Hypertension & antihypertensive drugs Dr.Mohamed Daood 12/10/2015

Hypertension is the most common cardiovascular disease. Sustained arterial hypertension damages blood vessels in kidney, heart, and brain and leads to an increased incidence of renal failure, coronary disease, heart failure, stroke, and dementia. Effective pharmacologic lowering of blood pressure has been shown to prevent damage to blood vessels and to substantially reduce morbidity and mortality rates.

Normal Regulation of Blood Pressure

According to the hydraulic equation, arterial blood pressure BP is directly proportionate to the product of the (cardiac output, CO) and the resistance to passage of blood through blood vessels (peripheral vascular resistance, PV(

BP = CO × PVR

CO α heart rate, stroke voume

PVR α arterioles, postcapillary venules

-The kidney contributes to maintenance of blood pressure by regulating the volume of intravascular fluid.

-Baroreflexes, mediated by autonomic nerves, act in combination with humoral mechanisms, including the renin-angiotensin-aldosterone system, to coordinate function to maintain normal blood pressure.

-Finally, local release of vasoactive substances from vascular endothelium may also be involved in the regulation of vascular resistance. For example, endothelin-1 constricts and nitric oxide dilates blood vessels.

All antihypertensive agents act by interfering with normal mechanisms of blood pressure regulation. A useful classification of these agents categorizes them according to the principal regulatory site or mechanism on which they act .Because of their common mechanisms of action, drugs under each category tend to produce a similar spectrum of toxicities. The categories include the following:

1-Diuretics:

(1)- Diuretics lower blood pressure primarily by depleting body sodium stores. 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 due to depleting body sodium stores. Sodium is believed to contribute to vascular resistance by increasing vessel stiffness and neural reactivity, possibly related to altered sodium-calcium exchange with a resultant increase in intracellular calcium. These effects are reversed by diuretics or sodium restriction.

Note; - “natriuretic” causes an increase in renal sodium excretion thus increase water excretion.

- “aquaretic” increases excretion of solute free water, 2 types are available; Osmotic diuretics and antidiuretic hormone antagonists .

Mechanism of action: The following figure summarizes the mechanism of diuretics at:

1) the proximal convoluted tubule

2) the descending loop of Henle

3) the ascending loop of Henle

4) the distal convoluted tubule

5) the collecting tubule and duct

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Table 1:electrolytes and metabolic changes caused by diuretics

Carbonic anhydrase inhibitors

Carbonic anhydrase is present in many nephron sites, but the predominant location of this enzyme is the epithelial cells of the PCT , where it catalyzes the dehydration of H2CO3 to CO2 at the luminal membrane and rehydration of CO2 to H2CO3 in the cytoplasm. By blocking carbonic anhydrase, CA inhibitors blunt NaHCO3 reabsorption and cause weak dieresis because Some HCO 3 − can still be absorbed at other nephron sites by carbonic anhydrase–independent mechanisms, so the overall effect of maximal acetazolamide dosage is only about 45% inhibition of whole kidney HCO 3 − reabsorption..

Carbonic anhydrase inhibitors were the forerunners of modern diuretics. With the development of newer agents, carbonic anhydrase inhibitors are now rarely used as diuretics. The prototypical carbonic anhydrase inhibitor is acetazolamide.

Pharmacokinetics

(3)The carbonic anhydrase inhibitors are well absorbed after oral administration. An increase in urine pH from the HCO3 – dieresis is apparent within 30 minutes, is maximal at 2 hours, and persists for 12 hours after a single dose. Excretion of the drug is by secretion in the proximal tubule also. Therefore, dosing must be reduced in renal insufficiency.

Clinical Indications

1-Glaucoma; The reduction of aqueous humor formation by carbonic anhydrase inhibitors decreases the intraocular pressure.

2-Urinary Alkalinization: Uric acid and cystine are relatively insoluble and may form stones in acidic urine. Therefore solubility of cystine and uric acid can be enhanced by increasing urinary pH with carbonic anhydrase inhibitors.

3- Metabolic Alkalosis

when the alkalosis is due to excessive use of diuretics in patients with severe heart failure, replacement of intravascular volume may be contraindicated. In these cases, acetazolamide can be useful in correcting the alkalosis as well as producing a small additional diuresis for correction of volume overload. Acetazolamide can also be used to rapidly correct the metabolic alkalosis that may appear following the correction of respiratory acidosis.

4- Acute Mountain Sickness

Weakness, dizziness, insomnia, headache, and nausea can occur in mountain travelers who rapidly ascend above 3000 m. The symptoms are usually mild and last for a few days. In more serious cases, rapidly progressing pulmonary or cerebral edema can be lifethreatening. By decreasing cerebrospinal fluid formation and by decreasing the pH of the cerebrospinal fluid and brain, acetazolamide can increase ventilation and diminish symptoms of mountain sickness.

5- Other Uses

Carbonic anhydrase inhibitors have been used as adjuvants in the treatment of epilepsy. They are also useful in treating patients with CSF leakage usually caused by tumor or head trauma, By reducing the rate of CSF formation and intracranial pressure, carbonic anhydrase inhibitors can significantly slow the rate of CSF leakage. Finally, they also increase urinary phosphate excretion during severe hyperphosphatemia.

Adverse effects:

A. Hyperchloremic Metabolic Acidosis

Acidosis results from chronic reduction of body HCO 3 − stores by carbonic anhydrase inhibitors and

limits the diuretic efficacy of these drugs to 2 or 3 days.

B. Renal Stones

(4)Phosphaturia and hypercalciuria occur during the bicarbonaturic response to inhibitors of carbonic anhydrase. Renal excretion of solubilizing factors (eg, citrate) may also decline with chronic use.

Calcium salts are relatively insoluble at alkaline pH, which means that the potential for renal stone formation from these salts is enhanced.

D. Other Toxicities

Drowsiness and paresthesias are common following large doses of acetazolamide. Carbonic anhydrase inhibitors may accumulate in patients with renal failure, leading to nervous system toxicity.

Hypersensitivity reactions (fever, rashes, bone marrow suppression, and interstitial nephritis) may also occur.

Contraindications

Carbonic anhydrase inhibitor–induced alkalinization of the urine decreases urinary excretion of NH 4 + (by converting it to rapidly reabsorbed NH3 ) and may contribute to the development of hyperammonemia and hepatic encephalopathy in patients with cirrhosis.

LOOP DIURETICS

Loop diuretics selectively inhibit NaCl reabsorption in the ascending loop of henle (ALH). Because of the large NaCl absorptive capacity of this segment, loop diuretics are the most efficacious diuretic agents currently available.

Note: Loop diuretics have also been shown to induce expression of one of the cyclooxygenases (COX-2), which participates in the synthesis of prostaglandins from arachidonic acid. At least one of these prostaglandins, PGE 2 , inhibits salt transport in the ALH and thus participates in the renal actions of loop diuretics. NSAIDs , eg, indomethacin, which blunt cyclooxygenase activity, can interfere with the actions of loop diuretics by reducing prostaglandin synthesis in the kidney.

Pharmacokinetics

-The loop diuretics are rapidly absorbed. They are eliminated by the kidney by glomerular filtration and tubular secretion.

-Absorption of oral torsemide is more rapid (1 hour) than that of furosemide (2–3 hours).

- The duration of effect for torsemide lasts 4–6 hours. The duration of effect for furosemide is usually 2–3 hours.

-Half-lifedepends on renal function.

-Metabolites of ethacrynic acid and furosemide have been identified, but it is not known if they

have any diuretic activity. Torsemide has at least one active metabolite. with a half-life considerably longer than that of the parent compound.

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Clinical Indications

1-Acute pulmonary edema and other edematous cases.

3- Acute hypercalcemia: Ca 2+ excretion can be usefully enhanced by treatment with loop diuretics combined with saline infusions.

4- Hyperkalemia: loop diuretics can significantly enhance urinary excretion of K +. This response is enhanced by simultaneous NaCl and water administration &/0r saline infusions .

5- Acute Renal Failure: Loop agents can increase the rate of urine flow and enhance K + excretion in acute renal failure thus help flush out intratubular casts and ameliorate intratubular obstruction.

6- Anion Overdose: Loop diuretics are useful in treating toxic ingestions of bromide,

fluoride, and iodide

Toxicity

A. Hypokalemic Metabolic Alkalosis

By inhibiting salt reabsorption in the ALH, loop diuretics increase Na + delivery to the collecting duct. Increased delivery leads to increased secretion of K + and H + by the duct, causing hypokalemic metabolic alkalosis. This toxicity is a function of the magnitude of the diuresis and can be reversed by K + replacement

and correction of hypovolemia.

B. Ototoxicity

Loop diuretics occasionally cause dose-related hearing loss that is usually reversible. It is most common in patients who have diminished renal function or who are also receiving other ototoxic agents such as aminoglycoside antibiotics.

C. Hyperuricemia

Loop diuretics can cause hyperuricemia and precipitate attacks of gout. This is caused by hypovolemia-associated enhancement of uric acid reabsorption in the proximal tubule. It may be prevented by using lower doses to avoid development of hypovolemia.

D. Hypomagnesemia

Magnesium depletion is a predictable consequence of the chronic use of loop agents and occurs most often in patients with dietary magnesium deficiency. It can be reversed by administration of oral magnesium preparations.

(6)E. Allergic and Other Reactions

All loop diuretics, with the exception of ethacrynic acid, are sulfonamides. Therefore, skin rash, eosinophilia, and less often, interstitial nephritis are occasional adverse effects of these drugs. This toxicity usually resolves rapidly after drug withdrawal.

Contraindications

Furosemide, bumetanide, and torsemide may exhibit allergic cross-reactivity in patients who are sensitive to other sulfonamides,but this appears to be very rare. Overzealous use of any diuretic is dangerous in hepatic cirrhosis, borderline renal failure, or heart failure.

THIAZIDES (hydrochlorothiazide, Chlorothiazide, Chlorthalidone, indapamide, metolazone)

thiazides inhibit NaCl (by blocking the Na + /Cl – transporter) and their action is predominantly in the DCT with small effect on the proximal tubule. The prototypical thiazide is hydrochlorothiazide (HCTZ).

Pharmacokinetics

-All thiazides can be administered orally.

- Chlorothiazide, the parent of the group, is not very lipid-soluble and must be given in relatively large doses. It is the only thiazide available for parenteral administration.

-HCTZ is considerably more potent and should be used in much lower doses.

- Chlorthalidone is slowly absorbed and has a longer duration of action.

- All thiazides are secreted in the proximal tubule and compete with the secretion of uric acid, As a result, thiazide use may blunt uric acid secretion and elevate serum uric acid level.

Note;

thiazides actually enhance Ca 2+ reabsorption. This enhancement has been postulated to result from effects in both at the proximal and distal convoluted tubules. In the proximal tubule, thiazide-induced volume depletion leads to enhanced Na + and passive Ca 2+ reabsorption. In the DCT, lowering of intracellular Na + by thiazide-induced blockade of Na + entry enhances Na + /Ca 2+ exchange in the basolateral membrane (near the interstitial ) and thus increases overall reabsorption of Ca 2+ .

Clinical Indications

The major indications for thiazide diuretics are

1- hypertension

(7)2- heart failure

3- nephrolithiasis due to idiopathic hypercalciuria: Approximately two thirds of kidney stones contain Ca 2+ phosphate or Ca 2+ oxalate. This can be treated with thiazide diuretics, which enhance Ca 2+ reabsorption in the DCT and thus reduce the urinary Ca 2+ concentration.

4- nephrogenic diabetes insipidus.

Diabetes insipidus is due to either deficient production of ADH or inadequate responsiveness to ADH. Thiazide diuretics can reduce polyuria and polydipsia in both types of diabetes insipidus.

Toxicity

A. Hypokalemic Metabolic Alkalosis and Hyperuricemia: These toxicities are similar to those observed with loop diuretics(

B. Impaired Carbohydrate Tolerance

Hyperglycemia may occur in patients who are overtly diabetic or who have even mildly abnormal glucose tolerance tests. The effect is due to both impaired pancreatic release of insulin and diminished tissue utilization of glucose. Hyperglycemia may be partially reversible with correction of hypokalemia.

C. Hyperlipidemia

Thiazides cause a 5–15% increase in total serum cholesterol and low-density lipoproteins (LDLs). These levels may return toward baseline after prolonged use.

D. Hyponatremia

Hyponatremia is an important adverse effect of thiazide diuretics. It is caused by a combination of hypovolemia-induced elevation of ADH, reduction in the diluting capacity of the kidney, and increased thirst. It can be prevented by reducing the dose of the drug or limiting water intake.

E. Allergic Reactions

The thiazides are sulfonamides and share cross-reactivity with other members of this chemical group. Photosensitivity or generalized dermatitis occurs rarely. Serious allergic reactions are extremely rare but do include hemolytic anemia, thrombocytopenia, and acute necrotizing pancreatitis.

F. Other Toxicities

Weakness and fatigability may occur. Impotence has been reported but is probably related to volume depletion.

Contraindications

(8)Excessive use of any diuretic is dangerous in patients with hepatic cirrhosis, borderline renal failure, or heart failure .

POTASSIUM-SPARING DIURETICS

Potassium-sparing diuretics prevent K + secretion by antagonizing the effects of aldosterone in collecting tubules. Inhibition may occur by direct pharmacologic antagonism of mineralocorticoid receptors (spironolactone, eplerenone) or by inhibition of Na + influx through ion channels in the luminal membrane (amiloride(.

Note:

-Spironolactone is a synthetic steroid that acts as a competitive antagonist to aldosterone. Onset and duration of its action are determined by the kinetics of the aldosterone response in the target tissue. Substantial inactivation of spironolactone occurs in the liver

-Eplerenone is a spironolactone analog with much greater selectivity

for the mineralocorticoid receptor. It is several hundredfold less

active on androgen and progesterone receptors than spironolactone,

and therefore, eplerenone has considerably fewer adverse

effects.

Pharmacokinetics

- Substantial inactivation of spironolactone occurs in the liver

- Triamterene is metabolized in the liver, but renal excretion is a major route of elimination for

the active form and the metabolites. Because triamterene is extensively

metabolized, it has a shorter half-life and must be given more frequently than amiloride (which is not metabolized).

Clinical Indications

Potassium-sparing diuretics are most useful in states of mineralocorticoid excess or hyperaldosteronism due either to primary hypersecretion (Conn’s syndrome, ectopic adrenocorticotropic hormone production) or secondary hyperaldosteronism (evoked by heart failure, hepatic cirrhosis, nephritic syndrome or other conditions associated with diminished effective intravascular volume). Use of diuretics such as thiazides or loop agents can cause or exacerbate volume contraction and may cause secondary hyperaldosteronism.

Toxicity

(9)A. Hyperkalemia: can cause mild, moderate, or even life-threatening hyperkalemia. The risk of this complication is greatly increased by renal disease (in which maximal K + excretion may be reduced) or by the use of other drugs that reduce or inhibit renin (β blockers, NSAIDs, aliskiren) or angiotensin II activity (angiotensin-converting enzyme inhibitors, angiotensin receptor inhibitors). Since most other diuretic agents lead to K + losses, hyperkalemia is more common when K + -sparing diuretics are used as the sole diuretic agent, especially in patients with renal insufficiency. With fixed-dosage combinations of K + -sparing and thiazide diuretics, the thiazide-induced hypokalemia and metabolic alkalosis are ameliorated.

B. Hyperchloremic Metabolic Acidosis

By inhibiting H + secretion in parallel with K + secretion, the K + - sparing diuretics can cause acidosis.

C. Gynecomastia

Synthetic steroids may cause endocrine abnormalities by actions on other steroid receptors. Gynecomastia, impotence, and benign prostatic hyperplasia (very rare) all have been reported with spironolactone. Such effects have not been reported with eplerenone, presumably because it is much more selective than spironolactone for the mineralocorticoid receptor and virtually inactive on androgen or progesterone receptors.

D. Acute Renal Failure

The combination of triamterene with indomethacin has been reported to cause acute renal failure. This has not been reported with other K + -sparing diuretics.

E. Kidney Stones

Triamterene is only slightly soluble and may precipitate in the urine, causing kidney stones.

Contraindications

Potassium-sparing agents can cause severe, even fatal, hyperkalemia in susceptible patients. Patients with chronic renal insufficiency are especially vulnerable and should rarely be treated with these diuretics. Oral K + administration should be discontinued if K + -sparing diuretics are administered. Concomitant use of other agents that blunt the renin-angiotensin system (β blockers, ACE inhibitors, ARBs) increases the likelihood of hyperkalemia.Patients with liver disease may have impaired metabolism of triamterene and spironolactone, so dosing must be carefully adjusted.

Strong CYP3A4 inhibitors (eg, erythromycin, fluconazole, diltiazem, and grapefruit juice) can markedly increase blood levels of eplerenone, but not spironolactone.

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CARBONIC ANHYDRASE INHIBITORS DOSES

LOOP DIURETICS DOSES

(11)THAIAZIDE DOSES

(12)K+-SPARING DIURETIC DOSES

Pharmacology-II Lec:1