Pharmacology of Cardiovascular System

Pharmacology of Cardiovascular System

Cardiac electrophysiology: Heart, blood, blood vessels and lungs constitute a significant physiological system that is responsible to supply nutrients and oxygen (via blood) to body tissues.  Adequate tissue perfusion is ensured by the pumping action of the heart. This pumping activity demands for certain specialized and unique features (owned by cardiac muscles) in addition to conventional properties of muscular contraction and relaxation (that are possessed by skeletal, smooth and cardiac muscles). Like skeletal and smooth muscles, the cardiac muscles also respond to membrane depolarization (as a result of action potential) that is followed by repolarization and ultimately attain resting membrane potential. But the cardiac muscles possess their own intrinsic system for the generation (and perhaps propagation) of action potential in the form of pace maker cells located in sino-atrial (SA) node (in case of skeletal and smooth muscles contraction, the action potential is produced and transmitted by nerves). Unlike skeletal muscles which display a graded pattern of contraction (the degree of muscle contraction depends upon the number of excited/stimulated cells), the cardiac muscle cells respond to stimulus as a single functional unit (quantal response). The cardiac action potential is unusually long and can be divided into five distinct phases.

Phase- “0” (Fast upstroke): This initial phase is marked by fast inward current resulting from the opening of Sodium channels (elevating the intracellular cation concentration).

Phase-1 (Partial repolarization): Opening of Potassium channels leads to transient outward flow of current (reducing the intracellular cation concentration) during this phase.

Phase-2 (Plateau phase): This step involves the opening of calcium channels (to balance the Potassium leakage) that causes slow inward current resulting in depolarization.

Phase-3 (Repolarization phase): Once again the opening of Potassium channels leads to repolarization.

Phase-4 (Depolarization phase): Inward flow of current is caused by the opening of Sodium channels and myocardial cell once again tries to attain the threshold value required for the generation of action potential (depolarization). Depolarization causes myocardial contraction (systole) while repolarization results in myocardial relaxation (diastole).

Cardiac contraction: The fundamental contractile machinery of cardiac muscle cells resembles that of striated muscles. The force of contraction of cardiac muscles is directly related to the concentration of free (unbound) cytosolic calcium. Calcium comes from two sources; calcium channels (located on the cell membrane) and intracellular sources (sarcoplasmic reticulum and mitochondria). This calcium is utilized by actin and myosin filaments (contained in myofibrils) to execute contraction that is followed by relaxation [during which the intra-cellular calcium level is reduced through the calcium efflux (performed by Sodium/Calcium exchanger) and reabsorption of calcium by sarcoplasmic reticulum and mitochondria]. This cycle is repeated as long as the myocardial cells are stimulated by intrinsic action potential. Removal of free cytosolic calcium is also performed by two mechanisms; sodium-calcium exchanger (that exchanges calcium ions for sodium ions across the cell membrane) and calcium uptake by sarcoplasmic reticulum and mitochondria. Sodium balance is restored by Na⁺-K⁺-ATP_ase pump.

Heart failure/Congestive heart failure (CHF): It is a progressive disorder that involves insufficient cardiac pumping and is characterized by dyspnea, edema and fatigue. It is of two types. Left sided heart failure involves the inability of left atrium to receive oxygenated blood from the lungs thereby causing pulmonary congestion (congestion is passive hyperemia, the accumulation of venous blood) that is clinically manifested by dyspnea (difficult/labored respiration or shortness of breath). In case of right sided heart failure, right side of the heart (right atrium and right ventricle) fails to receive deoxygenated blood from major veins (like anterior and posterior vena cava). Thus blood is collected inside larger as well as smaller veins and intense pressure (exerted by the blood) enables the plasma to leak out of the capillaries into interstitial spaces which causes peripheral edema. To overcome the problem of impaired cardiac contractility and associated pumping defect, body has three compensatory mechanisms (baroreceptors-induced sympathetic stimulation (resulting in tachycardia), activation of rennin angiotensin aldosterone system and myocardial hypertrophy) but none of them is properly effective.

Myocardial stimulants: These drugs are used to stimulate myocardium (in case of CHF) and include the following classes.

1. Cardiac glycosides: These are derived from Foxglove plant and each agent consists of distinct moities; glycone and aglycone. The glycone portion is responsible for pharmacological action (myocardial stimulation) of glycosides. Aglycone (concerned with pharmacokinetic parameters of glycosides) comprises of basic steroid nucleus, cyclopentanoperhydropenanthrene that is having 1-3 sugar molecules attached at carbon number 3 (C-3), a large lactone ring at C-17 and one or multiple OH^- ions (that impart water solubility).

Plant source	Derived glycoside(s)
Digitalis purpurea	Digoxin, Digitalin
Digitalis lanata	Digitoxin
Strophanthus gratus	Strophanthidin

Cardiac glycosides bind to Na⁺-K⁺-ATP_ase pump (at K⁺ binding site) and inhibit its function (influx of K⁺ and efflux of Na⁺). This results in enhanced intracellular Na⁺ level that favors the exchange of more and more Na⁺ for Ca⁺² thus promoting cardiac contraction (displays positive inotrophic effect by indirectly increasing intracellular Ca⁺² level, positive chronotrophic effect is the increase in force of cardiac contraction). Extracardiac effects of these agents include diuresis (as a result of increased renal blood flow due to improved cardiac output) and nausea, vomiting (via activation of CTZ).

Cardiac arrhythmia (associated with reduced level of K⁺ in myocardial cells) is their common adverse effect (in case of toxicosis) that implies the administration of Potassium chloride. Cholestyramine (an adsorbant) is also used to treat digitalis poisoning. In addition to CHF, these drugs are also used to prevent anesthesia-induced cardiac arrest. Prophylactic digitalization is sometimes used to maintain optimal cardiac functionality during open heart surgery. Cardiogenic shock, renal failure and hepatic insufficiency are important contraindication for these drugs. Cats are highly susceptible to digitalis intoxication and therefore they should not be treated with these agents. Co-administration of calcium (potentiate cardiac stimulation), diuretics (intensify K⁺ depletion) and β-agonists (chances of cardiac arrhythmia are increased) with cardiac glycosides should be avoided.

2. Phosphodiesterase (PDE) inhibitors:  Phosphodiesterase enzyme is responsible for the break down of cAMP and cGMP. The intracellular Ca⁺² level can be elevated through inhibiting PDE-mediated degradation of cAMP.

(a) Methylxanthines: Methylxanthines inhibit PDE enzyme and block adenosine receptors. Synthetic methylxanthines like Aminophylline and Theophylline to cause myocardial stimulation. Methylxanthines are also used as CNS stimulants, expectorants and bronchodilators. Their detailed pharmacological and toxicological profile has been already described.

(b) Bipyridine derivatives:  Amrinone and Milrinone are also PDE inhibitors that can be administered in CHF to facilitate myocardial stimulation.

3. Sympathomimetics: β-agonists like Adrenaline (α₁, α₂, β₁ and β₂ agonist), Dobutamine (selective β₁ agonist) and Isoproterenol (β₁ and β₂ agonist) are also advantageous in heart failure as they cause tachycardia and thus improve cardiac output. However their frequent use is limited by their common and unavoidable side effects.

Hypertension and anti-hypertensive drugs

Blood pressure (B.P) can be defined as that force which propels vascular fluid (blood) throughout circulation. This pressure is exerted as a result of cardiac pumping activity and it executes a decline in intensity as the flow is progressed from aorta (98 mm of Hg) to peripheral blood vessels (about 3 mm of Hg in vena cava). The endothelial lining of blood vessels also offers a resistance towards the flow of blood. Although this vascular resistance is inversely proportional to the diameter of blood vascular lumen, maximum resistance is experienced by arterioles not the capillaries and veins (due to their weak and thin walls). Net resistance is known as total peripheral resistance (TPR) and it is calculated by the following formula

TPR (mm of Hg/L/min.) = Mean aortic pressure (mm of Hg) – Pressure in vena cava (mm of Hg)

                                                                              Cardiac output (L/min.)

B.P = Cardiac output x TPR

Regulation of systemic blood pressure is carried out by two mechanisms.

1. Baroreceptors and sympathetic nervous system: Baroreceptors (located on arterioles) sense out hypotension and transmit signal to sympathetic nervous system which after stimulation releases norepinephrine. Norepinephrine occupies α₁ and β₁ adrenergic receptors to cause vasoconstriction (increases peripheral resistance) and tachycardia (enhances cardiac output) that ultimately lead to hypertension for normalizing blood pressure.

2. Renin-Angiotensin-Aldosterone system: Reduced renal blood flow, decreased volume and osmolarity of plasma result in the release of rennin from renal juxta-glomerular (JG) apparatus that converts angiotensinogen (synthesized by the liver and provided by the blood) into angiotensin-1. This angiotensin-1is further converted into angiotensin-2 by angiotensin converting enzyme (ACE). Angiotensin-2 can either itself act as a vasoconstrictor or it can facilitate the synthesis and liberation of aldosterone (a mineralocorticoid) from adrenal cortex that causes the retention of fluid and sodium ions by acting on its target cells (principal cells of collecting duct). This increases the volume as well as osmolarity of plasma and eventually increases blood pressure

Hypertension is defined as sustained elevated blood pressure that may be caused by chronic renal failure (improper glomerular filteration increasing the plasma volume and solute concentration), metabolic disturbances (abnormal solute concentration elevating plasma osmolarity) or endocrine disorders (inadequate aldosterone level). Hypertension can give rise to many serious outcomes like neurological disturbances (stroke-rupture of crainial vessels) and ocular defects (retinal edema, retinal detachment, retinal atrophy and glaucoma).

Treatment strategies for hypertension: Single agent or combination therapy must be used depending upon the requirement. Dietary salt restriction should be advised. Weight reduction (through exercise) is ideal to prevent obesity. Life-long treatment schedule must be followed if hypertension is due to chronic renal failure.

Antihypertensive drugs: These drugs are classified into following types.

1. Vasodilators: Hydroxyzine, Minoxidil (also used to treat androgenic alopecia [excessive hair loss due to enhanced androgen level) in men] and Nitroprusside are included in this category. Hydoxyzine overdosage results in hypotension. Co-administration of Hydoxyzine and sympathomimetics will result in additive tachycardia. After metabolized by red blood cells and endothelial cells, Nitroprusside forms nitric oxide that increases cGMP level (by stimulating guanyl cyclase enzyme) and finally vasodilation is caused. However it is not commonly used as it contains cyanide and can cause cyanide poisoning.

2. ACE inhibitors: Captopril, Enalapril and other ACE inhibitors display their antihypertensive action by blocking the synthesis of Angiotensin-2. Hypotension and hyperkalemia are their possible adverse effects.

3. Angiotensin receptor antagonists: Losartan and Valsartan can deprive angiotensin of its respective receptors and this action can be helpful to treat hypertension however these agents are used only in human medicine.

4. β-blockers: Cardioselective β-blockers (Atenolol, Metoprolol) or non-selective β-blockers (Propranolol) are also effective for hypertensive patients.

5. Diuretics: They reduce the volume as well osmolarity of plasma and thus decrease blood pressure.

It should be kept in mind that β-blockers and diuretics are always used only in adjunctive therapy (along with vasodilators, ACE-inhibitors or Angiotensin receptor antagonists) for hypertension as they cannot provide total relief when used alone.

Angina pectoris: It is a condition that is manifested by sudden, severe emergence of pain in chest (pectoral) muscles that can spread to arm, jaws, back and neck region. Atherosclerosis or vascular smooth muscles spasm reduces coronary perfusion that causes short-term ischemia (lasts for 15seconds to 15 minutes and is therefore unable to induce necrosis). There are three types of angina.

1. Stable or typical angina: It is caused by atherosclerosis and aggravated by high workload (physical or mental), exercise and emotional excitement. Appropriate rest or use of Nitroglycerine can relieve this problem.

2. Unstable or atypical angina: It occurs even during rest conditions and no relief is achieved with rest or Nitroglycerine administration. Some alternative method should be applied for therapy.

3. Prinzmetal or variant angina: It results from coronary artery spasm and shows good response to treatment with Nitoglycerine.

Treatment strategies for Angina pectoris:

1. Pharmacotherpy (use of drugs): Any of the following drugs can be used;

(a) Nitroglycerine: It is the drug of choice for angina pectoris and it enhances coronary perfusion by causing relaxation of coronary arterioles. It is usually administered through transdermal patches over the arm or chest region.

(b) β-blockers: Cardioselective β-blockers (Atenolol, Metoprolol) or non-selective β-blockers (Propranolol) are also effective for patients suffering from angina pectoris.

2. Smoking cessation is an integral part of medical counseling for angina patients.

3. Coronary angioplasty: It is a medical procedure that is conducted to remove stenosis or atheroma from coronary arteries.

4. Coronary artery bypass surgery: It is performed to provide an alternate way for blood (due to obstruction or stenosis of coronary artery) in-order to ensure adequate myocardial perfusion.

Cardiac arrhythmia/dysrrhythmia: It is defined as disorder of cardiac impulses characterized by abnormality in rate of origin of impulse generation or in conduction/propagation of impulse. Therefore it becomes clear that arrhythmogenesis involves either alteration in impulse generation (abnormal automatacity) or alteration in impulse propagation [abnormal conductivity; it may occur due to re-entry (recirculation of impulse) or atrio-ventricular block]. Classification of arrhythmias is based upon the nature of alteration in heart rate (whether increased or decreased) and site of origin of impulse abnormality.

Tachyarrhythmia: It is that arrhythmia which involves abnormally elevated heart rate. It is further subdivided into following subtypes.

(a)   Atrial tachycardia (ectopic pacemaker activity in atria)

(b)  Ventricular tachycardia (ectopic pacemaker activity in ventricles)

(c)  Junctional tachycardia (ectopic pacemaker activity in AV node)

(d)  Paroxysmal tachycardia (abnormality in any part of the heart causing rapid rhythmical discharge of impulse in all directions)

(e)  Fibrillation (it may be atrial or ventricular depending upon the site of origin but it always involve random propagation of impulse)

Bradyarrhythmia: It is that arrhythmia which involves abnormally decreased heart rate. It is further subdivided into following subtypes.

(a)   Sick sinus (slow depolarization/action potential generation at SA node)

(b)  Sinus arrest (failure of SA node to generate impulse)

(c)  Atrioventricular (AV) block (failure of impulse propagation from SA node to AV node)

(d)  Cardiac arrest (cessation/stoppage of all rhythmical impulses in the heart)

Classification of anti-arrhythmic drugs: Vaughan Williams and Singh (1969) classified anti-arrhythmic drugs into four classes while Harrison (1979) subdivided class-1 into three sub-classes.

Category	Mechanism of action	Examples	Comment
I-A	Na+ channel blockers	Quinidine, Procainamide	Slow down phase-0 depolarization. Due to decreased sodium influx, there is decreased potassium efflux which prolongs the duration of action potential.
I-B		Lidocaine, Mexilitine	Shorten phase-3 repolarization (decrease the duration of action potential)
I-C		Flecainide, Encainide	Markedly slow down phase-0 depolarization. Their action is similar to Quinidine and Procainamide but more pronounced than that.
II	β-blockers	Propranolol, Metoprolol	Suppress phase-4 depolarization (enhance the threshold value required for depolarization)
III	K+ channel blockers	Amiodarone, Bretylium	Prolong phase-3 repolarization (diminish outflow of potassium during replarization, therefore cells remain refractory even after full repolarization)
IV	Ca+2 channel blockers	Verapamil, Deltiazem	Shorten action potential (decrease calcium influx in phase-2)