Pharmacology of Anti-inflammatory Drugs

Pharmacology of Anti-inflammatory Drugs

Inflammation: (Latin, inflammare, to set on fire) is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The invasion of tissues by these noxious agents triggers the release of cytokines (IL-1, IL-6 and TNF_α). Moreover membrane phospholipids are broken down to yield arachidonic acid (through the catalytic action of phopholipase A₂) and then it is converted to eicosanides (PGE₂, PGI₂, PGF₂α and TXA₂) and leukotriens by cyclo-oxygenase (COX) and lipo-oxygenase respectively. Prostaglandins, leukotriens, thromboxanes, cytokines and histamine are called inflammatory mediators that are responsible for the manifestation of cardinal signs of inflammation; dolor (pain), calor (heat), rubor (redness), tumor (swelling) and functiolesa (loss of function). Although inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process, widespread and chronic inflammation may become detrimental and interrupt normal body functioning (can also lead to abscessation and fibrosis if left untreated) thereby requiring optimal intervention through the use of anti-inflammatory drugs.

Origin and functions of some inflammatory mediators

Mediator(s)	Source	Main Actions
PGE2	Membrane phospholipids, mast cells	Inhibition of gastric acid secretion, broncho-constriction
PGI2		Vasodilation, inhibition of platelet aggregation
PGF2α		Improves uterine motility and renal perfusion
TXA2	Membrane phospholipids, platelets	Stimulation of platelet aggregation, vasoconstriction
Leukotriens	Membrane phospholipids, leukocytes	Increase vascular permeability, broncho-constriction
Histamine	Mast cells	Vasodilation and stimulation of nociceptors
Cytokines	Macrophages, lymphocytes	Cartilage degeneration, necrosis

Anti-inflammatory drugs: These are broadly divided into two groups; Corticosteroids and Non-steroidal anti-inflammatory drugs (NSAIDs).

1. Corticosteroids: Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex to perform many significant physiological functions. Many synthetic steroids have been prepared that are used to achieve various therapeutic goals. Corticosteroids can strengthen the tolerance of organism to bacterial endotoxins, antagonize and relieve the reactions caused by bacterial endotoxins. However, they can’t neutralize bacterial endotoxins, and have no defensive effects on bacterial exotoxins. Large dose of Corticosteroids has the effect of antishock (by reducing peripheral vascular resistance, improving the blockage of microcirculation they incresase returned blood volume) and are widely used in various kinds of shock like toxic shock, septic shock, anaphylactic shock and hypovolumic shock.

Salient features of natural Corticosteroids (Adrenal steroids)

Portion	Functional zone	Secretion	Functions
Adrenal cortex	Zona Glomerulosa (outermost zone)	Mineralocorticoids (Aldosterone)	Regulate electrolyte and water levels, mainly by promoting sodium retention in the kidney
	Zona Fasiculata (middle zone)	Glucocorticoids (Cortisol)	Control carbohydrate, fat and protein metabolism and are anti-inflammatory by preventing leukotriene synthesis
	Zona Reticularis (inner zone)	Sex steroids (Androgens)	Affect the growth or function of reproductive organs, the development of secondary sex characteristics, and sexual behavioral of animals
Adrenal medulla	Chromaffin cells	Catecholamines (Epinephrine and Norepinephrine)	Catecholamines cause general physiological changes that prepare the body for physical activity (fight, flight or fright response). Some typical effects are increases in heart rate, blood pressure, blood glucose levels, and a general reaction of the sympathetic nervous system

Classification of Corticosteroids

Mode of action	Category	Biological half life	Examples	Anti-inflammatory potency
Inhibition of  leukotriene synthesis via blockage of lipo-oxygenase enzyme	Short acting corticosteroids	< 12 hours	Cortisone	0.7
			Hydrocortisone	1
	Intermediate acting corticosteroids	12-36 hours	Triamcinolone	3
			Prednisone	4
			Prednisolone	5
	Long acting corticosteroids	> 36 hours	Paramethasone	10
			Dexamethasone	25
			Betamethasone	25
			Flumethasone	30

Clinical uses: They are used in shock, allergic rhinitis, conjunctivitis, rheumatoid arthritis, bursitis, synovitis, tendinitis and otitis externa (inflammation of external ear). Corticosteroids can induce labor (inhibition of leukotriene synthesis favors the conversion of entire arachidonic acid reserves into prostaglandins, including PGF₂α that causes parturition by inducing uterine contraction) in cattle and has been used (as abortificient) to terminate pregnancy in bitches.

Adverse effects and contraindications: Corticosteroids should not be used in equines as they can cause laminitis or can worsen the already existing laminitis. These drugs suppress immune response and have many depressant effects on immunoreaction. They cause lymphocyte destruction, reduce the number of the lymphocyte by moving them outside the blood vessels, induce lymphocytic apoptosis and interrupt their division and proliferation. Therefore they should not be used in immuno-compromised patients. Animals receiving systemic corticosteroids may be more susceptible to bacterial or viral infections and the immune response to vaccination may be reduced when corticosteroids are given at the same time. Corticosteroids should be avoided during pregnancy and lactation unless the benefits outweigh the risks.

2. Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs by virtue of inhibiting cyclooxygenases, are effective in suppressing inflammation, alleviating pain, and lowering fever. Cyclooxygenases (COX) (localized in endoplasmic reticulum) are responsible for the formation of a group of local hormones comprising the prostaglandins, prostacyclin, and thromboxanes (from arachidonic acid). These enzymes possess an elongated pore into which the substrate arachidonic acid is inserted and converted to an active product. NSAIDs penetrate into this pore and thus prevent access for arachidonic acid, leading to reversible blockade of the enzyme. Two principal types of COX can be distinguished: COX-1 is constitutive, that is, always present and active; it contributes to the physiological function of organs. Inhibition inevitably produces unwanted effects, such as mucosal injury, renal damage, hemodynamic changes, and disturbances of uterine function. COX-2 is induced by inflammatory processes and produces prostaglandins that sensitize nociceptors, evoke fever, and promote inflammation by causing vasodilation and an increase in vascular permeability. However, in some organs, COX-2 is also expressed constitutively (kidney, vascular endothelium, uterus, and CNS).

Non-selective COX-inhibitors: These include Acetylsalicylic acid or Aspirin (Disprin), Paracetamol or Acetaminophen (Panadol), Ibuprofen (Brufen), Meclofenamic acid (Ponston), Diclofenac (Voren, Phlogen, Dyclo, Dicloron, Diclostar, Fenac), Metamizole (Dipyrone, Magnapyrol), Phenylbutazone (Butadin), Piroxicam (Feldene) and Naproxen (Neoprox).

Selective COX-inhibitors: Meloxicam and Celecoxib are included in this group.

Pharmacological actions of NSAIDs:

(a) Antipyretic effect: The hypothalamus that is responsible for thermo-regulation, is affected by exogenous pyrogens such as bacterial toxins and endogenous pyrogens (now considered to be IL -1). Pyrogens promote the synthesis and subsequent release of prostaglandin E (PGE). PGE can raise the set-point of body temperature, in order to increase heat production, dissipate heat production, and to raise the body temperature. NSAIDs being the inhibitors of prostaglandin synthesis are helpful to restore normal thermoregulatory control mechanism.

(b) Analgesic effect: Some inflammatory mediators like prostaglandins and bradykinins are also involved in pain sensation. Therefore the anti-prostaglandinic action of NSAIDs can provide good analgesia in many conditions such as neuralgia, myalgia, joint pain, muscle pain, and so on, but these agents are not effective for the suppression of acute pain and visceral pain.

(c) Anti-inflammatory effect: Prostaglandins are key mediators in inflammatory reaction, a large number of them exist in inflammation organizations. NSAIDs have the ability to subside inflammation by inhibiting the synthesis of prostaglandins.

Clinical uses: NSAIDs are generally indicated for the symptomatic relief of the many conditions like rheumatoid arthritis (auto-immune-mediated inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints), osteoarthritis, laminitis, dysmenorrhoea (menstrual pain), metastatic bone pain, headache and migraine, postoperative pain, pyrexia (fever), renal colic, myalgia and mild-to-moderate pain due to inflammation and tissue injury. Aspirin is used (for its inhibitory effect on platelet aggregation) in dissiminated intravascular coagulation (DIC), thrombo-embolic disorders and heartworm (Dirrofilaria immitis) infection in dogs.

Adverse effects: The following side effects are linked with improper administration of NSAIDs.

1. Some prostaglandins (like PGE) possess beneficial role in terms of suppression of gastric acid secretion and regulation of renal microperfusion. Thus prostaglandin inhibitors (NSAIDs) can cause (or aggravate) gastric hyperacidity and renal disturbances.

2. Inhibition of TXA₂ synthesis by NSAIDs results in profused bleeding and delayed clotting time (via inhibiting platelet aggregation). This property can be benefited to resolve intravascular thrombi (that can cause embolism and ischemia) in some cardiac disorders like myocardial infarction.

3. NSAIDs that are acidic in nature (like Aspirin and Paracetamol) undergo hepatic metabolism through glucoronide conjugation. Species that are inherently deficient in glucoronide conjugatory mechanism (such as glucoronyl transferase deficiency) are susceptible to serious toxicosis (the half life of these drugs is abnormally prolonged due to lack of sufficient biotransformation). Acetylcysteine (precursor of Glutathione and potent antioxidant) should be used to suppress free radical induced cellular damage that occurs during this idiosyncratic condition.

4. Large doses of Aspirin may cause hyperglycemia (by uncoupling phosphorylation during glycolysis) followed by glycosuria (release of glucose in urine) and deplete liver and muscle glycogen.

5. In humans the use of Aspirin has been implicated in the causation of salicylism (a syndrome that is characterized by dizziness, vertigo and reversible visual and auditory impairment) and Reye’s syndrome (occurs in infants suffering from viral infection and it is manifested by hepatic damage and encephalopathy).

6. Metamizole is known to cause agranulocytosis (decresed synthesis of agranuloctes; lymphocytes and monocytes).

Contraindications: NSAIDs are contraindicated in persons suffering from gastrointestinal ulceration, bleeding disorders and human infants (having viral infection). Aspirin therapy should be stopped one week before surgery (to avoid excessive bleeding), and it should be used cautiously in species with improper metabolizing potential (cats and fish).

Interactions: Aspirin enhances the action and toxicity of oral anticoagulants and Heparin by increasing risk of bleeding.  The urinary excretion of acidic NSAIDs is increased and decreased by the concomitant administration of urinary alkalizers (like sodium bi carbonate) and urinary acidifiers (like ammonium chloride) respectively.

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)