Block I Posting, Pharmacology Lectures

Dr. Aduragbenro Adedapo

ANTIPARKINSONIAN DRUGS
Parkinsonism: - extrapyramidal motor disorder Xterised by rigidity, tremor, hypokinesia = parkinsonian triad 10 IDIOPATHIC 20 CAUSES Drugs MPTP N-methyl-4phenyl1,2,3,6- tetrahydropyridine a chemical contaminant of heroin, atherosclerosis, encephalitis, drugs which block dopamine receptors e.g. neuroleptics for treating schizophrenia phenothiazines eg chlorpromazine Imbalance between dopaminergic (inhibitory ) & cholinergic (excitatory ) system in the striatum occurs giving rise to the motor defect. NB cholinergic system is not primarily affected but its suppression by anticholinergics tends to restore balance.

Antiparkinsonism Drugs
CLASSIFICATION Drugs affecting brain dopaminergic system i.e. increasing dopaminergic activity Dopamine precursors - Levodopa (L-dopa) Dopaminergic agonists e.g. bromocriptine, pergolide, lisuride, apomorphine, ropinirole, piribedil Peripheral decarboxylase inhibitors-carbidopa, benserazide Dopaminergic transmission facilitators - selegiline (MAOBinhibitor), Stimulate dopaminergic release - Amantadine

Antiparkinsonian drugs ctd

Drugs affecting brain cholinergic system Central anticholinergics:- Benzatropine, trihexyphenidyl (Benzhexol), procyclidine, Biperiden Antihistaminics :- Orphenadrine, Promethazine

Levodopa
Levodopa Inactive by itself. Immediate precursor of DA Greater than 95%of an oral dose is decarboxylated in the peripheral tissue (mainly gut & liver) high first pass metabolism DA thus formed causes adverse effects e.g. on the heart, (tachycardia), acting on adrenergic receptors, blood vessels, other peripheral organs and CTZ (nausea & vomiting), though located in the brain i.e. floor of 4th ventricle, not bound by BBB. Tolerance develop to the peripheral effect. 1-2% of admin. L-dopa crosses to the brain, is taken up by the surviving dopaminergic neurones, converted to Dopamine which is stored & released as transmitter.

Levodopa
Mech. of action L Dopa is decarboxylated to DA in the brain by dopa decarboxylase. Beneficial effects produced through the action of DA on D2 receptors. DA itself is not used because it does not cross the BBB. Route of admin. Oral

Levodopa
Pharmacokinetics -Peak plasma conc. reached in 1-2 hours, t 1-2 hours. -Only about 1% reaches the brain a result of peripheral metabolism. -Rapidly absorbed from the small intestines -Utilize the active transport process meant for aromatic amino-acids. -Bio-availability affected by: i. Gastric emptying:- If slow, L-dopa is exposed for a long time to the degrading enzymes in gut and liver, less will be available to penetrate BBB. ii. Amino-acids present in food: will compete for the same carrier for absorption hence blood levels are lower when taken with meals.

Levodopa ctd
Ldopa undergoes high first pass metabolism in g.i mucousa and liver by this pathway. L-Dopa(Decarboxylase) Dopamine(MAO)DOPAC(COMT) HVA DopamineNoradrenaline Pyridoxine is a co factor for the enzyme decarboxylase N.B. DOPAC=3, 4 dihydroxyl phenylacetic acid, HVA=Homovanillic acid (3 methoxyl-4-hydroxyl phenyl acetic acid)

Levodopa (ctd)
-Metabolites are excreted in urine mostly after conjugation. INDICATIONS: L-Dopa is used to treat parkinsonism (except drug induced extrapyramidal symptoms). CONTRAINDICATION: closed angle glaucoma. Caution: Elderly, Ischcemic Heart dx., Psychiatric dx., Hepatic dx., Renal dx., Gout, Peptic ulcer. ADVERSE EFFECTS: Nausea & Vomiting. Psychiatric Side Effects. Schizophrenia like symptoms vivid dreams, confusion due to excess dopamine action in the limbic system (antidopaminergic drugs are anti-psychotic). Cardiovascular effects- hypotension, cardiac arrythmias, exacerbation of angina. Dyskinesia. Alteration in taste sensation. Fluctuation in motor performance gradually ranging from end of dose deterioration, on-off effect, all or none response.

STRATEGIES TO MANAGEMENT
Optimize L-dopa treatment, minimize its unwanted peripheral effects and maximize the central effect with in the brain. Carbidopa Peripheral inhibitor of dopa decarboxylese which cannot penetrate the BBB, prevents the extracerebral conversion of L-Dopa to dopamine. Domperidone a dopamine antagonist, does not penetrate BBB, blocks peripheral stimulation of dopamine receptors. Selegiline and entacapone, MAOB and COMT inhibitors, respectively inhibit dopamine degradation centrally i.e. in the CNS. NOTE: Initial Rx with L-dopa is effective in 80% pts. with possible restoration of near normal motor function.

Strategies of mgt ctd

L-dopa restores dopamine levels in the short term but has no effect on the underlying degenerative dx process, with progression in neuronal degeneration, corpus striatum is unable to convert L-dopa to dopamine sufficiently enough, i.e. capacity to convert reduce after 2-5 years of therapy, fluctuation in the level of symptoms control sets in and manifests as End of dose deterioration (wearing off ) which is initially (i.e. a shortening of the duration of each dose of L-dopa) gradual, develops into rapid fluctuations or switches in clinical state or the on-off effect. This varies from increased mobility and a general improvement to increased rigidity and hypokinesia. With time all or none response develops when the patient is alternately well and disabled.

Levodopa
INTERACTIONS: 1. Pyridoxine:Abolishes therapeutic effect by enhancing peripheral decarboxylation of Ldopa, less drug available to cross BBB. 2. Phenothiazines:- Butyrophenones, metoclopramide block DA receptors & prevent therapeutic effect. Domperidone:- A peripheral DA receptor antagonist blocks Levodopa induced nausea & vomiting without affecting its anti-parkinsonian (since it does not cross the BBB). Reserpine abolishes L-dopa action by preventing entry of DA into synaptic vesicles.

Levodopa
3. Non selective MAOIs:- Prevents degradation of peripherally synthesized DA and NA Hypertensive crisis can occur.(MAO-A predominate in peripheral adrenergic neurones and intestines, while MAO-B occur in the brain and platelets) 4. Anti-HT sive:- Postural hypotension more pronounced, therefore reduce dose of anti HT if L-dopa is started. 5. Atropine and other anti-cholinergics:additive effect with low dose L-dopa. Atropine retards the absorption of L-dopa, giving more time for peripheral degradation to occur efficiency of L-dopa may be reduced.

Carbidopa and Benserazide are peripheral (l-dopa) decarboxylase inhibitors. They do not penetrate the BBB. They do not inhibit conversion of L-dopa to dopamine in the brain. Administered along with L-dopa. Dopamine agonist e.g. bromocriptine, selective for the D2 receptors, apomorphine also has agonist action at D1 receptors. Route of admin oral. With bromocriptine, improvement in symptoms occur within -1 hour, lasts 6-10 hours Adverse effects: nausea, vomiting, constipation, headache, hallucinations, hypotension, xs daytime sleepiness, nasal stuffiness, conjuctival injection, dyskinesia may occur but less than with l-dopa.

Amantadine: Stimulates the release of dopamine. Developed as an anti-viral drug for prophylaxis of influenza A2 but was found to benefit Parkinsonism. Acts rapidly but less efficient than if L-dopa. More efficient than anti-cholinergics. Mechanism of action Facilities presynaptic dopamine synthesis & release in the brain. Inhibits its uptake in Ns. Also possible action on glutamate receptors. Additional muscarinic blocking actions. Synergistic effect when used in conjunction with L-dopa to Rx Parkinsonism has short term benefit because most of its effectiveness is lost within 3/12 of initiating Rx

Amantadine ctd
Adverse Effects Anorexia, nausea. Hallucinations, insomnia, dizziness, confusion, nightmares. Livedo reticularis due to local release of catecholamines resulting in vasoconstriction. Ankle oedema. SE more marked when combined with anticholinergics.

MAOBI,
Selegiline (Deprenyl) Selectively inhibits MAOB enzyme in the brain (the enzyme is responsible for the degradation of dopamine). Route of admin.: oral Indication: used on its own to Rx Parkinsonism, and in conjuction with L-dopa to reduce end of dose deterioration. Adv. Effect Postural hypotension, nausea, confusion, accentuates Ldopa induced involuntary movements & psychosis Contra-indication: Convulsions Interaction: Pethidine excitement, hyperthermia, resp depression

Anti-cholinergics
Antagonize muscarinic receptors Reduce excess striated cholinergic activity Oral administration Adverse Effects dry mouth, Blurred vision, mild memory loss, acute confusional state Antihistamines less efficacious than anticholinergic, have antimuscarinic effect and are better tolerated by some adults. The sedative effect is also helpful. Orphenadrine has mild euphoriant effect

Myasthenia Gravis.
rare dx. Autoimmune dx, antibodies directed to nicotinic receptors in the skeletal muscle NMJ, affect 1 in 10,000 population. Reduction in number of free Nm cholinoceptors. Damage to NMJ weakness, easy fatigability on repeated activity with recovery after rest. Anticholinesterases are 1st line Rx for ocular dx, and adjunct to immunosuppressant therapy for generalised myasthenia gravis

Myasthenia Gravis
Neostigmine enhance neuromuscular transmission in voluntary and involuntary muscle improving contraction allow ACH released from prejunctional endings to accumulate and act on receptor of a large area. Directly depolarizing the end plate. Rx started with 15mg orally 6 hourly then adjust according to response. Produces therapeutic effect for up to 4hours

Pyridostigmine
an alternative, needs less frequent dosing Longer acting, but less powerful and slower in action than neostigmine. Distigmine: longest action but danger of cholinegic crisis makes it less useful therapeutically

Adverse effects
Nausea, vomiting, increased salivation, diarrhoea, abd cramps Bronchoconstriction, increased bronchial secretion, lacrimation, sweating, involuntary micturition and defeacation Miosis, nystagmus Bradycardia, heart block, arrhythmias, hypotension Atropine is useful for the muscarinic side effects

Myasthenia gravis Rx (ctd)

Corticosteroids: Immunosuppresant action, inhibits nicotinic receptor antibodies, may enhance synthesis of receptor e.g. Prednisolone 30-60 mg .day. Maintenance dose 10mg per day Other immunosuppresants: Azathioprine and cyclosporine Plasmapheresis: for removal of antibodies Thymectomy Short acting anticholinesterases for diagnosis Edrophonium for diagnosis of M.G.or cholinergic crisis, duration of action 2-10 min.

ANTI-COAGULANTS
Drugs used to reduce the coagulability of blood. In vitro. A - Heparin: 150 U to prevent clothing of 100ml blood. B Calcium complexing agents: Na citrate, Na oxalate, Na edetate In Vivo A. Parenteral B. oral Heparin, LMW heparin dalteparin, enoxaparin Heparinoids Danaparoid, Heparin sulphate, Dextran sulphate, Ancrod. Hirudins lepirudin, bivalirudin Epoprosterenol (prostacyclin) Fondaparinux synthetic pentasaccharide that inhibits activated factor X

B. Oral anticoagulants
Coumarin derivatives: Bishydroxycoumarin (dicumarol), Warfarin sulphate, Acenocoumarol Indandione derivatives: Phenindione

HEPARIN
Discovered by a medical student, McLean in 1916. Non-uniform mixture of straight chains mucopolysaccharide Reffered to as standard or unfractionated heparin MW 10,000 20,000 Active both in-vitro and in-vivo Initiates anticoagulation rapidly, but has a short duration of action Acts indirectly by activating plasma antithrombin III (AT III) The complex binds to & inactivates the clotting factors (Xa, IIa, IXa, XIa, XIIa and XIIIa) in the intrinsic and common pathway, but not factor VIIa in the extrinsic pathway Low concentration prolong aPTT without significant PT prolongation Low conc interfere mainly with intrinsic pathway while high conc affect the common pathway as well Sudden withdrawal of treatment may cause rebound coagulation May have antiplatelet effect and prolong bleeding time

Heparin
Not absorbed orally, does not cross BBB or placenta Metabolized in the liver by heparinase and excreted in the urine. Half-life abt 1-5hrs depending on the dose, it is prolonged in cirrhotics and renal failure, shorter in pulmonary embolism Dose i.v. bolus 5,000-10,000U 4-6hrly (50-100U/kg), or continuous infusion of 750-1000U/hr after an initial bolus dose. Subcutaneous injection 10,000-20,000U 8-12hrly. NO I.M. injection because of heamatoma formation. Low dose s.c. 5000U 8-12hrly to prevent DVT

 Do not mix with penicillin, TCN, hydrocortisone or NA in the same syringe or infusion bottle Adverse effects Bleeding, Thrombocytopenia, Alopecia, Osteoporosis, Hypersensitivity reaction urticaria, angioedema, anaphylaxis. Contraindication Bleeding disorders - haemophilia, Severe HT, Subacute bacterial endocarditis, recent cerebral haemorrhage, Ocular and neurosurgery, lumbar puncture, severe liver disease, oesophageal varices, cirrhosis, UFH given to maintain a PTT at 2.0-2.5 times control. Toxicity Bleeding: stop heparin, administer heparin antagonist Protamine sulphate.

Protamine Sulphate:
Heparin antagonist, strongly basic, LMW protein obtained from certain fish sperm Admin i.v., neutralizes heparin weight for weight 1mg needed for 100U of heparin. It exhibits weak anticoagulant effect even in the absence of heparin If used in excess, it has an anticoagulant effect May release histamine being basic, hypersensitivity may occur. Rapid i.v. injection causes flushing and breathing difficulty.

LMW Heparin
MW range 3,000-7,000. Selectively inhibits activated factor X but has less effect on AT and on coagulation in general. Less antiplatelet action Lower incidence of bleeding as complication Better s.c. bioavailability (79-90%) compared to UFH (20-30%) Longer half-life, longer duration of action, once daily dose Laboratory monitoring is not mandatory for the standard prophylactic dose, since aPTT/clotting times are not prolonged. This may be required in patients at increased risk of bleeding eg renal impairment, and I the underweight and overweight LMW Heparins- enoxaparin and dalteparin are effective in preventing development of DVT post op. Effective in Rx of acute venous thrombosis, acute coronary syndrome Dextan sulphate: is a sulphated polymeric sugar, less potent than heparin but has a longer duration of action.

Heparinoids
Semi synthetic Sulphated mucopolysaccharides Potent anticoagulants E.g. Danaparoid sodium indications: prevention of DVT, thromboembolic disease in patients with heparin induced thrombocytopenia

HIRUDIN.
Powerful & specific thrombin inhibitor available in recombinant form as lepirudin, bivalirudin its action, is independent of antithrombin III, it can reach and activate fibrin bound thrombin in thrombi. Route of admin S. C. ,I. V. Lepirudin has little effect on platelet or the bleeding time. administered like heparin, monitor by the aPTT, has a short half life accumulates in renal in sufficiency, no antidote.

Epoprostenol
Protacyclin Given to inhibit platelet aggregation alone or with heparin Half life - 3min Admin by continuous intravenous infusion Potent vasodilator Indicatons during renal dialysis, pry pulm HT Adverse effects headache, flushing, hypotension, bradycardia, tachycardia, pallor, sweating, agitation, dry mouth,chest pain

Fondaparinux
Synthetic pentasaccharide Inhibits acivated factor X Indications: prophylaxis and treatment of DVT and pulmonary embolism Caution: bleeding disorders, etc as for heparin CI: active bleeding, bacterial endocarditis Adverse effects: Oedema, haemorrhage, anaemia, hypotension, thrombocytopenia, purpura, GI disturbance, rashes, pruritus

WAR FARIN AND THE COUMARIN anticoagulant

Oral anticoagulants (also used as rodenticides) (discovered from spoiled sweet clover hay deficiency of plasma prothrombin and haemorrhage ensured). act as anticoagulant in-vivo and not in-vitro, act indirectly by interfering with the synthesis of Vit. K dependent clotting factors in the liver. They block the reduction of Vit.K epoxide, which is necessary for its action as a cofactor in the synthesis of factors VII, 1X. Anticoagulation develops over 1-3days, though the synthesis of clotting factors is reduced within 2-4hrs of Warfarin admin. Factor VII has the shortest half-life (6hr), factor IX (24hr), factor X(40hr) and prothrombin (60hr), therapeutic effect occurs when synthesis of clotting factors is reduce by 40-50% Warfarin is the drug of choice, others acenocoumarol and phenindione are seldom needed

Pharmacokinetic and adverse effects profile of oral anticoagulants

DRUG 1. Bishydroxycou marin (Dicumarol) 2. sod. Warfarin Half life (T ) (hr) 25-100 (dose dependent) 36-44 Duration of action (days) 4-7 Loading Dose (mg) 200 2/7 for Maintenance dose (mg) 50-100

Adverse ef (non-haem

Freq. Git d

3-6

10-15

2-10 (single dose, same time dly)

Alopecia, d diarrhea

3. Acenocoumarol
4.Ethylbiscoum acetate 5. Phenindione

18-24

2-3

8-12

2-8

Oral ulcer git distur dermatiti

2 5

1-3 1-3

900 200

300-600 50-100

Alopecia, b

Orange ur rashes, fev leukopeni nephropa agranuloc

Warfarin sodium
a racemic mixture of R (dextro-) and S (levo-) enantiomers, well absorbed from the intestine, 99% plasma protein bound, crosses placenta and is secreted in milk. Metabolized by ring oxidation (levorotatory) and side chain reduction (dextrorotatory), both are partially conjugated by glucuronic acid, undergo some enterohepatic circulation, excreted in urine. Indications Prophylaxis or the Rx of DVT and PE. Prophylaxis of embolism in Atrial fibrillation, Rheumatic dx and in pts with prosthetic heart valves.

Warfarin
Contraindications: as for heparin, pregnancy Adv. Effect Haemorrhage NOTICE: onset of action of vit K antagonists takes several hours, owing to the time needed for the degradation of factors that have already been decarboxylated (t VII= 6hrs. IX =24hrs. X = 40hrs. II=60hrs.).

Antiplatelet Agents
Aspirin Clopidogrel Dipyridamole Glycorotein IIb/IIIa Inhibitors- Abciximab Glycoprotein IIb/IIIa receptor inhibitors Eptifibatide, tirofiban

Aspirin
acetylsalicylic acid originally derived from the willow tree. blocks the synthesis of Thromboxane A2 (TXA2) from arachidonic acid in platelets. it acetylates and thus inhibiting the enzyme cycloxygenase and thromboxane synthetase. TXA2 stimulates phospholipase C thus increasing calcium levels and causing platelet aggregation ASA also blocks the synthesis of prostacyclin from endothelial cells (PGI2 is a strong inhibitor of platelet aggregation). This effect is short lived because endothelial cells unlike platelets, can synthesis new cycloxygenese.

 Admin. Orally Indications- prevention and Rx of Myocardial Infarction and ischaemic stoke also as an analgesic and antiinflammatory agent (increased dose) Contraindication: Children below 12 years (risk of Reyes syndrome), breastfeeding, haemophilia, peptic ulcer, known hypersensitivity. Adv. Effects bronchospasm GIT haemorrhage Dose:75-150mg dly

Membrane phospholipid

Phospholipase A (enzyme)

Arachidonic acid Lipooxgenase (enzyme) Cyclooxygenase (enzyme) I LTA4 Cyclic endoperoxides PGG2, PGH2 LTB4, LTC4 ->LTD4 ->LTE4->L I PGE2, PGD2, PGF2,; TXA2, PGI2 SRS-A

 Dipyridamole. - inhibits phosphodiesterase enzy that hydrolyse AMP. cAMP levels result in decreased calcium levels and inhibition of platelet aggregation. Admin orally. Used in conjuction with warfarin and other oral anticoagulant in the prophylaxis against thrombosis associated with prosthetic valve. Adv. Effect hypotension, nausea., diarrhea, and h/ache.

 Clopidogrel. inhibits activation of the glycoprotein II b / IIIa receptor on platelets surface which is required for aggregation to occur. Admininstered orally Indications: prevention of cardiovascular & cerebrovascular events Can be used in place of aspirin, in asprin allergy Ticlopidine similar action to clopidogrel.

FIBRINOLYTIC AGENTS
Streptokinase 47k Da protein produced from hemolytic streptococci group C, inactive but combines with circulating plasminogen to form an active complex degrading other plasminogen into plasmin. t 40-80 min. Indication - life threatening venous thrombosis pulm embolism arterial thromboembolism. Acute M. I C.I recent haemorrhage, trauma, surgery within 10 day organ biopsy puncture to non-compressible vessels, active bleeding, bleeding diathesis aortic dissection, coma, hx of CVD, (see BNF for more) serious GI bleeding within 3/12 or active intracranial process Hx of HT DBP > 110mmHg, acute pericarditis. Commonly used in conjuction with antiplatelet and anticoagulant drug . Derived from haemolytic streptococci.. antigemic. Repeated admin could result in anaphylaxis like rxn. If repeated admin required use non antigenic type tissue plasminogen activator

Anistreplase. (Anisoylated plasminogen streptokinase activator complex APSAC)- consists of a complex of purified human plasminogen and bacteria streptokinase. used for coronary thrombolysis. However, when it is given as a bolus injection at the recommended dose for coronary of 30U, marked systemic fibrinolysis occurs. Tissue plasminogen activators (t-PA): this activates plasminogen that is bound to fibrin, thus confining fibrinolysis to formed thrombus. Avoids systemic activation.

ANTIFIBRINOLYTIC AGENTS.
Inhibits plasminogen activation and clot dissolution Epsilon aminocaproic acid (EACA) A lysine analogue. Binds to lysine bindingof plasmin to target fibrin. Potent inhibitor of fibrinolysis. Can reverse hyperplasminemic states associated with excessive intravascular fibrinolysis resulting in bleeding e.g overdose of streptokinase/urokinase/alteplase. - rapidly absorbed after oral admin. -50% excreted unchanged in the urine rapidly within 12hrs. Indication: adjunctive treatment in haemophilia, anti dote for bleeding from fibrinolytic therapy, prophylaxis for bleeding from intracranial aneurysms. Adverse Effect. Hypotension, bradycardia, arrythmias, myopathy, nasal stuffiness, abdominal discomfort, diarrhea Contraindications: DIC, genitourinary bleeding of kidney and ureters because of the possibility of forming excessive clots. Thrombi that are formed during Rx with the drug are not lysed e.g. in patients with haematuria, urethral obstruction by clots may lead to renal failure after Rx with aminocaproic acid.