Antihypertensive Drugs part 1

 

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 Diuretics

·         Diuretics, sometimes called water pills, treat a variety of conditions, such as high blood pressure, glaucoma and edema.

·         Diuretics are drugs that increase urine volume by promoting the excretion of salt and water from the kidneys.

Classification of Diuretics:-

ü  Extrarenal (Prerenal):

o    Water and ethyl alcohol: decrease ADH release à decrease water reabsorption.

o    Digitalis only in heart failure: +ve inotropic à ↑CO à ↑ renal blood flow.

o    Albumin only in hypoalbuminemia: restore osmotic pressureà ↑ blood volume.

o    Dobutamine and dopamine: ↑ CO à ↑renal blood flow. (Dopamine: renal VD).

o    Methylxanthines e.g. theophylline: ↑ CO and renal VDà ↑renal blood flow.

ü  Renal:

A) Saluretics (facilitating the urinary excretion of salt; especially Na+):

o    High efficacy (high ceiling); loop diuretics e.g. furosemide.

o    Moderate efficacy; thiazide diuretics e.g. hydrochlorothiazide (HCTZ).

o    Low efficacy (low ceiling):

-Potassium (K+) sparing diuretics e.g. spironolactone and triamterene.

- Carbonic anhydrase inhibitors e.g. acetazolamide.

                                   B) Osmotic diuretics e.g. mannitol.

                                   C) Acidifying diuretics e.g. ammonium chloride (NH4CI).

Diuretics Used in High Blood Pressure:-

·         There are three types of diuretics used in high blood pressure: thiazide, loop and potassium-sparing. Each works by affecting a different part of the kidneys, and each may have different uses, side effects and precautions.

Major segments of the nephron and their function:-  

Segment	Function	Water permeability	Diuretic with major action
Glomerulus	-Formation of glomerular filtrate	Extremely high	None
Proximal convoluted tubule	- Reabsorption of 65% of filtered Na+,     K+, Ca2+ & Mg2+. -Reabsorption of 85% of NaHCO3. - Reabsorption of 100% of   glucose and amino acids.	Very high	Carbonic anhydrase inhibitors
Thin descending limb of Henle's loop	Passive reabsorption of water.	High	None
Thick ascending limb of Henle's loop	- Active reabsorption of 15-25% of filtered Na+, K+ & Cl-. -Secondary reabsorption of Ca2+ and Mg2+	Low	Loop diuretics
Distal convoluted tubule (DCT)	-Active reabsorption of 4-8% of  filtered Na+ & Cl-. - Ca2+ reabsorption under   parathyroid hormone control.	Very low	Thiazides
Cortical collecting tubule	- Na+ reabsorption (2-5%)  coupled to K+ and H+ secretion.	Variable	K-sparing diuretics

 

Action of Diuretics:-

·         Initially; diuretics reduce blood pressure by reducing blood volume and cardiac output:

peripheral vascular resistance may increase. After 6-8 weeks; cardiac output returns toward normal while peripheral vascular resistance declines.

·         Diuretics are effective in lowering blood pressure by 10-15 mmHg in most patients.

Thiazide Diuretics
- Thiazide is a type of molecule and a class of diuretics often used to treat hypertension and edema. - In most countries, the thiazides are the cheapest antihypertensive drugs available.
Hydrochlorothiazide (HCTZ, HCT or HZT) (Aquazide®)		Chlortalidone or Chlorthalidone (Thalitone®)
- Thiazide diuretics such as hydrochlorothiazide  & chlorthalidone, lower blood pressure initially by   increasing sodium and water excretion. - Thiazide diuretics are useful in combination therapy with a variety of other antihypertensive agents,   including β-blockers, ACE inhibitors, ARBS, and potassium-sparing diuretics. - Thiazide diuretics are not effective in patients with inadequate kidney function (estimated glomerular   filtration rate less than 30 mL/min/m2). Loop diuretics may be required in these patients. - Dose; Hydrochlorothiazide; 25-100 mg/day (single dose). Chlorthalidone; 25-50 mg/day (single).
Mechanism Of Action	- Decrease blood pressure by increasing sodium and water excretion by reducing   reabsorption of sodium and chloride at the early part of the distal convoluted tubule in   the nephrons. - Resulting in decrease extracellular volume, decrease cardiac outputà decrease blood   pressure. - Increase the reabsorption of Ca+ in response to sodium depletion. - The action of thiazides depends in part on renal prostaglandin production. - The action of thiazides can be inhibited by NSAIDS in certain conditions.
Therapeutic uses	1) Mild and moderate hypertension. 2) Congestive heart failure (CHF); due to decrease preload & afterload in heart. 3) Nephrolithiasis (Idiopathic hypercalciuria); Preventing calcium-containing kidney stones, useful in hypocalcemia and osteoporosis. 4) Nephrogenic diabetes insipidus; The evidence suggests the anti-diuretic effects of thiazides in nephrogenic diabetes insipidus is intimately related to depletion of body sodium or due to decrease GFR.
Side Effects	- Hypokalemia and metabolic alkalosis; due to ↑ secretion of K+ & H+. - Hypercalcaemia; due to ↑ reabsorption of Ca2+. - Hyperuricemia; due to ↑ reabsorption of uric acid, due to hypovolemia. - Hyperlipidemia; due to ↑ total cholesterol and LDL level. - Hyperglycemia; due to decrease insulin release in response to hypokalemia. - Hyponatremia (decrease Na+ in the blood) and hypomagnesaemia. - Hypersensitivity (thiazides are sulfonamide derivatives). - Fetotoxic; due to crosses the placental, cause toxic effects on a fetus.
Contra indication	- Digitalis toxicity; hypokalemia & hypercalcaemia worsen these toxicity. - Hepatic cirrhosis (overzealous use) and renal failure. - Patients with a history of sulfonamide allergy. - Gout; due to hyperuricemia. - Diabetes mellitus; due to hyperglycemia. - Pregnancy; due to fetotoxic effect.
Drug interactions	- Digitalis; due to ↑ digitalis toxicity. - Lithium; due to decrease renal lithium excretion. - NSAIDS; due to decrease diuretic effect of thiazide.

 

 

Thiazide-Like Diuretics (Thiazide Analogues)
Indapamide (Natrilix SR)
- Indapamide is the first of a new class of 'antihypertensive/diuretics'. - It have a unique mechanism of action; act by combining diuretic effects with a direct vasodilatation (Ca+ channels biocker) effect. - It used in hypertension and edema due to congestive heart failure. - Dose, 2.5-10 mg/day (single dose). - The drug produces toxicity similar to that of the thiazide diuretics.
Clopamide (Hypoten)	Xipamide (Epitens)
- Clopamide and Xipamide are a thiazide-like diuretic and works in similar way as the thiazide diuretics.

 

Loop Diuretics (High Ceiling)
- Loop diuretics are the most efficacious diuretic agents currently available. - Loop diuretics are more effective in patients with impaired kidney function.
Furosemide (Lasix®)		Torsemide (Examide®)
Bumetanide (Burinex®)
- Furosemide, Torsemide, Bumetanide are sulfonamide loop diuretics. Ethacrynic acid, not a sulfonamide   diuretics. - Absorption; absorption of oral torsemide is more rapid (1 hour) than that of furosemide (2-3 hours). - Duration of action; Furosemideà 2-3 hours, Torsemide à 4-6 hours. Drug Total daily dose Relative potency Furosemide 20-80 mg 1 Torsemide 5-20 mg 3 Bumetanide 0.5-2 mg 40 Ethacrynic acid 50-200 mg 0.7
Mechanism Of action	-Decrease blood pressure by increasing sodium and water excretion by reducing  reabsorption of Na+, K+ & Cl- at the thick ascending limb of Henle's loop (TAL) in the  nephrons. -Decrease renal vascular resistance and increase renal blood flow via increase the  production of vasodilator prostaglandins, so NSAIDS can reduce the efficacy of loop  diuretics.
Therapeutic uses	1) Edema; caused by congestive heart failure, it is also used for hepatic cirrhosis,     renal impairment, nephrotic syndrome, in adjunct therapy for cerebral or     pulmonary edema. 2) Hypertension; Oral; used in adults for hypertension alone or in combination.     IV; used in emergency hypertension. 3) oliguria (< 400 ml urine/day); Use only high dose tablet (Furosemide 500 mg) or     injection (Furosemide 250 mg) in the treatment of oliguria due to acute or chronic     renal failure with a glomerular filtration rate (GFR) of below 20mL/min. 4) Other non-specific uses; Hyperkalemia.
Side Effects	- Hypokalemia and metabolic alkalosis; due to increase secretion of K+ & H+. - Ototoxicity (toxic to the ear or deafness); loop diuretics occasionally cause dose-                         related hearing loss that is usually reversible, most common in patients                         who have diminished renal function or who are also receiving other                         ototoxic agents such as aminoglycosides antibiotics. - Hyperuricemia; due to ↑ reabsorption of uric acid, due to hypovolemia. - Hypomagnesaemia; only in chronic uses. - Hyponatremia; less common than thiazides, but patients who increase water intake   in response to hypovolemia-induced thirst can become severely hyponatremic with   loop agents. -Severe dehydration. Hyperlipidemia; less common than thiazides. - Hyperglycemia; less common than thiazides. - Hypersensitivity; especially with sulfonamide loop diuretics (furosemide torsemide and bumetanide).   - Ca2+ balance remain neutral, loop diuretics cause an increase in renal calcium   excretion, this appears to be compensated for by a parathyroid-dependent increase   in vitamin D levels, which increases intestinal calcium absorption, may lead to mild   hypocalcemia and secondary hyperparathyroidism. - Fetotoxic; due to crosses the placental, cause toxic effects on a fetus.
Contra    Indication	- Digitalis toxicity; hypokalemia worsen these toxicity. - Hepatic cirrhosis (overzealous use). - Patients with a history of sulfonamide allergy. - Gout; due to hyperuricemia. - Pregnancy; due to fetotoxic effect.
Drug interactions	- Aminoglycosides antibiotics; ↑ ototoxicity. - Lithium; due to decrease renal lithium excretion. - Digitalis; due to ↑ digitalis toxicity. - NSAIDS; due to diuretic effect of loop diuretics. - Warfarin; furosemide displace warfarin from plasma protein binding site. -Probenecid; due to decrease renal tubular excretion of furosemide.

 

Potassium (K+) Sparing Diuretics (Low Ceiling)
- Potassium-sparing diuretics prevent K+ secretion by antagonizing the effects of aldosterone in collecting tubules (aldosterone antagonists) or by inhibition of Na+ influx through ion channels in the luminal membrane (non-aldosterone antagonists).
Aldosterone Antagonists
Spironolactone (Aldactone)		Eplerenone (Eplorefix)
- Spironolactone  is a synthetic steroid that acts as a competitive antagonist to aldosterone at   mineralocorticoid receptors, it has a slow onset of action requiring several days before full therapeutic   effect is achieved. - Eplerenone is a spironolactone analogue with much greater selectivity for the mineralocorticoid receptors. - Eplerenone has a several hundredfold less active on androgen and progesterone receptors than spironolactone, therefore, eplerenone has considerably fewer adverse effects.
Mechanism Of action	-Inhibits the effects of aldosterone, by competitive antagonist at  mineralocorticoid receptors at the aldosterone-dependent Na+ /K+ exchange site  in the distal convoluted renal tubule ↑ Na+ and water excretion, while K+ is  retained, H+ excretion is decreased (Acidosis). - Spironolactone has other effects e.g.; antiglucocorticoidic (Inhibit production of   the glucocorticoid hormones), antiandrogenic (block androgen receptor),   progestogenic & estrogenic effects.
Therapeutic                uses	Spironolactone uses;      - Primary hyperaldosteronism (Conn's syndrome):             - Usual adult dose Initial dose: 100 mg orally once a day. This dosage may                                                                     be divided into two daily doses, and                                                                     increased as tolerated every two to three                                                                     days to a maximum recommended total                                                                     daily dose of 400 mg.      - Edema for patients with: Congestive heart failure (CHF), Cirrhosis or Nephrotic        syndrome: - Usual adult dose for CHF, 25 mg/day orally.   - Essential hypertension; may be used alone or in combination with thiazide or loop diuretics, due to; - Synergistic diuretic effect.                                          - Correct hypokalemia. Spironolactone 25 or 50 mg + HCTZ 25 or 50 mg (Aldactazide®) Spironolactone 50 or 100 mg+ Furosemide 20 or 50 mg (Lasilactone®)                  - Usual adult dose for HTN, 25 to 200 mg/day orally in 1 or 2 divided doses. - Hypokalemia: Usual adult dose. 25 to 200 mg/day orally in 1 or 2 divided doses. - Antiandrogen; Hirsutism, acne (in women) & androgenic alopecia.                     - Usual adult dose for Hirsutism 50 to 200 mg/day orally in 1 or 2 divided doses. - Eplerenone uses;        - Congestive heart failure post-myocardial infarction:                      - Usual adult dose; Initial dose 25 mg once daily and titrated to the recommended dose                        of 50mg once daily, preferably within 4 weeks as tolerated by the patient.       -  Hypertension: Usual adult dose, 50 mg once daily.
Side                Effects	-Hyperkalemia; due to reduce urinary excretion of K+, may cause life- threatening                             hyperkalemia (cause cardiac irregularities).                       - The risk of this complication is greatly increased by; of Renal disease.                         - K+ supplements and diet rich in K+.                                      - B-blockers. NSAIDS, ACEIS, ARBS and Aliskiren. - Metabolic acidosis; due to inhibiting H+ secretion. - Endocrine abnormalities; Gynecomastia, Impotence, and benign prostatic                         hyperplasia (BPH is very rare) all have been reported only with                         spironolactone.
Contra Indication	- Patients with;                    - Anuria and renal insufficiency.                    - Hyperkalemia. - With pregnancy;             - Diuretics in general; are contraindicated in pregnancy, except when               necessary, spironolactone is only recommended for use in pregnancy               when there are no alternatives and benefit outweigh risk (category C), it               showed feminization of male fetuses or endocrine dysfunction in both               male and female.
Drug Interactions	- Concomitant administration of spironolactone or eplerenone with;                   - Other K+sparing diuretics.                   - B-blockers. NSAIDS, ACEIS, ARBS and Aliskiren.                   - K+ supplements and diet rich in K+. - Eplerenone contraindicated with liver microsomal enzyme inhibitors   (e.g. erythromycin, fluconazole), can increase blood levels of eplerenone.

 

 

 

 

 

 

 

 

 

Non-aldosterone Antagonists (Epithelial sodium channel blockers)
Amiloride (Midamor®)	Triamterene (Dyrenium®)
- Amiloride and Triamterene are direct inhibitors of Na+ influx in the CCT (cortical collecting tubule). - Mechanism of action; Direct block epithelial sodium channel (ENAC)à decrease sodium reabsorption in   the late distal convoluted tubules and cortical collecting tubule in the nephronsà increase loss of Na+ and   water with decrease K+ and H+ secretion. - Used as adjunctive treatment with thiazide diuretics or loop diuretics in congestive heart failure or   hypertension to:                             - Synergistic diuretic effect.                             - Correct hypokalemia. Amiloride 5 mg + Hydrochlorothiazide 50 mg (Moduretic®) Triamterene 37.5 mg + Hydrochlorothiazide 25 mg (Dyazide®) - Side effects; - Hyperkalemia and metabolic acidosis.                           - Triamterene may cause kidney stones (due to slightly soluble in the urine). - Contraindications; Patients with renal insufficiency and hyperkalemia. - Drug interactions; - Concomitant administration with;                                                  - Other K-sparing diuretics.                                                  - B-blockers, NSAIDS, ACEIS, ARBS and Aliskiren.                                                  - K+ supplements and diet rich in K+.                                     - Triamterene with Indomethacin has been reported to cause acute renal failure.