Anti Parkinson's Drugs Parkinsonism A neurological syndrome usually resulting from deficiency of the neurotransmitter dopamine as the consequence of degenerative, vascular, or inflammatory changes in the basal ganglia. Characterized by rhythmical muscular tremors, rigidity of movement, bradykinesia, droopy posture.

Coronal slices of human brain showing the basal ganglia Coronal slices of human brain showing the basal ganglia. ROSTRAL: striatum, globus pallidus (GPe and GPi) CAUDAL: subthalamic nucleus (STN), substantia nigra (SN)

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

CLASSIC FEATURES SHUFFLING GAIT STOOPING POSTURE DECREASED ARM SWING TURNING EN BLOC DYSPHONIA MOOD DISTURBANCES SLEEP DISTURBANCES MEMORY LOSS

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Secondary Parkinsonism Sometimes parkinsonism like symptoms follow after viral encephalitis or multiple vascular lesions. Phenothiazines and Haloperidol – action block dopamine receptors – may produce Parkinson's symptoms. Strictly not used in the pt.’s with parkinsonism.

Dopamine Dopamine: does not cross: blood-brain barrier ineffective if administered peripherally

Drugs used Levodopa Carbidopa Bromocriptine Amantadine Anticholinergic agents Deprenyl ( Selegiline)

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

L-DOPA Rapid absorption from small intestine, influenced by: gastric emptying rate local pH Food– avoid heavy meals Excretion : urine Amount reaching brain : very less Rest : peripheral decarboxylation to dopamine.

To achieve therapeutic brain levels, either: Large quantities to be given With a dopa decarboxylase inhibitor, such as Carbidopa Carbidopa does not penetrate BBB

Clinical Use :Levodopa Does not stop disease progression May reduce Parkinson's disease mortality rate Most effective in diminishing bradykinesia

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

Behavioral Effect : depression, agitation, insomnia , anxiety, confusion, delusions Precipitation/worsening: Gout  Mydriasis– adrenergic action

Contraindications Psychotic patients Angle-closure glaucoma History of melanoma/suspicious undiagnosed skin lesions. Vit. B-6.- increases peripheral breakdown Careful management : CVS disease, PUD Not with MAO – I > HTN crisis.

Carbidopa Peripheral decarboxylase inhibitor which doesn't cross the BBB To decrease peripheral decarboxylation of L-dopa. Carbidopa leads to decreased side-effects and decreased dosage of L-dopa required.

Dopamine Agonists Directly activate dopamine receptors Not requiring enzymatic activation Bromocriptine

Clinical Use :Bromocriptine Compared with Levodopa: Less incidence of response fluctuation and Dyskinesias Adverse Effects GIT : nausea, vomiting Peptic ulceration with bleeding CVS : postural hypotension Behavioural : confusion, hallucinations, delusions

Contraindications History/presence of psychosis Recent myocardial infarction Relative contraindications : Peripheral vascular disease or peptic ulcer

Monoamine Oxidase Inhibitors MAO-A :  serotonin/ norepinephrine MAO-B :  metabolizes dopamine Selegiline : Selective MAO - B inhibitor Adjunctive treatment to L-DOPA C I : Meperidine Tricyclic antidepressants  SSRI

Amantadine Antiviral drug Mechanism of action: unclear Clinical Use Short-term benefits; less potent Levodopa Improves rigidity, tremor, bradykinesia

Adverse Effect Hallucinations, confusion, irritability, depression Over dosage: acute psychosis Livedo reticularis: -- reddish blue skin mottling, affecting extremities CHF, orthostatic hypotension , peripheral edema GIT: nausea, vomiting With caution : CHF, convulsions.

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

Benztropine Biperiden Orphenadrine Procyclidine Trihexyphenidyl CI : Prostatic hyperplasia Obstructive gastrointestinal disease

Catechol o methyl tranferace inhibitors When peripheral dopamine decarboxylase activity is inhibited, a significant amount of methyl dopa is formed which competes with levodopa for active transport into the CNS. Inhibition of COMT by Tolcapone /entacapone leads to increased central uptake of levodopa.

Physiologic postural tremor (normal) Drug-Induced– Bronchodilators Tricyclic antidepressants Lithium Rx : Propranolol.

Chorea Dopaminergic nigrostriatal pathway over activity Anti-Dopaminergic agents: Reserpine Phenothiazines and Butryophenones (haloperidol)

DRUGS USED IN ALZHEIMER DISEASE Alzheimer dementia 3 distinguishing features Accumulation of senile plaques Neurifibrillary tangles Loss of cortical neurons –cholinergic Drugs used—inhibition of acetyl choline esterace Donepezil, galantamine, rivastigmine & tacrine Galantamine competitive inhibitor Tacrine--hepatotoxic

NMDA receptor antagonist Antagonist of NMDA receptors are neuroprotective Memantine—slows the rate of memory loss Prevents loss of neurons

DRUGS USED IN MULTIPLE SCLEROSIS MS is an autoimmune inflammatory demyelinating disease of the CNS. Corticosteroids for acute attacks have been used Cyclophosphamide and azathioprine can also be tried Newer drugs interferon beta 1a and 1b Mitoxantrone, Dalfampridine and fingolimod are also used now