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Clinical Pharmacology of Clinical Pharmacology of Drugs for Controlling Drugs for Controlling Vascular Tone. Vascular Tone. Clinical Pharmacology of Clinical Pharmacology of Cardiac Glycosides. Clinical Cardiac Glycosides. Clinical Pharmacology of Diuretics Pharmacology of Diuretics

Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

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Page 1: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

Clinical Pharmacology of Clinical Pharmacology of Drugs for Controlling Drugs for Controlling Vascular Tone. Vascular Tone.

Clinical Pharmacology of Clinical Pharmacology of Cardiac Glycosides. Clinical Cardiac Glycosides. Clinical Pharmacology of DiureticsPharmacology of Diuretics

Page 2: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

FREQUENCY FREQUENCY of arterial hypertension (AH)of arterial hypertension (AH)

AP > 140/90 mm Hg

20-30 % in population20-30 % in population At elderly people - 45-50 %At elderly people - 45-50 %

Page 3: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

Principles of treatment of arterial hypertension 1. Treatment should be started as soon as possible and should be hold till the end of

life. Canceling antihypertensive drugs administration causes relapse of AH.2. All the individuals with increased arterial pressure should obtain drugless treatment

(modifying lifestyle):-rejection from smoking and alcohol;-increasing of physical activity;-restriction of salt consumption (less than 6 g per day);-decreasing of body weight in a case of obesity.

3. Scheme of drug treatment should be the most availably simple – 1 tablet per day if possible; it is better to use drugs with long duration of action (prophylaxis of considerable fluctuation of blood pressure during the day).

4. Rapid decreasing of blood pressure to low figures is dangerous, especially for elderly patients.

5. Main aim of the treatment is to decrease blood pressure to 140/90 mm Hg. To improve life prognosis is the aim that has a more significant meaning than character of drugs used to reach this aim. It is better to prescribe cheap and “non modern” drugs than don’t treat the patient at all.

Page 4: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

Treatment of arterial hypertensionTreatment of arterial hypertension

Drugs 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--α-adrenoblockersadrenoblockers ( (prasosine, terasosineprasosine, terasosine))-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 : :--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 hypertension

Drugs 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--α-adrenoblockersadrenoblockers ( (prasosine, terasosineprasosine, terasosine))-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 : :--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))

Page 5: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

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

Page 6: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

FUROSEMIDEFUROSEMIDE

High ceiling (loop) diureticHigh ceiling (loop) diuretic Properties :Properties :

1. diuretic action1. diuretic action

2. dilation of peripheral venous2. dilation of peripheral venous

3. decrease left ventricular filling pressure3. decrease left ventricular filling pressure

4. potent anti-inflammatory effect (similar to 4. potent anti-inflammatory effect (similar to indometacine and other NSAID)indometacine and other NSAID) Administration:Administration: hypertensive emergencies, hypertensive emergencies, long-term treatment of arterial hypertension long-term treatment of arterial hypertension Adverse reactions: Adverse reactions: dehydration, dehydration, hypokalemia, hearing loss - deafness, hypokalemia, hearing loss - deafness, hypocalcaemia hypocalcaemia

Page 7: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

THIAZIDES and RELATED DIURETICSTHIAZIDES and RELATED DIURETICS

Medium efficacy diureticsMedium efficacy diuretics Benzothiadiazines (chlorothiazide, Benzothiadiazines (chlorothiazide,

hydrochlorothiazide, clopamide), related hydrochlorothiazide, clopamide), related thiazide like (chlorthalidone, indapamide)thiazide like (chlorthalidone, indapamide)

for long-term treatment of arterial hypertesion for long-term treatment of arterial hypertesion (oral administration)(oral administration)

Duration of action (6-12 hours for Duration of action (6-12 hours for hydrochlorothiazide, 12-18 hours for hydrochlorothiazide, 12-18 hours for clopamide, 48-50 hours for chlorthalidone)clopamide, 48-50 hours for chlorthalidone)

Adverse reactions: dehydration,Adverse reactions: dehydration, hypokalemia, hypokalemia, hyperuricaemia (rise of blood urate level)hyperuricaemia (rise of blood urate level)

Page 8: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

Furosemid Furosemid ((diureticdiuretic))

Page 9: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

Furosemid Furosemid ((diureticdiuretic))

Page 10: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

TriampurTriampur((triamterentriamteren + + hydrochlorthiasidehydrochlorthiaside))

diureticdiuretic

Page 11: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of 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 of blood circulation

Decreasing of blood pressure

Page 12: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

ββ-adrenoblockers-adrenoblockers

Used for mostly mild to moderate cases Used for mostly mild to moderate cases of AH (frequently in combinations with of AH (frequently in combinations with other drugs)other drugs)

Stable hypotensive response develops Stable hypotensive response develops over 1-3 weeksover 1-3 weeks

Titration the effective doseTitration the effective dose Antihypertensive action is maintained Antihypertensive action is maintained

over 24 hr after single daily doseover 24 hr after single daily dose Withdrawal syndrome if discontinue Withdrawal syndrome if discontinue

quickly quickly Contraindications: bronchial asthma, Contraindications: bronchial asthma,

peripheral vascular disease, diabetesperipheral vascular disease, diabetes

Page 13: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

Atenolol Atenolol β - β - adrenoblockeradrenoblocker

Page 14: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

AnaprilinAnaprilin ββ11- β - β 2 2 adrenoblockeradrenoblocker

Page 15: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

Vasocardin Vasocardin 100 100 mgmgMethoprolol tartrateMethoprolol tartrate

Page 16: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

NadololNadolol(( ββ11, β , β 22 - - adrenoblockeradrenoblocker ) )

Page 17: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

TenoreticTenoretic(atenolol + chlortalidon)(atenolol + chlortalidon)

Page 18: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

αα11-adrenergic blockers-adrenergic blockers

(prazosin, terazosin, doxazosin)(prazosin, terazosin, doxazosin)

Do not block presynaptic Do not block presynaptic αα22-adreno--adreno-receptors, so do not cause reflex cardiac receptors, so do not cause reflex cardiac stimulation (as compared to nonselective stimulation (as compared to nonselective αα-adrenoblockers)-adrenoblockers)

Dilate resistance and capacitance vesselsDilate resistance and capacitance vessels

Adverse effects: postural hypotension Adverse effects: postural hypotension (“effect of first dose”), tolerance (“effect of first dose”), tolerance gradually develops with monotherapy gradually develops with monotherapy

Page 19: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

Prasosine Prasosine (α(α11 – –adrenoblockeradrenoblocker))

Page 20: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

αα, , ββ – adrenoreceptors blockers – adrenoreceptors blockers(labetalol, carvedilol)(labetalol, carvedilol)

Labetalol is used for long-term Labetalol is used for long-term treatment of AH and for emergencies treatment of AH and for emergencies (i. v. - hypertensive crisis, clonidine (i. v. - hypertensive crisis, clonidine withdrawal, cheese reaction)withdrawal, cheese reaction)

Carvedilol – produces vasodilatation, Carvedilol – produces vasodilatation, antioxidant/free radical scavenging antioxidant/free radical scavenging properties, it is used for HD and for properties, it is used for HD and for CHFCHF

Page 21: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

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)

Page 22: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

IACE (ANGIOTENSIN CONVERTING IACE (ANGIOTENSIN CONVERTING ENZYME INHIBITORS)ENZYME INHIBITORS)

Captopril, enalapril, ramipril, perindopril etc.Captopril, enalapril, ramipril, perindopril etc. Decrease the levels of mortality and morbidityDecrease the levels of mortality and morbidity When used for monotherapy control AP in 50% of When used for monotherapy control AP in 50% of

patientspatients Frequently combined with diuretics (not with Frequently combined with diuretics (not with

potassium-sparing diuretics !) and potassium-sparing diuretics !) and ββ-adrenoblockers-adrenoblockers - the effectiveness of therapy grows to 90%- the effectiveness of therapy grows to 90%

Adverse effects: cause the retention of potassium Adverse effects: cause the retention of potassium ions, dry persistent cough (requires discontinuation ions, dry persistent cough (requires discontinuation of IACE or treatment with NSAID)of IACE or treatment with NSAID)

Contraindicated for the patients with bilateral renal Contraindicated for the patients with bilateral renal artery stenosis)artery stenosis)

Page 23: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

Captopril Captopril ((IACEIACE))

Page 24: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

KOZAAR KOZAAR ((LosartanLosartan)) ААRRА ІІА ІІ

Page 25: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

CALCIUM CHANNEL BLOCKERS CALCIUM CHANNEL BLOCKERS (dihydropyridines – DHPs)(dihydropyridines – DHPs)

Short acting DHPs (nifedipine) can increase Short acting DHPs (nifedipine) can increase mortality as a result of reinfarction (long term mortality as a result of reinfarction (long term controlled trials)controlled trials)

Retard forms of DHPs (Retard forms of DHPs (AmlodipineAmlodipine) are used ) are used widely for AHwidely for AH

Do not contraindicated in asthma, do not impair Do not contraindicated in asthma, do not impair renal perfusion, do not affect male sexual renal perfusion, do not affect male sexual functionfunction

Can be used during pregnancy Can be used during pregnancy Can be given to diabeticsCan be given to diabetics Adverse reactions: Adverse reactions: ankle edema, slight negative ankle edema, slight negative

inotropic / dromotropic action, nifedipine inotropic / dromotropic action, nifedipine decreases insulin release (diabetes accentuating) decreases insulin release (diabetes accentuating)

Page 26: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

NIFEDIPINENIFEDIPINE(calcium channels blocker)(calcium channels blocker)

Page 27: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

NIFEDIPINENIFEDIPINE(calcium channels blocker)(calcium channels blocker)

Page 28: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

NIFEDIPINENIFEDIPINE(calcium channels blocker)(calcium channels blocker)

Page 29: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

NIFEDIPINENIFEDIPINE(calcium channels blocker)(calcium channels blocker)

Page 30: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

NORVASC (AMLODIPINE)NORVASC (AMLODIPINE) (calcium channels blocker)(calcium channels blocker)

Page 31: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

Arterial Arterial hypertensionhypertension

VerapamilVerapamil DilthiasemDilthiasem NiphedipinNiphedipin FelodipinFelodipin AmlodipinAmlodipin

Ischemic Ischemic heart diseaseheart disease

DilthiasemDilthiasem NiphedipinNiphedipin AmlodipinAmlodipinVerapamilVerapamil

SupraventriculeSupraventricule

tachicardia tachicardia

VerapamilVerapamil DilthiasemDilthiasem

Possibility to Possibility to combine with combine with beta-blockersbeta-blockers

DilthiasemDilthiasem

ДилтіаземДилтіазем

NiphedipinNiphedipin AmlodipinAmlodipin

recommended drug to use carefully

diseases DRUGS

FelodipinFelodipin

Calcium channels blockers administrationCalcium channels blockers administration

Page 32: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

CLOPHELINECLOPHELINE αα22 -- adrenergic receptorsadrenergic receptors agonistagonist (in brainstem (in brainstem

stimulates stimulates αα22 -- adrenergic receptorsadrenergic receptors andand

imidazoline receptors)imidazoline receptors) decreases vasomotor centers tone - reduces decreases vasomotor centers tone - reduces

sympathetic tone - fall in APsympathetic tone - fall in AP Increases vagal tone - bradycardiaIncreases vagal tone - bradycardia Has analgesic activityHas analgesic activity For hypertensive emergencies (i. v. dropply or For hypertensive emergencies (i. v. dropply or

very slowly)very slowly) Side effects and complications: Side effects and complications: postural postural

hypotension, sedation, mental depression, hypotension, sedation, mental depression, sleep disturbance, dry mouth, constipation, sleep disturbance, dry mouth, constipation, withdrawal syndromewithdrawal syndrome

Page 33: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

CLOPHELINECLOPHELINE(decreases vasomotor centers tone)(decreases vasomotor centers tone)

Page 34: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

SINEPRESSSINEPRESS

((dihydroergotoxine dihydroergotoxine + + reserpinereserpine ++ hydrochlorthiaside hydrochlorthiaside))

Page 35: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

TRIRESIDETRIRESIDE((reserpine reserpine + + hydralasine hydralasine ++ hydrochlorothiaside hydrochlorothiaside))

Page 36: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

CRISTEPINCRISTEPIN((clopamide + dihydroergocristineclopamide + dihydroergocristine + reserpine + reserpine))

Page 37: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

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

Drug Dose Onset Side effects

Sodiumnitroprussid

0,5-10 mcg/kg/min (dropply) immediately

nausea, vomiting, fibrillation of muscles, sweating

Nitroglyceri-num

5-10 mcg/kg (dropply) 2-5 min tachicardia, flushing, headache, vomiting,

Diazoxidum 50-100 mg (quickly)300 mg (during 10 min)

2-4 min nausea, vomiting,, hypotension, tachicardia, flushing, redness of skin, chest pain

Apressinum 10-20 mg 10 min flushing, redness of skin, headache, vomiting

Furosemidum

20-60-100 mg during 10-15 sec 2-3 min hypotension, fatigue

Clophelinum 0,5-1 ml 0,01 % solution (in 15-20 ml 0,9 % solution NaCI slowly)

15-20 min somnolence

Anaprilinum 5 ml 0,1 % solution (in 20 ml 0,9 % NaCI solution slowly)

20-30 min bradicardia

Magnesiumsulfas

5-10-20 ml 25 % solution (i. v. very slowly or dropply)

15-20 min redness of skin

Labetololum 20-80 mg (slowly – 10 min) or 2 mg/kg (dropply); the whole dose – 50-300 mg

5-10 min nausea, vomiting,, hypotension, dizzeness

Page 38: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

Factors which promote Factors which promote development ofdevelopment of

INTOXICATION WITH HEART INTOXICATION WITH HEART GLYCOZIDESGLYCOZIDES

DECREASING OF TOLERANCE TOWARDS HGDECREASING OF TOLERANCE TOWARDS HG – – in case of in case of considerable damage of myocardium with pathological considerable damage of myocardium with pathological processprocess

((acute MI, myocarditis, chronic lung heartacute MI, myocarditis, chronic lung heart) ) ““Patients which need HG the most are the most sensitive Patients which need HG the most are the most sensitive of of

diureticsdiuretics ( (furosemis, dychlothiazide)furosemis, dychlothiazide), , GCSGCS, , glucose with glucose with to themto them””

HYPOPOTASSIUMEMIA, HYPOPOTASSIUMHISTIA OF HYPOPOTASSIUMEMIA, HYPOPOTASSIUMHISTIA OF MYOCARDIUM, HYPOMAGNESIUMEMIAMYOCARDIUM, HYPOMAGNESIUMEMIA

-- administration insuline, amphotericine Badministration insuline, amphotericine B- secondary hyperaldosteronism, vomiting, secondary hyperaldosteronism, vomiting,

diarrheadiarrhea HYPERCALCIUMEMIA, KIDNEY, LIVER INSUFFICIENCYHYPERCALCIUMEMIA, KIDNEY, LIVER INSUFFICIENCY

Page 39: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

Factors which promote developmentFactors which promote developmentINTOXICATION WITH HEART INTOXICATION WITH HEART

GLYCOZIDESGLYCOZIDES

DigitoxinDigitoxin is a choice drugis a choice drug when HI is when HI is combined with combined with kidney insufficiencykidney insufficiency, , but but contraindicated if liver is damagedcontraindicated if liver is damaged ( (it is it is metabolized by livermetabolized by liver))

Digoxin Digoxin is not contraindicated even in is not contraindicated even in case of case of liver cirrhosis liver cirrhosis (it is not (it is not metabolized in livermetabolized in liver), ), but but contraindicated in case of kidney contraindicated in case of kidney insufficiencyinsufficiency ( (it is excreted by kidneysit is excreted by kidneys) )

Page 40: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

Intoxication with heart Intoxication with heart glycozidesglycozidesCardiac symptomsCardiac symptoms

Worsening of contractive function of Worsening of contractive function of myocardiummyocardium, , increasing of circulation increasing of circulation insufficiencyinsufficiency –– relapserelapse of HIof HI (18(18--26 %)26 %)Disturbance of heart rhythmDisturbance of heart rhythm(90(90--95 %, 95 %, уу 65 % 65 % -- single symptom of single symptom of intoxicationintoxication))

-- tachyarrhythmiatachyarrhythmia ((increasing of automatismincreasing of automatism))-- blockadesblockades-- combined disorders of rhythmcombined disorders of rhythm

Page 41: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

Intoxication with heart glycosidesIntoxication with heart glycosides

ExtracardiacExtracardiac symptomssymptomsGastroGastro--intestinalintestinal (40(40--50 %)50 %)Neurological and psychicalNeurological and psychical(25 %)(25 %)Eye symptomsEye symptoms (65 %)(65 %)Worsening of kidneys functionWorsening of kidneys function

Page 42: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

Treatment of intoxication Treatment of intoxication with heart glycosideswith heart glycosides

Immediate quitting of HG introductionImmediate quitting of HG introduction Correction of hypopotassiumemiaCorrection of hypopotassiumemia (KCl, (KCl,

panangin)panangin) Introduction of unitiolIntroduction of unitiol (1 (1 mlml of of 5 % 5 % solutionsolution / /

kg of weight i.m. kg of weight i.m. 2-3-5 2-3-5 times per daytimes per day)) Clearing of GI tract (vaseline oil, Clearing of GI tract (vaseline oil,

cholestyramincholestyramin, , magnesium sulfatemagnesium sulfate)) Treatment of arrhythmiasTreatment of arrhythmias ( (anaprilin, anaprilin,

verapamil, difenin, lidokain, atropine)verapamil, difenin, lidokain, atropine) Na Na ЕЕDTADTA ( (trilontrilon B)B), , Na citrateNa citrate Calcitrin Calcitrin Antibodies towards digoxinAntibodies towards digoxin ( (Digibind)Digibind) Oxygen therapy Oxygen therapy

Page 43: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

NONGLYCOSIDE CARDITONIC NONGLYCOSIDE CARDITONIC DRUGSDRUGS

Xantins, derivatives of isoquinolineXantins, derivatives of isoquinoline ( (ethophilineethophiline)) Pyridines, and bipyridinesPyridines, and bipyridines ( (amrinon, milrinonamrinon, milrinon)) Derivatives of imidazoleDerivatives of imidazole ( (vardaxvardax)) Derivatives of piperidineDerivatives of piperidine ( (buquineran, buquineran,

carbazerancarbazeran)) Polypeptides Polypeptides ((glucagonglucagon)) Carboxyl antibioticsCarboxyl antibiotics ( (lasolacid, calcimycinlasolacid, calcimycin)) Derivatives of other chemical groupsDerivatives of other chemical groups: : LL--

carnitin, heptaminol, creatinol-o-phosphate, carnitin, heptaminol, creatinol-o-phosphate, trapidil, etc.trapidil, etc.

Page 44: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

NONGLYCOSIDE CARDIOTONIC NONGLYCOSIDE CARDIOTONIC DRUGSDRUGS

DobutaminDobutamin – – betabeta11--adrenomimeticadrenomimetic - - in case of in case of

acute and chronic heart insufficiency acute and chronic heart insufficiency – – intravenously dropping intravenously dropping – 2,5-5-10 – 2,5-5-10 mcgmcg/(/(kgkg..minmin); ); in case of constant infusion in case of constant infusion tolerance develops after tolerance develops after 3-4 3-4 daysdays; ; in case of in case of increasing of doseincreasing of dose – – heart arrhythmiasheart arrhythmias

Amrinon, milrinonAmrinon, milrinon – – inhibitors of inhibitors of phosphodiesterasephosphodiesterase – – for temporary for temporary improvement of patient’s condition in terminal improvement of patient’s condition in terminal stage of HIstage of HI

Page 45: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

INHIBITORS OF ANGIOTENSINE INHIBITORS OF ANGIOTENSINE TRASFORMING ENZYMETRASFORMING ENZYME ( (IATE)IATE)

Captopril, enalapril, ramipril, Captopril, enalapril, ramipril, lysinorpillysinorpil

In case of HI they brake pathological In case of HI they brake pathological consequences of activation of renin-consequences of activation of renin-

angiotesine system by inhibiting ATEangiotesine system by inhibiting ATE:: production of angiotensineproduction of angiotensine IIII decreases decreases

((vasoconstrictorvasoconstrictor, , inductor of aldosterone, inductor of aldosterone, norepinephrine, endothelin secretion, myocardium norepinephrine, endothelin secretion, myocardium hypertrophyhypertrophy))

Accumulation of bradikinAccumulation of bradikin ( (inductor of inductor of prostacycline and nitrogen oxide synthesisprostacycline and nitrogen oxide synthesis))

Page 46: Clinical Pharmacology of Drugs for Controlling Vascular Tone. Clinical Pharmacology of Cardiac Glycosides. Clinical Pharmacology of Diuretics

INHIBITORS OF ANGIOTESINE INHIBITORS OF ANGIOTESINE TRANSFORMING ENZYMETRANSFORMING ENZYME ( (IATEIATE))

Increase duration and improve Increase duration and improve quality of life of patients with quality of life of patients with HIHI

Increase tolerance towards Increase tolerance towards physical loadsphysical loads

Decrease risk of recurring MIDecrease risk of recurring MI Brake development of Brake development of

miocardium hypertrophy miocardium hypertrophy

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CAPTOPRILCAPTOPRIL ( (CAPOTENCAPOTEN)) Dose titrationDose titration: : fromfrom 6,25-12,5 6,25-12,5 mg per day mg per day

toto 12,5-50 12,5-50 mgmg 3 3 times a day until times a day until appearance of effectappearance of effect

Side effectsSide effects: : dry coughdry cough ( (can be decreased can be decreased by nonsteroid antiinflammatoryby nonsteroid antiinflammatory), ), considerable decreasing of APconsiderable decreasing of AP, , worsening worsening of kidneys’ functionof kidneys’ function, , hyperpotassiumemia, tachycardia, hyperpotassiumemia, tachycardia, neutropenia, aphtose stomatitisneutropenia, aphtose stomatitis

Contraindicated Contraindicated in case of bilateral in case of bilateral stenosis of kidney arteries, should not be stenosis of kidney arteries, should not be combined with potassium drugscombined with potassium drugs

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ANTAGONISTS OF ANTAGONISTS OF ANGIOTESINE II RECEPTOS ANGIOTESINE II RECEPTOS (А(АRRА А IIII))

LOSARTANLOSARTAN ( (cosaar)cosaar)Blocks receptors of angiotensineBlocks receptors of angiotensine IIII

Decreases mortality of patients with HIDecreases mortality of patients with HI

onon 50 % 50 %

Breaks development of myocardium Breaks development of myocardium hypertrophy hypertrophy

It is approved to combine IATE with It is approved to combine IATE with ААRRА А IIII

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DIURETICSDIURETICS

DichlotiazideDichlotiazide, , hyhrotonehyhrotone ( (oxodolineoxodoline), ), clopamideclopamide ( (brinaldixbrinaldix))

FurosemidFurosemid, , etacrine acidetacrine acid

Spironolacton Spironolacton

improve currency of the disease, improve currency of the disease, increase tolerance of patients towards increase tolerance of patients towards physical loadsphysical loads, ,

spironolacton decreases quantity of spironolacton decreases quantity of relapses and mortalityrelapses and mortality

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PERIPHERAL PERIPHERAL VASODILATORSVASODILATORS

ArterialArterial:: hydralasin, calcium ions hydralasin, calcium ions antagonists, minoxydilantagonists, minoxydil

VenousVenous:: nitrates, molsidominnitrates, molsidomin Of mixed actionOf mixed action ( (influence on tone of influence on tone of

arterioles and venulesarterioles and venules): ): sodium nitroprusidesodium nitropruside, , prasosine, inhibitors of ATE, ARA IIprasosine, inhibitors of ATE, ARA II

Isosorbide dinitrateIsosorbide dinitrate (30-160 (30-160 mgmg//dayday) + ) + hydralasinhydralasin (50-300 (50-300 mgmg//dayday) – ) – for patients for patients

which have contraindications towards which have contraindications towards administration of IATEadministration of IATE

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PERIPHERAL PERIPHERAL VASODILATORSVASODILATORS

Unfavorable action in case of Unfavorable action in case of HIHI::

They activate sympatic-adrenalsystem They activate sympatic-adrenalsystem and intermediately renin-aldosterone and intermediately renin-aldosterone

system system

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BETA-ADRENOBLOCKERSBETA-ADRENOBLOCKERS

Carvedilol, methoprolol, bisoprololCarvedilol, methoprolol, bisoprolol They decrease mortality, improve disease currency They decrease mortality, improve disease currency

and quality of patients’ lives in case of stagnant HIand quality of patients’ lives in case of stagnant HI

Mechanism of treatment action in case of HIMechanism of treatment action in case of HI Renewing of quantity and sensitivity of beta-Renewing of quantity and sensitivity of beta-

adrenoreceptors in heart, which leads to increasing adrenoreceptors in heart, which leads to increasing of systolic volume after of systolic volume after 8-10 8-10 weeks of regular weeks of regular administration administration ((paradox of beta-adrenoblockadeparadox of beta-adrenoblockade))

Prevent calcium overload of myocardium, improve Prevent calcium overload of myocardium, improve coronary blood circulationcoronary blood circulation

Decrease production of reninDecrease production of renin Prevent arrhythmias Prevent arrhythmias Carvedilol Carvedilol – – alphaalpha11--adrenoblocking and antioxidant adrenoblocking and antioxidant

actionaction

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BETABETA--ADRENOBLOCKERSADRENOBLOCKERSScheme of administration of beta-Scheme of administration of beta-

adrenoblockers in case of HIadrenoblockers in case of HI The treatment is started from a small doseThe treatment is started from a small dose

(3,175-6,25 (3,175-6,25 carvedilolcarvedilol), ), everyevery 2-4 2-4 weeks it is doubled weeks it is doubled until obtaining the effectuntil obtaining the effect ( (usually develops afterusually develops after 2-3 2-3 monthsmonths))..

Average effective dosesAverage effective doses: :

carvedilolcarvedilol – 50 – 50 mgmg

metoprolol metoprolol – 100 – 100 mgmg

bisoprololbisoprolol – 5 – 5 mgmg

Administration of beta-blockers is possible only in Administration of beta-blockers is possible only in case of constant condition of the patientcase of constant condition of the patient, , before before development of stabile improvement of condition development of stabile improvement of condition temporary worsening may developtemporary worsening may develop

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DRUGS OF METABOLIC ACTIONDRUGS OF METABOLIC ACTION

VitaminsVitamins: Е, С, В: Е, С, В group group Ryboxin Ryboxin Mildronate Mildronate PhosphadenPhosphaden, , ATPATP Creatinphosphate Creatinphosphate Potassium orotatePotassium orotate, , anabolic steroidsanabolic steroids

Drugs manifest cardiocytoprotective Drugs manifest cardiocytoprotective action, improve energetic metabolism action, improve energetic metabolism

in myocardiumin myocardium

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PECULIARITIES OF TREATMENT OF PECULIARITIES OF TREATMENT OF DIASTOLIC DISFUNCTION OF DIASTOLIC DISFUNCTION OF

MYOCARDIUMMYOCARDIUM

IndicatedIndicated::

IATEIATE, А, АRRА А IIII, ,

BetaBeta--adrenoblockers, calcium ions adrenoblockers, calcium ions antagonistsantagonists

ContraindicatedContraindicated::

NitratesNitrates, , diuretics, heart diuretics, heart glycosidesglycosides

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DiureticsDiuretics

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Classifiction of diuretics Classifiction of diuretics

accordingaccordinglyly to power of action to power of actionІІ Strong Strong (slowing down of (slowing down of NaNa+ + reabsorbtion forreabsorbtion for

1010--20%)20%)

furosemide, etacrynic acid, clopamide, bfurosemide, etacrynic acid, clopamide, buufenoxfenox

ІІІІ Medial powerMedial power of action (slowing down of of action (slowing down of NaNa++ reabsorbtion for reabsorbtion for 5-8%) 5-8%)

dichlotdichlothhiaside, oxodolineiaside, oxodoline

ІІІІІІ Light Light (slowing down of (slowing down of NaNa+ + reabsorbtion not reabsorbtion not more more than for 3%)than for 3%)

diacarb, spironolactone, amiloride, triamteren, diacarb, spironolactone, amiloride, triamteren, xantxanthhines (theophylline)ines (theophylline)

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Mannitol

15 % solution15 % solution

rapid intravenous rapid intravenous introductionintroduction

intravenous dropping intravenous dropping introductionintroduction

dehydrating dehydrating actionaction

diuretic diuretic actionaction

diureticdiuretic actionaction

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MannitolMannitol

IndicatoinsIndicatoins

1. Brain oedema (in case of maintaining ofHEB permeability)2. Toxic lung oedema (poisoning with gasoline, gass, formaline,

skipidar etc.)3. Larynx oedema of allergic or inflammatory genesis4. Holding of forced diuresis (poisoning with barbiturates,

salycylates, sulphonamides, PASA, metanole, boric acid, haemolytic poisons, antifreezers; in case of trasfusing of incompatible blood, massive hemoglobinuria etc.

5. In oliguric phase of acute nephral insufficiency6. Burns, osteomielitis, peritonitis, sepsysContrainidications Contrainidications

Acute cardiac insufficiency, skull trauma, intracranial hemorrhages, arterial hypertension

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FUROSEMIDEFUROSEMIDE

High ceiling (loop) diureticHigh ceiling (loop) diuretic Properties :Properties :

1. diuretic action1. diuretic action

2. dilation of peripheral venous2. dilation of peripheral venous

3. decrease left ventricular filling pressure3. decrease left ventricular filling pressure

4. potent anti-inflammatory effect (similar to 4. potent anti-inflammatory effect (similar to indometacine and other NSAID)indometacine and other NSAID) Administration:Administration: hypertensive emergencies, hypertensive emergencies, long-term treatment of arterial hypertension long-term treatment of arterial hypertension Adverse reactions: Adverse reactions: dehydration, dehydration, hypokalemia, hearing loss - deafness, hypokalemia, hearing loss - deafness, hypocalcaemia hypocalcaemia

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Furosemide (lazix)Furosemide (lazix)

Effective even in case of decreased glomerular filtration less than 10 ml/min. (norm – 127ml/min)

IndicationsIndications

1. Acute left ventricular insufficiency, lung oedema2. Chronic cardiac insufficiency 3. Arterial hypertension, including hypertensive crisis 4. Brain oedema of any etiology5. Acute nephral insufficiency6. Performing of forced diuresis7. For excretion of Calcium ions (hypervitaminosis D)

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Side effects of furosemideSide effects of furosemide

1. Hypopotassiumaemia, hypopotassiumhystia2. Hypovolemia, vascular collapse, hyposodiumaemia,

hypocalciumaemia, hypochloraemia, metabolic alkalosis3. Ototoxic action4. Contrinsular action (manifestation of latent diabetes mellitus)5. Formation of oxalate and phosphate stones in urinary tracts6. Decreasing of secretion of uric acid (acute attack of gout)

It should not be combined with antibiotics, aminoglycosides and cephalosporines!

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Furosemide Furosemide (diuretic)(diuretic)

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THIAZIDES and RELATED DIURETICSTHIAZIDES and RELATED DIURETICS

Medium efficacy diureticsMedium efficacy diuretics Benzothiadiazines (chlorothiazide, Benzothiadiazines (chlorothiazide,

hydrochlorothiazide, clopamide), related hydrochlorothiazide, clopamide), related thiazide like (chlorthalidone, indapamide)thiazide like (chlorthalidone, indapamide)

for long-term treatment of arterial hypertesion for long-term treatment of arterial hypertesion (oral administration)(oral administration)

Duration of action (6-12 hours for Duration of action (6-12 hours for hydrochlorothiazide, 12-18 hours for hydrochlorothiazide, 12-18 hours for clopamide, 48-50 hours for chlorthalidone)clopamide, 48-50 hours for chlorthalidone)

Adverse reactions: dehydration,Adverse reactions: dehydration, hypokalemia, hypokalemia, hyperuricaemia (rise of blood urate level)hyperuricaemia (rise of blood urate level)

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Dichlotiaside (hypothiaside)Dichlotiaside (hypothiaside)

IndicationsIndications

1. Oedema in case of chronic cardiac insufficiency2. Oedema in case of chronic pathology of liver and kidneys 3. Treatment of arterial hypertension4. Diabetes insipidus

Side effectsSide effects

1. Hypopotassiumaemia, hypopotassiumhystia2. Hypochloraemic alkalosis3. Retention of uric acid - artralgy, acute attack of gout, chronic

nephropathy 4. Hyposodiumaemia of dilution: nausea, vomitting, diarrhea,

weakness5. Pancreatitis

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IndapamideIndapamide (ariphone – sulphamoil benzamide) (ariphone – sulphamoil benzamide)

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Drug Drug Way of Way of administrationadministration

Latent Latent periodperiod

Duration of Duration of actionaction

Sulfonyl derivates

Oxololin (chlortalidon, Oxololin (chlortalidon, hyhroton) hyhroton)

peroralperoral 2-4 hours2-4 hours Till 3 daysTill 3 days

Clopamide Clopamide peroralperoral 1-3 hours1-3 hours 8-18 (till 24) 8-18 (till 24) hours hours

Bufenox (bumetanide)Bufenox (bumetanide) intravenousintravenous 20-40 min.20-40 min.

2-5 min. 2-5 min.

4-6 hours4-6 hours

1-3 hours1-3 hours

Potassium-, magnesium-sparing

SpironolactoneSpironolactone peroralperoral 2-5 days2-5 days 2-3 days2-3 days

Triamteren (pterophen)Triamteren (pterophen) peroralperoral 20-30 min.20-30 min. 6-8 hours6-8 hours

Amiloride Amiloride peroralperoral 2 hours2 hours till 24 hourtill 24 hour

Pharmacokinetics of some diuretic drugsPharmacokinetics of some diuretic drugs

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SpironolactoneSpironolactone (aldactone) (aldactone)

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Combined administration of diureticsCombined administration of diuretics

1.1. Mannitol + furosemide (etacrynic acid)Mannitol + furosemide (etacrynic acid)2.2. Dichlotiaside + triamteren (spironolactone)Dichlotiaside + triamteren (spironolactone)3.3. Furosemide + spironolactoneFurosemide + spironolactone4.4. Furosemide (excretes Calcium ions) + Furosemide (excretes Calcium ions) +

dichlotiasidedichlotiaside (retains Calcium ions)(retains Calcium ions)

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TriampurTriampur (triamteren + hydrochlorthiaside)(triamteren + hydrochlorthiaside)

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Blue corn-flowers (Blue corn-flowers (Flores Flores Centaureae cyani)Centaureae cyani)

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Juniper berries (Fructus Juniperi)