| What is parkinsonism? | Progressive neurological disorder of muscle movement, destruction of DA neurons in substantia nigra, leads to reduced DA action in corpus striatum, leads to appearance of lewy bodies.
Features: bradykinesia, muscular rigidity, resting tremor, impairment of postural balance [gait disturbance].
Genetic factors and environmental toxic agents
2ary parkinsonism: drugs like phenithiazine and haloperidol which are D2 Rs antagonists. |
| How is the tx mechanism of parkinsonism? | Restoring DA in basal ganglia (DA therapy) + Antagonizing excitatory effects of cholinergic neurons (anticholinergic therapy) |
| How is anticholinergic therapy for Parkinson's? | Benzotropine, trihexyphenidyl, procyclidine, and biperiden.
Antimuscarinic agents: Less efficacious than levodopa.
Adjuvant role in antiparkinson's
Induce mood changes (xerostomia, constipation [interfere w/GI peristalsis] and visual problems)
Contraindicated for glaucoma |
| What are mechanisms of dopaminergic therapy? | Agents increasing DA synthesis (Levodopa), angents increasing DA release (Amantadine), Agents block DA metabolism (MAO-I, COMT-I), DA receptor antagonists (Bromocriptine, Ropirinole, Pramipexale, Rotigotine, Apomorphine) |
| What is levodopa? | Given oral, increase DA synthesis, absorbed in GI and crosses BBB, converted to DA in brain.
Effects: at periphery conversion to DA leads to GI irritation, stimulation of CTZ, leading to gastric upset w/nausea and vomit.
Activation of peripheral Rs also causes orthostatic Hypotension, renal vasodilation, cardiac arrythmias.
Dyskinesia (peak L-DOPA concentration leads to abnormal involuntary mvmnt)
To increase its crossing to brain we combine it with carbidopa blocks peripheral metabolism.
Drug-Drugs interaction: Vit B6, MAI-I cause HTA crisis |
| What are agents increasing DA release? | Amantadine
Lipophilic, unchanged renal excretion, less potent than L-DOPA, tolerance develops more
reversible adverse effects (insomnia, hallucinations, depression, confusion, agitation) |
| What are MAO-I? | Agent blocking DA metabolism.
Irreversible inhibitors (Selegiline and Rasagiline)
Block MAO stopping DA inactivation in the brain
Selegiline (metamphetamine, amphetamine, cause insomnia and vasoconstriction)
Rasagiline (aminoindan, no vasoactive activity) |
| What are COMT-I? | Tolcapone (acts peripherally and centrally, fatal hepatic failure)
Entacapone (acts peripherally)
COMT inhibited, L DOPA becomes 3-O methyldopa instead of DA which competes w/levodopa in active transport to CNS)
Staleva (levodopa, carbidopa, entacapone) |
| How is mechanism of action of DA Rs agonists? | Duration of action longer than L-DOPA, less risk of dyskinesia and motor fluctuation.
Include: Bromocriptine (D2), Ropinirole & Pramipexol (D2 D3), Rotigotine (D1 D2 D3), and Apomorphine (D1 D2) |
| What is Bromocriptine? | Vasoconstrictive, D2 agonist, low dose blocks prolcatin, high dose antiparkinsons.
Effect: Hallucination, confusion, nausea, delirium (more than dyskinesia)
Short T1/2 due to 1st pass. |
| What are Ropinirole and Pramipexole? | CYP1A2 metabolized (ropi) or kidney eliminated (pram)
non-ergot derivative (not vasoconstrictive), D2 and D3 agonists, dyskinesia less frequent, orally absorbed. |
| What is Apomorphine? | D1 and D2 agonist, 1st pass metabolism, emetic effects, SC injection, late stage parkinsons. |
| What is Rotigotine? | Non-ergot, D1D2D3 agonist, early stage parkinson's, transdermal patch (once daily) |
| What are anti alzheimer's drugs? | Acetylcholinesterase inhibitors
NMDA Rs antagonists |
| How are anticholinesterases antialzheimer? | Donepezil and Rivastigmine non-competitive
Galantamine competitive
Tacrine hepatotoxic
Effects: nausea, diarrhea, vomit, anorexia, bradycardia |
| How are NMDA Rs antagonists anti alzheimer? | Overstimulation of NMDA Rs lead to excess Ca2+ intracellular and thus damage to neurons and apoptosis
Memantine (EBIXA) At therapeutic dose causes partial block, leads to toxic intracellular Ca2+ levels not achieved and slows rate of memory loss |
| What is amyotropic lateral sclerosis and its tx? | Motor neuron disease, progressive degeneration of neurons and spinal cord, affects voluntary actions of limbs and trouble breathing.
Rilozole (blocks glutamate and Na+ and Ca2+ ,improves survival and delays need for ventilators. |
