Antihypertensive drugs Antihypertensive drugs

FREQUENCY of arterial hypertension (AH) FREQUENCY of arterial hypertension (AH) AP > 140/90 mm Hg  % in population  At elderly people %

Increased Blood Pressure = Cardiac Output + Circulating Fluid Cardiac Output + Circulating Fluid Volume + Peripheral Vascular Resistance Preload Contractility Heart Rate Circulating Fluid Volume RenalSodiumHandling SympatheticNervousSystem Renin Angiotensin AngiotensinAldosteroneSystem Arteriolar Venous Vasoconstriction Venous Vascular Smooth Muscle Vascular remodeling

V V Vasomotor center Afterload VolumeKidneys Preload Renin Ang II Aldosterone BP= CO x TPVR 1111 2222 1111 1111 Resistance arterioles Capacitance venules Total Peripheral Vascular Resistance (TPVR) Ang I Cardiac Output Heart 2222 TPVR VSMCsVascularSmoothMuscleCells

Factors which provoke AH

Treatment of arterial hypertension Drugs of first line -diuretics (furosemid, dichlothiazide, spironolacton) -inhibitors of ACE (captopril, enalapril, ramipril) -antagonists of angiotensine II receptors (АRА ІІ) (losartan) -β-adrenoblockers (anaprilin, atenolol, thymolol, nebivolol) -α-, β-adrenoblockers (labetolol, carvedilol) -Ca ions antagonists (niphedipine, amlodipine, verapamil) Drugs of second line : -α-adrenoblockers (prazosine, terazosine) - agonists of α 2 –adrenoreceptors of central action (clopheline, methyldopa) -sympatholytics (reserpin, octadin) -direct vasodilators (molsidomin, hydralasin) New drugs: -imidasolines (moxonidine, rilmenidine) -serotonin receptors blockers (ketanserin) -monateril (calcium antagonist, α 2 -adrenoblocker) Treatment of arterial hypertension Drugs of first line -diuretics (furosemid, dichlothiazide, spironolacton) -inhibitors of ACE (captopril, enalapril, ramipril) -antagonists of angiotensine II receptors (АRА ІІ) (losartan) -β-adrenoblockers (anaprilin, atenolol, thymolol, nebivolol) -α-, β-adrenoblockers (labetolol, carvedilol) -Ca ions antagonists (niphedipine, amlodipine, verapamil) Drugs of second line : -α-adrenoblockers (prazosine, terazosine) - agonists of α 2 –adrenoreceptors of central action (clopheline, methyldopa) -sympatholytics (reserpin, octadin) -direct vasodilators (molsidomin, hydralasin) New drugs: -imidasolines (moxonidine, rilmenidine) -serotonin receptors blockers (ketanserin) -monateril (calcium antagonist, α 2 -adrenoblocker)

DiureticsDiuretics

Diuretics Diuretics  Thiazides and thiazides-like diuretics  Aldosterone antagonists  Potassium sparing diuretics  Loop diuretics

Mechanism of action of thiazide diuretics in case of arterial hypertension Dychlothiazide (hypothiazide) Oxodolin (chlortalidon, hygroton) Thiazide diuretics Holding sodium and water Volume of circulating blood Cardiac output Peripheral vascular resistance Decreasing of arterial pressure

THIAZIDES and RELATED DIURETICS  Medium efficacy diuretics  Benzothiadiazines (chlorothiazide, hydrochlorothiazide, clopamide), related thiazide like (chlorthalidone, indapamide)  for long-term treatment of arterial hypertesion (oral administration)  Duration of action (6-12 hours for hydrochlorothiazide, hours for clopamide, hours for chlorthalidone)

Diuretics: Thiazides Diuretics: Thiazides Side Effects  At low doses thiazides are well tolerated  Hypokalemia  Lipid elevation  Glucose intolerance  Hyperuricemia  Hypercalcaemia  Very rarely: severe rash, thrombocytopenia and leucopenia. thrombocytopenia and leucopenia.

FUROSEMIDE  High ceiling (loop) diuretic  Properties : 1. diuretic action 1. diuretic action 2. dilation of peripheral venous 2. dilation of peripheral venous 3. decrease left ventricular filling pressure 3. decrease left ventricular filling pressure 4. potent anti-inflammatory effect (similar to indometacine and other NSAID) 4. potent anti-inflammatory effect (similar to indometacine and other NSAID)  Administration: hypertensive emergencies (i. v.), long-term treatment of arterial hypertension (orally)  Adverse reactions: dehydration, hypopotassiumaemia, hearing loss - deafness, hypocalcaemia

Furosemid (diuretic)

Triampur (triamteren + hydrochlorthiaside) diuretic

Spironolactone [ ALDACTON ] - Hyperaldosteronism - In severe heart failure (NYHA Class IV), improves survival and reduces hospitalization (RALES Study) - Hyperkalemia, Gynecomastia Spironolactone [ ALDACTON ] - Hyperaldosteronism - In severe heart failure (NYHA Class IV), improves survival and reduces hospitalization (RALES Study) - Hyperkalemia, Gynecomastia Aldosterone Antagonist Potassium-Sparing Diuretics

 Amiloride  Triamterene  Second line anti-hypertensive drugs  Used in combination, or for correction of hypokalemia

Beta-adrenoblockers

Mechanism of action of beta-adrenoblockers (anaprilin, atenolol, methoprolol etc.) in case of arterial hypertension β- adrenoblockers β 1 -adrenoreceptors of heart Cardiac output Angiotensine ΙΙ Renin Aldosterone Holding sodium and water Peripheral resist- ance of vessels Volume of blood circulation Decreasing of blood pressure NO production

V V Vasomotor center Afterload VolumeKidneys Preload Renin Ang II Aldosterone 1111 2222 1111 1111 Resistance arterioles Capacitance venules PVR Ang I Cardiac Output Heart 2222  - Blockers VSMCs ? ?

β-adrenoblockers  Used for mostly mild to moderate cases of AH (frequently in combinations with other drugs)  Stable hypotensive response develops over 1-3 weeks  Titration the effective dose  Antihypertensive action is maintained over 24 hrs. after single daily dose  Withdrawal syndrome if discontinue quickly

 Side Effects:  Bronchospasm  Bradicardia/heart block  Mask and prolong the symptoms of hypoglycemia  Abrupt withdrawal can precipitate MI  Cold extremities, Raynaud’s phenomenon, intermittent claudication  Decreased exercise tolerance; fatigue, depression and impotence  CNS: sleep disturbance, vivid dreams, nightmares  Effects of plasma lipids Beta Blockers Beta Blockers

Atenolol β - adrenoblocker

Anaprilin β 1 - β 2 adrenoblocker

Vasocardin 100 mg Methoprolol tartrate

Nadolol ( β 1, β 2 - adrenoblocker )

Tenoretic (atenolol + chlortalidon)

Nebilet (Nebivolol) Beta- adrenoblocker with excessive production of NO (nitric oxide) Beta- adrenoblocker with excessive production of NO (nitric oxide)

α, β – adrenoreceptors blockers (labetalol, carvedilol)  Labetalol is used for long-term treatment of AH and for emergencies (i. v. - hypertensive crisis, clonidine withdrawal, cheese reaction)  Carvedilol – produces vasodilatation, antioxidant/free radical scavenging properties, it is used for CHF

IACE (ANGIOTENSIN CONVERTING ENZYME INHIBITORS)

MECHANISM OF ACTION OF IACE Decrease of arterial pressure sympathetic tone peripheral vessels tone retention of Na+ and H 2 O bradicinine ANGIOTENSINOGEN ANGIOTENSIN (inactive) IACE Decrease angiotensine II production Decrease aldosterone production - ACE Renin (kidneys) NO

ACE Inhibitors ( … pril) ACE Inhibitors ( … pril) Captopril [CAPOTEN] Enalapril [VASOTEC] Lisinopril [PRINIVIL, ZESTRIL] Benazepril [LOTENSIN] Fosinopril [MONOPRIL] Quinapril [ACCUPRIL] Ramipril [ALTACE] Spirapril [RENOMAX] Moexipril [UNIVASC] Perindopril [ACEON] Trandolapril [MAVIK]

Captopril (IACE)

ACE Inhibitors side effects  Cough  Hypotension  Hyperkalemia  Angioedema  Renal Insufficiency  Fetal injury (2 nd & 3 rd trimesters)  “High-dose Captopril” Adverse effects ( Neutropenia, Impaired taste, Proteinuria )

KOZAAR (Losartan) АRА ІІ

ACE and Non-ACE Pathways of Angiotensin II Production Non-Renin Pathway Cathepsin G and Tonin Angiotensinogen Ang I Ang II Renin ACE Non-Renin Pathway Chymase

Angiotensin II Receptor Blockers (...sartans) Losartan [COZAAR] Valsartan [DIOVAN] Irbesartan [AVAPRO] Candesartan [ATACAND] Eprosartan [TEVETEN] Tasosartan [VERDIA] Telmisartan [MICARDIS]

Calcium Channel Blockers

Calcium Channel Blockers Mechanisms and Sites of Action Calcium Channel Blockers Mechanisms and Sites of Action Negative Inotropic and Chronotropic Effects Produce Vasorelaxation at Arterioles Reduced Peripheral Resistance Verap+Dilti>NifedNifed>Dilti+Verap Block transmembrane entry of calcium into arteriolar smooth muscle cells and cardiac myocytes thus inhibiting excitation- contraction L-type Ca ++ channels

Calcium Channel Blockers Calcium Channel Blockers  Dihydropyridines *  Amlodipine [NORVASC]  Felodipine  Isradipine  Nicardipine  Nimodipine [NIMOTOP]  Nifedipine [PROCARDIA, ADALAT] *  Phenylalkylamine Verapamil  Benzothiazepine Diltiazem * long-acting or slow-released formulations should be used formulations should be used for high blood pressure for high blood pressure

CALCIUM CHANNEL BLOCKERS (dihydropyridines – DHPs)  Short acting DHPs (nifedipine) can increase mortality as a result of reinfarction (long term controlled trials)  Retard forms of DHPs (Amlodipine) are used widely for AH  Do not contraindicated in asthma,  do not impair renal perfusion,  do not affect male sexual function  Can be used during pregnancy  Can be given to diabetics

Pharmacologic Effects of Calcium Channel Blockers EffectVerapamilDiltiazemDihydropyridines Peripheral Vasodilation↑↑↑↑ Heart Rate↓↓↓↑ Cardiac Contractility↓↓↓ 0 / ↓ SA / AV Nodal Conduction↓↓0 Coronary Blood Flow↑↑↑↑ Calcium Channel Blockers Calcium Channel Blockers

Side effects  Facial Flushing  Headaches  Non-pitting ankle edema  Constipation Calcium Channel Blockers

NIFEDIPINE (calcium channels blocker)

NORVASC (AMLODIPINE) (calcium channels blocker)

Diminished CNS Sympathetic Outflow Alpha-2 Agonist NE & EPI Pre-synaptic Neuron Alpha-2 Receptor Alpha-1 Receptor Beta Receptor Post-synapticEffector Activation of Pre-synaptic Alpha-2 Receptors Reduces NE & EPI Release at Synapse RostralVentrolateralMedulla Central  2 –Agonists

 Clonidine [CATAPRES]  Methyldopa [ALDOMET]  Old drugs:  Guanfacine  Guanabenz Central  2 –Agonists

CLOPHELINE  α 2 - adrenergic receptors agonist (in brainstem stimulates α 2 - adrenergic receptors and imidazoline receptors)  decreases vasomotor centers tone - reduces sympathetic tone - fall in AP  Increases tone of n. vagi - bradycardia  Has analgesic activity  For hypertensive emergencies (i. v. dropply or very slowly)  Side effects and complications: postural hypotension, sedation, mental depression, sleep disturbance, dry mouth, constipation, withdrawal syndrome

CLOPHELINE (decreases vasomotor centers tone)

CLOPHELINE proposed action via imidazoline receptors  Chemical structure of clonidine = imidazoline  Sites in brain and peripheral tissues that bind imidazolines but not catecholamines (i.e., sites are not alpha receptors)  Hypotensive responses to imidazolines may be mediated via imidazoline receptors in VL medulla Imidazoline receptor agonists: MOXONIDINE, RILMENIDINE N NH NH Cl Cl

 1 - Receptor Blockers Inhibition of Vasoconstriction Induced by Endogenous Catecholamines at Arterioles and Veins Reduced Peripheral Resistance and Reduced Preload

α 1 -adrenergic blockers (prazosin, terazosin, doxazosin)  Do not block presynaptic α 2 -adreno-receptors, so do not cause reflex cardiac stimulation (as compared to nonselective α-adrenoblocker - phentolamine)  Dilate resistance and capacitance vessels  Adverse effects: postural hypotension (“effect of first dose”), tolerance gradually develops with monotherapy

Prazosine (α 1 –adrenoblocker)

 Side effects:  First dose hypotension  Dizziness, lethargy, fatigue  Palpitation, syncope  Peripheral edema  ALLHAT study results:  Not to be used as first-line agents  1 - Receptor Blockers

 Hydralazine  Minoxidil *** Sodium Nitroprusside - i.v. dropply Diazoxide – i.v. by bolus Peripheral Vasodilators

SINEPRESS (dihydroergotoxine + reserpine + hydrochlorthiaside)

TRIRESIDE ( reserpine + hydralasine + hydrochlorothiaside)

CRISTEPIN (clopamide + dihydroergocristine + reserpine)

MANAGEMENT OF HYPERTENSIVE EMERGENCY (intravenously) DrugDoseOnsetSide effects Sodium nitroprussid 0,5-10 mcg/kg/min (dropply) immediately nausea, vomiting, fibrillation of muscles, sweating Nitroglyceri- num 5-10 mcg/kg (dropply)2-5 mintachycardia, flushing, headache, vomiting, Diazoxidum mg (quickly) 300 mg (during 10 min) 2-4 minnausea, vomiting,, hypotension, tachycardia, flushing, redness of skin, chest pain Apressinum mg10 minflushing, redness of skin, headache, vomiting Furosemidum mg during sec2-3 minhypotension, fatigue Clophelinum 0,5-1 ml 0,01 % solution (in ml 0,9 % solution NaCI slowly) min somnolence Anaprilinum 5 ml 0,1 % solution (in 20 ml 0,9 % NaCI solution slowly) min bradicardia Magnesium sulfas ml 25 % solution (i. v. very slowly or dropply) minredness of skin Labetololum mg (slowly – 10 min) or 2 mg/kg (dropply); the whole dose – mg 5-10 minnausea, vomiting,, hypotension, dizziness

SODIUM NITROPRUSSIDE (SNP) SNP NO guanylil cyclase cGMP Venules Arterioles VSMCs Mechanism of action Light chain of myosin dephosphorylation CN

SODIUM NITROPRUSSIDE (SNP)  Conversion to NO generates cyanide which, in the liver is converted to thiocyanate. Thiocyanates are eliminated by urine  Risk of toxicity  Doses >2  g/kg/min,  Prolonged administration >24-48h  Renal insufficiency  Tachycardia, “Coronary steal”  Hypoxemia  Increased velocity of ventricular ejection (in patients with aortic dissection) Side Effects

NO Venules Arterioles Mechanism of action INTRAVENOUS NITROGLYCERIN (NTG) NTG Lower concentrations Higher concentrations guanylil cyclase cGMP VSMCs Light chain of myosin dephosphorylation

Side Effects INTRAVENOUS NITROGLYCERIN (NTG) May not be the drug of choice in patients with  Increased intracranial pressure  Glaucoma  Severe anemia (methemoglobin)  Constrictive pericarditis  Pregnancy category C drug

AGENTS GIVEN BY INTERMITTENT IV INJECTION  Labetalol  Enalaprilat  Hydralazine  Diazoxide

DIAZOXIDE  Direct vasodilating agent; Activates K+ channels  Reduces TPVR; Reflex increase in HR (heart rate) and CO (cardiac output)  Onset of action 3-5 minutes, duration variable  Increases blood glucose levels  Rarely used as IV agent for treatment of HTN crisis [HYPERSTAT®; PROGLYCEM ®