By Prof. Hanan Hagar Pharmacology unit Medical College

ILOs: At the end of this lecture you will be able to:- Recognize the symptoms and pathophysiology of parkinsonism Understand the pharmacology of drugs used for treatment of parkinsonism. Define pharmacokinetics, pharmacodynamics and side effects of different drugs used for the treatment of parkinsonism.

A progressive neurological disorder that occurs mainly in the elderly.

Characters of Parkinson's disease: Tremors at rest Bradykinesia (slowness in initiating and carrying out voluntary movements) or Akinesia Muscle rigidity Postural and gait abnormalities

occurs mainly due to reduction of dopamine content in substantia nigra & corpus striatum that are involved in motor control. Parkinson’s disease

Deficiency of dopamine Predominance of Ach Parkinson’s disease

Causes Parkinson’s disease is an idiopathic disease but some causes may be:  Genetic.  Toxins.  Head trauma.  Cerebral anoxia.  Oxidative stress  Drug-induced Parkinson's disease e.g. antipsychotics like haloperidol.

Drugs to increase dopaminergic activity Drugs to block cholinergic activity or/and

1) Drugs that increase dopaminergic activities: Dopamine precursor: (the most widely used) L-dopa + usually combined with carbidopa Dopamine agonists  Ergot derivatives: bromocriptine  Non ergot derivatives: pramipexole Dopamine releaser: amantadine COMT inhibitors: entacapone MAO-B inhibitors: selegiline 2) Drugs that decrease cholinergic activity Muscarinic antagonists e.g. benzatropine

Levodopa (L-dopa)  First line treatment  a precursor of dopamine (converted centrally and peripherally into dopamine).  98-99% is decarboxylated in gut and liver  1-2% crosses BBB and dopamine is formed  given combined with carbidopa

Carbidopa: Is a peripheral dopa decarboxylase inhibitor Inhibits peripheral conversion of L-dopa to dopamine L-dopa Dopamine dopa decarboxylase

Why carbidopa is combined with L-dopa? decrease metabolism of L-dopa in GIT and peripheral tissues (thus increasing t 1/2 ). increase availability of levodopa. reduce dose of levodopa and side effects.

Levodopa (L-dopa)  absorbed from the small intestine (active transport)  High protein meal interferes with its absorption and transport into CNS (should be taken on empty stomach).  Short duration of action (t½ =2 h) (fluctuation of plasma concentration).  L-Dopa ameliorates the signs of parkinsonism particularly bradykinesia & rigidity but does not cure the disease.

Adverse drug effects  On-off phenomenon (Off=Akinesia or hypomobility).  Wearing-off effect (duration of “on” states becomes shorter).  Dyskinesia (involuntary movements occurs in 40 to 90% of patients) due to fluctuating plasma levels of levodopa.

Adverse drug effects Peripheral effects:  anorexia, nausea, vomiting (due to stimulation of emetic center).  mydriasis, orthostatic hypotension, cardiac arrhythmias. CNS effects: (Psychological disorders) mainly psychosis, delusions, hallucinations, confusion, sleep disturbances and depression

Drug Interactions:- Proteins ingested with meals. Pyridoxine (Vitamin B6). Nonselective MAO inhibitors (phenelzine).

Psychotic patient. Glaucoma (due to mydriatic effect). Patients with history of melanoma Why? Note: L-dopa is a precursor of melanin

Dopamine receptor agonists Bromocriptine, pergolide, Pramipexole  Ergot derivatives: Bromocriptine, pergolide  Non ergot derivatives: Pramipexole  Have longer duration of action than L-dopa (less likely to cause dyskinesias than levodopa)  Dopamine agonists are used in advanced Parkinson's disease with fluctuation and dyskinesia.

 Is an ergot derivative  D 2 agonist  Is given orally  Half life= 6-8 h Uses:  Parkinson’s disease  Hyperprolactinemia (galactorrhea).  Infertility in women.

Adverse drug effects  Nausea, vomiting, postural hypotension  Confusion, hallucinations, delusions  Dyskinesias (less prominent). Contraindications  Psychosis  Peripheral vascular disease  Recent myocardial infarction

Non Ergot dopamine agonist Used alone or in combination with L-Dopa. Side effects: similar to L-Dopa, but less dyskinesias. Has the advantage of being free radicals scavenger.

Amantadine  originally introduced as an antiviral.  Amantadine increases dopamine release.  acts as an antagonist at muscarinic and NMDA (N- methyl-D-aspartate) receptors.  given orally with short half life  most of the drug being excreted unchanged in the urine

Amantadine  modestly effective in treating symptoms of parkinsonism but last only for short period (few weeks) and only used for L-Dopa resistance. Adverse effects  Nausea, anxiety, insomnia, confusion, hallucinations (dopamine like side effects).  Dry mouth, urinary retention (anticholinergic effects).  Restlessness and hallucinations (NMDA antagonist).

Selegiline  Selegiline is an irreversible inhibitor of MAO-B  It inhibits dopamine degradation by MAO-B in CNS.  It increases endogenous dopamine available for its receptors.

Selegiline  It has antioxidant activity against toxic free radicals produced during dopamine metabolism.  Selegiline is metabolized to desmethylselegiline, Which is antiapoptotic.

Selegiline  used for the newly diagnosed patient with parkinsonism (as monotherapy).  Combined with levodopa / carbidopa in later- stage parkinsonism to:  reduce the required dose of levodopa  delay the onset of dyskinesia and motor fluctuations that usually accompany long-term treatment with levodopa.

Adverse drug effects At high doses, selegiline may inhibit MAO-A (hypertensive crises). May cause insomnia when taken later during the day. Contraindications Selegiline should not be co-administered with tricyclic antidepressants, or selective serotonin reuptake inhibitors (may cause hyperpyrexia, agitation, delirium, coma).

COMT Inhibitors (Catechol-O- methyl transferase) Inhibitors Entacapone Acts peripherally and centrally to inhibit COMT enzyme required for dopamine degradation It is used: as adjuvant to L-Dopa to: –Decrease fluctuations –Improve response –Prolonged the ON-Time Side effects: L-Dopa side effects. Orange discoloration of urine.

Anticholinergic Drugs Benztropine, Trihexphenidyl  muscarinic antagonist.  Has modest anti- parkinsonian actions.  Tremor is benefited more than rigidity  used during the early stages of the disease or as an adjunct to levodopa therapy.  Provide benefit in drug-induced parkinsonism (due to antipsychotics).

Adverse effects  Cycloplegia, d ry mouth, urinary retention, constipation.  Confusion, delirium, and hallucinations may occur at higher doses. Contraindications Prostatic hypertrophy Glaucoma Intestinal obstruction

 In mild cases, selegiline, amantadine or anticholinergics can be used.  Levodopa and carbidopa is the main treatment  All other medications are adjuncts to levodopa therapy  Other useful drugs include bromocriptine (dopamine agonist), selegiline (monoamine oxidase-B inhibitor), amantadine (enhances dopamine release) and benztropine (muscarinic receptor antagonist, used for parkinsonism caused by antipsychotic drugs.