Antiparkinsonian drugs Presented by K.Lakshmi Department of pharmacology Assistant professor SSPC

Neurodegenerative diseases (NDDs): Neurodegenerative diseases (NDDs) are traditionally defined as disorders with selective loss of neurons and distinct involvement of functional systems defining clinical presentation.  Examples of neurodegenerative diseases are: Alzheimer's disease, Parkinson's disease, Huntington’s disease, Amyotrophic lateral sclerosis, Frontotemporal dementia and Spinocerebellar ataxias.  These diseases are diverse in their pathophysiology with some causing memory and cognitive impairments and others affecting a person’s ability to move, speak and breath.

Who is he?

PARKINSON`S DISEASE (PD):- History – Parkinson's disease was first formally described in 1817 by a London physician named James Parkinson.

DEFINITION Parkinsonism is an extra pyramidal motor disorder, symptoms includes- rigidity, tremors, with defective gesture and posture. Parkinsonism is a result of imbalance between acetylcholine and dopamine. When there is remarkably decrease in dopamine level or increase in acetylcholine level, Parkinsonism take place. As cause is clear their treatment is also very clear. Treatment goal is to restore the balance between above said neurotransmitters either by increasing dopamine by external source or by decreasing the level of acetylcholine.

TYPES OF PD Idiopathic Parkinson's disease:- Idiopathic Parkinson's disease - or Parkinson's - is the most common type of parkinsonism. Unlike some other forms which have specific causes it is not known why idiopathic Parkinson's occurs. The main symptoms of idiopatic Parkinson's are tremor, rigidity and slowness of movement.

Vascular Parkinsonism:- Vascular parkinsonism is one of the atypical forms of parkinsonism. The most likely causes of vascular parkinsonism are hypertension and diabetes. A stroke (cerebrovascular accident), cardiac disease or carotid artery pathology (another form of stroke) may also be involved. Symptoms of vascular parkinsonism may include difficulty speaking, making facial expressions or swallowing. Other signs can include problems with memory or confused thought, cognitive problems and incontinence.

Inherited Parkinson's:- It is thought that although it is not directly inherited, some people may have genes that increase the possibility of developing Parkinson's. People who have genes that are prone to Parkinson's may be more likely to develop the condition when combined with other factors, such as environmental toxins or viruses. At present, it is estimated that up to 5% of people with Parkinson's may have a genetic cause.

Drug Induced Parkinsonism:- Antipsychotics: Chlorpromazine, Fluphenazine and Haloperidol Antihypertensive like Reserpine Antiemetics: Metoclopramide and Prochlorperazine Most people will recover within months, and often within hours or days, of stopping the drug that caused the dopamine block. Not associated with loss of nerve cells in the substantia nigra

PATHOGENESIS  Degeneration of dopamine-producing neurons in the substantia nigra of the midbrain.  Disrupts the balance of: A. dopamine (DA) – neurotransmitter for normal functioning of the extra pyramidal motor system (control of posture, support, and voluntary motion) B. Acetylcholine (Ach)in the basal ganglia Symptoms do not occur until 80% of the neurons in the substantia nigra are lost

Imbalance primarily between the excitatory neurotransmitter Acetylcholine and inhibitory neurotransmitter Dopamine in the Basal Ganglia

Antiparkinsonian Drugs Definition:- Antiparkinsonian agents are drugs which are used to treat Parkinson's disease (PA). Classification:- I.Drug affecting brain dopaminergic system:- 1.Dopamine Precursor -Levodopa (L-dopa) 2.Peripheral decarboxylase inhibitor - Carbidopa, Benserazide

3.Dopaminergic Agonist -Bromocriptine, Ropinirole, Pramipexole 4.MAO- B Inhibitor –Selegiline,Rasagiline 5.COMT Inhibitor -Entacapone, Tolcapone 6. Dopamine Facilitators (glutamate / NMDA receptor agonist)- Amantadine II. Drug affecting brain cholinergic system:- 1. Central Anticholinergics -Trihexyphenidyl, Procyclidine, Biperiden, Benztropine, Benhexol 2. Antihistaminic - Orphenadrine,Promethazine,Diphenhydramine

Mechanism of action

Pharmacology Levodopa Single most effective agent in PD 95% is decarboxylated to dopamine in gut and liver 1 - 2% crosses BBB, taken up by neurones and DA is formed

Mechanism 1. Because dopamine does not cross the blood-brain barrier levodopa, the precursor of dopamine, is given instead. 2. Levodopa is formed L-tyrosine and is an intermediate in the synthesis of catecholamines. 3. Levodopa itself has minimal pharmacologic activity, in contrast to its decarboxylated product, dopamine. 4. Levodopa is rapidly decarboxylated in the gastrointestinal tract. Prior to the advent of decarboxylase inhibitors (carbidopa), large oral doses of levodopa were required; thus, toxicity from dopamine was a limiting factor.

Pharmacological actions CNS:  Effective in Eliminating Most of the Symptoms of Parkinson Disease  Bradykinesia and Rigidity Respond Quickly  Reduction in Tremor Effect with Continued therapy  Handwritting, speech, facial expression and interest in life improves gradually  L Dopa less Effective in Eliminating Postural Instability  Neurotransmitters Are Involved in Parkinson Disease

CVS : Cardiac Stimulation Due to Beta adrenergic effect on Heart Though stimulates peripheral adrenergic receptor – no rise in BP Orthostatic Hypotension - some individuals – central DA and NA action In elderly cardiovascular problems -tachycardia, cardiac arrhythmias and hypertension Tolerance to CVS action develops within few weeks CTZ: DA receptors cause stimulation – nausea and vomiting ENDOCRINE: Decrease in Prolactin level and increase in GH release

Behavioural Effects: Partially Changes Mood by elevating mood, and increases Patient sense of well being General alerting response Disproportionate increase in sexual activity No improvement in dementia

Pharmacokinetics Absorbed rapidly from small intestine – aromatic amino acid transport system High First Pass Effect – large doses Peak plasma conc. 1-2 hrs and half life - 1 to 3 Hrs Metabolized in liver and peripherally - secreted in urine In CNS – Decarboxylated and DA is formed – therapeutic effectiveness metabolized by MAO and COMT

Adverse effect: Principal adverse effects include: (1) Anorexia, nausea, and vomiting upon initial administration, which often limit the initial dosage. (2) Cardiovascular effects, including tachycardia, arrhythmias, and orthostatic hypotension. (3) Mental disturbances, including vivid dreams, delusions, and hallucination. (4) Hyperkinesia (5) On-off phenomena-Sudden discontinuation can result in fever, rigidity, and confusion. The drug should be withdrawn gradually over 4 days.

Drug Interactions Pyridoxine – abolishes therapeutic effect of levodopa Antipsychotic Drugs – Phenothiazines, butyrophenones block the action of levodopa by blocking DA receptors. Antidopeminergic – domperidone abolishes nausea and vomiting Reserpine – blocks levodopa action by blocking vesicular uptake Anticholinergics – synergistic action but delayed gastric emptying – reduced effect of levodopa Nonspecific MAO Inhibitors – Prevents degradation of peripherally synthesized DA – hypertensive crisis by the tyramine-cheese effect (tyramine is found in cheese, coffee, beer, pickles and chocolate),

CARBIDOPA:- Carbidopa is an inhibitor of dopa decarboxylase. Because it is unable to penetrate the blood-brain barrier, it acts to reduce the peripheral conversion of levodopa to dopamine. As a result, when carbidopa and levodopa are given concomitantly: a. It can decrease the dosage of levodopa. b. It can reduce toxic side effects of levodopa.

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