Ramipril

Mechanism of Action:

An angiotensin-converting enzyme (ACE) inhibitor. It is a prodrug that is metabolised to the active agent Ramiprilat, mostly in the liver, but also in kidney.

Indications:

  • Hypertension
  • Heart failure
  • Prophylaxis after myocardial infarction
  • Proteinuric renal disease, including diabetic nephropathy
  • Microalbuminuria caused by diabetes

The enzyme ACE is part of the renin angiotensin aldosterone system (RAAS). Circulating angiotensinogen is converted to angiotensin I [ATI] by the enzyme renin. ACE is responsible for the conversion of ATI to ATII. ATII is a potent vasoconstrictor, and AT III, a metabolite of ATII, stimulates aldosterone secretion. Aldosterone-mediated retention of salt and water leads to increased extracellular fluid volume and subsequently raises blood pressure and increases cardiac output. Lisinopril competes with angiotensin ATI for binding to ACE. Conversion of ATI to ATII is thus prevented and the effects of RAAS diminished.

Learning materials:

Details:

Alternative drug name
Not specified
Effects
Decreases angiotensin II production and so reduces effects on vasoconstriction and aldosterone release. This reduces arterial blood pressure. As well as reducing ‘afterload’ also venodilates and so reduces venous return (‘preload’) making it an effective agent in chronic heart failure.
Adverse actions
Persistent non-productive cough (~1 in 10 patients) which resolves with drug discontinuation, renal impairment (especially in patients with bilateral renal artery stenosis or impaired renal function), hypotension, hyperkalaemia (decreased aldosterone leading to increased potassium blood levels). Rash (uncommon).

The cough is the result of bradykinin accumulation in the lungs which acts as an irritant (ACE inhibitors prevent the breakdown of bradykinin). This is also an important mechanism in a rare but serious problem of angioedema (1 in 1000).

Renal impairment is attributed to the disruption of homeostatic mechanisms (e.g. renal blood flow) controlled by ATII which serves to support renal blood flow in circumstances such as hypotension or dehydration. Risk of severe drop in blood pressure with the first dose of ACE inhibitors (first dose hypotension) is mostly seen in those who are volume-deplete, usually through being on diuretics, but it can also be seen in those who have RAAS greatly upregulated for other reasons (e.g. renal artery stenosis).

ACE inhibitors are contraindicated in pregnancy, at least in mid-pregnancy, as they cause oligohydramnios and may cause other severe abnormalities if exposure in mid-pregnancy.

Rare but severe allergic reaction can occur affecting the bowel and secondarily causing abdominal pain. This “anaphylactic” reaction is very rare but requires immediate attention.

Dose
Usually once daily administration in the range 2.5 to 10 mg). Twice daily dosing is sometimes recommended in heart failure. Doses are usually doubled at intervals of 1-4 weeks for outpatients. Its half life is >24h after multiple doses at 2.5mg daily; 15h at 5-10mg daily.

Lower doses are recommended in patients with low GFR. (EMC on Ramipril)

Interactions
Renal impairment with other drugs affecting renal blood flow e.g. NSAIDs, diuretics. Hypotension with other antihypertensives. Hyperkalaemia with other drugs tending to preserve potassium e.g. potassium sparing diuretics such as spironolactone.
Contraindications
Symptomatically very low blood presssure.
Comments
Other ACE inhibitors include enalapril, lisinopril, perindopril, captopril etc. They vary in their pharmacokinetics but all work in much the same way. Angiotensin receptor blockers such as Losartan have a similar clinical profile to ACE inhibitors.

Not directly related, but of interest for treatment of pulmonary hypertension: ET-1 (endothelin-1) is a potent vasoconstrictor acting via ETA receptors (plus weak dilator action via ETB receptors) and its effects can be antagonized by bosentan, which is slightly more effective at blocking ETA receptors in comparison with ETB. The antagonist is used in treating pulmonary hypertension.

Contributors
Added by ANT Mar 2017 revised 2021

Doxazosin

UNDER REVIEW (September 2016)

Mechanism of Action:

Alpha-1 adrenoreceptor antagonist (blocker). Alpha-1 adrenoceptors in smooth muscle of resistance blood vessels (arterioles) are physiologically activated by the (nor)adrenergic transmitter, noradrenaline (norepinephrine), to cause vasoconstriction and a rise in mean arterial blood pressure. ‘Alpha blockers’ inhibit this action, and reduce vascular tone. This action is also useful at the prostate gland where relaxation improves urinary flow in patients with benign prostatic hypertrophy.

Lecture and CAL materials:

Losartan

Mechanism of Action:

Angiotensin II subtype 1 (AT1) receptor antagonist (angiotensin II receptors are limited in adults). This class of drugs is often loosely described as ARBs (angiotensin receptor blockers). Indications are mostly the same as for ACE inhibitors (see Ramipril).

Indications:

  • Hypertension
  • Heart failure
  • Prophylaxis after myocardial infarction
  • Proteinuric renal disease, including diabetic nephropathy
  • Microalbuminuria caused by diabetes

Angiotensin II, a potent vasoconstrictor, is part of the renin-angiotensin system, which controls blood pressure. Angiotensin III, a metabolite of Angiotensin II, stimulates aldosterone secretion from the adrenal cortex, which increases salt and water reabsorption from the kidney. This serves to increase extracellular fluid volume and so increase preload and cardiac output. (BP = CO x SVR) Therefore, angiotensin II directly and indirectly raises blood pressure and cardiac load. Losartan inhibits angiotensin II from binding to its receptor, thereby preventing it from exerting most of its effects.

Lecture and CAL materials:

Bisoprolol

Indications:

  • Chronic heart failure
  • Angina pectoris
  • Myocardial infarction
  • Cardiac arrhythmias
  • Hypertension

Mechanism of Action:

Bisoprolol is a highly beta1-selective-adrenoceptor blocking agent. It has little affinity to beta2-receptors of the smooth muscle of bronchi and vessels as well as the beta2-receptors involved in metabolic regulation. Therefore bisoprolol is not likely to influence the airway resistance or has beta2-mediated metabolic effects.

Lecture and CAL materials: (under review)

Bendroflumethiazide

Mechanism of Action:

A thiazide diuretic inhibits sodium and chloride ion co-transporter in the cortical thick ascending limb and early distal tubule. It has a milder diuretic action than the loop diuretics because this nephron site reabsorbs less sodium ion than the thick ascending limb. This then allows a bit more sodium to arrive in the late distal tubule and collecting duct where there is aldosterone-stimulated sodium reabsorption in exchange for potassium and hydrogen ion excretion. This underlies the important metabolic adverse effects of hypokalaemia and alkalosis. Other metabolic effects stem from the increase in urate and calcium reabsorption in the proximal tubule.

Lecture and CAL materials:

Amlodipine

UNDER REVIEW (April 2017)

Mechanism of Action:

Amlodipine is a long-acting calcium channel blocker used as an anti-hypertensive and in the treatment of angina. Calcium channel blocker – prevents Ca2+ entry through voltage-operated calcium channels. There are 3 classes of calcium channel blockers – all block the L-type calcium channel, but bind to different sites. Amlodipine belongs to the dihydropyridine class, and binds to the N binding site. (Other classes – phenylalkylamines eg verapamil: V binding site, benzothiazepines eg diltiazem: D binding site). Amlodipine causes significant vasodilation of peripheral arterioles and coronary arteries. It also decreases cardiac contractility, AV node conduction and SA node automaticity (but less so compared to other calcium channel blockers i.e. the drug has less effect on cardiac tissue). The tissue selectivity results from the drugs having more affinity for the particular channel conformation in one tissue compared to another. Amlodipine is almost entirely metabolised to inactive metabolites. Ten per cent of the parent substance and 60% of the metabolites are excreted in urine.

Lecture and CAL materials: