Anti Parkinsonian Drugs

Parkinsons Disease
Parkinson's disease is a slowly progressive disorder that affects movement, muscle control, and balance. Parkinsons develops as cells are destroyed in certain parts of brain stem, particularly crescent shaped cell mass known as the substantia nigra. Nerve cells in the substantia nigra send out fibers to corpus stratia, grey and white bands of tissue located in both sides of brain.

 There the cells release DOPAMINE, an essential neurotransmitter . Loss of dopamine in the corpus stratia is the primary defect in Parkinsons disease This leads to imbalance in Dopamine and Acetylcholine.

Classification of Anti Parkinsonian Drugs

Drugs affecting brain Dopaminergic system Dopamine precursor: Levodopa (L-dopa) Peripheral decarboxylase inhibitors: Carbidopa, Benserazide Dopaminergic agonists: Bromocriptine, Pergolide, Piribedil MAO-B inhibitor: Selegiline COMT inhibitors: Entacapone, Tolcapone Dopamine facilitator: Amantadine.

 Drugs affecting brain cholinergic system: Central anticholinergics: Trihexiphenidyl, Biperidine, procyclidine. Antihistaminics: Orphenadrine, Promethazine.

LEVODOPA
1.It is the immediate precursor of the transmitter DA . 2.About 1-2% of administered levodopa crosses to the brain which is taken by surviving dopaminergic neurons , which is converted to DA and released as transmitter. ACTIONS :A) CNS:- Levodopa hardly produces any effect in normal individuals.Marked improvement occurs in Parkinsonian patient.Hypokinesia and rigidity resolve first then tremors. B) CVS:- The peripherally formed DA cause tachycardia acting on beta adrenergic receptors . C) CTZ :- DA acts as excitatory transmitter , peripherally formed DA stimulates CTZ cause nausea and vomiting. D) Endocrine :- DA inhibit prolactin release and increase GH release.

 1.Levodopa is not used alone , it is used along with carbidopa ( 1: 4, 1:10 ) 2.Carbidopa is a peripheral decarboxylase inhibitor which retard peripheral conversion of L-dopa to dopamine.

ADVERSE EFFECTS
1. At the initiation of therapy:a. Nausea and vomiting:- occurs in almost every patient , tolerance gradually develops. b. Postural hypotension :- when given along with antihypertensives causing fainting attacks. c. Cardiac arrhythmias and exacerbation of angina Due to beta adrenergic action of peripherally formed dopamine . d. Alteration in taste sensation .

2.After prolong therapy :a. Abnormal movements :- facial tics etc b. Behaviour effects :- mild anxiety , night mares , severe depression , hallucination , mental confusion. c. Fluctuation in motor performance :During duration of therapy , gradually with time on or off effect is seen. it means patient is alternating well and disabled .

Interaction
1. Pyridoxine:- enhances peripheral decarboxylation of levodopa 2. Phenothiazines, butyrophenones, metoclopromide :- it reverses therapeutic effect by blocking DA receptor . 3. Atropine , Anticholinergic drugs:- they have anti parkinsonism action with low doses of levodopa but retard its absorbtion

PERIPHERAL DECARBOXYLASE INHIBITOR

1. CARBIDOPA:- it competes with enzyme dopa decarboxylase therby retarding peripheral breakdown of L-dopa Carbidopa does not cross BBB . It does not interfere with the conversion of L-dopa to dopamine in CNS .

2. Beserazide :- it has same mechanism of action as

carbidopa , used in combination with Levodopa at ratio 1:4.

DOPAMINERGIC AGONISTS
1. BROMOCRIPTINE :- it is a dopamine agonist directly acting on postsyaptic dopamine receptor . It is used orally and adjuant therapy to provide additional therapeutic control in patient maintained on levodopa .. BROMOCRIPTINE also activates dopamine receptor in dopaminergic system of pituatary resulting in secrection of prolactin inhibitor factor from hypothalamus . Used in treatment of amenorrhoea,female infertility .

MAO B INHIBITOR
SELEGILINE :- Selegiline irreverisbly inhibits MAO-B enzyme in nerve endings in brain , thus increasing the intraneural level of dopamine It facilitates dopamine release , also interferes with dopamine reuptake into nerve endings. Side effects:- confusion , hallucination ,insomnia, depression , urinary retention , palpitation.

COMT INHIBITORS
They are also used as adjuant to levodopa carbidopa for advanced PD . When peripheral decarboxylation of levodopa is blocked by carbidopa , it is mainly metabolized by COMT to 3-O methyl Dopa. Entacapone Tolcapone Side effects :- same as MAO B inhibitors

DOPAMINE FACILITATOR
1. AMANTADINE :-It is a synthetic antiviral agent originally used for influenza but it is used in parkinsonism for akinesia and rigidity. Mode of action :- It causes release of DA from presynaptic nerve ending and blocks its presynaptic reuptake .

Side effects:- anxiety , nausea , diziness , depression, urinary retention , oedema .

ANTI HISTAMINIC AGENTS

Tri hexyl phenidyl, biperiden Mode of action :-These agent exhibit post synaptic blocking effect on central cholinergic excitatory pathways . They also retard reuptake of dopamine into presynaptic nerve endings thereby blocking inactivation .

Adverse effects:- Dryness of mouth,blurred vision, dizziness , nausea , vomiting , confusion , hallucination , depression , tachycardia , palpitation.