Antiarrhythmic Drugs: Application and Classification | Veterinary Pharmacology

The drugs under this group prevent or treat the irregularities of cardiac rhythm.

Cardiac Arrhythmias:

Cardiac arrhythmias are the abnormalities in the rate, regularity, site of origin of the cardiac impulse, or a disturbance in conduction of the impulse such that the normal sequence of activation of atria and ventricles is altered. The arrhythmias occur due to either faulty impulse initiation (automaticity), or con­duction or both of them.

Flutter:

It is a form of arrhythmia where a rapid vibration or pulsation occur.

Fibrillation:

It is another form of arrhythmia wherein a small local involuntary muscular contraction occurs due to spontaneous activation of single muscle cell or muscle fibre.

Atrial Flutter:

It is a cardiac arrhythmia in which the atrial contractions are rapid (200-300/min. in man), but regular.

Atrial Fibrillation:

This is the atrial arrhythmia marked by rapid randomized contrac­tions of the atrial myocardium, causing a totally irregular and often rapid ventricular rate.

Ventricular Fibrillation:

It is the cardiac arrhythmia characterised by fibrillary contractions of the ventricular muscle due to rapid repetitive excitation of myocardial fibres without coordinated ventricular contraction.

Cardiac Electrophysiology:

Action Potential Phases:

The voltage changes of the AP are associated with changes in the ionic conductance across the cell membrane. The following phases of AP give only major ionic currents.

(a) Phase O:

Phase of rapid depolarization in which Na⁺ ions rapidly enter into the cell through fast Na⁺ channels.

(b) Phase 1:

Phase of transient rapid repolarization in which K⁺ briefly leaves the cell.

(c) Phase 2:

Plateau phase or phase of sustained depolarization caused by entry of Ca²⁺ through slow Ca²⁺ channels.

(d) Phase 3:

Phase of rapid repolarization caused by K⁺ efflux.

(e) Phase 4:

Phase of slow diastolic depolarization caused due to leakiness of Na⁺ ions through the membrane of specialised (automatic) cells, like S.A. node, A.V. node and His-Purkinje fibres, until an impulse is generated. Other cells remain resting until activated.

Automaticity:

It is the ability of a cardiac cell to reach the threshold potential and generate impulses of its own spontaneously. In the cardiac automatic cells, the resting potential depolarizes during phase 4 until a threshold potential is reached and an AP is initi­ated.

The S.A. nodal fibre has the steepest slope of phase 4 depolarization and the most rapid firing rate. That’s why it acts as “normal pacemaker”. On failing of this fibre to function, the specialized atrial conduction fibres (between S.A. and A.V. node), A.V. nodal fibres and His-Purkinje fibres can genenate impulses of their own and hence are “Latent pacemakers.”

The abnormalities in cardiac rhythm arise from alterations in the state of normal automaticity and abnormal generation of impulses. Most antiarrhythmic agents depress the automaticity of latent pacemakers more effectively than the S.A. node by reducing the rate of phase 4 depolarization, threshold potential, or by decreasing the excitability of pacemaker cells.

Conduction Velocity:

It is the speed at which an impulse is propagated. There are three main factors which can modify the conduction velocity in heart. These are (a) maximum rate of phase O depolarization, (b) the threshold potential, and (c) the resting membrane potential. The depolarization of membrane is associated with a decrease in conduction velocity.

Disturbances in cardiac conductance may lead to supraventricular or ven­tricular arrhythmias. In the injured myocardial areas, conduction may be slow, or refractoriness shortened, or both, resulting in the “reentry of aberrant impulse” and hence a cardiac arrhythmia.

Effective Refractory Period (ERF):

It is the period of repolarization during which no normal AP can be elicited. In other way, ERP is the minimum time interval between two propagating APs, during which a normal cardiac impulse cannot re-excite an already excited area of cardiac muscle. Shortening of the ERP during tachycardia may produce arrhythmia. An effec­tive antiarrhythmic agent increases the ERP/APD ratio.

Mechanisms of Producing Cardiac Arrhythmias:

Mechanical injury, ischaemia, stretching, neurogenic and drug influences, electro­lyte and pH imbalance can cause arrhythmias by the following ways.

(i) Conduction block

(ii) Enhanced Pacemaker activity

(iii) Fractionation of impulse

(iv) After depolarizations and

(v) Re-entry

Conduction Block:

Due to ischemia, injury or drugs’ influence, the conduction of impulse through the automatic or specialised tissues may be blocked. Among them the partial or complete A.V. block is most commonly found.

Enhanced Pacemaker Activity:

In the automatic or even in non-automatic ordinary fibres a pathological condition may lead to increase in the slope of phase 4 depolarization to cause sinus tachycardia, atrial flutter, or atrial and ventricular extra systoles (tachycardia).

Fractionation of Impulse:

When the atrial ERP is brief and not homogenous (may be due to vegal over-activity), an impulse generated early in diastole (premature depolarization) gets conducted irregularly over the atrium, i.e., it moves rapidly through the fibres which have completely recovered due to short ERP, slowly through the fibres which are partially recovered due to long ERP, and not at all through those still refractory. It leads to atrial fibrillation.

The atrial fibrillation is commonly found in dilated atria (mitral stenosis), because the number of sustained impulses is directly proportional with the mass of tissue.

After-depolarizations (AD):

Sometime, a normal AP may be followed by a premature secondary depolariza­tion started before completion of the APD. This secondary depolarization is termed as after-depolarization. It is of two types early and delayed AD.

(i) Early AD:

Here, premature secondary depolarization or AD is started during phase 3 (repolarization) of an action potential. There may have multiple early ADs.

(ii) Delayed AD:

It starts after attaining the resting membrane potential to produce a secondary depolarization which reaches to threshold potential and initiate a single premature action potential. As an action potential is needed to trigger ADs, arrhythmias based on these ADs are termed as “triggered arrhythmias.” Examples are extra systoles, tachycardia, cou­pled beats, etc.

Re-Entry:

Normally, a cardiac impulse travels through the entire extent of the ventricles and finds no place else to go because all parts of the ventricular muscle is at that time refractory and can not conduct the impulse further.

Therefore, that impulse dies and the heart waits for a new impulse to generate in the S.A. node. Due to decrease in conduction velocity of impulse or shorter refractory period of the muscle, an impulse may Re-circulate in the heart and cause repetitive activation without generation of a new impulse. It is termed as “Re-entrant arrhythmia.”

When a premature impulse with low conduction velocity is temporarily blocked in one direction by refractory tissue a one way transit around an obstacle (natural orifices in heart, infracted myocardium, junction of a branched Purkinje fibre and ventricular fibre, etc.) is produced.

As the impulse reaches its original spot, the spot is found recovered. The impulse then Re-enters to the same path and follows it repeatedly to produce recurrent activation of the adjacent myocardium.

The re-entry of impulses may cause atrial flutter, paroxysmal supraventricular (atrial or A.V. nodal) tachycardia, or ventricular tachycardia. For re-entry to occur, the path length of the circuit should be greater than the wave length (ERXP conduction velocity) of the impulse.

Classification of Antiarrhythmic Drugs:

According to mechanism of action:

Therapy of Choice in Some Common Cardiac Arrhythmias:

1. Supraventricular Arrhythmias:

(a) Atrial flutter or fibrillation → Digitalis and/or DC Shock.}

(Quinidine is used to suppress recurrence)

(b) Paroxysmal atrial or nodal tachycardia → Digitalis, Vagotonic maneuver.

(alternative → Verapamil)

2. Ventricular arrhythmias:

(a) Ventricular premature depolarization → Lidocaine (Quinidine for long action).

(b) Ventricular tachycardia → DC shock (alternative → Lidocaine, procainamide).

3. Digitalis-induced arrhythmias → Lidocaine, or Phenytoin.

Quinidine:

Quinidine is an alkaloid obtained from the cinchona bark. It is available in the market as its sulphate and gluconate forms. Both of them are well absorbed from GIT and maximum effect is achieved within 1-2 hrs. of administration. Only gluconate form is used for i.m. injection. The drug remains in blood 80% bound with plasma protein. It is metabolised in liver and excreted out through urine.

Pharmacological Effects:

(i) Quinidine, at higher concentrations, directly acts on cardiac cells, but at lower concentrations, the drug has an indirect anticholinergic effect.

(ii) Quinidine blocks Na⁺ channels. So the V_max of phase O depolarization is reduced in atrial, ventricular and purkinje fibres. Thus, effective refractory period (ERP) is increased and conduction velocity is decreased in these tissues.

(iii) By inhibiting Na⁺ channels, quinidine depresses the slope of phase 4 depo­larization resulting in decreased automaticity in ventricular tissues. Auto­maticity of S.A. node remain unaltered in this case.

(iv) Quinidine markedly alters ECG. It prolongs QRS complex by decreasing conduction through bundle of His and Purkinje fibres. It increases Q-T interval and alters T waves by delaying repolarization. P-R interval is also increased due to reduction in conduction and ERP of A-V node.

(v) Quinidine can also block α₁ adrenoceptors of blood vessels which results in relaxation of vascular smooth muscles.

Clinical Uses:

(i) Quinidine is usually used to prevent the recurrence of paroxysmal supraventricular tachycardia.

(ii) The drug is effective in atrial flutter or fibrillation; but “direct current cardio-version” is the treatment of choice in this condition. Quinidine is used to prevent its recurrence.

(iii) Quinidine is used for both the treatment as well as prevention of recur­rence of ventricular tachycardia.

(iv) It should always be used after prior digitalization because of its vegolytic effect. The dose of digitalis should be proper as quinidine increases the serum level of digitalis and can lead to digitalis toxicity.

Lidocaine:

Lidocaine is an amide local anaesthetic. It should not be administered orally because a maximum percentage of the drug is metabolized in liver before reaching into the circulation.

Pharmacological Effects:

(i) By its Na⁺ channel blocking property lidocaine depresses the slope of phase 4 depolarization of atrial and Purkinje fibres. Thus, automaticity at these sites is depressed. But, the drug does not alter the automaticity of S.A. node.

(ii) Atrial conduction, refractoriness and responsiveness are generally not al­tered by lidocaine. V_max of phase ‘O’ and membrane responsiveness in His- Purkinje system are reduced.

(ill) In normal Purkinje fibres, the V_max phase O is slightly depressed by lidocaine; while in diseased condition, resting membrane potential is re­duced and extracellular K⁺ level is increased, the V_max is severely reduced by the drug.

(iv) Lidocaine shortens action potential duration (APD) and ERP of Purkinje fibres.

(v) It has little effect on ECG and autonomic tone.

Clinical Uses:

(i) Ventricular arrhythmia.

(ii) Some emergency conditions like myocardial infarction, open-heart surgery, digitalis intoxication, etc.

Flecainide and Encainide:

These drugs are only recommended in life-threatening arrhythmias like “sus­tained ventricular tachycardia.” They are not used in less severe ventricular arrhythmias because they can cause cardiac arrest.

Propranolol:

Propranolol is a nonselective β adrenoceptor blocker having three important therapeutic indications – cardiac arrhythmia, angina pectoris and hypertension.

Pharmacological Effects:

(i) Propranolol depresses the automaticity of S.A. node and Purkinje fibres by blocking β receptors of these areas.

(ii) It causes a substantial increase in the ERP of the A-V node which is the main reason behind antiarrhythmic action of the drug.

(iii) Propranolol does not alter the ERP of S.A. node and atrial and ventricular muscle fibres; bit shortens the ERP of Purkinje fibres.

(iv) Propranolol prolongs the P-R interval of ECG due to increase in ERP of A-V node.

Clinical Uses:

(i) Propranolol is used in supraventricular tachyarrhythmias like atrial flutter or fibrillation, paroxysmal supraventricular tachycardia.

(ii) It is also useful in sympathomimetic-induced ventricular arrhythmias (from emotional stress, exercise, etc.)

Bretylium:

Bretylium is a quarternary ammonium compound and an adrenergic neuron block­ing agent. It enters into the postganglionic adrenergic nerve terminals, where it ini­tially enhances the release of norepinephrine but later on inhibits the same even in response to neuronal stimulation. The drug also has direct effects on heart.

Pharmacological Effects:

(i) Bretylium has no direct effect on automaticity. It is one of the few antiarrhythmic drugs which do not affect automaticity of His Purkinje fibres.

(ii) Bretylium increases the ventricular fibrillation threshold. However, RMPs of other cardiac cells are not greatly altered.

(iii) Bretylium prolongs the APD and ERP of atrial, ventricular muscle fibres and A.V. node, but does not alter the responsiveness or conduction.

(iv) It increases the P-R and Q-T intervals of ECG due to above changes.

Clinical Use:

(i) Life-threatening ventricular arrhythmias that are not curable by other drug.

Verapamil:

Verapamil is a Ca²⁺ -channel blocker. It is the drug of choice for supraventricular tachycardia given intravenously.

Pharmacological Effects:

(i) Verapamil markedly depresses A-V nodal conduction. Therefore, it is highly effective in paroxysmal supraventricular tachycardia and in reducing the ventricular responses to atrial flutter or fibrillation.

(ii) The drug is not very effective in ventricular arrhythmias.

Antihypertensive Drugs:

Hypertension:

Hypertension is defined as an elevation of mean arterial pressure from the upper range of accepted normality. Usually, in human being, a mean arterial pressure greater than 110 mm of Hg under resting conditions is considered to be hypertensive, this level normally occurs when the diastolic b.p. is greater than 90 mm Hg and the systolic b.p. > 140 mm Hg.

In very severe hypertension the mean arterial pressure (MAP) can rise to as high as 150 to 170 mm Hg, with diastolic pressure as high as 130 mm Hg and systolic arterial pressures occasionally as great as 250 mm Hg.

Systemic arterial B.P. is determined by cardiac output (c.o.) and total peripheral resistance (t.p.r.). In most of the cases, rise in B.P. is due to ↑ in t.p.r. while c.o. and heart rate (HR) are not high.

Even moderate elevation of arterial pressure leads to shortened life expectancy.

The lethal effects of hypertension are caused mainly in three ways:

(i) Excessive workload on the heart leads to early development of CHF (congestive heart failure), coronary heart disease, or both, often causing death as a result of a heart attack.

(ii) The high pressure frequently ruptures a major blood vessel in the brain, followed by clotting of the blood and death of major portions of the brain, this is a “cerebral infarct”. Clinically it is called a “stroke”.

Depending on what part of the brain is involved, a stroke can cause paraly­sis, dementia (loss of intellectual function), blindness, or multiple other serious brain disorders.

(iii) Very high pressure almost always causes multiple haemorrhages in the kidneys, producing many areas of renal destruction and eventually kidney failure, uremia and death.

Arterial Pressure Regulation:

Arterial pressure is not regulated by a single pressure controlling system but instead by several inter-related systems each of which performs a specific function. There are different arterial pressure control mechanisms (approximately eight) which increase b.p. in hypotension and vice versa. These mechanisms can be divided into three separate groups.

1. Those that react very rapidly, within seconds or minutes: (nervous mechanisms)

(a) The baroreceptor feedback mechanism

(b) The CNS ischemic mechanism and

(c) The chemoreceptor mechanism.

2. The intermediate time-period pressure control mechanisms:

(a) The renin-angiotensin vasoconstrictor mechanism.

(b) Stress-relaxation of the vasculature and

(c) Shift of fluid through the capillary walls in and out of the circulation to re-adjust the blood volume as needed.

3. The long-term mechanisms for arterial pressure regulation:

(a) Renal-blood volume pressure control mechanism (same as the renal-body fluid pressure control mechanism).

Factors affecting renal blood volume pressure control mechanisms:

(i) Aldosterone

(ii) Interaction of renin-angiotension system with the aldosterone and renal fluid mechanism,

Types of Hypertension:

Hypertension are of main two types:

(i) Primary

(ii) Secondary

(i) Primary Hypertension:

The hypertension is of unknown origin/cause. Also known as “essential hypertension” or “idiopathic hypertension” or “benign hyperten­sion”. It is chronic hypertension of relatively mild degree. Approx. 90% of all persons who have hypertension are said to have “essential hypertension”. This hypertension is a major risk factor for stroke, CHF, and coronary artery disease.

(ii) Secondary Hypertension:

Hypertension associated with other diseases like diabetes mellitus, chronic pyelonephritis, pheochromocytoma.

Malignant hypertension:

A severe hypertensive state with papilledema of the ocular fundus and vascular haemorrhagic lesions, thickening of the small arteries and arterioles, left ventricular hypertrophy, and poor prognosis. (Popilledema – Edema of the optic disk.)

Classification of Antihypertensive Drugs:

1. Diuretics:

(i) Thiazides and related agents:

(a) Hydrochlorothiazide

(b) Clorethalidone

(ii) Loop diuretics:

(a) Furosemide

(b) Bumetanide

(c) Ethacrynic acid

(iii) K⁺ sparing diuretics:

(a) Spironolactone

(b) Triamterene

(c) Amiloride

2. Sympatholytic drugs:

(i) Centrally acting agents:

(a) Methyldopa

(b) Clonidine

(c) Guanabenz

(d) Guanfacin

(ii) Ganglionic blocking agents:

(a) Trimethaphan

(iii) Postsynaptic adrenergic neuron blocking agents:

(a) Reserpine

(b) Guanethidine

(c) Guanadrel

(iv) β-adrenergic antagonists:

(a) Propranolol

(b) Metoprolol,

(v) α adrenergic antagonists:

(a) Prazosin

(b) Terazosin

(c) Phenoxybezamine

(d) Phentolamine

(vi) Mixed antagonists:

(a) labetalol (α₁, β₁, β₂)

3. Vasodilators:

(i) Arterial:

(a) Hydralazine

(b) Minoxidil

(c) Diazoxide

(ii) Arterial and venous:

(a) Nitroprusside

4. Ca²⁺ Channel blockers:

(a) Verapamil

(b) Diltiazem

(c) Nifedipine

(d) Nicardipine

(e) Nitrendipine

5. Angiotensin converting enzyme inhibitors:

(a) Captopril

(b) Enalapril

(c) Lisinopril.

Important Features of Antihypertensive Therapy:

As the etiology of essential hypertension is not yet clear, a nonspecific treatment of this condition is commonly adopted. Initially, treatment may be started with any one group of drug. In case, the first agent is not effective or poorly tolerated, another drug may be tried in place of previous one.

Now-a-days, combined drug therapy is recommended to increase the efficacy and to reduce the untoward effects. In case of hypertensive emergencies, either nitroprusside, or diazoxide, or labetalol is indicated parenterally (mostly i.v.) or nifedipine is given sublingually. This should be followed by oral maintenance therapy.