Clinical Pharmacology of Clinical Pharmacology of Drugs for Controlling Drugs for Controlling

Vascular Tone.Vascular Tone. ANTIHYPERTENSIVEANTIHYPERTENSIVE

DRUGSDRUGS

ANTIHYPERTENSIVE DRUGSANTIHYPERTENSIVE DRUGS

I. DIURETICSI. DIURETICSBumetanide, furosemide, hydrochlorthiazide, spironolactone, triamtereneBumetanide, furosemide, hydrochlorthiazide, spironolactone, triamterene II. II. -BLOCKERS-BLOCKERSAtenolol, labetalol, metoprolol, propranolol, timololAtenolol, labetalol, metoprolol, propranolol, timololIII. ACE INHIBITORSIII. ACE INHIBITORSCaptopril, benazepril, enalapril, fosinopril, lisinopril, moexipril, quinapril, Captopril, benazepril, enalapril, fosinopril, lisinopril, moexipril, quinapril, ramiprilramiprilIV. ANGIOTENSIN II ANTAGONISTIV. ANGIOTENSIN II ANTAGONISTLosartanLosartanV. Ca++CHANNEL BLOCKERSV. Ca++CHANNEL BLOCKERSAmlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, Amlodipine, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nisoldipine, verapamilnisoldipine, verapamilVI. VI. -BLOCKERS-BLOCKERSDoxazosin, prazosin, terazosinDoxazosin, prazosin, terazosinVII. OTHERVII. OTHERClonidine, diazoxide, hydralazine, Clonidine, diazoxide, hydralazine, -methyldopa, minoxidil, sodium -methyldopa, minoxidil, sodium nitroprussidenitroprusside

TREATMENT STRATEGIESTREATMENT STRATEGIESMild hypertension can often be controlled with a Mild hypertension can often be controlled with a single drug. More severe hypertension may single drug. More severe hypertension may require treatment with several drugs that are require treatment with several drugs that are selected to minimize adverse effects of the selected to minimize adverse effects of the combined regimen. Treatment is initiated with combined regimen. Treatment is initiated with any of four drugs depending on the individual any of four drugs depending on the individual patient: a diuretic, a patient: a diuretic, a -blocker, an ACE inhibitor, -blocker, an ACE inhibitor, or a calcium channel blocker. If blood pressure or a calcium channel blocker. If blood pressure is inadequately controlled, a second drug is is inadequately controlled, a second drug is added. A added. A -blocker is usually added if the initial -blocker is usually added if the initial drug was a diuretic, or a diuretic is added if the drug was a diuretic, or a diuretic is added if the first drug was a first drug was a -blocker. A vasodilator can be -blocker. A vasodilator can be added as a third step for those patients who still added as a third step for those patients who still fail to respond. fail to respond.

Treatment of arterial hypertensionTreatment of arterial hypertensionDrugs of first rowDrugs of first row--diureticsdiuretics ( (furosemid, dichlothiazide, spironolactonfurosemid, dichlothiazide, spironolacton) ) --inhibitors of ACEinhibitors of ACE ( (captopril, enalapril, ramiprilcaptopril, enalapril, ramipril))--antagonists of angiotesine II receptorsantagonists of angiotesine II receptors (А (АRRА ІІ) А ІІ) (losartan)(losartan)-β--β-adrenoblockersadrenoblockers ( (anaprilinanaprilin, , atenololatenolol, , thymololthymolol) ) -α-, β--α-, β-adrenoblockersadrenoblockers ( (labetolol, carvedilollabetolol, carvedilol))--Ca ions antagonistsCa ions antagonists ( (niphedipine, amlodipine, verapamilniphedipine, amlodipine, verapamil))Drugs of second rowDrugs of second row : :-α--α-adrenoblockersadrenoblockers ( (prasosine, terasosineprasosine, terasosine))--agonists of agonists of αα22 – –adrenoreceptors of central actionadrenoreceptors of central action ( (clophelineclopheline, ,

methyldopamethyldopa))--sympatholytics sympatholytics ((reserpin, octadinreserpin, octadin))--direct vasodilatorsdirect vasodilators ( (molsidominmolsidomin, , hydralasinhydralasin))New drugsNew drugs::--imidasolinesimidasolines ( (moxonidine, rilmenidinemoxonidine, rilmenidine))--serotonin receptors blockersserotonin receptors blockers ( (ketanserinketanserin) ) --monaterilmonateril ( (calcium antagonistcalcium antagonist, α, α22 - -adrenoblockeradrenoblocker))

Treatment of arterial hypertensionTreatment of arterial hypertensionDrugs of first rowDrugs of first row--diureticsdiuretics ( (furosemid, dichlothiazide, spironolactonfurosemid, dichlothiazide, spironolacton) ) --inhibitors of ACEinhibitors of ACE ( (captopril, enalapril, ramiprilcaptopril, enalapril, ramipril))--antagonists of angiotesine II receptorsantagonists of angiotesine II receptors (А (АRRА ІІ) А ІІ) (losartan)(losartan)-β--β-adrenoblockersadrenoblockers ( (anaprilinanaprilin, , atenololatenolol, , thymololthymolol) ) -α-, β--α-, β-adrenoblockersadrenoblockers ( (labetolol, carvedilollabetolol, carvedilol))--Ca ions antagonistsCa ions antagonists ( (niphedipine, amlodipine, verapamilniphedipine, amlodipine, verapamil))Drugs of second rowDrugs of second row : :-α--α-adrenoblockersadrenoblockers ( (prasosine, terasosineprasosine, terasosine))--agonists of agonists of αα22 – –adrenoreceptors of central actionadrenoreceptors of central action ( (clophelineclopheline, ,

methyldopamethyldopa))--sympatholytics sympatholytics ((reserpin, octadinreserpin, octadin))--direct vasodilatorsdirect vasodilators ( (molsidominmolsidomin, , hydralasinhydralasin))New drugsNew drugs::--imidasolinesimidasolines ( (moxonidine, rilmenidinemoxonidine, rilmenidine))--serotonin receptors blockersserotonin receptors blockers ( (ketanserinketanserin) ) --monaterilmonateril ( (calcium antagonistcalcium antagonist, α, α22 - -adrenoblockeradrenoblocker))

Mechanism of action of thiaside diureticsin case of arterial hypertension

Dychlothiaside(hypothiaside)

Oxodolin (chlortalidon, hygroton)

Thiaside diuretics

Holding sodium and water

Volume of circulating blood

Cardiac output Peripheral vascular

resistance

Decreasing of arterial pressure

Hydrochlorothiazide+LosartanHydrochlorothiazide+Losartan

Thiazide diuretics. Thiazide diuretics. Adverse effectsAdverse effects::

Thiazide diuretics induce hypokalemia and Thiazide diuretics induce hypokalemia and hyperuricemia in 70 % of patients, and hyperglycemia in hyperuricemia in 70 % of patients, and hyperglycemia in 10 % of patients. Serum potassium levels should be 10 % of patients. Serum potassium levels should be monitored closely on patients who are predisposed to monitored closely on patients who are predisposed to cardiac arrhythmias (with left ventricular hypertrophy, cardiac arrhythmias (with left ventricular hypertrophy, ischemic heart disease, or chronic congestive heart ischemic heart disease, or chronic congestive heart failure) (to prevent development of fatigue, cramps, and failure) (to prevent development of fatigue, cramps, and arrhythmias) and who are concurrently being treated with arrhythmias) and who are concurrently being treated with both thiazide diuretics and digitalis glycosides. Diuretics both thiazide diuretics and digitalis glycosides. Diuretics should be avoided in the treatment of hypertensive should be avoided in the treatment of hypertensive diabetics or patients with hyperlipidemiadiabetics or patients with hyperlipidemia

Loop diureticsLoop diuretics

The The loop diureticsloop diuretics act promptly, even in act promptly, even in patients who have poor renal function or patients who have poor renal function or who have not responded to thiazides or who have not responded to thiazides or other diuretics.other diuretics.

Mechanism of action of beta-adrenoblockers(anaprilin, atenolol, methoprolol etc.)

in case of arterial hypertension

β-adrenoblockers

activation of β1-adrenoreceptors

of heart

Cardiac output

Angiotensine ΙΙ Renin

Aldosterone

Holding sodium and water

Peripheral resist- ance of vessels

Volume ofbloodcirculation

Decreasing of blood pressure

-blockers. Therapeutic uses-blockers. Therapeutic uses

The The -blockers are more effective for -blockers are more effective for treating hypertension in white young treating hypertension in white young patients. They are useful in treating patients. They are useful in treating conditions that may coexist with conditions that may coexist with hypertension, such as hypertension, such as supraventricular tachyarrhythmia, supraventricular tachyarrhythmia, previous myocardial infarction, previous myocardial infarction, angina pectoris, angina pectoris, glaucoma, and glaucoma, and migraine headache.migraine headache.

ββ-adrenoblockers-adrenoblockers

Used for mostly mild to moderate cases of AH Used for mostly mild to moderate cases of AH (frequently in combinations with other drugs)(frequently in combinations with other drugs)Stable hypotensive response develops over Stable hypotensive response develops over 1-3 weeks1-3 weeksTitration the effective dose. Titration the effective dose. The The -blockers may -blockers may take several weeks to develop their full effectstake several weeks to develop their full effects

Antihypertensive action is maintained over Antihypertensive action is maintained over 24 hr after single daily dose24 hr after single daily dose

ContraindicationsContraindications: bronchial asthma, : bronchial asthma, peripheral vascular disease, diabetesperipheral vascular disease, diabetes

ACE-INHIBITORSACE-INHIBITORS

The angiotensin-converting enzyme (ACE) The angiotensin-converting enzyme (ACE) inhibitors (inhibitors (captopril, enalapril, lisinopril, captopril, enalapril, lisinopril, perindopril) perindopril) are recommended when the are recommended when the preferred first-line agents (diuretics or preferred first-line agents (diuretics or --blockers) are contraindicated or blockers) are contraindicated or ineffective.ineffective.

MECHANISM OF ACTION OF IACE

Decrease of arterial pressure

sympathetic tone

peripheral vessels tone

retention of Na+ and H2O

bradicinine

ANGIOTENSINOGEN

ANGIOTENSIN

(inactive)

IACE

Decrease angiotensine II

production

Decrease aldosteroneproduction

-

ACE

Renin (kidneys)

Therapeutic usesTherapeutic uses

Like Like -blockers, ACE inhibitors are most -blockers, ACE inhibitors are most effective effective in hypertensive patientsin hypertensive patients who are who are white and youngwhite and young. . However, when used in combination with a However, when used in combination with a diuretic, the effectiveness of ACE inhibitors is diuretic, the effectiveness of ACE inhibitors is similar in white and black hypertensive patients. similar in white and black hypertensive patients. ACE inhibitors are effective ACE inhibitors are effective in the management in the management of patients with chronic congestive heart of patients with chronic congestive heart failurefailure. . ACE inhibitors are now a standard in the care of ACE inhibitors are now a standard in the care of a patient following a patient following a myocardial infarctiona myocardial infarction. . Therapy is started 24 hours after the end of the Therapy is started 24 hours after the end of the infarction. infarction.

ACE inhibitors ACE inhibitors adverse effectsadverse effects Common side effects include Common side effects include

dry cough, rashes, fever, altered taste, dry cough, rashes, fever, altered taste, hypotension, and hyperkalemia. hypotension, and hyperkalemia. Potassium levels must be monitored, and Potassium levels must be monitored, and potassium supplements or spironolactone are potassium supplements or spironolactone are contraindicated.contraindicated. Because of the risk of angioedema and first Because of the risk of angioedema and first dose syncope, ACE inhibitors are first dose syncope, ACE inhibitors are first administered in the physician’s office with close administered in the physician’s office with close observation. observation. Reversible renal failure can occur in patients Reversible renal failure can occur in patients with severe renal artery stenosis. with severe renal artery stenosis. ACE inhibitors are fetotoxic and ACE inhibitors are fetotoxic and should not be should not be used in pregnant women.used in pregnant women.

ANGIOTENSIN II ANTAGONISTSANGIOTENSIN II ANTAGONISTSLosartan (Cozaar®), Valsartan (Diovan®), Losartan (Cozaar®), Valsartan (Diovan®),

Irbesartan (Avapro®), Candesartan Irbesartan (Avapro®), Candesartan

(Atacand®).(Atacand®). The nanopeptide The nanopeptide losartanlosartan, a highly , a highly selective angiotensin II receptor blocker, selective angiotensin II receptor blocker, has recently been approved for has recently been approved for antihypertensive therapy. Its antihypertensive therapy. Its pharmacologic effects are similar to ACE pharmacologic effects are similar to ACE inhibitors in that it produces vasodilation inhibitors in that it produces vasodilation and blocks aldosterone secretion. Its and blocks aldosterone secretion. Its adverse effects is improved over the ACE adverse effects is improved over the ACE inhibitors, although it is inhibitors, although it is fetotoxicfetotoxic..

ANGIOTENSIN II ANTAGONISTSANGIOTENSIN II ANTAGONISTS

CALCIUM CHANNEL BLOCKERSCALCIUM CHANNEL BLOCKERS

– Calcium channel blockers are recommended when Calcium channel blockers are recommended when the preferred first-line agents are contraindicated or the preferred first-line agents are contraindicated or ineffective. ineffective.

– Calcium channel antagonists block the inward Calcium channel antagonists block the inward movement of calcium by binding to L-tipe calcium movement of calcium by binding to L-tipe calcium channels in the heart and in the smooth-muscle of the channels in the heart and in the smooth-muscle of the coronary and peripheral vasculature. This causes coronary and peripheral vasculature. This causes vascular smooth muscle to relax, dilating mainly vascular smooth muscle to relax, dilating mainly arterioles.arterioles.

– Calcium channel blockers have an intrinsic natriuretic Calcium channel blockers have an intrinsic natriuretic effecteffect ; therefore, they do not usually require the ; therefore, they do not usually require the addition of a diuretic. addition of a diuretic.

ArterialArterialhypertensionhypertension

VerapamilVerapamil DilthiasemDilthiasem NiphedipinNiphedipin FelodipinFelodipin AmlodipinAmlodipin

IschemicIschemicheart diseaseheart disease

DilthiasemDilthiasem NiphedipinNiphedipin AmlodipinAmlodipinVerapamilVerapamil

SupraventriculeSupraventricule

tachicardiatachicardia

VerapamilVerapamil DilthiasemDilthiasem

Possibility toPossibility tocombine withcombine withbeta-blockersbeta-blockers

DilthiasemDilthiasem

ДилтіаземДилтіазем

NiphedipinNiphedipin AmlodipinAmlodipin

recommended drug to use carefully

diseases DRUGS

FelodipinFelodipin

Calcium channels blockersCalcium channels blockersadministrationadministration

-ADRENERGIC BLOCKING AGENTS-ADRENERGIC BLOCKING AGENTS

Prazosin,Prazosin, doxazosin doxazosin andand terazosinterazosin produce a produce a competitive block of competitive block of 1 adrenoreceptors. They decrease 1 adrenoreceptors. They decrease peripheral vascular resistance and lower arterial blood peripheral vascular resistance and lower arterial blood pressure by causing the relaxation of both arterial and pressure by causing the relaxation of both arterial and venous smooth muscle. These drugs cause only minimal venous smooth muscle. These drugs cause only minimal changes in cardiac output, renal blood flow, and changes in cardiac output, renal blood flow, and glomerular filtration rate. Postural hypotension may glomerular filtration rate. Postural hypotension may occur in some individuals. Prazosin is used to treat occur in some individuals. Prazosin is used to treat mild to moderate hypertension and is prescribed in mild to moderate hypertension and is prescribed in combination with propranolol or a diuretic for additive combination with propranolol or a diuretic for additive effectseffects

PrasosinePrasosine((αα11 – –adrenoblockeradrenoblocker))

CENTRALLY-ACTING CENTRALLY-ACTING ADRENERGIC DRUGSADRENERGIC DRUGS

ClonidineClonidine – – 2-agonist – diminishes central adrenergic 2-agonist – diminishes central adrenergic outflow. Clonidine does not decrease renal blood flow or outflow. Clonidine does not decrease renal blood flow or glomerular filtration and therefore glomerular filtration and therefore is useful in the is useful in the treatment of hypertension complicated by renal diseasetreatment of hypertension complicated by renal disease. . Because it causes sodium and water retention, clonidine Because it causes sodium and water retention, clonidine is usually administered in combination with diuretic. is usually administered in combination with diuretic.

CENTRALLY-ACTING CENTRALLY-ACTING ADRENERGIC DRUGSADRENERGIC DRUGS

Adverse effects are generally mild, but the Adverse effects are generally mild, but the drug can produce drug can produce sedationsedation and and drying of drying of nasal mucosanasal mucosa. . Rebound hypertensionRebound hypertension occurs following abrupt withdrawal of occurs following abrupt withdrawal of clonidine. The dug therefore should be clonidine. The dug therefore should be withdrawal slowly if the clinician wishes to withdrawal slowly if the clinician wishes to change agents. change agents.

CENTRALLY-ACTINGCENTRALLY-ACTING ADRENERGIC DRUGS ADRENERGIC DRUGS

-Methyldopa-Methyldopa. This . This 2-agonist is converted to 2-agonist is converted to methylnorepinephrine centrally to diminish the methylnorepinephrine centrally to diminish the adrenergic outflow from the CNS, leading to adrenergic outflow from the CNS, leading to reduced total peripheral resistance and a reduced total peripheral resistance and a decreased blood pressure. Because blood flow decreased blood pressure. Because blood flow to the kidney is not diminished by its use, to the kidney is not diminished by its use, --methyldopa methyldopa is especially valuable is especially valuable in treating in treating hypertensive patients with renal insufficiencyhypertensive patients with renal insufficiency. . The most common side effects of The most common side effects of -methyldopa -methyldopa are are sedationsedation and and drowsinessdrowsiness..

VASODILATORSVASODILATORS

The direct-acting smooth muscle relaxants, such The direct-acting smooth muscle relaxants, such as as hydralazinehydralazine and and minoxidilminoxidil, have traditionally , have traditionally not been used as primary drugs to treat not been used as primary drugs to treat hypertension. They act by producing relaxation hypertension. They act by producing relaxation of vascular smooth muscle, which decreases of vascular smooth muscle, which decreases resistance and therefore decreases blood resistance and therefore decreases blood pressure. These agents produce reflex pressure. These agents produce reflex stimulation of the heart. They may prompt stimulation of the heart. They may prompt angina pectoris, myocardial infarction, or cardiac angina pectoris, myocardial infarction, or cardiac failure in predisposed individuals. failure in predisposed individuals.

VASODILATORSVASODILATORS

Mechanisms of Action of Vasodilators.

Mechanism Examples

Release of nitric oxide from drug or endothelium Nitroprusside, hydralazine, nitrates, histamine, acetylcholine

Reduction of calcium influx Verapamil, diltiazem, nifedipine

Hyperpolarization of smooth muscle membrane through opening of potassium channels

Minoxidil, diazoxide

Activation of dopamine receptors Fenoldopam

PRINCIPLES OF THERAPYPRINCIPLES OF THERAPY

Therapeutic RegimensTherapeutic Regimens

Once the diagnosis of hypertension is established, a Once the diagnosis of hypertension is established, a therapeutic regimen must be designed and therapeutic regimen must be designed and implemented. The goal of management for most implemented. The goal of management for most clients is to achieve and maintain normal blood clients is to achieve and maintain normal blood pressure range (below 140/90 mm Hg). If this goal pressure range (below 140/90 mm Hg). If this goal cannot be achieved, lowering blood pressure to any cannot be achieved, lowering blood pressure to any extent is still considered beneficial in decreasing the extent is still considered beneficial in decreasing the incidence of coronary artery disease and stroke.incidence of coronary artery disease and stroke.

PRINCIPLES OF THERAPYPRINCIPLES OF THERAPY(cont’d)(cont’d)

If the initial drug (and dose) does not produce the If the initial drug (and dose) does not produce the desired blood pressure, options for further management desired blood pressure, options for further management include increasing the drug dose, substituting another include increasing the drug dose, substituting another drug, or adding a second drug from a different group. If drug, or adding a second drug from a different group. If the response is still inadequate, a second or third drug the response is still inadequate, a second or third drug may be added, including a diuretic if not previously may be added, including a diuretic if not previously prescribed. When current management is ineffective, prescribed. When current management is ineffective, reassess the client’s compliance with lifestyle reassess the client’s compliance with lifestyle modifications and drug therapy. In addition, review other modifications and drug therapy. In addition, review other factors that may decrease the therapeutic response,such factors that may decrease the therapeutic response,such as over-the-counter appetite suppressants, dietary or as over-the-counter appetite suppressants, dietary or herbal supplements, or nasal decongestants, which herbal supplements, or nasal decongestants, which raise blood pressure.raise blood pressure.

HYPERTENSIVE EMERGENCYHYPERTENSIVE EMERGENCY

– – is a life-threatening situation in which the is a life-threatening situation in which the diastolic blood pressure is either over 150 diastolic blood pressure is either over 150 mm Hg (with systolic blood pressure mm Hg (with systolic blood pressure greater than 210 mm Hg) in an otherwise greater than 210 mm Hg) in an otherwise healthy person, or 130 mm Hg in an healthy person, or 130 mm Hg in an individual with preexisting complications, individual with preexisting complications, such as encephalopathy, cerebral such as encephalopathy, cerebral hemorrhage, left ventricular failure, or hemorrhage, left ventricular failure, or aortic stenosis. The therapeutic goal is to aortic stenosis. The therapeutic goal is to rapidly reduce blood pressure. rapidly reduce blood pressure.

MANAGEMENT OF HYPERTENSIVE EMERGENCY (intravenously)MANAGEMENT OF HYPERTENSIVE EMERGENCY (intravenously)

DrugDrug DoseDose OnsetOnset Side effectsSide effects

SodiumSodiumnitroprussidnitroprussid

0,5-10 0,5-10 mcg/kg/minmcg/kg/min ( (dropplydropply)) immediatelyimmediately nauseanausea,, vomiting vomiting,, fibrillation of fibrillation of muscles, sweatingmuscles, sweating

Nitroglyceri-Nitroglyceri-numnum

5-10 5-10 mcg/kg mcg/kg ((dropplydropply)) 2-52-5 min min tachicardiatachicardia,, flushing flushing, , headacheheadache,, vomitingvomiting,,

DiazoxidumDiazoxidum 50-100 50-100 mg mg ( (quicklyquickly))300 300 mg mg ( (during 10 minduring 10 min))

2-4 2-4 minmin nauseanausea,, vomiting vomiting,,,, hypotension, hypotension, tachicardiatachicardia,, flushing flushing,, redness of skin, redness of skin, chest painchest pain

ApressinumApressinum 10-20 10-20 mgmg 10 10 minmin flushingflushing,, redness of skin, headache redness of skin, headache, , vomitingvomiting

FurosemidumFurosemidum 20-60-100 20-60-100 mg duringmg during 10-15 10-15 secsec 2-3 2-3 minmin hypotension,hypotension, fatiguefatigue

ClophelinumClophelinum 0,5-1 0,5-1 mlml 0,01 % 0,01 % solutionsolution ( (inin 15-20 15-20 ml ml 0,9 % 0,9 % solution solution NaCI slowlyNaCI slowly))

15-2015-20 min min somnolencesomnolence

AnaprilinumAnaprilinum 5 5 mlml 0,1 % 0,1 % solutionsolution ( (inin 20 20 mlml 0,9 % 0,9 % NaCI NaCI solution slowlysolution slowly) )

20-30 20-30 minmin bradicardiabradicardia

MagnesiumMagnesiumsulfassulfas

5-10-20 5-10-20 mlml 25 % 25 % solutionsolution ( (i. v. very i. v. very slowly or dropply)slowly or dropply)

15-20 15-20 minmin redness of skinredness of skin

LabetololumLabetololum 20-80 20-80 mgmg ( (slowly – 10 minslowly – 10 min) ) oror 2 2 mgmg//kgkg ((dropplydropply); ); the whole dosethe whole dose – 50-300 – 50-300 mgmg

5-10 5-10 minmin nauseanausea,, vomiting vomiting,,,, hypotension, hypotension, dizzenessdizzeness

REFERENCESREFERENCES

http://www.escardio.org

http://www.cardiosmart.org

http://www.medscape.com/cardiology