Anti Parkinson's DrugsAnti Parkinson's Drugs

ParkinsonismParkinsonism A neurological syndrome usually resulting A neurological syndrome usually resulting

from deficiency of the neurotransmitter from deficiency of the neurotransmitter dopamine as the consequence of degenerative, dopamine as the consequence of degenerative, vascular, or inflammatory changes in the basal vascular, or inflammatory changes in the basal ganglia. ganglia.

Characterized by rhythmical muscular tremors, Characterized by rhythmical muscular tremors, rigidity of movement, bradykinesia, droopy rigidity of movement, bradykinesia, droopy posture. posture.

Coronal slices of human brain showing the basal Coronal slices of human brain showing the basal

ganglia.ganglia.ROSTRAL: striatum, globus pallidus (GPe and GPi)ROSTRAL: striatum, globus pallidus (GPe and GPi)CAUDAL: subthalamic nucleus (STN), substantia CAUDAL: subthalamic nucleus (STN), substantia nigra (SN)nigra (SN)

Signs Signs

Remember RAFTRemember RAFT

R R = rigidity of skeletal muscles= rigidity of skeletal musclesA A = akinesia (loss of voluntary movement)= akinesia (loss of voluntary movement)F F = flat facies= flat faciesT T = tremor at rest (not always)= tremor at rest (not always)

CLASSIC FEATURESCLASSIC FEATURES

SHUFFLING GAIT SHUFFLING GAIT STOOPING POSTURE STOOPING POSTURE DECREASED ARM SWING DECREASED ARM SWING TURNING EN BLOCTURNING EN BLOC DYSPHONIA DYSPHONIA MOOD DISTURBANCES MOOD DISTURBANCES SLEEP DISTURBANCESSLEEP DISTURBANCES MEMORY LOSSMEMORY LOSS

P E T SCAN P E T SCAN

Secondary Parkinsonism Secondary Parkinsonism

Sometimes parkinsonism like symptoms Sometimes parkinsonism like symptoms follow after viral encephalitis or multiple follow after viral encephalitis or multiple vascular lesions.vascular lesions.

Phenothiazines and Haloperidol – action block Phenothiazines and Haloperidol – action block dopamine receptors – may produce Parkinson's dopamine receptors – may produce Parkinson's symptoms.symptoms.

Strictly not used in the pt.’s with Strictly not used in the pt.’s with parkinsonism. parkinsonism.

Dopamine Dopamine

Dopamine: Dopamine:

does not cross: blood-brain barrier does not cross: blood-brain barrier

ineffective if administered peripherallyineffective if administered peripherally

Drugs usedDrugs used

LevodopaLevodopa CarbidopaCarbidopa BromocriptineBromocriptine AmantadineAmantadine Anticholinergic agentsAnticholinergic agents Deprenyl ( Selegiline)Deprenyl ( Selegiline)

Levodopa Levodopa

L-DOPA: L-DOPA: metabolic precursor of dopamine metabolic precursor of dopamine enters the brain enters the brain decarboxylation to dopamine decarboxylation to dopamine

L-DOPA L-DOPA

Rapid absorption from small intestine, Rapid absorption from small intestine, influenced by: influenced by:

gastric emptying rate gastric emptying rate local pH local pH Food– avoid heavy mealsFood– avoid heavy meals Excretion : urineExcretion : urine Amount reaching brain : very lessAmount reaching brain : very less Rest : peripheral decarboxylation to dopamine.Rest : peripheral decarboxylation to dopamine.

To achieve therapeutic brain levels, To achieve therapeutic brain levels, either: either:

Large quantities to be givenLarge quantities to be given

With a dopa decarboxylase inhibitor, such as With a dopa decarboxylase inhibitor, such as Carbidopa Carbidopa

Carbidopa does not penetrate BBBCarbidopa does not penetrate BBB

Clinical Use :Levodopa Clinical Use :Levodopa

Does not stop disease progression Does not stop disease progression

May reduce Parkinson's disease mortality rate May reduce Parkinson's disease mortality rate

Most effective in diminishing bradykinesia Most effective in diminishing bradykinesia

Adverse Effects :Levodopa Adverse Effects :Levodopa

GIT ; vomiting, tolerance develops.GIT ; vomiting, tolerance develops. CVS : Tachycardia, Ventricular extra systolesCVS : Tachycardia, Ventricular extra systoles MC : Postural/orthostatic hypotensionMC : Postural/orthostatic hypotension HTN : if large doses takenHTN : if large doses taken Arrhythmias Arrhythmias Dyskinesias Dyskinesias MC: Choreoathetosis MC: Choreoathetosis

Behavioral Effect : depression, agitation, Behavioral Effect : depression, agitation, insomnia , anxiety, confusion, delusions insomnia , anxiety, confusion, delusions

Precipitation/worsening: Gout Precipitation/worsening: Gout

  Mydriasis– adrenergic action Mydriasis– adrenergic action

Contraindications Contraindications

Psychotic patients Psychotic patients Angle-closure glaucoma Angle-closure glaucoma History of melanoma/suspicious undiagnosed History of melanoma/suspicious undiagnosed

skin lesions. skin lesions. Vit. B-6.- increases peripheral breakdownVit. B-6.- increases peripheral breakdown Careful management : CVS disease, PUDCareful management : CVS disease, PUD Not with MAO – I > HTN crisis.Not with MAO – I > HTN crisis.

Carbidopa Carbidopa

Peripheral decarboxylase inhibitor which Peripheral decarboxylase inhibitor which doesn't cross the BBBdoesn't cross the BBB

To decrease peripheral decarboxylation of To decrease peripheral decarboxylation of

L-dopa.L-dopa. Carbidopa leads to decreased side-effects and Carbidopa leads to decreased side-effects and

decreased dosage of L-dopa required.decreased dosage of L-dopa required.

Dopamine Agonists Dopamine Agonists

Directly activate dopamine receptors Directly activate dopamine receptors Not requiring enzymatic activation Not requiring enzymatic activation

Bromocriptine Bromocriptine

Clinical Use :Bromocriptine Clinical Use :Bromocriptine

Compared with Levodopa: Compared with Levodopa: Less incidence of response fluctuation and Less incidence of response fluctuation and

Dyskinesias Dyskinesias

Adverse Effects Adverse Effects GIT : nausea, vomiting GIT : nausea, vomiting Peptic ulceration with bleeding Peptic ulceration with bleeding CVS : postural hypotensionCVS : postural hypotension Behavioural : confusion, hallucinations, delusionsBehavioural : confusion, hallucinations, delusions

Contraindications Contraindications

History/presence of psychosis History/presence of psychosis Recent myocardial infarction Recent myocardial infarction

Relative contraindications :Relative contraindications : Peripheral vascular disease or peptic ulcerPeripheral vascular disease or peptic ulcer

Monoamine Oxidase InhibitorsMonoamine Oxidase Inhibitors MAO-A :  serotonin/ norepinephrine MAO-A :  serotonin/ norepinephrine MAO-B :  metabolizes dopamine MAO-B :  metabolizes dopamine

Selegiline : Selective MAO - B inhibitorSelegiline : Selective MAO - B inhibitor Adjunctive treatment to L-DOPA Adjunctive treatment to L-DOPA

C I : C I : Meperidine Meperidine Tricyclic antidepressants Tricyclic antidepressants   SSRISSRI

Amantadine  Amantadine 

Antiviral drug Antiviral drug Mechanism of action: unclear Mechanism of action: unclear

Clinical Use Clinical Use Short-term benefits; less potent Levodopa Short-term benefits; less potent Levodopa Improves rigidity, tremor, bradykinesia Improves rigidity, tremor, bradykinesia

Adverse Effect Adverse Effect Hallucinations, confusion, irritability, Hallucinations, confusion, irritability,

depression depression Over dosage: acute psychosis Over dosage: acute psychosis Livedo reticularis: -- reddish blue skin Livedo reticularis: -- reddish blue skin

mottling, affecting extremities mottling, affecting extremities CHF, orthostatic hypotension , peripheral CHF, orthostatic hypotension , peripheral

edema edema GIT: nausea, vomitingGIT: nausea, vomiting With caution : CHF, convulsions.With caution : CHF, convulsions.

AnticholinergicsAnticholinergics

Clinical Use Clinical Use Improvement: rigidity/tremor Improvement: rigidity/tremor Minor effect: bradykinesia Minor effect: bradykinesia

Benztropine Benztropine Biperiden Biperiden Orphenadrine Orphenadrine Procyclidine Procyclidine Trihexyphenidyl Trihexyphenidyl

CI :CI : Prostatic hyperplasia Prostatic hyperplasia Obstructive gastrointestinal disease Obstructive gastrointestinal disease

Catechol o methyl tranferace inhibitorsCatechol o methyl tranferace inhibitors When peripheral dopamine decarboxylase When peripheral dopamine decarboxylase

activity is inhibited, a significant amount of activity is inhibited, a significant amount of methyl dopa is formed which competes with methyl dopa is formed which competes with levodopa for active transport into the CNS.levodopa for active transport into the CNS.

Inhibition of COMT by Tolcapone Inhibition of COMT by Tolcapone /entacapone leads to increased central uptake /entacapone leads to increased central uptake of levodopa. of levodopa.

Physiologic postural tremor Physiologic postural tremor (normal)(normal)

Drug-Induced– Drug-Induced– Bronchodilators Bronchodilators Tricyclic antidepressants Tricyclic antidepressants Lithium Lithium

Rx : Propranolol. Rx : Propranolol.

Chorea Chorea

Dopaminergic nigrostriatal pathway over Dopaminergic nigrostriatal pathway over activity activity

Anti-Dopaminergic agents:Anti-Dopaminergic agents: Reserpine Reserpine Phenothiazines and Butryophenones Phenothiazines and Butryophenones

(haloperidol) (haloperidol)

DRUGS USED IN ALZHEIMER DRUGS USED IN ALZHEIMER DISEASEDISEASE

Alzheimer dementia 3 distinguishing featuresAlzheimer dementia 3 distinguishing features Accumulation of senile plaquesAccumulation of senile plaques Neurifibrillary tanglesNeurifibrillary tangles Loss of cortical neurons –cholinergicLoss of cortical neurons –cholinergic Drugs used—inhibition of acetyl choline esteraceDrugs used—inhibition of acetyl choline esterace Donepezil, galantamine, rivastigmine & tacrineDonepezil, galantamine, rivastigmine & tacrine Galantamine competitive inhibitorGalantamine competitive inhibitor Tacrine--hepatotoxicTacrine--hepatotoxic

NMDA receptor antagonistNMDA receptor antagonist Antagonist of NMDA receptors are Antagonist of NMDA receptors are

neuroprotectiveneuroprotective Memantine—slows the rate of memory lossMemantine—slows the rate of memory loss Prevents loss of neuronsPrevents loss of neurons

DRUGS USED IN MULTIPLE DRUGS USED IN MULTIPLE SCLEROSISSCLEROSIS

MS is an autoimmune inflammatory MS is an autoimmune inflammatory demyelinating disease of the CNS.demyelinating disease of the CNS.

Corticosteroids for acute attacks have been Corticosteroids for acute attacks have been usedused

Cyclophosphamide and azathioprine can also Cyclophosphamide and azathioprine can also be triedbe tried

Newer drugs interferon beta 1a and 1bNewer drugs interferon beta 1a and 1b Mitoxantrone, Dalfampridine and fingolimod Mitoxantrone, Dalfampridine and fingolimod

are also used noware also used now