DRUGS FOR PARKINSONISM

Parkinsonism is a movement disorder due to defective function of basal ganglia : Caudate nucleus, Putamen, Globus pallidus, Substantia nigra, and Subthalamic nucleus . The combination of caudate nucleus + putamen is known as striatum . The basal ganglia controls movements and posture by 2 main balanced mechanisms : A. Cholinergic muscarinic : stimulatory; due to small cholinergic neurons are present in striatum B. Dopaminergic : inhibitory ; this comes from nigrostrial tract that originate from substantia nigra of midbrain and ends in striatum.

In parkinsonism, the inhibitory dopaminergic transmission is reduced in the striatum so that the stimulatory cholinergic transmission predominates , leading to the main symptoms of : tremor , rigidity of muscles , and hypokinesia , with loss of protective postural reflexes . These clinical features occur when dopamine (DA) content is < 20% of normal in striatum

Parkinsonism is usually caused by idiopathic degeneration of the dopaminergic fibers of nigrostriatal tract (Parkinson”s disease) . Organic (secondary) causes of parkinsonism are : 1. Toxins : e.g. environmental toxins e.g. MPTP (1-methyl-4-phenyl- 1,2,3,6- tetrahydropyridine ) which is catabolized by MAO-B in glial cells in striatum into MPP+ and damaging free radicals ; its metabolism and toxicity is prevented by MAO-B inhibitor Selegiline. Others toxins are Mn,& CO 2. Post-encephalitis 3. Ischemia : due to atherosclerosis 4. Tumours ; granulomas 5. Trauma e.g. boxers 6. Drugs e.g. DA2 receptors blockers , rarely by alpha-methyldopa, or large doses of reserpine

Treatment of Parkinsonism : Find cause ,if present; and treat it or avoid it ,if possible Reduce symptoms of the disease : by the drugs that restore the balance of chemical neurotransmission in striatum , namely : A. Central antimuscarinic drugs B. Drugs that increase dopaminergic activity in striatum

A. Central anti-muscarinic drugs : Include benzhexole (trihexyphenidyl) (trade name : Artane) , benztropine , as well as : Anti-H1 drugs with anti-muscarinic action e.g. procyclidine, diphenhydramine , orphenadrine . These drugs are useful in mild parkinsonism in young patients ; they decrease tremor and rigidity but have little effect on hypokinesia . They are first choice drugs for treatment of drug-induced parkinsonism S.Es: some peripheral antimuscarinic side effects : dry mouth, difficult urination, blurred vision In overdose , they can cause acute confusional state . So, Avoided in elderly patients

B. Dopaminergic drugs : 1. L-DOPA : amino acid precursor of DA. DA is not used as it poorly enters CNS. L-DOPA is the drug of first choice in moderate to severe parkinsonism; it relieves all symptoms. Given orally , it is 30% absorbed in small intestine by active transport ; peak plasma levels occur in 1-2 h; food reduces its absorption About 95% of absorbed fraction is decarboxylated by peripheral tissues to DA, then oxidized to NA . Only about 5% enter CNS to be converted by remaining nigrostriatal fibers into dopamine that is released into striatum . Its plasma t½ is 1-3 h. Large doses are needed which cause side effects

S.Es : A. Peripheral : Nausea and Vomiting due to stimulation of DA2 receptors in CRTZ . Vomiting is decreased by cyclizine or domperidone Postural hypotension Cardiac arrhythmias Increased intra-ocular pressure B. Central : - psychiatric (depression or hallucination) - involuntary movement or dyskinesias These side effects are dose-related C. Long term central adverse effects : a. Reduction in therapeutic efficacy , b. Clinical fluctuations : causing end-of-dose deterioration , and later the “on-off “ effect .

The peripheral side effects esp The peripheral side effects esp. vomiting can be reduced or prevented by peripheral decarboxylase inhibitors that do not cross the blood-brain barrier (i.e. do not enter CNS) e.g. : A. Carbidopa : the combination of L-DOPA + carbidopa (in ratio of 4 or 10 :1 in tablet ) is called Co- careldopa (Sinemet) B. Bensarazide :The combination of L-DOPA + benserazide is called Co-beneldopa (Madopar) These combinations inhibit peripheral tissue decarboxylation of L-DOPA, thus causing increase in its plasma level and t½, and allow more L-DOPA to enter CNS from plasma; thus they reduce the effective dose of L-DOPA needed by about 75%

But central side effects of L-DOPA still occur with these combinations and may increase in incidence Drug interactions of L-DOPA preparations : 1. Hypertensive crisis may occur with : 1. Amphetamine (not with tyramine ) 2. MAO inhibitors esp. tranylcypromine 2. Pyridoxine (which is coenzyme for decarboxylase) reduces therapeutic benefit from L-DOPA by enhancing its peripheral decarboxylation; this interaction does not occur with the combined L-DOPA / carbidopa preparation Sinemet

2. Inhibitors of DA catabolism : A. Selegiline : selective MAO-B inhibitor This drug increases DA content in synapses of striatum. It may be used in early parkinsonism . It may also be given with L-DOPA or Sinemet to treat end-of-dose deterioration due to L-DOPA Its side effects include insomnia . B. COMT inhibitor: Entacapone prolongs action of dopamine formed from L-DOPA in striatum; In plasma it also inhibits conversion of L-DOPA to 3-O-methyldopa which competes with L-DOPA for entry into brain. it is used for end-of-dose deterioration of L-DOPA

3. Amantadine : it stimulates DA synthesis and release by remaining nigrostriatal fibers and may inhibit DA reuptake .It is used in early parkinsonism , and may be given with antimuscarinic drugs or L-DOPA to enhance their effect . If used alone, tolerance occurs to its beneficial effect in few months S.E. vomiting , ankle oedema , livedo reticularis, CNS stimulation with insomnia, hallucination, seizures NOTE : Amantadine has independent ANTIVIRAL action and is used in preventing influenza A2

4. Direct dopamine receptor (DA2) agonists : A. Ergot derivative 1. Bromocryptine : has DA2- receptor agonist action; eliminated by liver; t½ is about 5 h. It may be used : a. With L-DOPA to enhance motor response b. For end-of-dose deterioration of L-DOPA , or for on-off attacks to replace L-DOPA S.Es include: nausea & vomiting; postural hypotension In high doses: delusions & hallucination (so avoided in psychotic patients); dyskinesia may also occur; ergot effects with chronic use include lung infiltrates and erythromelalgia 2. Cabergoline : long t½ 80 h, used once/d or twice/W

B. Non-ergot derivatives : 1. Ropinirole (relatively pure DA2 agonists) & Pramipexole (has higher affinity for DA3 receptors than DA2) : Either of these drugs can be used as monotherapy in early mild disease; Pramipexole may also have a neuro-protective action by acting as scavenger for hydrogen peroxide radical. Both may also be used later for clinical fluctuations of L-DOPA 2. Apomorphine stimulates DA2 receptors; it may be used SC to terminate the freezing on-off attacks of chronic L-DOPA therapy in young patients; Vomiting is common side effect; it is prevented by domperidone