Antihypertensive drugs

multisystemic disease: no particular treatment/agents

1) DIURETICS

-minimal compensatory mechanisms

-increase sodium and water excretion->decreasing BP

-sodium ions have to be removed cause high sodium level contributes to high calcium level ( vasoconstriction): low level of sodium=vasodilation= FIRST STEP OF HYPERTENSION TREATMENT ( less kitchen salt used while meals)

#THIAZIDES used in mild hypertension, are weaker, maximal hypertensive effect is achieved with doses lower than doses required for maximal diuretic effect.

-Can increase LDL fraction, cannot be prescribed for diabetics and hyperlipidemic patients!!!! Gout is also contradication

*HYDROCHLOROTHIAZIDE: blocks Na/Cl transporter in renal distal conv. tubule; reduces blood flow, used in mild hypertension and mild HF, edema; oral, duration 8-12 h, may cause hypokalemia, hyperglycemia, hyperuricemia, hyperlipidemia

#LOOP DIURETICS used in moderate and severe hypertension and in hypertensive emergencies

-gout is a contadication!!

-can be prescribed only for severe hypertension with other drugs (polytherapy)

-for HF, renal insufficiency, cirrhosis are very useful

*FUROSEMIDE: blocks Na/K/2Cl transporter in renal Henle's loop; greater efficiacy than thiazides; used in severe hypertension and HF, oral or parenteral, duration 2-3h, may cause hypokalemia, hypovolemia, ototoxicity

#POTASSIUM SPARING DIURETICS

*SPIRONOLACTONE : blocks aldosterone receptor (antagonist) in renal collecting tubule, inreases Na excretion, decreases K excretion ( increases reabsorption), used in aldosteronism, HF, hypertension

-prevents potassium vasting ( suitable in HF patients)

-contradicated in renal insufficient patients (may cause hyperkalemia)

*EPLERENONE : as spironolactone but less toxic ( thus more potent)

2)SYMPHATOPLEGICS= BLOCKERS OF RECEPTORS

-interfere with symphatetic (SANS) control of cardiovascular function: reduction of venous tone, HR, heart contractility and force, CO and TPR

-marked compensatory mechanisms ( salt and water retention, tachycardia (alpha1selective blockers), minimal in beta blockers)

a) alpha/beta receptor blockers

alpha blockers:

*PRAZOSIN: selectively blocks alpha1 rec., prevents symp. vasoconstriction, reduces peripheral vascular R, reduces prostatic smooth mm. muscle tone; used in hypertension and benign prostatic hyperplasia; oral, duration 6-8 h, may cause orthostatic hypotension

*DOXAZOSIN: similar to prazosin but longer action

*TERAZOSIN: similar to prazosin but longer action

beta blockers:

-decrease CO

-influence on kindney ( influence renin release)

-nonselective (propranolol) ale contradicated in COPD and asthma!!!

-contradicated in diabetes ( all beta blockers!) : reduce glucose tolerance

-selective beta blockers when long used can reduce mortality-> for hypertensive and HF patients

-use with diuretics is not recommended-> increases risk of developing diabetes

*PROPRANOLOL: prototype, nonselective beta blocker, reduces CO, possible secondary reduction ine renin release, prevents sympath. cardiac stimulation; used in hypertension and HF, oral or parenteral, duration 6-8 h ( xr forms available), may cause bronchospas in asthamtics, excessive cardiac depression, sexual dysfunction, sedation, sleep disturbances

*ATENOLOL: very widely used, beta1 selective, fewer adverse effects

*METOPROLOL: beta1 selective

*LABETALOL/CARVEDILOL: combined alpha1 and beta blockade , oral or parenteral, heart kidney and vessels influenced, used fory hypertensive emergencies or pheochromocytoma

*ESMOLOL: used only for hypertensive mergencies and hypertension during surgery, very short acting

*NEBIVOLOL: nonselective beta blcoker with additional vasodilating property; less side effects than other beta blockers; does not worsen glucose tolernace!!

b) postganglionic sympathetic nerve terminals blockers

-compensatory response is salt and water retention

*RESERPINE: blocks vesicular pump (VMAT) in adrenergic neurons and depletes transmitter stores; reduces all sympathetic effects especially cardiovascular, reduces BP, obsolete in hypertention( rarely) and Huntington disease; oral, duration 5 days; may cause sedation, severe psychiatric depression ( high doses), GI distorbances

*GUANETHIDINE: interferes with amine release and replaces norepi.in vesicles; effects like reserpine; applications as reserpine; may cause severe orthostatic hypotension, sexual dysfunction

*GUANADREL: blocks reuptake of norepi (NET) and depletes stores; oral, long duration, may cause severe orthostatic hypotension

c) ganglia blockers

-powerful BP lowering drugs

*HEXAMETHONIUM: obsolete prototype nicotinic ACh receptor blocker in ganglia, blocks all ANS transmission; has NO CLINICAL APPLICATIONS, can be used oral or parenteral , may cause orthostatic hypotension, costipation, blurred vision, sexual dysfunction

*TRIMETHAPAN: iv, rarely used short-acting ganglion blocker for hypertensive emergencies, controlled hypotension

*MECAMYLAMINE: oral ganglion blocker, several hours of duration, experimental use in smoking cssation

d) CNS sympathetic outflow blockers=centrally acting

-cause decrease in symp. outflow by activation of alpha2 receptors in the CNS

-enter CNS when given orally

-reduce BP by reducing CO, vascular R or both

-major compensatory mechanism is salt retention

-Clonidine therapy cannot be stopped suddenly ( causes rebound hypertension) or it can be controlled by reinstitution or administration of alpha blockers (ex.phentolamine)

*CLONIDINE: agonist at alpha2 receptors, in CNS this results in decreased SANS outflow; used in hypertension; used orally (2-3 days) or transdermal(1wk); may cause sedation, danger of severe rebound hypertension if suddenly stopped, dry mouth

*METHYLDOPA: prodrug converted to methylnorepinephrine in brain in CNS with result like clonidine; used in hypertension (in pregnancy); used orally with duration 12-24 h; may cause sedation (even in therapeutic doses), induces hemolytic antibodies (positive Coomb's test)

3) VASODILATORS

Oral: for chronic(long term) treatment: hydralazine, minoxidil

Parenterally: just for hypertensive emergencies: nitroprusside, fenoldopam, diazoxide

-for all vasodilators headaches and flushing are adverse effects

a) older oral vasodilators

*HYDRALAZINE: probably causes release of NO by endothelial cells, causes arteriolar dilation, used in severe hypertension also in HF ( in combination with isosorbide dinitrate); oral, duartion 6-8 h; may cause reflex tachycardia (contradicated in ischaemic heart disease), salt and water retention, sweating, headaches, lupus-like syndrome, very potent, weak bioavailability cause it is extensively metab.in the liver by rapid acetylators ( dep. on patient). In low acetylators may cause lupus-like syndromes, which is reversible by discontinuation of hydralazine.

*MINOXIDIL: prodrug; sulfate metabolite opens K+ channel causing arteriolar smooth mm. hyperpolarization and vasodilation; used in severe hypertension and male-pattern baldness(topically); used orally or topically with duration 6-8 h; may cause marked, more reflex tachycardia, salt( Na) and water retention, hirsutism, edema; must be used in polytherapy with loop diuretics!!!

b) calcium channel blockers

*VERAPAMIL, DILTIAZEM: acts mostly on myocardial cells (verapamil): decreased BP is a result of decreased CO, heart& vessels (diltiazem), prototype L-type calcium channel blockers ( nonselective), combines moderate vascular effect with strong cardiac effect; reduces cardiac rate and CO, reduces vascular R; diltiazem: used in hypertension, verapamil: angina, arrtyhmias; orally or parenteral, duartion 6-8 h; may cause excessive cardiac depression and constipation

#DIHYDROPYRIDINES: influencing mostly vascular smooth muscle, selective vasodilators ( amlodipine, clevidipine, nifedipin, nicardipin)

-side effects: headaches, flushing, edema

* NIFEDIPINE, AMLODIPINE: blocks vascular calcium channels more than cardiac calcium channels ( greater vasodilator than cardiodepressant effect); reduces vascular resistance; used in chronic hypertension and angina; cannot be used in hypertesive emrgencies ( have long half lifes) ; in sustained release tablets (xr)

*CLEVIDIPINE : given iv as emulsion; for hypertension during surgery

*NICARDIPINE: for hypertensive emergencies ( short, rapidly acting); first choice drug!

c) parenteral vasodilators: all cause powerful vasodilation, widely used in hypertensive emrgencies

*NITROPRUSSIDE : activates guanyl cyclase directly and indirectly ( one of the metabolite is NO that activates guanyl cyclase-> increased cAMP-> muscle relaxation) releases NO from drug molecule; very sensitive to light (must be 'fresh' when used; used in hypertensive emrgencies, cardiac decompensation; used parenterally only, duration: muntes, requires constant infusion; may cause excessive hypotension, prolong infusion may cause thiocyanate and cyanide toxicity( mainly the most toxic ones of its metabolites); cyanide- metab. acidosis, arrythimias, death; thiocyanate may accumulate is given for longer time: causing weakness, disorientation, psychosis, convulsions; also nitrate ions are formed that may cause methemoglobinemia= THIS DRUG IS REALLY TOXIC!

*DIAZOXIDE: nor frequently used; rapid onset of action ( duration 12 hours) ; K+ channel opener in smooth muscle, secretory cells; used in hypertensive emrgencies, hypoglycemia due to insulin-secreting tumours; used perenterally for hypertension, orally for insulinoma; may cause hyperglycemia, edema, excessive hypotension, reflex tachycardia ( contrad. in IHD), water and Na retention, inhibits insulin release from pancreas

*FENOLDOPAM: D1 agonist, cause arteriolar dilation; used in hypertensive emrgencies; used parenterally only, very short duration; may cause excessive hypotension, contrad. in glaucoma cause in increase IOP!! side effects similar to other vasodilating agents

*LABETALOL: aplha1 beta blocker

4) ANGIOTENSIN ANTAGONISTS

a) ACE inhibitors

-inhibiting ACE ( decrease in BP)

-inhibition of bradykinin metabolism, so degradation. ( bradykinin: vasodilator ->NO and prostaglandin synthesis) (decrease in BP)

-useful in HF patients ( no influence of CO= no reflex tachycardia), chronic kidney disease ( stabilize renal hemodynamics), diabetis ( prevent diabetic nephropathy)

-long-termed use reduces mortality in post-infarct patients

-all given orally, become activated in the liver

-side effects: renail failure, hypotension, hyperkalemia ( in renal insufficient patients), increased concentr. of bradykinin= angioedema, dry cough

-pregnancy is contratication ( are teratogenic!!)

-end with PRIL so:

*CAPTOPRIL: ACE inhibitor, reduces angiotensin II synthesis, reduces aldosterone secretion, increases bradykinin; used in hypertension, diabetic renal disease, HF; used orally ( half life 2.2 h but larger doses provide duration of 12 h); may cause hyperkalemia, teratogen, cough

others acting like capropril but longer duration of time:

*BENAZEPRIL

*ENALAPRIL: metabolized to enalaprilat ( in liver), but this form is also available as a drug in ampulla for iv injection ( hypertensive emrgencies)

*LISINOPRIL

*PERINDOPRIL

b) receptor blockers (ARBS-angiotensin receptor blockers)

-efficacy similar to ACE inhibitors

-may cause angioedema

-pregnancy is contradication!! (teratogenic)

-cannot be used together with ACE inhibitors!!! ( similar effect)

*LOSARTAN: blocks AT1 angiotensin receptors; used in hypertension; used orally, duration 6-8h; mau cause hyperkalemia, teratogen

also

*CANDESARTAN

*IRBESARTAN

*VALSARTAN

6)RENIN INHIBITOR

*ALISKIREN: renin inhibitor, reduces angiotensin II synthesis; reduces angiotensin I and II and aldosterone; used in hypertension; used orally, duration 12 h; may cause angioedema, renal impairment; ase effective as other RAA influencing drugs; especially used for young and elderly patients in mono or polytherapy; contradicated in pregnancy!!

In US: diuretics are most commonly used

In Europe: beta blockers, ACE inhibitors

In pregnancy: methyldopa and beta blcokers can be used

Prescriptions

1) diuretic for essential (chronic) hypertension-> thiazide!

2) ACE inhibitor for hypertension

Rp. Captopril 25mg

tab.

Lag.orig.No 1

D.S. take one tablet

orally twice daily

3) Calcium channel blocker

Rp. Amlodipine 10mg

tab.

Lag.orig.No 1

D.S.take one tablet

orally once daily