Drugs acting on the cardiovascular system

Akos Jerzsele DVM

Antiarrhytmic drugs

Arrhythmia, dysrhythmia:

1. Ectopic impulse!

2. Cardiomyopathy

3. Re-entry

4. Drugs

5. Electrolite imbalances

6. Primary cause

Vaughan-Williams conductance

Group

I. Na-channel blockers

("membrane-stabilizers")

II. Beta receptor blockers

III Potassium channel blockers

IV. Calcium channel blockers

V. Other substances

Digoxin, atropine

I. class antiarrhythmic drugs

Na-channel blockers (membrane stabilizers)

Open inactive state!

Myocardial cells

I.A. e.g. quinidine

I.B. e.g. lidocaine

I.C. e.g. flecainide

ERP= effective refractory period

Quinidine

Vagal effect (+direct effect!)

Negative inotropic (heart failure!)

Dog (GI and CV side effects), cat (short t1/2) ??

Horse IV. or PO.

frequent side effects

supraventricular arrhytmias

I. A. class antiarrhythmic drugs

Procainamide

Side effect (IV.) negative inotropic, arrhytmogenic

Unfavorable pharmacokinetics (short t1/2)

Ventricular arrhytmias IV. if refractory to lidocaine

I. A. class antiarrhythmic drugs

LidocaineImmediate treatment of life threatening ventricular arrhytmias!

Supraventricular effect

Advantages

Short t1/2

Damaged cells normal cells

Hypokalaemia reduces effect

Pharmacokinetics

orally? (first pass)

intravenously

2-4 mg/kg loading dose, then continous infusion (Ca)

0,25-0,75 mg/kg iv., then cont. inf. (Fe)

I. B. class antiarrhythmic drugs

LidocaineSide effects (Fe!)

CNS ( diazepam)

heart (sick sinus syndrome)

negative inotropic effect, hypotension, conductance failure safe to use

I. B. class antiarrhythmic drugs

MexiletineTreatment of ventricularis arrhytmias at home! (DCM, HCM)

Similar characteristics to lidocaine

Can be given orally (F=85%)

Rare side effects (GI, CNS)

5-10 mg/kg per os TID

Frequently combined with β-blockers (atenolole, sotalole)

I. B. class antiarrhythmic drugs

„Beta-blockers”

=β-receptor antagonists

Catecholamines frequency, conductance, refractory period

Indications

1. Supraventricular and ventricular arrhytmias

preventing sudden death

2. HCM

3. Hyperthyroidism, methylxanthine poisoning

Contraindications (severe bradycardia, AV-block)

II. Class antiarrhythmic drugs

1. generation (β1 + β2)

Propranolol

2. generation (β1)

Metoprolol

Atenolol

Esmolol (short t1/2)

3. generation (β1 + peripherial + !)

Carvedilol

slowly developing effect

II. class antiarrhytmic drugs

Ca: combination with mexiletine

III. class antiarrhytmic drugs

K+ channel blockers ERP increases! excellent in re-entry

III. class drugs

Sotalol

excellent in boxer cardiomyopathy

Amiodarone

I+II+III+IV effects!

supraventricular + ventricular

IV. class antiarrhytmic drugs

Ca2+ channel blockers

SA-node and AV-node! bradycardia

Mainly supraventricular

Decreased Ca2+-influx decreased contraction and vasodilatation!!

1. Dihydropyridine type (vessels) amlodipine, nifedipine

2. Non-dihydropyridine type (heart) verapamil, diltiazem

Verapamil (negative inotropic structural deficiencies)

Diltiazem

Heart failure

Congestive heart failure (CHF)

Acute heart failure

cause: sudden deterioration of heart pump function (e.g. myocardial infarction, ventricular fibrillation)

Chronic heart failure

cause: gradual and slow deterioration in heart pump function and performance

Heart failure

Factors affecting heart performance

CONTRACTILITY

AFTERLOAD

~ peripherial resistance

PRELOAD

~ blood inflow into atria

+ FREQUENCY

Treatment options of CHF

1. Increasing frequency: only in life threatening cases!

e.g. epinephrine positive inotropic, chronotropic increases myocardial oxygen demand

Treatment options of CHF

2. Increasing contractility: digitalis glycosides

3. Decreasing preload and afterload: ACE inhibitors

4. Inodilators (2+3): PDE inhibitors

5. Vasoactive substances (arterial and venous vasodilators): e.g. nitroglycerine

6. Diuretics: decrease preload

Positive inotropic drugs, cardiotonics

Cardiotonics

In acute heart failure

Epinephrine

Dobutamine

Dopamine

Cardiotonics

In chronic heart failure

Digitalis glycosides

Pimobendan

Digitalis glycosides = cardiac glycosides

Digitalis purpurea Digitalis lanata

Digitoxin Digoxin

Cardiotonics

Pharmacological effects

1. direct cardiac action

positive inotropic cardiac output

improves RBF water and Na+ excretion

2. increases vagal tone

negative chronotropic

negative dromotropic

CardiotonicsDigitoxin, strofantine

Digoxin

pharmacokinetics

orally

protein binding interactions!

accumulation in myocytes

measuring plasma levels after 3-5 days

excretion via kidney

small therapeutic index (hypokalaemia!)

CardiotonicsDigoxin

small therapeutic index

side effects:

cardiac: arrhythmias, bradycardia (lidocaine, Digibind®)

hypokalaemia!

extracardial: GI-signs (vomiting)

CardiotonicsDigoxin

Usage

prolong survival time in heart failure

supraventricular tachyarrhytmias

Contraindication

outflow obstruction (HCM, stenosis)

Initial dosage 5-10 µg/kg per os BID

6+1 days

PDE inhibitors

PDE inhibitors

Pimobendan (Vetmedin A.U.V.)Multiple mechanisms:

• Phosphodiesterase (PDE3) inhibition cAMP accumulated in myocardial cells Ca2+ concentration positive inotropic effect

• Ca2+ sensitizer positive inotropic effect

• PDE inhibition arterial and venous vasodilation

= „INODILATOR”

Oxygen consumption is not increased!

Contraindicatedoutflow obstruction (HCM, stenosis)

Kinetics: per os, bioavailability (feeding!)

Extensive protein binding!

Side effects?

D: 0,1-0,3 mg/kg BID po.

PDE inhibitorsPimobendan

Pharmacology of volume regulation and vasoregulation

Angiotensin convertase enzyme (ACE) inhibitors

ACE inhibitors – captoprilBothrops jararaca

ACE inhibitors

Mechanism of effect

decrease in blood RBF

angiotensinogen (liver)

Renin

angiotensin-I

ACE

angiotensin-II

Vasoconstriction Aldosterone ADH Salt hunger, thirst

(20x epinephrine)

inactivatesbradykinin!

ACE inhibitors

Pharmacological effects

• arterial vasodilation peripherial resistance, afterload

• venodilation CVP decreases preload

• water excretion preload

• does not alter contractility (but…)

Heart performance INCREASES!

+ decrease blood pressure

ACE inhibitors

Indications

• heart failure (species!)

• hypertension

• proteinuria

ACE inhibitors

Pharmacokinetics

• oral administration good absorption ( captopril)

• metabolism: enalapril enalaprilat,

benazepril benazeprilat

ramipril ramiprilat

• Onset of action: approx. 4-6 hours

• Duration of action: approx. 12-14 hours (ramipril, enalapril)

• 12-24 hours benazepril, lisinopril

• lisinopril no activation in liver

• excretion: kidney (chronic renal failure!), but benazepril…

ACE inhibitors

Side effects

• azotaemia (LD50=100-200 mg/kg)

• blood biochemistry!

• hypotension tiredness, faintness! (humansdogs)

• GI-disturbances: anorexia, vomiting, diarrhea

• Ho: dry cough

ACE inhibitorsCaptopril

Enalapril

D: 0,5 mg/kg BID or SID

Ramipril

similar attributes ~ enalapril

D: 0,125 mg/kg BID or SID

Benazepril

D: 0,25 – 0,5 mg/kg

SID usage preferred, 50-50% kidney-liver

Lisinopril

not activated in liver hepatic failure!

Angiotensin II receptor antagonists

Advantages

more effective

no bradykinin activation

Losartan, valsartan, telmisartan