ANTIPARKINSONIAN DRUGS2

7/31/2019 ANTIPARKINSONIAN DRUGS2

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Block I Posting, Pharmacology

Lectures

antiparkisonian drugs

Dr. Aduragbenro Adedapo


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ANTIPARKINSONIAN DRUGS

Parkinsonism: - extrapyramidal motor disorder Xterisedby rigidity, tremor, hypokinesia = parkinsonian triad

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

1,2,3,6- tetrahydropyridine a chemical contaminant ofheroin, atherosclerosis, encephalitis, drugs which blockdopamine receptors e.g. neuroleptics for treatingschizophrenia phenothiazines eg chlorpromazine

Imbalance between dopaminergic (inhibitory ) &cholinergic (excitatory ) system in the striatum occursgiving rise to the motor defect.

NB cholinergic system is not primarily affected but itssuppression by anticholinergics tends to restore balance.


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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 Drugs affecting brain cholinergic system Central anticholinergics:- Benzatropine, trihexyphenidyl (Benzhexol),

procyclidine, Biperiden

Antihistaminics :- Orphenadrine, Promethazine


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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 organsand CTZ (nausea & vomiting), though located in the brain i.e. floor of 4thventricle, 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 survivingdopaminergic neurones, converted to Dopamine which is stored & releasedas transmitter.

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.


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Levodopa

Route of admin.OralPharmacokinetics -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 absorptionhence blood levels are lower when taken with meals.

Ldopa undergoes high first pass metabolism in g.i mucousa and liver by thispathway.

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)


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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 performancegradually ranging from end of dosedeterioration, on-off effect, all or none response.


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STRATEGIES TO MANAGEMENT

Optimize L-dopa treatment, minimize its unwanted peripheral effects and maximizethe central effect with in the brain.

Carbidopa Peripheral inhibitor of dopa decarboxylese which cannot penetrate theBBB, prevents the extracerebral conversion of L-Dopa to dopamine.

Domperidone a dopamine antagonist, does not penetrate BBB, blocks peripheralstimulation 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.

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


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Levodopa

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 Levodopainduced 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.

3. Non selective MAOIs:- Prevents degradation of peripherallysynthesized DA and NAHypertensive crisis can occur.(MAO-A predominate inperipheral adrenergic neurones and intestines, while MAO-B occur in the brain andplatelets)

4. Anti-HT sive:- Postural hypotension more pronounced, therefore reducedose 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 degradationto occur efficiency of L-dopa may be reduced.


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Carbidopa and Benserazide are peripheral (l-dopa)decarboxylase inhibitors. They do not penetrate theBBB. They do not inhibit conversion of L-dopa todopamine in the brain. Administered along with L-dopa.

Dopamine agonist e.g. bromocriptine, selective for the D2receptors, apomorphine also has agonist action at D1receptors.

Route of admin oral.

With bromocriptine, improvement in symptoms occurwithin -1 hour, lasts 6-10 hours

Adverse effects: nausea, vomiting, constipation,headache, hallucinations, hypotension, xs daytimesleepiness, nasal stuffiness, conjuctival injection,dyskinesia may occur but less than with l-dopa.


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Amantadine:-

Stimulates the release of dopamine.

Developed as an anti-viral drug for prophylaxis of influenza A2 but was found tobenefit 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 initiatingRx

Adverse Effects

Anorexia, nausea.

Hallucinations, insomnia, dizziness, confusion, nightmares. Livedo reticularisdue to local release of catecholamines resulting in

vasoconstriction.

Ankle oedema.

SE more marked when combined with anti-cholinergics.


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MAOBI,

Selegiline (Deprenyl)

Selectively inhibits MAOB enzyme in the brain (theenzyme is responsible for the degradation of dopamine).

Route of admin.: oral

Indication: used on its own to Rx Parkinsonism, and inconjuction with L-dopa to reduce end of dosedeterioration.

Adv. Effect

Postural hypotension, nausea, confusion, accentuates L-

dopa induced involuntary movements & psychosisContra-indication: Convulsions

Interaction: Pethidine excitement, hyperthermia, respdepression


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Anti-cholinergics

Antagonize muscarinic receptors

Reduce excess striated cholinergic activity

Oral administration

Adverse Effects dry mouth, Blurred vision, mildmemory loss, acute confusional state

Antihistamines less efficacious thananticholinergic, have antimuscarinic effect and

are better tolerated by some adults. Thesedative effect is also helpful. Orphenadrine hasmild euphoriant effect


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Myasthenia Gravis.

rare dx.

Autoimmune dx, antibodies directed to nicotinicreceptors in the skeletal muscle NMJ, affect 1 in

10,000 popn. Reduction in no of free Nm cholinoceptors.

Damage to NMJ weakness, easy fatigability onrepeated activity with recovery after rest.

Anticholinesterases are 1st line Rx for ocular dx,and adjunct to immunosuppressant therapy forgeneralised myasthenia gravis


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Myasthenia Gravis

Neostigmine

enhance neuromuscular transmission involuntary and involuntary muscle improvingcontraction

allow ACH released from prejunctional endingsto accumulate and act on receptor of a largearea.

Directly depolarizing the end plate.

Rx started with 15mg orally 6 hourly then adjustaccording to response.

Produces therapeutic effect for up to 4hours


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Pyridostigmine

an alternative, needs less frequent dosing

Longer acting, but less powerful and slower

in action than neostigmine.

Distigmine: longest action but danger ofcholinegic crisis makes it less useful

therapeutically


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Adverse effects

Nausea, vomiting, increased salivation,

diarrhoea, abd cramps

Bronchoconstriction, increased bronchial

secretion, lacrimation, sweating, involuntarymicturition and defeacation

Miosis, nystagmus

Bradycardia, heart block, arrhythmias,hypotension

Atropine is useful for the muscarinic side effects


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Myasthenia gravis Rx (ctd)

Corticosteroids: Immunosuppresant action,inhibits nicotinic receptor antibodies, mayenhance synthesis of receptor e.g. Prednisolone30-60 mg .day. Maintenance dose 10mg per day

Other immunosuppresants: Azathioprine andcyclosporine

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.


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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.

Hirudinslepirudin, bivalirudin

Epoprosterenol (prostacyclin)

Fondaparinux synthetic pentasaccharide that inhibits activatedfactor X


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B. Oral anticoagulants

Coumarin derivatives: Bishydroxycoumarin

(dicumarol), Warfarin sulphate,

Acenocoumarol

Indandione derivatives: Phenindione


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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 notfactor VIIa in the extrinsic pathway

Low concentration prolong aPTT without significant PT prolongation

Low conc interfere mainly with intrinsic pathway while high concaffect the common pathway as well

Sudden withdrawal of treatment may cause rebound coagulation

May have antiplatelet effect and prolong bleeding time


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Heparin

Not absorbed orally, does not cross BBB or placenta

Metabolized in the liver by heparinase and excreted inthe urine.

Half-life abt 1-5hrs depending on the dose, it is

prolonged in cirrhotics and renal failure, shorter inpulmonary embolism

Dose i.v. bolus 5,000-10,000U 4-6hrly (50-100U/kg), orcontinuous infusion of 750-1000U/hr after an initial bolusdose. Subcutaneous injection 10,000-20,000U 8-12hrly.NO I.M. injection because of heamatoma formation. Lowdose s.c. 5000U 8-12hrly to prevent DVT


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Do not mix with penicillin, TCN, hydrocortisone or NA in the samesyringe or infusion bottle

Adverse effects Bleeding, Thrombocytopenia, Alopecia, Osteoporosis,

Hypersensitivity reaction urticaria, angioedema, anaphylaxis.

Contraindication Bleeding disorders - haemophilia, Severe HT, Subacute bacterialendocarditis, recent cerebral haemorrhage, Ocular andneurosurgery, lumbar puncture, severe liver disease, oesophagealvarices, cirrhosis,

UFH given to maintain a PTT at 2.0-2.5 times control.

Toxicity Bleeding: stop heparin, administer heparin antagonist -Protamine sulphate.


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Protamine Sulphate:

Heparin antagonist, strongly basic, LMW proteinobtained from certain fish sperm

Admin i.v., neutralizes heparin weight for weight1mg needed for 100U of heparin.

It exhibits weak anticoagulant effect even in theabsence 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.


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LMW Heparin

MW range 3,000-7,000.

Selectively inhibits activated factor X but has less effect on AT andon 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 prophylacticdose, since aPTT/clotting times are not prolonged. This may berequired in patients at increased risk of bleeding eg renalimpairment, and I the underweight and overweight

LMW Heparins- enoxaparin and dalteparin are effective inpreventing development of DVT post op. Effective in Rx of acutevenous thrombosis, acute coronary syndrome

Dextan sulphate: is a sulphated polymeric sugar, less potent thanheparin but has a longer duration of action.


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Heparinoids

Semi synthetic

Sulphated mucopolysaccharides

Potent anticoagulants E.g. Danaparoid sodium

indications: prevention of DVT, thrombo-

embolic disease in patients with heparininduced thrombocytopenia


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HIRUDIN.

Powerful & specific thrombin inhibitor

available in recombinant form as lepirudin,bivalirudin

its action, is independent of antithrombin III, itcan reach and activate fibrin bound thrombin inthrombi.

Route of admin S. C. ,I. V.

Lepirudin has little effect on platelet or the

bleeding time. administered like heparin, monitorby the aPTT, has a short half life

accumulates in renal in sufficiency, no antidote.


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Epoprostenol

Protacyclin

Given to inhibit platelet aggregation alone orwith 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


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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

WARFARIN AND THE COUMARIN


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WARFARIN AND THE COUMARIN

anticoagulant

Oral anticoagulants (also used as rodenticides) (discovered fromspoiled sweet clover hay deficiency of plasma prothrombin andhaemorrhage ensured).

act as anticoagulant in-vivoand not in-vitro, act indirectly byinterfering with the synthesis of Vit. K dependent clotting factors inthe 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 ofclotting factors is reduced within 2-4hrs of Warfarin admin. Factor VIIhas the shortest half-life (6hr), factor IX (24hr), factor X(40hr) andprothrombin (60hr),

therapeutic effect occurs when synthesis of clotting factors is reduceby 40-50%

Warfarin is the drug of choice, others acenocoumarol andphenindione are seldom needed


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DRUG

Half life

(T ) (hr)

Duration

of action

(days)

Loading

Dose (mg)

Maintenance

dose (mg)

Adverse effects

(non-haemorhagic)

1.

Bishydroxycou

marin

(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

effects profile of oral anticoagulants


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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 someenterohepatic 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.


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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 thedegradation of factors that have already been

decarboxylated (t VII= 6hrs.

IX =24hrs. X = 40hrs.

II=60hrs.).


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Antiplatelet Agents

Aspirin

Clopidogrel

DipyridamoleGlycorotein IIb/IIIa Inhibitors- Abciximab

Glycoprotein IIb/IIIa receptor inhibitors

Eptifibatide, tirofiban


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Aspirin

acetylsalicylic acid originally derived from the willow tree.

blocks the synthesis of Thromboxane A2 (TXA2) fromarachidonic acid in platelets.

it acetylates and thus inhibiting the enzymecycloxygenase and thromboxane synthetase.

TXA2 stimulates phospholipase C thus increasingcalcium levels and causing platelet aggregation

ASA also blocks the synthesis of prostacyclin from

endothelial cells (PGI2 is a strong inhibitor of plateletaggregation). This effect is short lived becauseendothelial cells unlike platelets, can synthesis newcycloxygenese.


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Admin. Orally

Indications- prevention and Rx of Myocardial Infarctionand ischaemic stoke also as an analgesic and anti-inflammatory agent (increased dose)

Contraindication: Children below 12 years (risk ofReyes syndrome), breastfeeding, haemophilia, pepticulcer, known hypersensitivity.

Adv. Effects bronchospasm

GIT haemorrhage Dose:- 75-150mg dly


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Membrane phospholipid

Phospholipase A (enzyme)

Arachidonic acid

yclooxygenase (enzyme)

I

Cyclic endoperoxides

PGG2, PGH2I

PGE2, PGD2, PGF2,; TXA2, PGI2

Lipooxgenase (enzyme)

LTA4

LTB4, LTC4 ->LTD4 ->LTE4->

SRS-A


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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 oralanticoagulant in the prophylaxis against

thrombosis associated with prosthetic valve. Adv. Effect hypotension, nausea., diarrhea,

and h/ache.


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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.


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FIBRINOLYTIC AGENTS

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

t 40-80 min.

Indication - life threatening venous thrombosis

pulm embolism

arterial thromboembolism.

Acute M. IC.I - recent haemorrhage, trauma, surgery within 10 dayorgan 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 activeintracranial 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


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Anistreplase.

(Anisoylated plasminogen streptokinase activatorcomplex APSAC)- consists of a complex of purifiedhuman plasminogen and bacteria streptokinase. used for

coronary thrombolysis. However, when it is given as abolus injection at the recommended dose for coronary of30U, marked systemic fibrinolysis occurs.

Tissue plasminogen activators (t-PA): this activatesplasminogen that is bound to fibrin, thus confining

fibrinolysis to formed thrombus. Avoids systemicactivation.


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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 intravascularfibrinolysis 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 fibrinolytictherapy, 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 thepossibility of forming excessive clots.

Thrombi that are formed during Rx with the drug are not lysed e.g. in patients withhaematuria, urethral obstruction by clots may lead to renal failure after Rx withaminocaproic acid.

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ANTIPARKINSONIAN DRUGS2