Extrapyramidal Dysfunction

Causes: Idiopathic, iatrogenic (MPTP), encephalitis, arteriosclerosis, CO poisoning, manganese intoxication.

Pathogenesis: Degeneration of dopaminergic neurons with cell bodies in the substantia nigra pars compacta and terminals in the striatum (caudate and putamen). These neurons exert an inhibitory influence on neurons in the caudate. Release of the intact cholinergic caudate neurons from this inhibitory influence leads to rigidity and akinesia.

MPTP: Found in designer drugs. Conversion by MAO-B to MPP+, which functions as a mitochondrial poison, resulting in dopaminergic cell death. MAO-B inhibitors (deprenyl) fully protect against MPTP-induced neurotoxicity. MPTP is believed to be oxidized outside dopaminergic neurons, possibly in astrocytes or serotonergic neurons.

Levodopa – Crosses BBB via neutral AA transporter. 95-98% of L-DOPA is converted to dopamine in the periphery via dopa decarboxylase. Beneficial actions are thought to be due to influence on D2 receptors. Significant improvement in symptoms (tremor is more resistant but can be improved with anticholinergics).

• Side effects: Orthostatic hypotension of central origin (not preventable, tolerance develops); arrhythmias and tachycardia of peripheral origin (preventable with carvidopa); nausea, vomiting, and anorexia due to stimulation of CTA (reduced with carvidopa, DO NOT USE ANTINAUSEA DRUGS SUCH AS METOCLOPRAMIDE, domperidone, diphenidol, and trimethobenzamide can be used); inhibition of prolactin secretion due to excessive dopamine; behavioral and personality changes. Bottom line: All side effects are preventable except orthostatic hypotension, adverse mental effects, and dyskinesthias.

• Pharmacokinetics: Gastric emptying time can markedly alter absorption because drug needs to make it to small intestine.

• Precautions and drug interactions: Contraindicated in psychotics and patients with narrow-angle glaucoma. Pyroxidine (B6) enhances peripheral conversion of L-DOPA (blocked by carvidopa). MAOIs can precipitate a hypertensive crisis. Antipsychotics and reserpine will diminish function of L-DOPA.

Carbidopa – Inhibits peripheral dopa decarboxylase but does not cross the BBB in appreciable amounts. Fixed-dose combination with L-DOPA called Sinemet. Alleviates all side effects except orthostatic hypotension, dyskinesias, and adverse mental effects (which actually may appear earlier).

Review of motor fluctuations with L-DOPA therapy

• Wearing-off effect – Relief of symptoms last 2-3 hrs instead of 4-5. Clear relation to plasma concentration. Sustained-release formulations may benefit some, while direct agonists such as bromocriptine may help others.

• Peak-dose dyskinesias – Correlate with dose and plasma concentration. Drug holiday may help alleviate these symptoms.

• Freezing episodes – Not related to time or dose, and vary in time of onset.

• On-off phenomenon – Not related to time or dose. Most disabling and very difficult to treat. Continuous administration may help, as may apomorphine (direct dopaminergic agonist) or selegiline (MAO-B inhibitor).

Anticholinergics (benztropine & trihexyphenidyl) – Much less effective than L-DOPA with more side effects.

Amantadine – Releases DA from stores inside cell. May decrease uptake and have some direct agonist activity. Does not have long-lasting effects.

Dopamine agonists (apomorphine, bromocriptine, pergolide) – Side effects can be blocked by domperidone (DA receptor blocker).

Ropinirole – D2 agonist.

Pramipexole – Selective for D3/D4. Side effect is narcolepsy.

Selegiline – MAO-B inhibitor. Potentiates effects of L-DOPA. May be neuroprotective.

Tolcapone – COMT inhibitor.

Huntington’s disease: Genetic; degeneration of cortex and basal ganglia; not curable; noncoding DNA repeats.

Tourette’s syndrome: DOC is haloperidol.

Category: Pharmacology Notes