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 in to 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 utilisation of L-dopa
MOA:
  • Dopaminergic neurons originating in the substantia nigra normally inhibit the GABAergic out put from the straitum , whereas cholinergic neurons exert an excitatory effect. On-off phenomenon in Parkinsonism:
  1. In parkinsonism the motor symptoms remain stabilized 2-3 years after therapy.
  2. But after 2-3 years of levodopa therapy the effect of the drug gradually begins to wear offi.e., the motor symptoms begins to appear. This is also called "end of dose" 
  3. deterioration.
  4. After some period of time, the motor symptoms begins 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: 
  1. Anorexia, Nausea & Vomiting (Occur about 80% patients
  2. Antacid 30-60 minutes before meals is also prescribed.
  3. Cardiovascular effects: 
  • Cardiac arrhythmias 
  1. Tachycardia 
  2. Ventricular extra systoles
  3. Arterial fibrillation – rarely 
  4. Postural hypotension 
  5. Hypertension
  • Other effects: 
  1. Dyskinesia 
  2. Depression
  3. Anxiety 
  4. Insomnia 
  5. Confusion 
  6. Hallucinations
  7. Euphoria 
  8. Mydriasis 
  9. Precipitation of gout 
  10. Brownish discolouration 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 reduces 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 pitutary tumours,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 and 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 – MAAOI)
  • Rasagiline:MAO B inhibitor.
  • Patient on treatment on carbidopa + levodopa for 10 yrs now has weaning 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- metyldopa (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 discolouration 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 :
  1. The drug is also commonly used to treat extrapyramidal side effects occurring during antipsychotic treatment. 
  2. It is active in postencephalitic, arteriosclerotic, and idiopathic forms.
  • Contraindication:
  • Hypersensitivity to trihexyphenidyl
  • Narrow angle glaucoma
  • Ileus
Exam Question
  • Carbidopa is used in the treatment of Parkinsonism because It decreases peripheral utilisation of L-dopa
  • Contraindication to breast milk feeding is Bromocriptine therapy for mother
  • Bromocriptine Inhibits prolactin release
  • Bromocriptine , Ropinerole & Pramipexole are dopaminergic agonists used for parkinsonism 
  • Pyridoxine abolishes the therapeutic effect of levodopa by enhancing peripheral decarboxylation of levodopa 
  • In Parkinsonism, phenothiazines reduces the efficacy of levodopa
  • Levodopa is a prodrug
  • Levodopa can cause On-off phenomenon
  • Entacapone enhances the bioavailability of levodopa
  • Rotigotine is intended to be delivered through transdermal patches, so as to ensure a slow and constant dosage in a 24-hour period.
  • Antiparkinson drug known to cause cardiac valvular fibrosis is Pergolide & cabergoline
  • Drug of choice for drug induced parkinsonism Anticholinergic
  • Benzhexol is Drug of choice in drug induced Parkinsonism
  • Drug of choice for the initial treatment of parkinsonism is Ropinirole
  • Central anticholinergics are used in treatment of Akathisia, Parkinsonism & Acute dystonia
  • Bromocriptine is used in Type II DM, Parkinsonism ,Hepatic Coma & Cyclical mastalgia
  • Rotigotine is Dopamine agonist
  • Patient on treatment on carbidopa + levodopa for 10 yrs now has weaning off effect should be given Rasagiline
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