DR.UMA KADAM M.B.B.S. MD ASSOCIATE PROFESSOR PHARMACOLOGY SKNMC
1. Selective loss of dopaminergic neurons in the nigro-striatal fibers.
2. Clinical picture is rigidity, bradykinesia,
tremor and postural instability.
Imbalance primarily between the excitatory neurotransmitter Acetylcholine and inhibitory neurotransmitter Dopamine in the Basal Ganglia
GABA DOPAMINE ACETYLCHOLINE PARKINSONISM + -
The Dopaminergic Neurons in the Basal Ganglia Are mainly affected
Acetylcholine within striatum is a tonically activated neuron
It impinges on GABA Neuron by an Excitatory Action
GABA Neuron Has an Inhibitory Action on the Substantia Nigra from Substantia Nigra, Has a Dopaminergic Feed Back Loop Back to Striatum Which Gets Loss Giving Signs and Symptoms of Parkinson Disease
Acetylcholine Blocking Drugs
Dopamine and Tyrosine Are Not Used for Parkinson Disease Therapy Dopamine Doesn't Cross the Blood Brain Barrier
Huge amount of tyrosine decreases activity of rate limiting enzyme Tyrosine Hydroxylase That normally Converts Tyrosine to dopamine by overwhelming enzyme tyrosine hydroxylase, has a feedback loop that will turn off tyrosine hydroxylase
1. Levodopa crosses blood brain barrier and is decarboxylated to dopamine in the CNS.
5. On-off phenomenon ( fluctuations in clinical state). “On” means improved mobility with
marked dyskinesia. “Off” means marked akinesia. They alternate with each other.
1. Pyridoxine (B6) increases extracerebral
metabolism of levodopa.
2. MAOIs with levodopa will cause hypertensive
2. Angle closure glaucoma
3. Malignant melanoma
4. Peptic ulcer
5. Cardiac arrhythmias
1. Bromocriptine* 3. Pramipexole**
2. Pergolide* 4. Ropinirole**
This group directly stimulates dopamine receptors
Bromocriptine a D2 receptor agonist, is excreted in bile and feces. Pergolide stimulates both D1 &
D2 receptors. Pramipexole has more affinity for D3 receptors. Ropinirole is a D2 receptor agonist.
GIT upsets, peptic ulcer with bleeding, postural
hypotension, painless digital vasospasm, oedema
dyskinesias, hallucinations, delusions, erythro-
-myalgia, retroperitoneal fibrosis.
1. Psychotic illness
2. Recent myocardial infarction
3. Active peptic ulceration
4. Peripheral vascular disease
1. Selegiline (Deprenyl) 2. Rasagiline
Selegiline inhibits MAO-B which metabolizes
dopamine, so dopamine is increased in the CNS. It has also neuroprotective effect.
Rasagiline is more potent than selegiline. MAOIs
are not used with levodopa to avoid hypertensive crisis.
1. Tolcapone 2. Entacapone
They prolong the actions of levodopa by decreasing its peripheral metabolism.
Dyskinesias, nausea, confusion, diarrhea,
abdomonal pain, orthostatic hypotension,sleep
disturbances, orange colored urine.
It potentiates dopaminergic function by influenc-
-ing the synthesis, release or reuptake of
dopamine. Side effects are acute toxic psychosis
postural hypotension, heart failure.
ACETYLCHOLINE BLOCKING DRUGS
1. Benztropine 4. Procyclidine
2. Biperiden 5. Trihexyphenidyl
They block the muscarinic receptors in the
striatal cholinergic fibres. They improve tremor &
rigidity but have little effect on bradykinesia.
Drowsiness, confusion, dry mouth, blurred vision,
mydriasis, urinary retention, constipation,
CONTRAINDICATIONS: Prostate hyperplasia,
pyloric stenosis, paralytic ileus.
Pathophysiology of Parkinson’s Disease Increased production of free radicals (reactive oxygen species) and deficiency of antioxidant mechanisms O 2 O 2 H 2 O 2 OH • - 2H 2 O Hydroxyl radical Hydrogen peroxide Superoxide radical +e - +e - + OH - 2H + +e - +e -
Natural Antioxidant mechanisms:
In mitochondria radicals are tightly bound and reduced to water
O 2 - dismutated by SOD to H 2 O 2 and then cleared by catalase or glutathione peroxidase
Free radical scavengers (vit. E, ascorbate) which can react directly with free radicals
Evidence for Free Radical Hypothesis
Polyunsaturated fats major constituent and substrate for lipid peroxidation -> free radicals
Free Fe ++ level high in S. nigra –promotes radical formation
Fe ++ binding capacity is limited in brain
Brain contains almost no catalase, and low levels of glutathione, glutathione peroxidase and vit. E
Oxidative metabolism of dopamine potential to generate radicals
↓ GSH Mitochondrial Damage ↑ H 2 O 2 FREE RADICALS Cell Death Mitochondrial Damage Excitotoxicity ↑ Cytosolic Ca 2+ Ca 2+ activated Degradative enzymes DA Fe 2+ ↑ Free radical Production (?PD) ↓ Free radical Defenses (?ALS)
"On/off" Effect Is like a Light Switch ; Without Warning, All of a Sudden, Person Goes from Full Control to Complete Reversion Back to Bradykinesia, Tremor, Etc. Lasting from 30 Minutes to Several Hours and Then Get Control Again
"On/off" Effect Occurs after usually after 2 or more years on L Dopa
Related to Denervation Hypersensitivity
Treat by Giving Small Dose Regimens from 16 to 20 Hours
"On/off" Effect May Be Due to Composite of Amino Acids That Use Same Dopamine Transporter across Gastric Mucosa causing extremely low levels of L Dopa in CNS thereby causing symptoms of Parkinson Disease to reappear.
Changing diet (to low protein), may cause large conc of L Dopa in CNS Giving thus producing an 'off' Effect of Symptoms of Parkinson Disease
DRUG INTERACTIONS WITH L DOPA:
Vitamin B6 - Vitamin B6 Is a Cofactor for Decarboxylation of L Dopa; Vitamin B6 Enhances Conversion of L Dopa to Dopamine in Periphery Making it less Readily for Use in the CNS
L Dopa Is co-administered with Carbidopa
Carbidopa Is Antagonistic to Peripheral L Dopa Decarboxylation Carbidopa Doesn't Cross Blood Brain Barrier
By co-administering Carbidopa, will decrease metabolism of L Dopa in GI Tract and Peripheral Tissues thereby increasing L Dopa conc. into CNS; meaning we can decrease L Dopa dose and also control the dose of L Dopa to a greater degree.
Anticholinergics - Used Synergistically with L Dopa as an Antiparkinson Agent, but Anticholinergics Act to decrease L Dopa absorption since Anticholinergics have an effect on gastric emptying time which delays crossing of GI Membrane by L Dopa
DRUG INTERACTIONS CONT…….
Nonspecific MAO Inhibitors - Interfere with L Dopa Breakdown and exaggerate the CNS effects the Nonspecific MAO Inhibitors Can Precipitate Hypertensive Crisis by the tyramine-cheese effect (Tyramine Is Found in Cheese, Coffee, Beer, Pickles, Chocolate, and Herring), when given to a person taking a MAO Inhibitor Tyramine Is not broken down therefore producing a tremendous release of Norepinephrine)
On the Horizon
A number of potential Parkinson's treatments in research laboratories now show much promise. They include:
Neurotrophic proteins -- These appear to protect nerve cells from the premature death that prompts Parkinson's. One hurdle is getting the proteins past the blood-brain barrier.
Neuroprotective agents -- Researchers are examining naturally occurring enzymes that appear to deactivate "free radicals," chemicals some scientists think may be linked to the damage done to nerve cells in Parkinson's and other neurological disorders.
Classify Drug used in treatment of parkinsonism .Explain the mechanism of action & ADRs of L-dopa (2+2+2+=6 )
Mention two atropine substitutes used in parkinsonism. Explain the rational of it’s use (4 marks)
L-dopa is not useful in treatment of drug induced parkinsonism. Why? Explain (4 marks).
What is the rationale of use of Carbidopa with Levodopa? (4 marks)