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Nitric oxide can activate guanylate cyclase in the same cells that producte it, givingrise to autocrine effects. The resulting increase in cGMP affects protein kinase G,cyclic nucleotide phosphodiesterases, ion channels and possibly other proteins. Thisinhibits Ca2+ induced smooth muscle contraction and platelet aggregation that occurin response to agonists. NO inhibits monocyte adhesion and migration, adhesion andaggregation of platelets and smooth muscle and fibroblast proliferation.

- Vascular effects: mutant mice that lack the gene coding for eNOS are hypertensive,consistent with a role for NO biosynthesis in the physiological control of bloodpressure.- Neuronal effects: It is implicated in the control of neuronal development and ofsynpaptic plasticity in the CNS. Mice carrying a mutation disrupting the gene codingnNOS have grossly distended stomachs similar to those seen in human hypertrophicpyloric stenosis.- Host defence: cytotoxic and/or cytostatic effects of NO are implicated in primitivenon-specific host defence mechanisms against numerous pathogens.

Therapeutic approaches.Inhalation of high concentrations of NO causesacute pulmonary oedema andmethaemoglobineamia, but concentrations below55 ppm are not toxic. NO inhibitsbronchoconstriction, but the main action of inhaledNO is pulmonary vasodilatation. Therapeuticallyuseful in respiratory distress syndrome.

ADMA, approximately equipotent with l-NMMA, ispresent in human plasma and is excreted in urine.Its plasma concentration correlates with vascularmortality in patients receiving haemodialysis forchronic renal failure, and is increased in peoplewith hypercholesterolaemia. Infusion of a low doseof L-NMMA into the brachial artery causes localvasoconstriction, owing to inhibition of the basal production of NO in resistancevessels of the infused arm, without influencing blood pressure or causing othersystemic effects.

Nitric oxide in pathophysiology.Nitric oxide is synthesized under physiogical andpathological circumstances. Either reduced orincreased NO production can contribute todisease. Underproduction of neuronal NO (nNOS)is reported in babies with hypertrophic pyloricstenosis. Endothelial NO production is reduced inpatients with hypercholesterolaemia and someother risk factos for atherosclerosis, and this maycontribute to atherogenesis. Overproduction of

NO may be important in neurodegenerativediseases and in septic shock.

Chapter. 18. The heart.

Cardiac rate and rhythm.Physiological sinus rhythm is characterized byimpulses arising in the sinoarterial (SA) node and conducted in sequence through theatria, the AV node, bundle of his, purkinje fibres and ventricles. Electrophysiological


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- Increased heart rate;- Increased automaticity;- Repolarisation and restoration of function following generalized cardiacdepolarization;- Reduced cardiac efficiency.All result from activation of Beta1-adrenoceptors. All occur through increased

intracellular cAMP. Increases the probability that the channels will open, increasinginward Ca2+ current and hence force of cardiac contraction. Also increases the Ca2+sensitivity of contractile machinery. It facilitates Ca2+ capture by sarcoplasmicreticulum, thereby increasing amount of Ca2+ available for release. The increase inheart rate results from an increased slope of pacemaker potential.

Parasympathetic system.Has little effect on contractility, main effects being on rate and rhythm:- cardiac slowing and reduced automaticity.- Inhibition of AV conduction.Result from occupation of muscarinic (m2) acetylcholine receptors. Receptors arenegatively coupled to adenylate cyclase and thus reduce cAMP formation, acting toinhibit to slow Ca2+ current. They also open a potassium channel. The resultingincrease in K+ permeability produces a hyperpolarising current that opposes theinward pacemaker current, slowing the heart and reducing automaticity. Coronaryvessels lack cholinergic innervation.

Cardiac natriuretic peptides.Atrial cells contain secretory granules, and store and release atrial natriuretic peptide(ANP). This has powerful effects on the kidney and vascular system. Release occursduring volume overload in response to stretching of the atria. Main effects are toincrease Na+ and water excretion by the kidney; relax vascular smooth muscle;increase vascular permeability; and inhibit the release and/or actions of severalhormones and mediators , including aldosterone, ang-II.

Ischaemic heart disease.Angina.Occurs when the oxygen supply to the myocardium is insufficient for its needs.Chemical factors released by ischaemic muscle stimulate nociceptors.- Stable angina: produced by an increased demand on the heart and is caused by afixed narrowing of the coronary vessels, almost always by atheroma.- Unstable angina: pain that occurs with less and less exertion, culminating in pain atrest. Myocardial infarction, namely platelet-fibrin thrombus associated with aruptured atheromatous plaque, but without complete occlusion of the vessel.- Variant angina: uncommon. It occurs at rest and is caused by coronary arteryspasm.

Myocardial infarction.Cardiac myocytes rely on aerobic metabolism. If the supply of oxygen remains belowa critical value, a sequence of events leading to cell death. Apoptosis may be an

adaptive process in hypoperfused regions, sacrificing come jeopardised myocytes butthereby avoiding the disturbance of membrane function and risk of dysrhythmiainherent in necrosis. Prevention of irreversible ischaemic damage:- Thrombolytic and antiplatelet drugs to open the blocked artery and prevent theirreocclusion;- Oxygen;- Opioids to prevent pain -> reduce sympathetic activity;- Beta-adrenoceptor antagonists.- Ace-inhibitors.


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Effects are increased if plasma K+ decreases, because of reduced competition at theK+-binding site on the Na+/K+ ATPase.

2. Other drugs that increase myocardial contractility.Certain B1-adrenoceptor agonists are used to treat acute but potentially reversibleheart failure. On the basis of their positive inotropic action. Dobuatmine produces

less tachycardia. Glucagon increases myocardial contractility by increasing synthesisof cAMP.

Antianginal drugs.

1. Organic nitrates.Organic nitrates relax vascular and some other smooth muscles. In healthy subjects,this reduces stroke volume. Venous pooling occurs on standing and can causepostural hypotension and dizziness. There is a marked effect on larger musculararteries. Reduces pulse wave reflection from arterial branches and consequentlyreduces central (aortic) pressure and cardiac afterload.- Myocardial oxygen consumption is reduces because of the reduction in both cardiacpreload and afterload;- Redistribution of coronary flow towards ischaemic areas via collaterals;- Relief of coronary spasm.Nitrates are absorbed with release of NO. NO activates soluble guanylate cyclase ,increasing formation of cGMP, which activates protein kinase G -> sequestration ofintracellular Ca2+, with consequent relaxation.

Repeated administration results in diminished relaxation, possibly because ofdepletion of free SH groups. It does not occur with ordinary formulations of short-acting drugs (e.g. glyceryl trinitrate), but does occur with longer-acting drugs (e.g.isosorbide mononitrate). Main adverse effects include postural hypotension andheadache.

Glyceryl trinitrate is rapidly inactivated by hepatic metabolism. Well abosorbed fromthe mouth and is taken as a tablet under the tongue, producting its effect within afew minutes. If swallowed, it is ineffective becuase of first-pass metabolism. Itseffective duration is 30 minutes. Isosorbide is longer acting but has similarpharmacological actions. It is swallowed rather than taken sublingually

2. Beta-adrenoceptor antagonists.Prophylaxis of angina, and in treating patients with unstable agina. Reducing cardiacoxygen consumption. They reduce the risk of death following myocardial infarction.

3. Calcium antagonists.They bind to alfa1-subunit of the cardiac L-type calcium channel but at distinct sites.They prevent the channel from opening, thus reducing Ca2+ entry. Many showproperties of use dependence. They also show voltage-dependent blocking actions,

blocking more strongly when the membrane is depolarized ,causing calcium channelopening inactivation.- Cardiac actions: Can cause AV block and cardiac slowing by their actions onconducting tissues, but this is offset by a reflex increase in sympathetic activitysecondary to their vasodilator action. They also have a negative inotropic effect,which results from the inhibition of the slow inward current during the actionpotential plateau.- Vascular smooth muscle: cause generalized arterial/arteriolar dilatation, therebyreducing blood pressure, but do not much affect the veins. They cause coronary


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vasodilatation and are used in patients with coronary artery spasm.

They are well absorbed from the gastrointestinal tract, and are given by mouth.Short-acting dihydropyridines cause flushing and headache because of theirvasodilator action, and in chronic use dihydropyridines often cause ankle swellingrelated to arteriolar dilatation and increased permeability of postcapillary venules.

Verapimil canse cause constipation probably because of effects on calcium channelsin gastrointestinal nerves or smooth muscle.

Ch. 19. The vascular system.

Vascular smooth muscle is controlled by mediators secreted by sympathetic nervesand vascular endothelium, and by circulating hormones. Smooth muscle cellcontraction is initiated by arise in Ca2+, which activates myosin ligh-chain kinase,causing phosphorylation of myosin, or by sensitisation of the myofilaments to Ca2+by inhibition of myosin phopshatase. Agents cause vasoconstriction via one ore moremechanisms:- Release of intracellular Ca2+ via inositol triphosphate;- Depolarizing the membrane, opening voltage-gated calcium channels and causing

Ca2+ entry;- Increasing sensitivity to Ca2+ via actions on myosin light-chain kinase and/ormyosin phosphatase.Agents causing relaxation by:- Inhibiting Ca2+ entry through voltage-gatedcalcium channels either directly or indirectly byhyperpolarizing the membrane;- Increasing intracellular cAMP or cGMP; cAMPinactivates myosin light-chain kinase andfacilitates Ca2+ efflux, cGMP opposes agonist-induced increases Ca2+.

Endothelin.

Stimuli to synthesis include many noxiousvasoconstrictor mediators released by traumaor inflammation , including activated platelets,endotoxin etc. Inhibitors of ET synthesis includeNO, natriuretic peptides, PGE2, PGI2, heparinand high shear stress. Endothelin receptorcause vasodilatation when infused directly intothe brachial artery. ET-1 has an elimination halflife of


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The renin-angiotensin system.Synergises with the sympathetic nervous system. Itstimulates aldosterone secretion and plays a central role inthe control of Na+ excretion and fluid volume, as well asvascular tone. Renin is a proteolytic enzyme that is secreted

by the juxtaglomerular apparatus. It is secreted in responsto various physiological stimuli, including a fall in Na+. TheNa+ concentration in distale tubule is senses by the maculadensa. Ang-II causes feedback inhibition. Angiotensinconverting enzyme is a membrane bound enzyme on thesurface of endothelial cells. The common isoform of ACE isalso present in other vascular tissues, including the brain,heart, striated muscle and kidney. ACE inactivatesbradykinin. The main actions of Ang-II are mediated via AT1and/or AT2-receptors. Effects mediated by AT1-receptorsinclude:- Generalised vasoconstriction;- Increased release of nor-adrenaline from sympatheticnerve terminals;- Stimulation of proximal tubular reabsorption of Na+;- Secretion of aldosterone;- Cell growth in the heart and arteries.

Vasoactive drugs.

Vasoconstrictor drugs.1. Angiotensin II: is roughly 40 times as potent as noradrenaline in raising bloodpressure. It constricts mainly cutaneous, splanchnic and renal vasculature, with lesseffect on blood flow to brain and skeletal muscle. No routine clinical uses.

2. Antidiuretic hormone.Is a posterior pituitary peptide hormone. A powerful vasoconstrictor in skin and someother vascular beds. Water retention is mediated through V2 receptors. ADH causesgeneralized vasoconstriction, including the coeliac, mesenteric and coronary vessels.

3. Endothelin.They have vasodilator and vasoconstrictor actions, but vasoconstrictionpredominates. Intravenous administration cause transient vasodilatation followed byprofound and very long-lived vasoconstriction. Even more potent than ANG-II.

Vasodilator drugs.Calcium antagonists: L-type calcium antagonists are discussed. Cause generalizedarterial vasodilatation. Dihydropyridines act preferentially on vascular smoothmuscle, whereas verapamil acts also on the heart.

They act to : increase local tissue blood flow, reduce arterial pressure, reduce central

venous pressure. Net effect is a reduction of cardiac preload, and afterload, hencereduction of cardiac work. Main uses are:- Antihypertensive therapy (e.g. At1 antagonists, calcium antagonists and alfa1antagonists);- Treatment/prophylaxis angina (e.g. calcium antagonists, nitrates);- treatment of cardiac failure (e.g. angiotensin-converting enzyme inhibitors, AT1antagonists).

Hydralazine had unknown mechanism of action: acts mainly on arteries and


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arterioles, causing a fall in blood pressure accompanied by reflex tachycardia and anincreased cardiac output. It interferes with the action of inositol triphosphate onCa2+ release from the sarcoplasmic reticulum. It can cause an immune disorderresembling systemic lupus erythematosus.

Ethanol: dilates cutaneous vessels, causing the familiar drunkards flush.

Indirectly acting vasodilator drugs.Two main groups:- Sympathetic vasoconstriction;- The renin-angiotensin system.

1. Renin inhibitors: reduce plasma renin activity, but their effects on blood pressurein patients with hypertension are dissapointing.

2. Angiotensin-converting enzyme inhibitors ACE: ACE cleaves the C-terminal pair ofamino acids from peptide substrates. It active site contains a zinc atom. Captoprilcontains a sulfhydryl group appropriately placed to bind the zinc atom, coupled to aproline residue that binds the site on the enzyme that normally accommodates theterminal leucine of AG-I. ACE inhibitors affect capacitance and resistance vessels, andreduce cardiac load as well as arterial pressure. They do not effect cardiaccontractility, so cardiac output normally increases. Unwanted effects in large dosesare rashes, taste disturbance, neutropenia and heavy proteinura. ACE inhibitors thatdo not posses a sulfhydryl group do not cause these unwanted effects. A dry cough(bradykinin build up) -> commonest adverse effect.Clinical uses:- Hypertension;- Cardiac failure;- People at high risk ofischaemic heart disease;- Diabetic nephropathy

3. ANG-II receptor subtype 1antagonists (sartans): Arenon-peptide , orally activeAT1 receptor antagonists. It isnot known whether any of thebeneficial effects of aceinhibitors are bradykinin/NO-mediated, so it is unwise toassume that AT1 receptorantagonists will necessarilyshare all the therapeuticproperties of ACE inhibitors.

Clinical uses of vasoactive

drugs.

1. Hypertension.Essential hypertension:increased cardiac output maybe an early feature, but bythe time it is diagnosed there is usually increased peripheral resistance and thecardiac output is normal. The main systems include the sympathetic nervous system,the renin-angiotensin-aldosterone system, and tonically active endothelium-derived


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autocoids. Start treatment with wither an ACE inhibitor or an AT1 antagonist. Beta-adrenoceptor antagonists are less well tolerated than ACE inhibitors or AT1antagonists. They are useful for hypertensive patients with some additional indicationfor beta-blockade, such as angina or heart failure. Addition of a third or fourth drug isoften needed, and a long-acting alfa1 antagonist is one option in this setting.Spironolactone (a competitive antagonist of aldosterone) needs careful monitoring of

plasma K+ concentration because it inhibitsurinary K+ excretion as well as causingoestrogen-related adverse effects.

2. Cardiac failure.The underlying abnormality is a cardiac outputthat is inadequate to meet the metaboicdemands of the body during excercise. WhenCO is insufficient, an increase in fluid volumeoccurs, partly because increased venouspressure causes increased formation of tissuefluid, and partly because reduced renal bloodflow activates the RAAS, causing Na+ andwater retention. Drugs used for treatment dothe following:- Increases natriuresis: increasing salt andwater excretion;- Inhibit the RAAS: this is inappropriatelyactivated in patients with cardiac failure. Beta-adrenoceptor antagonists inhibit reninsecretion. ACE-inhibitors and AT1 antagonistsblock the formation of ANG-II and inhibit itsaction, thereby reducing vascular resistanceimproving tissue perfusion and reducing cardiac afterload.- Antgonise Beta-adrenoceptor: heart failure is accompanied by potentially harmfulactivation of the sympathetic nervous system. Proving a rationale for using betablockers for this disorder.- Inhibit ADH: vasopressin isreleased inappropriately in heartfailure and may contribute to thehyponatraemia.- Relax vascular smooth muscle:Glyceryl trinitrate, its venodilatoreffect reduces venous pressure,and its effects on arterialcompliance and wave reflectionreduce cardiac work.- Increase the contractility: cardiacglycosides are used either inpatients with heart failure who also

have chronic rapid atrial fibrillation,or in patients who remainsymptomatic despite treatmentwith diuretic and ACE inhibitor.

3. Shock and hypotensive state.Is medical emergency byinadequate perfusion of vitalorgans, usually because of a very


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low blood pressure. Leads to anaerobic metabolism and hence to increased lactateproduction. Mediators promoting vasodilatation in shock converge on two mainmechanisms:- Activation on ATP-sensitive potassium channels by reduced cytoplasmic ATP andincreased lactate and protons.- Increased synthesis of NO, which activates myosin light-chain phosphate and

activates Kca-channels. Patients with shock are not homogenous population makingit hard to perform valid clinical trial.

4. Peripheral vascular disease.Commonest symptom is pain in the legs on walking (claudication), followed by painat rest and in severe cases gangrene of the feet or legs. Treatment is often surgicalor by angioplasty. Drug treatment includes antiplatelet drugs, a statin and an ACEinhibitor.

5. Raynauds disease.Inappropriate vasoconstriction of small arteries and arterioles gives rise to raynaudsphenomenon. Treatment involves stopping smoking and avoiding cold.

5. Pulmonary hypertension.Systolic pulmonary pressure in adults is normally 20mmHg. Pulmonary arterypressure is difficult to measure and requires cardiac catheterization. If pulmonarypressure is raised, it usually causes some leak of the tricuspid valve, allowingregurgitation of blood from the right ventricle to the right atrium. Increasedpulmonary pressure can result form an increased cardiac output.

Ch. 20 Atherosclerosis and lipoproteinmetabolism.

Atherogenesis.Atheroma is a focal disease of the intima of large and medium-sized arteries. Fattystreaks are earliest structurally apparent lesion and progress to fibrous and/or fattyplaques. Symptoms depend on the vascular bed and occur only when blood flowthrough the vessel is reduced below that needed to meet the metabolic demands oftissues downstream from obstruction.1. Endothelial dysfunction with altered PG and NO;2. Injury of dysfunctional endothelium leads to expression of adhesion molecules.Encourages monocyte attachment and migration of monocytes from the lumen intothe intima.3. LDL particles are transported into the vessel wall and generate free radicals thatoxidase LDL (oxLDL) resulting in lipid peroxidation;4. oxLDL is taken up by macrophages;5. Subendothelial collections of foam cells and T lymphocytes form fatty streaks;6. Cholesterol can be mobilised from the artery wall and transported in plasma in theform of HDL-c;7. Activated platelets, macrophages, causing proliferation of smooth muscle anddeposition of connective tissue components.8. A plaque can rupture, forming a substrate for thrombosis.

Lipoprotein transport in blood.There are four main classes, differin gin the relative proportion of the core lipids, andin the type of apoprotein. They also differ in size and density:


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- HDL-c: particles adsorb cholesterol derived from cell breakdown in tissues andtransfer it to VLDL and LDL particles.- LDL-c: particles with large component of cholesterol; some LDL cholesterol is takenup by the tissues and some by the liver, by endocytosis via specific LDL receptors.- VLDL: which transport cholesterol and newly synthesized triglycerides to thetissues, where triglycerides are removed as before leaving LDL particles.

- Chylomicrons: transport triglycerides adn cholesterol from gastrointestinal tract tothe tissues, where tiglyceride is split by lipoprotein lipase, releasing free fatty acidsand glycerol. These are taken up in muscle and adipose tissue. Chylomicronremnants are taken up in the liver, where cholesterol is stored, secreted in bile,oxidized to bile acids or converted into VLDL.

Lipid-lowering drugs.

1. Satins: HMG-CoA reductase inhibitors.Main biochemical effect of statins is to reduce plasma LDL-c. Short-acting statins aregiven by mouth at night to reduce peak cholesterol synthesis in the early morning.Mild unwanted effects include myalgia, gastrointestinal disturbance, raisedconcentrations of liver enzymes in plasma, insomnia and rash.

2. Fibrates.Cause a marked reduction in circulating VLDL. The mechanism of action is complex.

They are agonists for PPARs; in humans , the main effects are to increasetranscription of the genes for lipoprotein lipase, apoA1 and apoA5. They increasehepatic LDL-c uptake. Fibrates reduce plasma-c reactive protein and fibrinogen,improve glucose tolerance, and inhibit vascular smooth muscle inflammation.

3. Drugs that inhibit cholesterol absorption.


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Their effect is modest and they are bulky, unpalatable and cause diarrhoea. Agentsthat interfere with cholesterol absorption usually as an adjunct to diet plus statin:- Ezetimibe;- Stanol-enriched foods;- Bile acid-binding resins.

4. Fish oil derivatives.Omega-3 marine triglyceride reduce plasma triglyceride concentrations but increasecholesterol. Mechanism of action of fish oil on plasma triglyceride is unknown.

Ch. 21. Haemostasis and thrombosis.

Haemostasis is arrest of blood loss from damaged blood vessels. A wound causesvasoconstriction accompanied by:- Adhesion and activation of platelets;- Fibrin formation.

Thrombosis is the pathological formation of a haemostatic plug within the

vasculature in the absence of bleeding. Virchows triad. This comprises injury to thevessel wall; altered blood flow and abnormal coagulability of the blood. A thrombus ,which forms in vivo, should be distinguished from a clot, which forms in static bloodin vitro. Clots are amorphous, consisting of a diffuse fibrin meshwork in which red andwhite blood cells are trapped indiscriminately. An arterial thrombus -> whitethrombus consisting mainly of platelets and leucocytes in a fibrin mesh, associatedwith atherosclerosis. Venous thrombus -> red thrombus and consists of a small whitehead and a large jelly-like red tail. Drugs affecting heamostasis and thrombosis inthree distinct ways:- Affecting blood coagulation;- affecting patelet function;- affecting fibrin removal (fibrinolysis).

Blood coagulation.

Coagulation cascade.Means the conversion of fluid blood to a solid gel or clot. Main event is the conversionby thrombin of soluble fibrinogen to insoluble strands fibrin. Important inhibitor isantithrombin III, which neutralizes all the serine proteases in the cascade. Vascularendothelium also actively limits thrombus extension. Thrombin cleaves fibrinogen,producing fragments that polymerise to form fibrin. It also activates factor XIII, afibrino ligase, which strengthens fibrin-to-fibrin links, thereby stabilizing thecoagulum. Thrombin also causes platelet aggregation, stimulates cell proliferationand modulates smooth muscle contraction.

Vascular endothelium in haemostasis and thrombosis.

Normally, it provides a non-thrombogenic surface by virtue of surface heparansulfate, a cofactor for antithrombin III. It also plays an active part in haemostasis,synthesising and storing several key haemostatic components; VWF, TF and


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plasminogen activator inhibitor (PAI-1).

Drugs that act on the coagulation cascade.

Vitamin K.It is essential for the formation of clotting factors II, VII, IX, X. These are allglycoproteins with several gamma-carboxyglutamic acid (Gla). Gamma-carboxylationoccurs after the syntehsis of the chain. Carboxylase enzyme requires vit K as acofactor. Ca2+ binding does not occur in the absence of gamma-carboxylation.Protein C and S are also vitamin K dependent.

Thrombosis.

Main drugs used to prevent or treat red thrombus are:- Injectable anticoagulants (heparin);- Oral anticoagulants (warfin).Heparins act immediately. Consequently patients with venous thrombosis are treatedimmediately with an injectable anticoagulant.

Injectable anticoagulants.Heparin: doses are specified in units of activity ratherthan of mass. Heparin fragments or a syntheticpentasaccharide referred to as low-molecular-weightheparins (LMWHs) are used increasingly in place ofunfractionated heparin. Heparin inhibits coagulationby activating antithrombin III. Antithrombin III inhibits

thrombin. Thrombin is considerably more sensitive toinhibitory effect of heparin than is factor X. To inhibitheparin, it is necessary for heparin to bind to theenzyme ad well as to antithrombine III; to inhibit factorX, it is necessary only for heparin to bind toantithrombin III. The LMWHS increase the action ofantithrombin III on factor Xa but not on thrombin, because the molecules are toosmall to bind both enzymes. Heparin acts immediately following IV injection. LMWHSare given subcutaneously, they have longer elimination half-life than unfractionatedheparin, and this is independent of dose -> do not prolongs aPTT. Unwanted effects


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are:- Haemorrhage: treated by stopping therapy, giving protramine sulfate -> heparinantagonist which forms an inactive complex with heparin.- Thrombosis: uncommon but serious adverse effect of heparin -> heparin-induced-thrombocytopenia (HIT). More serious thrombocytopenia occuring 2-14 days after thestart of therapy and is caused by IgM or IgG antibodies against complexes of heparin

and platelet factor IV. Circulating immune complexes bind to Fc receptors oncirculating platelets, therby activation them and releasing more platelet factor IV andcausing thrombocytopenia. LMWHs are less liable than standard heparin to activateplatelets to release platlet factor IV, and they bind less avidly to platelet factor IV.

Vitamin K antagonists: warfin.Is the most important oral anticoagulant; warfin and other vit K antagonists requirefrequent blood tests to individualize dose. They interfere with the posttranslationalgamma-carboxylation of glutamix acid residues in clotting factors II, VII, IX, X. Theireffect takes several days to develop because of the time taken for degradation ofperformed carboxylated clotting factors. The peak concentration in the blood occurswithin an hour of ingestion, but because of the mechanism of action this does notcoincide with the peak pharmacological effect, which occurs about 48hours later.Warfin crosses the placenta and is not given in the first months of pregnancybecause it is teratogenic, nor in the later stages because it can cause intracranialhaemorrhage in the baby during delivery. It appears in milk during lactation. Factorsthat potentiate oral anticoagulants:- Liver disease: interferes with synthesis of clotting factors;- Agents that inhibit hepatic drug metabolism (co-trimoxazole);- Drugs that inhibit platelet function (e.g. aspirin);- Drugs that displace warfarin from binding sites on plasma albumin (result in atransient increased in the concentration of free warfarin in plasma;- Drugs that inhibit reduction of vitamin K;- Drugs that decrease the availability of vitamin K.

Platelet adhesion and activation.A low platelet count results in thrombocytopenic purpura. When platelets areactivated, they undergo a sequence of reactions:- Adhesion following vascular damage;- Shape change;- Secretion of the granule contents (including agonists, ADP and 5-hydroxytrypatamine);- Biosynthesis of labile mediator such as platelet-activating factor and thromboxane(TX) A2;- Aggregation , promoted by various agonists, including collagen, thrombin, ADP, 5-hydroxytrypatamine and TXA2, acting on specific receptors on the platelet surface;activation by agonists leads to expression of GPIIB/IIIa receptors that bind fibrinogen;- Exposure of acidic phospholipid on the platelet surface, promoting thrombinformation.

Antiplatelet drugs.

Aspirin.Alters the balance between TXA2, which promotes aggregation, and PGI2, whichinhibits it. It inactivates COX by irreversibly acetylating a serine residue in its activesite. This reduces both TXA2 synthesis in platelets and PGI2 synthesis inendothelium. Vascular endothelial cells can synthesise new enzyme via regenerationof COX-1 and via COX-2, whereas platelets cannot. Platelets are replaced in 7-10days. Adverse effects of aspirin are mainly on gastrointestinal tract -> clearly dose-


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related.

Dipyridamole.A phophodiestarase inhibitor. A modified release of dipyridamole reduced the risk ofstroke and death in such patients by around 15%- a similar effect to that of aspirin.Headache was the commonest adverse effect -> cause no excess risk of bleeding.

Thienopyridine derivatives.Ticlopidine inhibits ADP-dependent aggregation. Its efficacy is reducing stroke issimilar to that of aspirin, but idosyncratic unwanted effects, including severdyscrasias.Clopidogrel is structurally related to ticlopidine and also inhibits ADP-inducedaggregation through an active metabolite. It can cause rash or diarrhoea, butneutropenia is no more common than with aspirin.

Fibrinolysis.

Fibrinolytic drugs.Drugs are used clinically principally to repon the occluded coronary artery in patientswith acute myocardial infarction, less commonly in patients with life-threateningvenous thrombosis or pulmonary embolism. Streptokinase is a protein extracted formcultures of streptococci. It activates plasminogen. Alteplase and duteplase are singleand double-chain recombinant tPA. They are more active on fibrin-boundplasminogen than on plasma plasminogen.

Unwanted effects.Main hazard is bleeding, including gastrointestinal haemorrhage and stroke.Streptokinase can cause allergic reactions and low-grade fever.


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