Anti-Parkinsonism Drugs

CLASSIFICATION:

Drugs influencing brain dopaminergic system

• Levodopa
• Bromocriptine, Pramipexole, Ropinirole 
• Amantadine 
• Selegiline 
• Tolcapone, Entacapone 
• Carbidopa, Benserazide 

Drugs affecting brain cholinergic system

• Centrally acting anticholinergics: benztropine, benzhexol, procyclidine 
• Antihistaminics (H1 blockers) with anticholinergic activity: promethazine, diphenhydramine Large amount of levodopa is converted to dopamine in the peripheral tissues by peripheral dopa decarboxylase enzyme 
• Low bioavailability in the CNS 

LEVODOPA:

• Dopamine itself does not cross the blood-brain barrier. 
• Therefore Levodopa is the immediate metabolite of dopamine, which can cross the blood-brain barrier. 
• In brain it decarboxylated back into dopamine. 
• Levodopa is the levorotary stereoisomer of DOPA.
•  DOPA is the amino acid precursor of dopamine and norepinephrine.
• Entacapone enhances the bioavailability of levodopa
• L-Dopa is combined with carbidopa in treatment of parkinsonism because Carbidopa decreases peripheral utilization of L-dopa

MOA:

• Dopaminergic neurons originating in the substantia nigra normally inhibit the GABAergic output from the striatum, whereas cholinergic neurons exert an excitatory effect.

On-off phenomenon in Parkinsonism:

• In parkinsonism, the motor symptoms remain stabilized 2-3 years after therapy.
• But after 2-3 years of levodopa therapy, the effect of the drug gradually begins to wear offi.e., the motor symptoms begin to appear. This is also called “end of dose” deterioration.
• After some period of time, the motor symptoms begin to appear frequently. This is called ‘switches’ or ‘on-off effect.
• In parkinsonism, there is a selective loss of dopaminergic neurons. 
• Therefore, dopamine/ Levodopa is covering the loss of dopamine effectiveness.

ADVERSE EFFECT:

Gastrointestinal effects: 

• Anorexia, Nausea & Vomiting (Occur about 80% patients
• Antacid 30-60 minutes before meals is also prescribed. 

Cardiovascular effects: 

• Cardiac arrhythmias 
• Tachycardia 
• Ventricular extrasystoles
• Arterial fibrillation – rarely 
• Postural hypotension 
• Hypertension

Other effects: 

• Dyskinesia 
• Depression
• Anxiety 
• Insomnia 
• Confusion 
• Hallucinations
• Euphoria 
• Mydriasis 
• Precipitation of gout 
• Brownish discoloration of saliva

DRUG INTERACTION:

• Pyridoxine (Vit B6 ) enhances the extracerebral metabolism of levodopa. Thus decreases its efficacy.
•  Levodopa should not given to patients taking MAO inhibitors or within 2 weeks of their discontinuance.
• In Parkinsonism, phenothiazines reduce the efficacy of levodopa

CONTRAINDICATION:

• Psychotic patients 
• Angle-closure glaucoma
•  Chronic open-angle glaucoma 
• Cardiac arrhythmias 
• Active peptic ulcers

DOPAMINE RECEPTOR AGONIST:

• Drugs acting directly on dopamine receptors – MoA 
• Not require enzymatic conversions. 
• No potentially toxic metabolites. 
• Not compete food or other substances. 
•  Limited adverse effects than Levodopa. 
•  First line therapy drugs for parkinsonism. 

DRA DRUGS:

• Bromocriptine: D2 receptor agonist,
• Inhibits prolactin release
• Used in  Type II DM,  Parkinsonism, Acromegaly due to small pituitary tumors, Hepatic Coma & Cyclical mastalgia
• Pergolide :D1 & D2 receptor agonists.
• Pramipexole: D3 receptor agonists. 
• Ropinirole: Pure D2 receptor agonists. (Drug of choice for the initial treatment of parkinsonism)
• Rotigotine: Delivered daily through a skin patch. 

DRA – Adverse Effects

• Anorexia 
• Nausea & Vomiting 
• Constipation
• Dyspepsia
• Postural hypotension 
• Cardiac valvular fibrosis(by Pergolide & cabergoline)
• Peripheral edema 
• Dyskinesia 
• Confusion 
• Hallucinations 
• Delusions
• Headache

DRA – Contraindications

• Psychotic illness 
• Recent myocardial infarction 
• Active peptic ulceration
• Peripheral vascular diseases
• Breast milk feeding: Bromocriptine 

MONOAMINE OXIDASE INHIBITORS:

• Monoamine oxidase A metabolizes norepinephrine, serotonin & dopamine. 
• Monoamine oxidase B metabolizes dopamine selectively.
• Combination with Levodopa should avoid as it may cause hypertensive crisis.

MOI DRUGS:

• Selegiline: Selective irreversible inhibitor of MABO at normal doses. (Higher – MAOI)
• Rasagiline: MAO B inhibitor.
• Patient on treatment on carbidopa + levodopa for 10 yrs now has weaned off effect should be given Rasagiline

CATECHOL-O- METHYL TRANSFERASE INHIBITOR :

• Inhibition of dopa decarboxylase is associated with compensatory activation of other pathways of levodopa metabolism, as COMT. 
• It increases plasma levels of 3-O- methyldopa (OMD). 
• Elevated levels of 3-OMD cause poor therapeutic response to Levodopa. 
• There are selective inhibitors of COMT such as Tolcapone & Entacapone

Adverse effects:

• Dyskinesia
• Nausea 
• Confusion 
•  Diahorrea 
• Abdominal pain
• Sleep disturbances
• Orange discoloration of the urine

Acetylcholine Blocking Drugs:

• Antimuscarinic drugs.
• Central anticholinergics are used in treatment of  Akathisia, Parkinsonism & Acute dystonia
• Improve the tremor and rigidity of parkinsonism.
• Little effect of dyskinesia.
• Started with lower doses, then gradually being increased.
• But may occur dyskinesia
• Central anticholinergics are not used in tardive dyskinesia and neuroleptic malignant syndrome.
• Drug of choice for drug-induced parkinsonism Anticholinergic

Benzhexol :

• The drug is also commonly used to treat extrapyramidal side effects occurring during antipsychotic treatment. 
•  It is active in postencephalitic, arteriosclerotic, and idiopathic forms.

Contraindication:

• Hypersensitivity to trihexyphenidyl
• Narrow-angle glaucoma
• Ileus