprilat. (Enalaprilat is available as a separate drug for hypertensive emergencies).
  • It is a tripeptide analogue in contrast with captopril which is dipeptide.
  • Enalapril has the same pharmacological therapeutic and adverse effect profile as captopril but offers certain advantages which are :
  • Absorption is not affected by food.
  • More potent.
  • Onset of action is slower : Less likely to cause first dose hypotension.
  • Duration of action is longer : Single daily administration.
  • Rashes and dysgeusia is less frequent: (less side effects).

Q. 18

Which of the following ATI receptor blocker ‑

 A Spironolactone

 B

Losartan

 C

Captopril

 D

None

Ans. B

Explanation:

Ans. is ‘b i.e., Losartan


Q. 19

Which of the following is renin inhibitor ‑

 A

Losartan

 B

Benazepril

 C

Remikiren

 D

Imidapril

Ans. C

Explanation:

Ans. is ‘c’ i.e., Remikiren



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