Pharma Drugs PDF

- Awacoid , Asmotherapy. o Pharma Drugs...  Cardio Vascular System > - Anti-Arrhythmica > - Anti-Anginal Vascular Disease > - Peripheral > - Calcium channel blockers > - Anti-Hypertensives. ...

- Awacoid , Asmotherapy. o Pharma Drugs...  Cardio Vascular System > - Anti-Arrhythmica > - Anti-Anginal Vascular Disease > - Peripheral > - Calcium channel blockers > - Anti-Hypertensives.  AntiArrhythmic Drugs 573 CHAPTER 39 A simplified clinical classification of anti- effect on resting channels. They also moderately arrhythmic drugs is given at the end of the delay channel recovery (channel recovery time chapter. τrecovery 1–10s), suppress A-V conduction and prolong refractoriness. The Na+ channel blockade CLASS I is greater at higher frequency (premature depolarization is affected more). These actions The primary action of drugs in this class is to serve to extinguish ectopic pacemakers that are limit the conductance of Na+ (and K+) across often responsible for triggered arrhythmias and cell membrane—a local anaesthetic action. They abolish reentry by converting unidirectional also reduce rate of phase-4 depolarization in automatic cells. block into bidirectional block. The class I drugs bind easily to the activated Quinidine and/or inactivated state of the Na + channel, but poorly to the resting state. As such, they It is the dextro isomer of the antimalarial alkaloid quinine found in cinchona bark. In addition to Na+ channel block- block more when activation and inactivation is ade, quinidine has cardiac antivagal action which augments fast, i.e. in rapidly firing fibres. This is also prolongation of atrial ERP and minimizes RP disparity called ‘use dependent’ blockade. Further, the of atrial fibres. A-V node ERP is increased by direct action of quinidine, but decreased by its antivagal action; partially depolarized fibres are blocked to a overall effect is inconsistent. Quinidine depresses myocar- greater extent, because in them greater number dial contractility; failure may be precipitated in damaged of Na+ channels are in the inactivated state. hearts. ECG: Quinidine increases P-R and Q-T intervals and SUBCLASS IA tends to broaden QRS complex. Changes in the shape of T wave may be seen reflecting effect on repolarization. The subclass IA containing the oldest anti- Mechanism of action: Quinidine blocks myocardial Na+ arrhythmic drugs quinidine and procainamide channels in the open state—reduces automaticity and rate are open state Na+ channel blockers with little of 0 phase depolarization in a frequency dependent manner.  AntiAnginAl And Other Anti-ischAemic drugs 585 Chronically reduced blood supply causes atrophy of cardiac muscle with fibrous replace­ ment (reduced myocardial work capacity → CHF) and may damage conducting tissue to produce unstable cardiac rhythms. Antianginal drugs relieve cardiac ischaemia but do not alter the course of coronary artery disease (CAD); no permanent benefit is afforded. On the other hand, aspirin, ACE inhibitors and statins (hypocholesterolaemic) can modify coronary artery disease and improve prognosis. Glyceryl trinitrate, the drug unsurpassed in its ability to abort and terminate anginal attack, was introduced by Murrell in 1879. Other organic nitrates were added later, but a breakthrough was achieved in 1963 when propranolol was used for chronic prophylaxis. The calcium channel blockers have been a major contribution of the 1970s. A number of vasodilator and other drugs have been promoted from time to time, but none is uniformly effective. Some potassium channel openers (nicor- andil), metabolic modulator (trimetazidine), late Na+ current CHAPtEr 40 inhibitor (ranolazine) and heart rate lowering (ivabradine) have been introduced lately. Clinical classification A. Used to abort or terminate attack GTN, Fig. 40.2: Diagrammatic representation of coronary artery Isosorbide dinitrate (sublingually). calibre changes in classical and variant angina B. Used for chronic prophylaxis All other drugs. deposition and progressive occlusion of the coronary artery; occasionally with associated nitrAtEs (gtn as prototype) coronary vasospasm. Patients with UA are at All organic nitrates share the same action; differ high risk of myocardial infarction (MI). only in time course. The only major action is  AntiAnginAl And Other Anti-ischAemic drugs 601 drugs FOr PEriPHErAl diesterase (PDE) inhibitor, which has been shown VAsCulAr disEAsEs to increase blood flow in ischaemic areas by Peripheral vascular diseases (PVDs) are either primarily reducing whole blood viscosity and by improving occlusive (Buerger’s disease with intermittent claudication flexibility of RBCs. The rheological (dealing with of legs), or mainly vasospastic (Raynaud’s phenomenon property of flow) action rather than vasodilatation with episodic blanching ± cyanosis of fingers followed by hyperaemia), or both as in arteriosclerotic/diabetic vascular is said to be responsible for improving passage insufficiency, ischaemic leg ulcers, frost bite, gangrene, of blood through microcirculation. Oral doses cerebrovascular inadequacy, etc. Increased cardiovascular do not affect heart rate, t.p.r. or BP. risk is associated with all PVDs. Measures that reduce Pentoxiphylline is usually well tolerated: side cardiovascular risk (smoking cessation, BP normalization, antiplatelet drugs, diabetes control, statins, weight manage- effects are nausea, vomiting, dyspepsia and ment, exercise training) have salutary effect on PVDs as bloating which can be minimized by taking well. In addition, vasodilators and many other types of the drug after meals. drugs are used (see Chart). Most of these drugs have other primary indications and are described elsewhere in Dose: 400 mg BD–TDS; TRENTAL-400, FLExITAL 400 the book. The remaining are briefly considered below. mg SR tab, 300 mg/15 ml for slow i.v. injection. 1. Cyclandelate It is a papaverine like general smooth Pentoxiphylline is mainly used in intermittent claudication muscle relaxant which increases cutaneous, skeletal muscle (calf pain on walking) due to occlusive vascular disease and cranial blood flow in normal individuals. However, (Buerger’s disease). Other conditions claimed to be improved benefits in PVD are minor and restricted to conditions are: trophic leg ulcers, transient ischaemic attacks (TIAs), CHAPtEr 40 with vasospasm. Side effects are flushing, palpitation and and chronic cerebrovascular insufficiency. However, overall headache. benefits are minimal. Dose: 200–400 mg TDS; CYCLOSPASMOL, CYCLASYN 4. Cilostazol This is a PDE-3 inhibitor (like 200, 400 mg tab/cap. the inodilator inamrinone and milrinone, (see 2. Xanthinol nicotinate (nicotinyl xanthinate) It is p. 568) which increases intracellular cAMP in a compound of xanthine and nicotinic acid, both of which platelets and vascular smooth muscle resulting are vasodilators. It increases blood flow in many vascular beds and has been promoted for cerebrovascular disorders in antiaggregatory and vasodilator effects. In and PVDs, but therapeutic benefits are insignificant. clinical trials it has increased walking distance Dose: 300–600 mg TDS oral; 300 mg by i.m. or slow in patients with intermittent claudication and i.v. injection; COMPLAMINA 150 mg tab, 500 mg retard appears to be more effective than pentoxiphyl- tab, 300 mg/2 ml inj. line. Since long-term oral milrinone therapy for 3. Pentoxiphylline (Oxpentifylline) An heart failure has increased cardiac mortality and analogue of theophylline and a weak phospho- has been discontinued, concern is expressed  592 cArdiOvAsculAr drugs Voltage sensitive calcium channels l-type t-type n-type (Long lasting current) (Transient current) (Neuronal) 1. Conductance 25 pS 8 pS 12–20 pS 2. Activation threshold High Low Medium 3. Inactivation rate Slow Fast Medium 4. Location and function Excitation-contraction SA node—pace-maker Only on neurones in coupling in cardiac and activity CNS, sympathetic and smooth muscle ‘T’ current and repetitive myenteric plexuses — SA, A-V node— spikes in thalamic and transmitter release conductivity other neurones Endocrine cells— Endocrine cells— hormone release hormone release Neurones—transmitter Certain arteries— release constriction 5. Blocker Nifedipine, diltiazem, Mibefradil, flunarizine, ω-Conotoxin verapamil ethosuximide sECtiOn 8 (a) Voltage sensitive channel Activated when membrane Skeletal muscle L-channels are: α1s. α2/δa. β1. γ potential drops to around –40 mV or lower. Cardiac muscle L-channels are: α1ca. α2/δc. β2 (b) Receptor operated channel Activated by Adr and Smooth muscle L-channels are: α1cb. α2/δ. β3 other agonists—independent of membrane depolarization Even smooth muscle L-channels differ between vascular (NA contracts even depolarized aortic smooth muscle by and nonvascular. Moreover, distribution may be heteroge- promoting influx of Ca2+ through this channel and releasing neous in different parts of the vascular bed. Ca2+ from sarcoplasmic reticulum). Only the voltage sensitive L-type channels are blocked by the CCBs. All CCBs bind primarily to the open and (c) Leak channel Small amounts of Ca2+ leak into the inactivated states of the channel, and minimally to the resting cell and are pumped out by Ca2+ATPase. Mechanical resting state. The 3 groups of CCBs viz. phenylalkylamines stretch promotes inward movement of Ca2+, through the (verapamil), benzothiazepine (diltiazem) and dihydropyridines leak channel or through separate stretch sensitive channel. (nifedipine) bind to their own specific binding sites on the The voltage sensitive Ca2+ channels are heterogeneous: α1 subunit; all restricting Ca2+ entry, though characteristics three major types have been identified (see box): of channel blockade differ. Further, different drugs may All voltage sensitive Ca2+ channels are membrane spanning have differing affinities for various site specific isoforms funnel shaped glycoproteins that function as ion selective of the L-channels. This may account for the differences valves. They are composed of a major α1 subunit which in action exhibited by various CCBs. The vascular smooth encloses the ion channel and other modulatory subunits muscle has a more depolarized membrane (RMP about like α2,β, γ and δ. In L-type Ca2+ channels each subunit –40 mV) than heart. This may contribute to the vascular exists in multiple isoforms which may be site specific, e.g. selectivity of certain CCBs.  Antihypertensive Drugs 605 CHAPTER 41 DIURETICS megatrials have been carried out with these two only. Chlorthalidone is longer acting Diuretics have been the standard antihypertensive (~ 48 hours) than HCZ (< 24 hours) and may drugs over the past nearly 5 decades, though have better round-the-clock action; favoured by they do not lower BP in normotensives. Their the NICE guidelines. Indapamide (see later) is pharmacology is described in Ch. 42. also mainly used as antihypertensive, and is Thiazides Hydrochlorothiazide (HCZ) and equally effective. Other members of the thiazide chlorthalidone are the diuretic of choice for class should not be considered interchangeable uncomplicated hypertension; have similar ef- with these as antihypertensive. The proposed ficacy and are dose to dose equivalent. All mechanism of antihypertensive action is:  Drugs Affecting Coagulation, Chapter 45 Bleeding and Thrombosis Haemostasis (arrest of blood loss) and blood In addition to its critical role in cleaving and coagulation involve complex interactions between polymerizing fibrinogen, thrombin activates many the injured vessel wall, platelets and coagulation upstream factors (especially f. XI, VIII and factors. For blood to clot, a cascading series of V) of the intrinsic and common pathways— proteolytic reactions (Fig. 45.1) is started by: amplifying its own generation and continuation (i) Contact activation of Hageman factor: of clot formation. It is also a potent activator intrinsic system, in which all factors needed of platelets. for coagulation are present in the plasma. This On the other hand, factors like antithrombin, pathway is responsible for clotting when blood protein C, protein S, antithromboplastin and the is kept in a glass tube, and for amplification of fibrinolysin system tend to oppose coagulation the common pathway. This is slow and takes and lyse formed clot. Thus, a check and bal- several minutes to activate factor X. ance system operates to maintain blood in a (ii) Tissue thromboplastin: extrinsic system, fluid state while in circulation and allows rapid needs a tissue factor, but activates factor X in haemostasis following injury. seconds. In the normal course, coagulation after injury to vessel wall occurs by this pathway. COAGULANTS The subsequent events are common in the These are substances which promote coagulation, two systems and result in polymerization of and are indicated in haemorrhagic states. fibrinogen to form fibrin strands. Blood cells Fresh whole blood or fresh frozen plasma are trapped in the meshwork of fibrin strands provide all the factors needed for coagulation producing clot. and are the best therapy for deficiency of any Two in vitro tests ‘activated partial thromboplastin time’ (aPTT) and ‘prothrombin time’ (PT) are employed for testing clotting factor. Moreover, they act immediately. integrity of the intrinsic, extrinsic and common pathways Other drugs used to restore haemostasis are: of the coagulation cascade. The results are interpreted as: PT aPTT Intrinsic pathway Normal Prolonged interfered (12–14S) Extrinsic pathway Prolonged Normal interfered (26–32S) Common pathway Prolonged Prolonged interfered Most clotting factors are proteins present in plasma in the inactive (zymogen) form. By partial proteolysis they themselves become an active protease and activate the next factor.  Drugs Affecting coAgulAtion, BleeDing AnD thromBosis 663 is inadequate. Astringents such as tannic acid Heparin carries strong electronegative charges or metallic salts are occasionally applied for and is the strongest organic acid present in the bleeding gums, bleeding piles, etc. body. It occurs in mast cells as a much bigger molecule (MW ~75,000) loosely bound to the SCLEROSING AGENTS granular protein. Thus, heparin is present in all These are irritants, cause inflammation, coagulation tissues containing mast cells; richest sources are and ultimately fibrosis, when injected into haemorrhoids (piles) lung, liver and intestinal mucosa. Commercially or varicose vein mass. They are used only for local injection. it is produced from ox lung and pig intestinal 1. Sod. tetradecyl sulfate (3% with benzyl alcohol 2%): 0.5–2 ml at each site. SETROL 2 ml inj. mucosa. 2. Polidocanol (3% inj): 2 ml; ASKLEROL 2 ml inj. Actions 1. Anticoagulant Heparin is a powerful and ANTICOAGULANTS instantaneously acting anticoagulant, effective These are drugs used to reduce the coagulability both in vivo and in vitro. It acts indirectly of blood. They are classified in the chart. by activating plasma antithrombin III (AT III, a serine proteinase inhibitor). The heparin-AT HEPARIN III complex then binds to clotting factors of CHAPTER 45 McLean, a medical student, discovered in 1916 that liver the intrinsic and common pathways (Xa, IIa, contains a powerful anticoagulant. Howell and Holt (1918) IXa, XIa, XIIa and XIIIa) and inactivates them named it ‘heparin’ because it was obtained from liver. but not factor VIIa operative in the extrinsic However, it could be used clinically only in 1937 when pathway. At low concentrations of heparin, fac- sufficient degree of purification was achieved. tor Xa mediated conversion of prothrombin to Chemistry and occurrence Heparin is a thrombin is selectively affected. The anticoagu- non-uniform mixture of straight chain mucopoly- lant action is exerted mainly by inhibition of saccharides with MW 10,000 to 20,000. It contains factor Xa as well as thrombin (IIa) mediated polymers of two sulfated disaccharide units: conversion of fibrinogen to fibrin. iduronic acid  D-glucosamine-L- chain length and proportion of the two disaccharide units Low concentrations of heparin prolong aPTT without significantly prolonging PT. High concen-  D-glucosamine-D- varies. Some glucosamine trations prolong both. Thus, low concentrations glucuronic acid  residues are N-acetylated. interfere selectively with the intrinsic pathway,  Drugs Affecting coAgulAtion, BleeDing AnD thromBosis 677 Prostacyclin (PGI2), synthesized in the intima of blood Inhibition of COX-1 by aspirin in vessel vessels, is a strong inhibitor of platelet aggregation. A wall decreases PGI2 synthesis as well. However, balance between TXA2 released from platelets and PGI2 released from vessel wall appears to control intravascular since intimal cells can synthesize fresh enzyme, thrombus formation. Platelets also play a role in atherogenesis. COX activity returns rapidly. It is possible that at low doses (75–150 mg/day or 300 mg twice In the above scheme, various drugs act on weekly), TXA2 formation by platelets is selectively different targets to interfere with platelet function. suppressed, whereas higher doses (> 900 mg/day) Therefore, given together, their actions are CHAPTER 45 may decrease both TXA2 and PGI2 production. synergistic. The clinically important antiplatelet drugs are classified in the chart: Aspirin inhibits the release of ADP from platelets and their sticking to each other, but Aspirin It acetylates the enzyme COX1 and has no effect on platelet survival time and their TX-synthase—inactivating them irreversibly. adhesion to damaged vessel wall. TXA2 activates platelets to change shape and ASA 50 mg tab., COLSPRIN, DISPRIN CV-100: aspirin 100 release mediator rich granules which promote mg soluble tab, LOPRIN 75 mg tab, ASPICOT 80 mg tab, ECOSPRIN 75, 150 mg tab. aggregation. Because TXA2 is the major ara- Other NSAIDs are reversible inhibitors of COX, pro- chidonic acid product generated by platelets, duce short-lasting inhibition of platelet function—are not and that platelets are exposed to aspirin in clinically useful. the portal circulation before it is deacetylated Dipyridamole It is a vasodilator that was during first pass in the liver, and because introduced for angina pectoris (see Ch. 40). platelets cannot synthesize fresh enzyme (have It inhibits phosphodiesterase as well as blocks no nuclei), TXA2 formation is suppressed at uptake of adenosine to increase platelet cAMP very low doses and till fresh platelets are which in turn potentiates PGI2 and interferes formed. Thus, aspirin induced prolongation with aggregation. Levels of TXA2 or PGI2, are of bleeding time lasts for 5–7 days. Effect of not altered, but platelet survival time reduced daily doses cumulates and it has been shown by disease is normalized. that doses as low as 40 mg/day have some Dipyridamole alone has little clinically effect on platelet aggregation. Maximal inhibi- significant effect, but improves the response tion of platelet function occurs at 75–150 mg to warfarin, along with which it is used to aspirin per day. The American (ACC/AHA)* decrease the incidence of thromboembolism in guidelines recommend a dose of 75–162 mg/ patients with prosthetic heart valves. day for long-term aspirin prophylaxis. However, Dipyridamole has also been used to enhance aspirin may not effectively inhibit platelet the antiplatelet action of aspirin. This combination aggregation in certain individuals, who are may additionally lower the risk of stroke in labelled as ‘aspirin resistant’. patients with transient ischaemic attacks (TIAs), * ACC/AHA—American College of Cardiology/American Heart Association  Hypolipidaemic drugs 683 way as on Chy and the fatty acids pass into adipose (b) Multiple genetic, dietary and physical acti- tissue and muscle; the remnant called intermediate den- sity lipoprotein (IDL) now contains more CHE than TG. vity related causes: ‘polygenic’ or multi- CHAPTER 46 About half of the IDL is taken back by the liver cells factorial. by attachment to another receptor (LDL receptor), while On the whole, LDL is the primary carrier of the rest loses the remaining TGs gradually and becomes low density lipoprotein (LDL) containing only CHE. The plasma CHE, and VLDL that of TGs. The LDL circulates in plasma for a long time; its uptake into important features of major types of hyperli- liver and other tissues is dependent on the need for CH. poproteinaemias are given in Table 46.2. The rate of LDL uptake is regulated by the rate of LDL The mechanism of action and profile of lipid receptor synthesis in a particular tissue. Cholesterol is lowering effect of important hypolipidaemic also synthesized in the body by reduction of 3-Hydroxy-3 methyl glutaryl coenzyme A (HMG-CoA) to mevalonate drugs is summarized in Table 46.3. (rate limiting step). The CHE of LDL is deesterified and used mainly for HMG-CoA REDuCTAsE InHIbIToRs cell membrane formation. The CH released into blood (statins) from degradation of membranes is rapidly incorporated in high density lipoproteins (HDL), esterified with the Introduced in the 1980s, this class of compounds help of an enzyme lecithin: cholesterol acyltransferase are the most efficacious, most commonly used (LCAT) and transferred back to VLDL or IDL, complet- and best tolerated hypolipidaemic drugs. They ing the cycle. competitively inhibit conversion of 3-Hydroxy- The excess lipoproteins in plasma are phagocytosed by macrophages for disposal. When too much of lipoproteins 3-methyl glutaryl coenzyme A (HMG-CoA) to have to be degraded in this manner, CH is deposited in mevalonate (rate limiting step in CH synthesis) atheromas (in arterial walls) and xanthomas (in skin and by the enzyme HMG-CoA reductase. Therapeutic tendons). Raised levels of VLDL, IDL and LDL (rarely Chy doses reduce CH synthesis by 20–50%. This and Chy. rem. also) are atherogenic, while HDL may be pro- results in compensatory increase in LDL receptor tective, because HDL facilitates removal of CH from tissues. expression on liver cells and causes increased Hyperlipoproteinaemias can be: receptor mediated uptake and catabolism of IDL (i) Secondary: associated with diabetes, myxo- and LDL. Over long-term, feedback induction edema, nephrotic syndrome, chronic alcoholism, of HMG-CoA reductase tends to increase CH drugs (corticosteroids, oral contraceptives, β synthesis, but a steady-state is finally attained with blockers) etc. a dose-dependent lowering of LDL-CH levels. (ii) Primary: due to: Different statins differ in their potency and (a) A single gene defect: is familial and called maximal efficacy in reducing LDL-CH. The dose ‘monogenic’ or genetic. dependent effect of various statins on plasma  Antirheumatoid and Chapter 15 Antigout Drugs AntirheumAtoid drugs Rheumatoid arthritis (RA) is an autoimmune disease in which there is joint inflammation, These are drugs which (except corticosteroids), synovial proliferation and destruction of articular can suppress the rheumatoid process, bring about cartilage. Immune complexes composed of IgM a remission and retard disease progression, but activate complement and release cytokines do not have nonspecific antiinflammatory or (mainly TNFα and IL-1) which are chemotactic analgesic action. They are used in rheumatoid for neutrophils. These inflammatory cells secrete arthritis (RA) in addition to NSAIDs, and are lysosomal enzymes which damage cartilage also referred to as disease modifying antirheumatic and erode bone, while PGs produced in the drugs (DMARDs) or slow acting antirheumatic process cause vasodilatation and pain. RA is a drugs (SAARDs). The onset of benefit with chronic progressive, crippling disorder with a DMARDs takes a few months of regular waxing and waning course. Multiple small joints treatment, and relapses occur at least a few of hands and feet are preferentially affected; months after cessation of therapy. Recently, deformities are produced as the disease progresses. some biological agents (antibodies and other NSAIDs are the first line drugs which afford proteins) have been added for resistant cases. symptomatic relief in pain, swelling, morning  ANTIRhEUmATOID AND ANTIGOUT DRUGS 231 it precipitates and deposits in joints, kidney over colchicine. Their strong antiinflammatory and subcutaneous tissue (tophi). (not uricosuric) action is responsible for the Secondary hyperuricaemia occurs in: benefit. Naproxen and piroxicam specifically inhibit chemotactic migration of leucocytes (a) Leukaemias, lymphomas, polycythaemia— into the inflamed joint. After the attack is especially when treated with chemotherapy or over, NSAIDs should be continued at lower radiation. This is due to enhanced nucleic acid doses for 3–4 weeks while drugs to control metabolism and uric acid production. hyperuricaemia take effect. (b) Drug induced—thiazides, furosemide, pyra- ChAPter 15 zinamide, ethambutol, levodopa reduce uric acid 2. Colchicine excretion by kidney. It is an alkaloid from Colchicum autumnale ACUTE GOUTy ArThriTis which has been used in gout since 1763. The pure alkaloid was isolated in 1820. Colchicine Acute gout manifests as sudden onset of severe is neither analgesic nor antiinflammatory, but inflammation in a small joint (commonest is it specifically suppresses gouty inflammation. It metatarso-phalangeal joint of great toe) due to does not inhibit the synthesis or promote the precipitation of urate crystals in the joint space. excretion of uric acid. The joint becomes red, swollen and extremely An acute attack of gout is started by the painful and requires immediate treatment with precipitation of urate crystals in the synovial strong antiinflammatory drugs, without attempting fluid. On being engulfed by the synovial cells, to lower blood urate level. When the attack they release mediators and start an inflammatory subsides, urate lowering therapy is instituted, and response. Chemotactic factors are produced → antiinflammatory cover is continued for several granulocytes migrate into the joint; they phago- weeks. If hyperuricaemia is not controlled, the cytose urate crystals and release a glycoprotein attacks recur, involve many joints, and result which aggravates the inflammation by: in chronic deforming arthritis. Increasing lactic acid production from inflam- matory cells → local pH is reduced → more 1. nsAids urate crystals are precipitated. One of the strong antiinflammatory drugs, e.g. Releasing lysosomal enzymes which cause naproxen, piroxicam, diclofenac, indomethacin joint destruction. or etoricoxib is given in relatively high Colchicine does not affect phagocytosis of urate and quickly repea ted doses. They are quite crystals, but inhibits release of chemotactic effective in terminating the attack, but may take factors and of the glycoprotein, thus suppressing 12–24 hours, while complete resolution takes the subsequent events. By binding to fibrillar 5–10 days. Response is somewhat slower than protein tubulin, it inhibits granulocyte migration with colchicine, but they are generally better into the inflamed joint and thus interrupts the tolerated. Majority of patients prefer NSAIDs vicious cycle. Other actions of colchicine are: Chapter 42 Diuretics Diuretics (natriuretics) are drugs which cause a was produced in 1957, and by early 1960s its conge- net loss of Na+ and water in urine. However, ners (thiazide diuretics) were already in common use. Availability of furosemide and ethacrynic acid by mid when a diuretic is given regularly, Na+ balance 1960s revolutionized the pattern of diuretic use. The is soon restored by compensatory homeostatic aldosterone antagonist (spironolactone) and other K + mechanisms of the body, albeit with a certain sparing diuretics (triamterene/amiloride) were developed degree of persisting Na+ deficit and reduction in parallel to these. in extracellular fluid volume. Diuretics are among the most widely pres- Based on the diuretic action of calomel, organomercu- cribed drugs. Application of diuretics in the rials given by injection were introduced in the 1920s management of hypertension has outstripped and dominated for nearly 40 years. The CAse inhibitors their use in edema. Availability of diuretics has were developed in the 1950s from the observation that early sulfonamides caused acidosis and mild diuresis. also had a major impact on the understanding The first modern orally active diuretic chlorothiazide of renal physiology. Chapter 43 Antidiuretics Antidiuretics (more precisely ‘anti-aquaretics’, release ADH even before plasma osmolarity is because they inhibit water excretion without increased by the ingested salt. Impulses from affecting salt excretion) are drugs that reduce baroreceptors and higher centres also impinge urine volume, particularly in diabetes insipidus on the nuclei synthesizing ADH and affect its (DI) which is their primary indication. release. The two main physiological stimuli for ADH release are rise in plasma osmolarity and contraction of e.c.f. volume. Several neurotransmitters, hormones and drugs modify ADH secretion. It is enhanced by angiotensin II, prostaglandins (PGs), histamine, neuropeptide Y and ACh, while GABA and atrial natriuretic peptide (ANP) decrease its release. Opioids have agent-specific and dose dependent action. Low-dose morphine inhibits ADH secretion, but high doses enhance it. Opioid peptides are mostly inhibitory. Nicotine and imipramine stimulate, while alcohol, haloperidol, phenytoin and glucocorticoids decrease ADH release. ANTIDIURETIC HORMONE (Arginine Vasopressin—AVP) The 8-lysine-vasopressin (lypressin) is found in swine and has been synthetically prepared The human antidiuretic hormone (ADH) is for clinical use. Other more potent and longer 8-arginine vasopressin (AVP), which is a acting peptide analogues of AVP having agonistic nonapeptide secreted by posterior pituitary as well as antagonistic action have also been (neurohypophysis) along with oxytocin (see prepared. Ch. 23). It is synthesized in the hypothalamic (supraoptic and paraventricular) nerve cell ADH (Vasopressin) receptors bodies as a large precursor peptide along with These are G protein coupled cell membrane its binding protein ‘neurophysin’. Both are receptors; two subtypes V1 and V2 have been transported down the axons to the nerve endings identified, cloned and structurally characterized. in the median eminence and pars nervosa. Osmoreceptors present in hypothalamus and V 1 Receptors All vasopressin receptors volume receptors present in left atrium, ventricles except those on renal collecting duct (CD) and pulmonary veins primarily regulate the rate cells, thick ascending limb of loop of Henle of ADH release governed by body hydration. (TAL) cells and vascular endothelium are of Osmoreceptors are also present in the hepatic the V1 type. These are further divided into V1a portal system which sense ingested salt and and V1b subtypes:  DruGs for PePtic ulcer anD GastroesoPhaGeal reflux Disease 697 CHAPTER 47 1. H2 blockade All clinically used H2 block- response to not only histamine but all other stimuli ers are competitive antagonists of histamine (ACh, gastrin, insulin, alcohol, food) is attenuated. at the H2 receptors, but with famotidine the This reflects the permissive role of histamine antagonism is partly noncompetitive due to in amplifying responses to other secretagogues. stronger binding to the H 2 receptors. These The volume of gastric juice, pepsin content and drugs block histamine-induced gastric secretion, intrinsic factor secretion are all reduced, but the cardiac stimulation (prominent only in isolated most marked effect is on acid secretion. Despite preparations, especially in guinea pig), uterine reduction in intrinsic factor secretion, normal relaxation (in rat) and bronchial relaxa tion vit B12 absorption is not interfered: no vit B12 (in sheep). Human bronchial muscles express deficiency occurs even after prolonged use. both contractile H1 and relaxant H2 receptors. The usual ulcer healing doses produce Normally the H1 response predominates, but 60–70% inhibition of 24 hr acid output. The H2 mediated relaxation can be demonstrated H2 blockers have antiulcerogenic effect. Gastric after H1 blockade. As such, H2 blockers can ulceration due to stress and drugs (NSAIDs, potentiate histamine-induced bronchospasm. H2 cholinergic, histaminergic) is prevented. H2 blockers attenuate fall in BP due to histamine, blockers have no direct effect on gastric or especially the late phase response seen with high esophageal motility or on lower esophageal doses. This is due to blockade of relaxant H2 sphincter (LES) tone. receptors located directly on vascular smooth Pharmacokinetics Cimetidine is adequately muscle. These antagonists are highly selective: absorbed orally, though bioavailability is 60–80% have no effect on H1 mediated responses or on due to first pass hepatic metabolism. It crosses the action of other transmitters/autacoids. placenta and reaches milk, but penetration in 2. Gastric secretion The only significant in brain is poor because of its hydrophilic nature. vivo action of H2 blockers is marked inhibition About 2/3 of a dose is excreted unchanged in of gastric secretion. All phases (basal, psychic, urine and bile, the rest as oxidized metabolites. neurogenic, gastric) of secretion are suppressed The elimination t½ is 2–3 hr, but duration of dose-dependently, but the basal nocturnal acid action is longer, and to some extent dose depen- secretion is suppressed more completely. Secretory dent. Dose reduction is needed in renal failure.  antiemetic, Prokinetic anD DiGestant DruGs 711 CHAPTER 48 ANTICHOLINERGICS (See Ch. 8) antihistaminic, weak antidopaminergic and Hyoscine (0.2–0.4 mg oral, i.m.) is the most sedative properties. effective drug for motion sickness. However, it Promethazine, diphenhydramine, dimenhydri- has a brief duration of action; produces seda- nate These drugs afford protection from motion tion, dry mouth and other anticholinergic side sickness for 4–6 hours, but produce sedation effects. Hyoscine is suitable only for short brisk and dryness of mouth. Driving is not advisable journies. Antiemetic action is exerted probably after taking these anti-motion sickness drugs. By by blocking conduction of nerve impulses their central anticholinergic action they block the across a cholinergic link in the pathway leading extrapyramidal side effects of metoclopramide from the vestibular apparatus to the vomiting while supplementing its antiemetic action. Pro- centre and has poor efficacy in vomiting of methazine is a phenothiazine; has weak central other etiologies. antidopaminergic action as well. Combination A transdermal patch containing 1.5 mg of hyoscine, to be of these antihistaminics with other antiemetics delivered over 3 days has been developed. Applied behind has been used in chemotherapy-induced nausea the pinna, it suppresses motion sickness while producing only mild side effects. and vomiting (CINV). Dicyclomine (10–20 mg oral) has been used Promethazine theoclate (AVOMINE 25 mg tab.) for prophylaxis of motion sickness and for This salt of promethazine has been specially morning sickness (see p. 129). It has been promoted as an antiemetic, but the action does cleared of teratogenic potential. not appear to be significantly different from promethazine HCl. H1 ANTIHISTAMINICS (See Ch. 11) Doxylamine It is a sedative H1 antihistaminic Some antihistaminics are antiemetic. They are with prominent anticholinergic activity. Marketed useful mainly in motion sickness and to a lesser in combination with pyridoxine, it is specifi- extent in morning sickness, postoperative and cally promoted in India for ‘morning sickness’ some other forms of vomiting. Their antiemetic (vomiting of early pregnancy), although such use effect appears to be based on anticholinergic, is not made in UK and many other countries.  Drugs for Constipation Chapter 49 and Diarrhoea LAXATIVES MECHANISM OF ACTION (Aperients, Purgatives, Cathartics) All purgatives increase the water content of These are drugs that promote evacuation of the faeces by: bowels. A distinction is sometimes made (a) A hydrophilic or osmotic action, retaining according to the intensity of action. water and electrolytes in the intestinal (a) Laxative or aperient: milder action, lumen—increase volume of colonic content elimination of soft but formed stools. and make it easily propelled. (b) Purgative or cathartic: stronger action resulting in more fluid and forceful evacuation. (b) Acting on intestinal mucosa, decrease net Many drugs in low doses act as laxative absorption of water and electrolyte; intesti- and in larger doses as purgative. The distinction, nal transit is enhanced indirectly by the fluid thus is vague. bulk.  DruGs for Constipation anD Diarrhoea 731 CHAPTER 49 norfloxacin, doxycycline or cotrimoxazole reduce The tolerability profile of rifaximin is similar the duration of diarrhoea and total fluid needed to placebo. Side effects are flatulence, abdominal only in severe cases. pain, defecation urgency and headache. Because Rifaximin It is a minimally absorbed oral rifa- of poor absorption, systemic toxicity is not mycin (related to rifampin) active against E. coli expected. Dose: For empiric treatment of diarrhoea 200–400 mg and many other gut pathogens. It is approved TDS for 3 days; for prevention of hepatic encephalopathy by US-FDA for the empiric treatment of travel- 550 mg TDS. lers’ diarrhoea and is frequently used in India RIFAGUT, TORFIX, RACFAX 200, 400 mg tabs, RIXIMIN now in a dose of 400 mg TDS for 3 days. 200, 400, 550 mg tabs. A review of data from controlled trials using (3) Invasive diarrhoea: Severe cases with blood rifaximin 200 mg TDS for 3 days has rated it and mucus in stools, fever, cramps caused by to be superior to placebo, and as effective as EPEC, Shigella, non-typhoid Salmonella, Yersinia ciprofloxacin in reducing duration of travellers’ enterocolitica, etc. need to be treated empiri- diarrhoea, irrespective of whether the causative cally with ciprofloxacin, ofloxacin, norfloxacin, pathogen was identified or not. It has also been cotrimoxazole or doxycycline for symptomatic used in diarrhoeal phase of IBS as well as relief as well as for eradicating the pathogen. for prophylaxis before and after gut surgery. A C. Antimicrobials are useful in all cases: higher strength (550 mg) tablet is marketed for Cholera: Though only fluid replacement is reducing the risk of hepatic encephalopathy recur- life saving, tetracyclines reduce stool volume rence by suppressing NH3 forming gut bacteria. to nearly half. Cotrimoxazole is an alterna- Patients with complaints of bloating, flatulence tive, especially in children. Lately, multidrug and flatus have reported subjective relief while resistant cholera strains have arisen. These taking rfaximin 400 mg BD, probably due to can be treated with norfloxacin/ciprofloxacin. suppression of gas producing colonic bacteria. Ampicillin and erythromycin are also effective. Section 4 Respiratory System Drugs Drugs for Cough and Chapter 16 Bronchial Asthma DRUGS FOR COUGH to drain the airway; its suppression is not Cough is a protective reflex, its purpose being desirable; may even be harmful, except when expulsion of respiratory secretions and foreign the amount of expectoration achieved is small particles from air passages. It occurs due to compared to the effort of continuous coughing. stimulation of mechano- or chemoreceptors The commonest cause of acute cough (lasting in throat and respiratory passages or stretch < 3 weeks) is respiratory viral infections. Apart receptors in the lungs. Cough may be useful or from specific remedies (antibiotics, etc. see useless. Useless (nonproductive) cough should box on p. 238), cough may be treated as a be suppressed. Useful (productive) cough serves symptom (nonspecific therapy) with: O more d recommended -Read depress della-Notcenters children  242 RESPIRATORY SYSTEM DRUGS SECTION 4 8. Directly acting bronchodilators—methyl- Salbutamol (Albuterol) A highly selective β2 xanthines. agonist; cardiac side effects are less prominent. Selectivity is further increased by inhaling the SYMPATHOMIMETIC DRUGS (see Ch. 9) drug. Inhaled salbutamol delivered mostly from Adrenergic drugs cause bronchodilatation through pressurized metered dose inhaler (pMDI) produces β 2 receptor stimulation → increased cAMP bronchodilatation within 5 min and the action formation in bronchial muscle cell → relaxation. lasts for 2–4 hours. It is, therefore, used to In addition, increased cAMP in mast cells and abort and terminate attacks of asthma, but is not other inflammatory cells decreases mediator suitable for round-the-clock prophylaxis. Muscle release. Since β2 receptors on inflammatory tremors are the dose related side effect. Palpita- cells desensitize quickly, the contribution of tion, restlessness, nervousness, throat irritation and the latter action to the beneficial effect of β2 ankle edema can also occur. Hypokalaemia is a agonists in asthma where airway inflammmation possible complication. Oral salbutamol undergoes is chronic, is uncertain, and at best minimal. presystemic metabolism in the gut wall, bioavaila- Adrenergic drugs are the mainstay of treatment bility is 50%. Oral salbutamol acts for 4–6 hours, of reversible airway obstruction, but should is longer acting and safer than isoprenaline, but be used cautiously in hypertensives, ischaemic not superior in bronchodilator efficacy. Muscle heart disease patients and in those receiving tremor is the principal side effect. digitalis. The β2 agonists are the most effective Because of more frequent side effects, oral and fastest acting bronchodilators when inhaled. β2 agonist therapy is reserved for patients who Though adrenaline (β1+β2+α receptor agonist) cannot correctly use inhalers or as alternative/ and isoprenaline (β1+β2 agonist) are effective adjuvant medication in severe asthma. Dose: 2–4 mg oral, 0.25–0.5 mg i.m./s.c., 100–200 µg bronchodilators, it is the selective β2 agonists by inhalation. that are now used in asthma to minimize ASTHALIN 2, 4 mg tab., 8 mg SR tab., 2 mg/5 ml cardiac side effects. syrup, 100 µg/metered dose inhaler; 5 mg/ml respirator  916 Chemotherapy of NeoplastiC Diseases SECTION 13 apparent cure, especially in early breast, lung because the most important target of action and colonic cancers. are the nucleic acids and their precursors, and rapid nucleic acid synthesis occurs during GENERAL TOXICITY OF cell division. Many cancers (especially large CYTOTOXIC DRUGS solid tumours) have a lower growth fraction Majority of the cytotoxic drugs have more (lower percentage of cells are in division) profound effect on rapidly multiplying cells, than normal bone marrow, epithelial linings,  aNtiCaNCer Drugs 917 CHAPTER 64 reticuloendothelial (RE) system and gonads. (specific as well as nonspecific) are broken These tissues are particularly affected in a down → susceptibility to all infections is dose-dependent manner by majority of drugs; increased. Of particular importance are the though, there are differences in susceptibility opportunistic infections due to low pathogenicity to individual members. organisms. Infections by fungi (Candida and 1. Bone marrow Depression of bone marrow others causing deep mycosis), viruses (Herpes results in granulocytopenia, agranulocytosis, zoster, cytomegalovirus), Pneumocystis jiroveci thrombocytopenia, aplastic anaemia. This is the (a fungus) and Toxoplasma are seen primarily most serious toxicity; often limits the dose that in patients treated with anticancer drugs. can be employed. Infections and bleeding are 3. Oral cavity: The oral mucosa is particularly the usual complications. susceptible to cytotoxic drugs because of high 2. Lymphoreticular tissue Lymphocytopenia epithelial cell turnover. Many chemotherapeutic and inhibition of lymphocyte function results drugs, particularly fluorouracil, methotrexate, in suppression of cell mediated as well as daunorubicin, doxorubicin produce stomatitis humoral immunity. as an early manifes tation of toxicity. The Because of action (1) and (2) + damage to gums and oral mucosa are regularly subjected epithelial surfaces, the host defence mechanisms to minor trauma, and breaches are common  404 Drugs Acting on centrAl nervous system concentration of anaesthetic breathed by the patient cannot Properties of an ideal anaesthetic be determined. It is wasteful—can be used only for a cheap anaesthetic. However, it is simple and requires no special A. For the patient It should be pleasant, non- apparatus. Use now is limited to peripheral areas. Ether is the irritating, should not cause nausea or vomiting. only agent administered by this method, especially in children. Induction and recovery should be fast with 2. Through anaesthetic machines Use is made no after effects. of gas cylinders, specialized graduated vaporizers, flow meters, unidirectional valves, corrugated rubber tubing B. For the surgeon It should provide adequate and reservoir bag. analgesia, immobility and muscle relaxation. The gases are delivered to the patient through a tightly It should be noninflammable and nonexplosive fitting face mask or endotracheal tube. Administration of the so that cautery may be used. anaesthetic can be more precisely controlled and in many situations its concentration estimated. Respiration can be C. For the anaesthetist Its administration controlled and assisted by the anaesthetist. should be easy, controllable and versatile. (a) Open system The exhaled gases are allowed to escape Margin of safety should be wide—no fall in BP. through a valve and fresh anaesthetic mixture is drawn Heart, liver and other organs should not in each time. No rebreathing is allowed—flow rates are be affected. high—more drug is consumed. However, predetermined O2 and anaesthetic concentration can be accurately delivered. It should be potent so that low concentrations (b) Closed system The patient rebreaths the exhaled are needed and oxygenation of the patient does not suffer. SECTION 7 gas mixture after it has circulated through sodalime which absorbs CO2. Only as much O2 and anaesthetic Rapid adjustments in depth of anaesthesia as have been taken up by the patient are added to the should be possible. circuit. Flow rates are low. This is especially useful for It should be cheap, stable and easily stored. expensive and explosive agents (little anaesthetic escapes in the surrounding air). Halothane, isoflurane, desflurane It should not react with rubber tubing or can be used through closed system. However, control of soda lime. inhaled anaesthetic concentration is imprecise. The important physical and anaesthetic proper- (c) Semiclosed system Partial rebreathing is allowed ties of inhalational anaesthetics are presented through a partially closed valve. Conditions are intermediate with moderate flow rates. in Table 27.1. Cyclopropane, trichloroethylene, methoxyflurane and enflurane are no longer used.  Sedative-HypnoticS 425 Fig. 29.1: A normal sleep cycle CHAPTER 29 Stage 4 (cerebral sleep) δ activity predominates in the are marked, irregular and darting eye movements; dreams EEG, K complexes cannot be evoked. Eyes are practically and nightmares occur, which may be recalled if the sub- fixed; subjects are difficult to arouse. Night terror may ject is aroused. Heart rate and BP fluctuate; respiration occur at this time. It comprises 10–20% of sleep time. is irregular. Muscles are fully relaxed, but irregular body During stage 2, 3 and 4 heart rate, BP and respiration are movements occur occasionally. Erection occurs in males. steady and muscles are relaxed. Stages 3 and 4 together About 20–30% of sleep time is spent in REM. are called slow wave sleep (SWS). Normally stages 0 to 4 and REM occur in succession REM sleep (paradoxical sleep) The EEG has waves over a period of 80–100 min. Then stages 1–4–REM are of all frequency, K complexes cannot be elicited. There repeated cyclically.  Antiepileptic Drugs 439 tuberculoma, cysticercosis, cerebral ischaemia, Phenytoin (Diphenylhydantoin) etc. Treatment is symptomatic, depends mostly It was synthesized in 1908 as a barbiturate on the seizure type, but not on the etiology of analogue, but shelved due to poor sedative seizure or whether it is primary or secondary. property. Its anticonvulsant activity was speci- Experimental models These models for testing antiepi- fically tested in 1938 in the newly developed leptic drugs have also shed light on the etiopathogenesis of epilepsy. electroshock seizure model, and till recently it was a major antiepileptic drug. 1. Maximal electroshock seizures Brief high intensity shock is applied to the head of a rodent (just as in ECT): produces tonic flexion—tonic extension—clonic convul­ sions. The tonic phase (especially extensor) is selectively abolished by drugs effective in GTCS and complex partial seizures. Activity in this model represents action on spread of seizure discharge. 2. Pentylenetetrazol (PTZ) clonic seizures Injection of PTZ in rats or mice produces clonic convulsions which are prevented by drugs effective in absence and myo- clonic seizures. Activity in this model represents action on seizure focus itself. 3. Chronic focal seizures Produced by application of CHAPTER 30 alumina cream on the motor cortex of monkey. Phenytoin is not a global CNS depressant; 4. Kindled seizures Brief bursts of weak electrical only mild sedation occurs at therapeutic doses. impulses are applied to the brain (especially amygdala) The most prominent action is abolition of tonic intermittently over days. After-discharges increase progres- phase of maximal electroshock seizures, with sively and tonic­clonic seizures are produced after 10–15 shocks. With time spontaneous seizures set in, usually no effect on or prolongation of clonic phase. after >100 shocks. This indicates that seizures have a It limits spread of seizure activity. Threshold self perpetuating and reinforcing effect: more neuronal for PTZ convulsions is not raised. circuits are facilitated and recruited in the seizure process. Kindling is probably involved in the genesis of complex Mechanism of action Phenytoin prevents partial seizures and GTCS. repetitive detonation of normal brain cells. This Perampanel, retigabine, stiripentol, rufinamide and few other newer antiseizure drugs have been introduced in some countries as second line/add-on drugs for refractory partial seizures.  AntipArkinsoniAn Drugs 453 CHAPTER 31 the remaining acts on heart, blood vessels, frank psychosis may occur. Embarrassingly other peripheral organs and on CTZ (though disproportionate increase in sexual activity has located in the brain, i.e. floor of IV ventricle, also been noted. Dementia, if present, does not it is not bound by blood-brain barrier). About improve; rather it predisposes to emergence of 1–2% of administered levodopa crosses to the psychiatric symptoms. brain, is taken up by the surviving dopaminergic Levodopa has been used to produce a non- neurones, converted to DA which is stored and specific awakening effect in hepatic coma. released as a transmitter. This is supported by Two subtypes of DA receptors (D1, D2) were origi- the finding that brains of parkinsonian patients nally described. Three more (D3, D4, D5) have now been identified and cloned. All are G protein coupled receptors treated with levodopa till death had higher DA and are grouped into two families: levels than those not so treated. Further, those D1 like (D1, D5) Are excitatory: act by increasing cAMP patients who had responded well had higher DA formation and PIP2 hydrolysis thereby mobilizing intracellular levels than those who had responded poorly. Ca2+ and activating protein kinase C through IP3 and DAG. D2 like (D2, D3, D4) Are inhibitory: act by inhibiting adeny- ACTIONS lyl cyclase/opening K+ channels/depressing voltage sensitive Ca2+ channels. 1. CNS Levodopa hardly produces any effect The various subtypes of DA receptors are differentially in normal individuals or in patients with other expressed in different areas of the brain, and appear to neurological diseases. Marked symptomatic play distinct roles. Both D1 and D2 receptors are present improvement occurs in parkinsonian patients. in the striatum and are involved in the therapeutic response Hypokinesia and rigidity resolve first, later tremor to levodopa. They respectively regulate the activity of two as well. Secondary symptoms of posture, gait, pathways having opposite effects on the thalamic input to the motor cortex (Fig. 31.1). Thus, stimulation of excitatory handwriting, speech, facial expression, mood, self D1 as well as inhibitory D2 receptors in the striatum care and interest in life are gradually normalized. achieves the same net effect of smoothening movements Therapeutic benefit is nearly complete in early and reducing muscle tone. disease, but declines as the disease advances. Dopamine receptor in SN-PC and in pituitary is also The effect of levodopa on behaviour has been of D2 type. The D3 receptors predominate in nucleus accumbans and hypothalamus, but are sparse in caudate described as a ‘general alerting response’. In and putamen, while D4 and D5 are mostly distributed in some patients this progresses to excitement— neocortex, midbrain, medulla and hippocampus.  464 drugs Acting on centrAl nervous system Many more drugs have been marketed in other is relieved. Hyperactivity, hallucinations and countries but do not deserve special mention. delusions are suppressed. SECTION 7 Pharmacology of chlorpromazine (CPZ) is All phenothiazines, thioxanthenes and buty- described as prototype; others only as they rophenones have the same antipsychotic efficacy, differ from it. Their comparative features are but potency differs in terms of equieffective presented in Table 32.1. doses. The aliphatic and piperidine side chain phenothiazines (CPZ, triflupromazine, thiorida­ PHARMACOLOGICAL ACTIONS zine) have low potency, produce more sedation 1. CNS Effects differ in normal and psychotic and cause greater potentiation of hypnotics, individuals. opioids, etc. The sedative effect is produced promptly, while antipsychotic effect takes weeks In nonpsychotic individuals CPZ produces to develop. Moreover, tolerance develops to indifference to surroundings, paucity of thought, the sedative but not to the antipsychotic effect. psychomotor slowing, emotional quietening, Thus, the two appear to be independent actions. reduction in initiative and tendency to go off Performance and intelligence are relatively to sleep from which the subject is easily arous- unaffected, but vigilance is impaired. Extrapyra- able. Spontaneous movements are minimized but midal motor disturbances (see adverse effects) slurring of speech, ataxia or motor incoordina- are intimately linked to the antipsychotic effect, tion does not occur. This is mostly perceived but are more prominent in the high potency to be unpleasant, and has been referred to as compounds and least in thioridazine, clozapine the ‘neuroleptic syndrome’. The typical antipsy- and other atypical antipsychotics. A predominance chotic drugs have potent dopamine D2 receptor of lower frequency waves occurs in the EEG blocking property and produce extrapyramidal and arousal response is dampened. However, motor side effects. As such, they are called no consistent effect on sleep architecture has ‘Neuroleptic drugs’. been noted. The disturbed sleep pattern in a In a psychotic CPZ reduces irrational beha- psychotic is normalized. viour, agitation and aggressiveness and controls Chlorpromazine lowers seizure threshold psychotic symptomatology. Disturbed thought and can precipitate fits in untreated epileptics. and behaviour are gradually normalized, anxiety The piperazine side chain compounds have a  474 drugs Acting on centrAl nervous system by i.m. injection to control exacerbations or DRUGS fOR mANIA AND violent behaviour. BIPOLAR DISORDER In a depressed psychotic, a tricyclic/SSRI antidepressant may be combined with relatively lower dose of an antipsychotic. One of the atypical agents is mostly used because they are effective in bipolar disorder. Quetiapine is the preferred drug, because it is effective as monotherapy as well. Benzodiazepines may be added for brief periods in the beginning. Low dose maintenance or intermittent regi- mens of antipsychotics have been tried in relapsing cases. Depot injections, e.g. fluphena- LITHIUM CARBONATE zine/haloperidol decanoate given at 2–4 week intervals are preferable in many cases. Lithium is a small monovalent cation. In 1949, 2. Anxiety Antipsychotics have antianxiety it was found to be sedative in animals and to action but should not be used for simple anxi- exert beneficial effects in manic patients. ety because they produce psychomotor slowing, In the 1960s and 1970s the importance of SECTION 7 emotional blunting, autonomic and extrapyramidal maintaining a narrow range of serum lithium side effects. Benzodiazepines are the primary concentration was realized and unequivocal drugs used in anxiety. However, low dose of evidence of its clinical efficacy was obtained. quetiapine, risperidone or olanzepine have been Lithium is a drug of its own kind to suppress found useful as adjuvants to SSRIs in general- mania and to exert a prophylactic effect in ized anxiety disorder. bipolar (manic) disorder at doses which have 3. As antiemetic The typical neuroleptics are no overt CNS effects. Lithium is established potent antiemetics. They control a wide range as the standard antimanic and mood stabilizing of drug and disease induced vomiting at doses drug. However, over the past 2–3 decades, sev- much lower than those needed in psychosis. eral anticonvulsants and atypical antipsychotics However, they should not be given unless the have emerged as equally effective and more cause of vomiting has been identified. Though manageable alternatives to lithium. effective in morning sickness, they should not be used for this condition. Neuroleptics are not effective in motion sickness: probably Actions and mechanism because dopaminergic pathway through the CTZ 1. CNS Lithium has practically no acute is not involved. With the availability of 5-HT3 effects in normal individuals as well as in antagonists and other antiemetics, use of neu- bipolar patients. It is neither sedative nor eu- roleptics for control of vomiting has declined. phorient; but on prolonged administration, it 4. Other uses acts as a mood stabiliser in bipolar disorder. (a) To potentiate hypnotics, analgesics and anaes- Given to patients in acute mania, it gradually thetics: such use is rarely justified now. suppresses the episode taking 1–2 weeks; con- (b) Intractable hiccough: may respond to tinued treatment prevents cyclic mood changes. parenteral CPZ. The markedly reduced sleep time of manic (c) Tetanus: CPZ is an alternative drug to patients is normalized. relieve skeletal muscle spasm. The mechanism of antimanic and mood stabi- (d) Alcoholic hallucinosis and Huntington’s lizing action of lithium is not known. However, disease are the other indications. the following mechanisms have been proposed:  Drugs Used in Mental Illness: Chapter 33 Antidepressant and Antianxiety Drugs Major depression and mania are two extremes of a psychotic basis with delusional thinking or affective disorders which refer to a pathological occur in isolation and induce anxiety. On the change in the mood state. Major depression other hand, pathological anxiety may lead to is characterized by symptoms like sad mood, depression. Anxiety and depression are the loss of interest and pleasure, low energy, leading psychiatric disorders now. worthlessness, guilt, psychomotor retardation or agitation, change in appetite and/or sleep, ANTIDEPRESSANTS melancholia, suicidal thoughts, etc. It may be a unipolar or a bipolar cyclic disorder in which These are drugs which can elevate mood in cycles of mood swings from mania to depression depressive illness. Practically all antidepressants occur over time. The mood change may have affect monoaminergic transmission in the brain Many other drugs like Protriptyline, Maprotiline, Nafazodone, etc. are marketed in other countries.  AntiDepressAnt AnD AntiAnxiety Drugs 493 ANTIANXIETY DRUGS BENZOdIAZEPINES Anxiety It is an emotional state, unpleasant The pharmacology of benzodiazepines (BZDs) in nature, associated with uneasiness, discomfort as a class is described in Ch. 29. and concern or fear about some defined or Some members have a slow and prolonged undefined future threat. Somatic symptoms like action, relieve anxiety at low doses without anorexia, breathlessness, palpitation, paresthesias, producing significant CNS depression. They etc. often accompany. Some degree of anxiety have a selective taming effect on aggressive is a part of normal life. Treatment is needed animals and suppress induced aggression. They when it is disproportionate to the situation also suppress the performance impairing effect and excessive. Some psychotics and depressed of punishment. In contrast to barbiturates, they patients also exhibit pathological anxiety. are more selective for the limbic system and Cardiac neurosis (unfounded fear of heart disease—pal- pitation, functional precordial pain); g.i. neurosis (fixation have proven clinically better in both quality on bowel movement, distention, eructation, reflux, acidity); and quantity of improvement in anxiety and social anxiety (fear of being observed and evaluated by stress-related symptoms. others); obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD) and various forms of phobias are At antianxiety doses, cardiovascular and some specific types of anxiety disorders. respiratory depression is minor. Antianxiety drugs These are an ill­defined Because anxiety is a common complaint and CHAPTER 33 group of drugs, mostly mild CNS depressants, is a part of most physical and mental illness, which are aimed to control the symptoms of and because the BZDs— anxiety, produce a restful state of mind with- have little effect on other body systems out interfering with normal mental or physical have lower dependence producing liability functions. The anxiolytic-sedative drugs differ than barbiturates and other sedatives; with- markedly from antipsychotics, and more closely drawal syndrome is milder and delayed due resemble sedative-hypnotics. They: to their long half lives 1. Have no therapeutic effect to control thought are relatively safe even in gross overdosage, disorder of schizophrenia. Benzodiazepines are presently one of the most 2. Do not produce extrapyramidal side effects. widely used class of drugs. Potent BZDs like 3. Have anticonvulsant property. lorazepam and clonazepam injected i.m. have 4. Produce physical dependence and carry abuse adjuvant role in the management of acutely liability. psychotic and manic patients. In addition to the above drugs, antidepressants, especially the SSRIs and SNRIs are effective in OCD, phobias, panic, PTSD and severe generalized anxiety disorder (GAD).  502 Drugs Acting on centrAl nervous system PRECAUTIONS AND 7. Elderly male: Chances of urinary retention CONTRAINDICATIONS are high. 8. Hypothyroidism, liver and kidney disease Morphine is a drug of emergency, but due care patients are more sensitive to morphine. has to be taken in its use. 9. Unstable personalities: Are able to continue 1. Infants and the elderly are more susceptible with its use and become addicted. to the respiratory depressant action of morphine. 2. It is dangerous in patients with respiratory Interactions insufficiency (emphysema, pulmonary fibrosis, cor pulmonale); sudden deaths have occurred. Phenothiazines, tricyclic antidepressants, MAO Morphine accentuates sleep apnoea; hypoxic inhibitors, amphetamine and neostigmine brain damage can occur. poten tiate morphine and other opioids, 3. Bronchial asthma: Morphine can precipitate either by retar ding its metabolism or by a an attack by its histamine releasing action. pharmacodynamic interaction at the level of A high potency opioid with lower histamie central neurotransmitters. Exaggerated CNS releasing potential (e.g. fentanyl) should be depression can occur if morphine is given used, if unavoidable, in an asthmatic. with a sedative-hypnotic. 4. Head injury: Morphine is contraindicated in Morphine retards absorption of many orally patients with head injury. Reasons are— administered drugs by delaying gastric emptying. SECTION 7 Dose: 10–50 mg oral, 10–15 mg i.m. or s.c. or 2–6 mg i.v.; 2–3 By retaining CO2, it increases intracranial mg epidural/intrathecal; children 0.1–0.2 mg/kg. i.m. or s.c. tension which will add to that caused by MORPHINE SULPHATE 10 mg/ml inj; MORCONTIN 10, head injury itself. 30, 60, 100 mg continuous release tabs; 30–100 mg BD; RILI- Even therapeutic doses can cause marked MORF 10, 20 mg tabs, 60 mg SR tab. respiratory depression in these patients. Vomiting, miosis and altered mentation pro- OTHER OPIOIDS duced by morphine interfere with assessment 1. Codeine It is methyl-morphine, occurs of progress in head injury cases. naturally in opium, and is partly converted 5. Hypotensive states and hypovolaemia exag- in the body to morphine. It is less potent gerate fall in BP due to morphine. than morphine (1/10th as analgesic), also less 6. Undiagnosed acute abdominal pain: Morphine efficacious; is a partial agonist at µ opioid can aggravate certain conditions, e.g. diverti- receptor with a low ceiling effect. The degree culitis, biliary colic, pancreatitis. Inflamed of analgesia is comparable to aspirin (60 mg appendix may rupture. Morphine can be given codeine ~ 600 mg aspirin). Codeine can relieve after the diagnosis is established. Pentazocine, mild to moderate pain only. buprenorphine are less likely to aggravate However, codeine is more selective cough biliary spasm. sup pres sant (1/3rd as potent as morphine); Chapter 35 CNS Stimulants and Cognition Enhancers CNS STIMULANTS an allosteric site and prevents Cl¯ channel opening (see p. 429). Diazepam, which facilitates GABAergic transmission, These are drugs whose primary action is to is the drug of choice to treat picrotoxin poisoning. stimulate the CNS globally or to improve 3. Bicuculline This synthetic convulsant has picrotoxin- specific brain functions. like actions. It is a competitive GABAA receptor (intrinsic Cl¯ channel receptor) antagonist. It is only a research tool. I. CONVULSANTS 4. Pentylenetetrazol (PTZ) It is a powerful CNS stimulant, believed to be acting by direct depolarization of central neurones. 1. Strychnine It is an alkaloid from the seeds of Strychnos However, it has also been shown to interfere with GABAergic nux-vomica, that is a potent convulsant. The convulsions are inhibition—may be acting in a manner analogous to picrotoxin. reflex, tonic-clonic and symmetrical. Strychnine acts by blocking Low doses cause excitation, larger doses produce post-synaptic inhibition produced by the inhibitory transmitter convulsions which are similar in pattern to those caused glycine. One of the sites that has been clearly demonstrated by picrotoxin. Antagonism of PTZ induced convulsions is is the Renshaw cell-motoneurone junction in the spinal cord an established method of testing anticonvulsant drugs in through which inhibition of antagonistic muscles is achieved. laboratory animals (see Ch. 30). Accidental strychnine poisoning may occur, especially in children. Treatment of poisoning is similar to that of status epilepticus (see Ch. 30). II. ANALEPTICS (Respiratory stimulants) 2. Picrotoxin It is obtained from ‘fish berries’ of East These are drugs which stimulate respiration and were believed Indies Anamirta cocculus. Picrotoxin is a potent convulsant— to have resuscitative value in coma or fainting. They do stimu- convulsions are clonic, spontaneous and asymmetrical. The late respiration in subconvulsive doses, but margin of safety convulsions are accompanied by vomiting, respiratory and is narrow. vasomotor stimulation. Doxapram and some other analeptics injected i.v. were used Picrotoxin acts by blocking presynaptic inhibition in the past as an expedient measure in fainting, barbiturate mediated through GABA. However, it is not a competitive poisoning, suffocation, drowning, ventilatory failure in COPD, antagonist; does not act on GABA receptor itself, but on but are outmoded now.  518 DRUGS ACTING ON CENTRAL NERVOUS SYSTEM 2–3 decades, the above therapeutic field is two decades 4 cerebroselective antiChEs have barren and commercially highly profitable. A been introduced and 3 are widely used in AD. variety of drugs have been briskly promoted Tacrine It was the first centrally acting anti-ChE to by manufacturers and wishfully prescribed by be introduced for AD, but has gone out of use due to physicians. The mechanism by which they are hepatotoxicity. believed to act are: Rivastigmine This carbamate derivative of Increasing global/regional cerebral blood physostigmine inhibits both AChE and BuChE, flow (CBF) but is more selective for the G1 isoform of Direct support of neuronal metabolism. AChE that predominates in certain areas of the Enhancement of neurotransmission. brain. Rivastigmine is highly lipid-soluble—enters Improvement of descrete cerebral functions, brain easily. Greater augmentation of choliner- e.g. memory. gic transmission in the brain is obtained with All cerebroactive drugs are tested for their vaso- mild peripheral effect. The carbamyl residue dilator activity. The basic assumption has been introduced by rivastigmine into AChE molecule that selective improvement in cerebral circulation dissociates slowly resulting in inhibition of is possible, real and therapeutically useful. How- cerebral AChE for upto 10 hours despite the ever, precise measurements have shown that in 2 hr plasma t½ of the drug. many cases such claims are merely expectations. In clinical trials an average of 3.8 point SECTION 7 A global vasodilator effect may even be harmful improvement in Alzheimer’s Disease Assessment in stroke by worsening cerebral edema and induc- Scale (ADAS-cog) has been obtained compared ing ‘steal’ phenomenon, i.e. diversion of blood to placebo. Other symptoms like apathy, delu- flow to non-ischaemic areas to the detriment of sions, hallucinations and agitation also improve, ischaemic area. No doubt, cerebral blood flow but to a lesser extent. Disease progression is is reduced in AD, but this is probably a conse- not affected. Peripheral cholinergic side effects quence of loss of neurones and not its cause. are mild. It has not produced liver damage. 1. Cholinergic activators Since brain ACh Rivastigmine is indicated in mild-to-moderate and choline acetyl transferase levels are mark- cases of AD, but not in advanced disease. edly reduced and cholinergic neurotransmission Dose: Initially 1.5 mg BD, increase every 2 weeks by 1.5 mg/ is the major sufferer in AD, various approaches day upto 6 mg/BD. to augment brain ACh have been tried. Precur- EXELON, RIVAMER 1.5, 3, 4.5, 6.0 mg caps. sor loading with choline or lecithin have failed Transdermal patches delivering 4.6 mg, 9.5 mg or 13.3 mg rivastigmine per 24 hours have also been produced. because there is no shortage of these substrates in the brain. Cholinergic agonists (arecoline, Donepezil This cerebroselective and reversible bethanechol, oxotremorine) and conventional anti-AChE produces measurable improvement anticholinesterases (anti-ChEs) like physostigmine in several cognitive as well as non-cognitive produce symptom improvement, but at the cost (activities of daily living) scores in AD, which of marked peripheral side effects. Over the past is maintained upto 2 years. The benefit is  894 AntimicrObiAl Drugs SECTION 12 involved in extraintestinal amoebiasis. In the NITROIMIDAZOLES tissues, only trophozoites are present; cyst for- mation does not occur. Tissue phase is always Metronidazole secondary to intestinal amoebiasis, which may It is the prototype nitroimidazole introduced be asymptomatic. In fact, most chronic cyst in 1959 for trichomoniasis and later found to passers are asymptomatic. In the colonic lumen, be a highly active amoebicide. It has broad- the Entamoebae live in symbiotic relationship spectrum cidal activity against anaerobic protozoa, with bacteria, and a reduction in colonic bacteria including Giardia lamblia in addition to the reduces the amoebic population. above two. Many anaerobic and microaerophilic The ‘Brazil root’ or Cephaelis ipecacuanha was used bacteria, such as Bact. fragilis, Fusobacterium, for the treatment of dysentery in the 17th century. The Clostridium perfringens, Cl. difficile, Helico­ pure alkaloid emetine obtained from it was found to be a potent antiamoebic in 1912. Emetine remained the bacter pylori, Campylobacter, peptococci, most efficacious and commonly used drug for amoebiasis spirochetes and anaerobic Streptococci are till 1960.