Block I Posting, Block I Posting, Pharmacology LecturesPharmacology Lectures

Dr. Aduragbenro AdedapoDr. Aduragbenro Adedapo

ANTIPARKINSONIAN DRUGSANTIPARKINSONIAN DRUGS

• Parkinsonism: - extrapyramidal motor disorder Xterised by rigidity, tremor, hypokinesia = parkinsonian triad

• 10 IDIOPATHIC• 20 CAUSES – Drugs – MPTP N-methyl-4–phenyl-

1,2,3,6- 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 DrugsAntiparkinsonism 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 ctdAntiparkinsonian drugs ctd

• Drugs affecting brain cholinergic system

• Central anticholinergics:- Benzatropine, trihexyphenidyl (Benzhexol), procyclidine, Biperiden

• Antihistaminics :- Orphenadrine, Promethazine

LevodopaLevodopa

• 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 β –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 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

LevodopaLevodopa

Pharmacokinetics –• -Peak plasma conc. reached in 1-2 hours, t½ 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 ctdLevodopa ctd

• L–dopa undergoes high first pass metabolism in g.i mucousa and liver by this pathway.

• L-Dopa(Decarboxylase)→ Dopamine(MAO)→DOPAC(COMT) →HVA

• Dopamine→Noradrenaline• 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)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 (anti-dopaminergic 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 MANAGEMENTSTRATEGIES 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 ctdStrategies 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.

LevodopaLevodopa

• INTERACTIONS:• 1. Pyridoxine:- Abolishes therapeutic effect

by enhancing peripheral decarboxylation of L-dopa, 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 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 ½ -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:-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 ctdAmantadine 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 anti-

cholinergics.

MAOMAOBBI,I,

• 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 L-

dopa induced involuntary movements & psychosisContra-indication: ConvulsionsInteraction: Pethidine – excitement, hyperthermia, resp

depression

Anti-cholinergicsAnti-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.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 GravisMyasthenia 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

PyridostigminePyridostigmine

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 effectsAdverse 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)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• ThymectomyShort acting anticholinesterases – for diagnosis• Edrophonium for diagnosis of M.G.or cholinergic

crisis, duration of action 2-10 min.

ANTI-COAGULANTSANTI-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 edetateIn 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 anticoagulantsB. – Oral anticoagulants

• Coumarin derivatives: Bishydroxycoumarin (dicumarol), Warfarin sulphate, Acenocoumarol

• Indandione derivatives: Phenindione

HEPARINHEPARIN

• 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

HeparinHeparin

• 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: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 HeparinLMW 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.

HeparinoidsHeparinoids

• Semi synthetic

• Sulphated mucopolysaccharides

• Potent anticoagulants

• E.g. Danaparoid sodium

• indications: prevention of DVT, thrombo-embolic disease in patients with heparin induced thrombocytopenia

HIRUDIN.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.

EpoprostenolEpoprostenol

• Protacyclin• Given to inhibit platelet aggregation alone or with

heparin• Half life - 3min• Admin by continuous intravenous infusion• Potent vasodilatorIndicatons – during renal dialysis, pry pulm HTAdverse effects – headache, flushing,

hypotension, bradycardia, tachycardia, pallor, sweating, agitation, dry mouth,chest pain

FondaparinuxFondaparinux

• 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 WAR FARIN AND THE COUMARIN anticoagulant 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

DRUGHalf life(T ½) (hr)

Duration of action (days)

Loading Dose (mg)

Maintenance dose (mg)

Adverse effects (non-haemorhagic)

1. Bishydroxycoumarin (Dicumarol)

25-100 (dose dependent)

4-7 200 for 2/7

50-100 Freq. Git disturbance

2. Warfarin sod.

36-44 3-6 10-15 2-10 (single dose, same time dly)

Alopecia, dermatitis, diarrhea

3. Acenocoumarol

18-24 2-3 8-12 2-8 Oral ulceration, git distur, dermatitis urticaria

4.Ethylbiscoumacetate

2 1-3 900 300-600 Alopecia, bad taste

5. Phenindione 5 1-3 200 50-100 Orange urine, rashes, fever, leukopenia, hepatitis, nephropathy, agranulocytosis

Pharmacokinetic and adverse Pharmacokinetic and adverse effects profile of oral anticoagulantseffects profile of oral anticoagulants

Warfarin sodiumWarfarin 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.

WarfarinWarfarin

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 ½ VII= 6hrs.

• IX =24hrs.• X = 40hrs.• II=60hrs.).

Antiplatelet AgentsAntiplatelet Agents

Aspirin

Clopidogrel

Dipyridamole

Glycorotein IIb/IIIa Inhibitors- Abciximab

Glycoprotein IIb/IIIa receptor inhibitors – Eptifibatide, tirofiban

AspirinAspirin

• 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 anti-inflammatory agent (increased dose)

• Contraindication: Children below 12 years (risk of Reye’s syndrome), breastfeeding, haemophilia, peptic ulcer, known hypersensitivity.

• Adv. Effects – bronchospasm• GIT haemorrhage• Dose:- 75-150mg dly

Membrane phospholipid

Phospholipase A (enzyme)

Arachidonic acidCyclooxygenase (enzyme)

ICyclic endoperoxides

PGG2, PGH2

I

PGE2, PGD2, PGF2,; TXA2, PGI2

Lipooxgenase (enzyme)

LTA4

LTB4, LTC4 ->LTD4 ->LTE4->LTF4SRS-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 AGENTSFIBRINOLYTIC AGENTS

Streptokinase 47k Da protein produced from β hemolytic streptococci group C, inactive but combines with circulating plasminogen to form an active complex degrading other plasminogen into plasmin.

• t ½ 40-80 min.Indication - life threatening venous thrombosis • pulm embolism• arterial thromboembolism.• Acute M. IC.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. ANTIFIBRINOLYTIC AGENTS.

• Inhibits plasminogen activation and clot dissolutionEpsilon 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, diarrheaContraindications: 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.