PARKINSON’S DISEASE

ETIOLOGY 1) Idiopathic 2)Exposure to : neurotoxin Oxidative stress Drugs Oxidative stress Drugs 3)Genetic factors. 3)Genetic factors.

Pathology &Principal treatment 1)The normally high concentration of dopamine in the basal ganglia is reduced and attempts to restore dopaminergic activity with levodopa and dopamine agonist. 2)Restore the normal balance of cholinergic and dopaminergic influences on the basal ganglia with antimuscarinic drugs.

DRUGS AFFECTING DOPAMINERGIC NEUROTRANSMISSION

Drugs  LEVODOPA  Metabolic precursor of dopamine  Pharmacokinetics  Half –life= 1-2 hrs   Rapidly absorbed from small intestine.  Food delay absorption.  Certain amino acids from ingested food compete for absorption & drug transport from blood to brain.

Pharmacokinetics  Main metabolic products: HVA & DOPAC  Only 1-3% of given dose enters the brain.  Given with dopa decarboxylase inhibitor  ( CARBIDOPA). Combination Called Sinemet  1- Reduce peripheral biotransformation of levodopa  2- Increase plasma level & half-life of levodopa  3- Reduce daily requirement of levodopa ( 75%)  Excreted by kidneys

Clinical Benefits of levodopa  Can ameliorate all of the clinical symptoms of parkinsonism  It is mainly effective in relieving bradykinesia  Other drugs can be added to levodopa

Clinical considerations  “ON” and “OFF” Phenomenon  Tolerance to therapeutic response  It does not arrest disease progress  Only effective in the first few years  Taking drug in divided doses to reduce gastric symptoms.  Sudden withdrawal causes severe akinetic state.

Clinical Consideration  Postural hypotension is common, so patient should take care when he stand up.  Dyskinesias occur up to 80% ( uncontrollable muscle jerks)

Adv. Effects of Levodopa 1. G.I.T : Nausea, vomiting, and anorexia 2. Cardiovascular: - Tachycardia - Ventricular extrasystoles - Atrial fibrillation (rare) - Postural hypotension - Postural hypotension - Hypertension - Hypertension 3. Dyskinesias ( with chronic treatment)

Side effects con’d 4- Behavioral effects are more common in patients taking levodopa in combination with carbidopa 4- Behavioral effects are more common in patients taking levodopa in combination with carbidopa - Depression - Anxiety - Agitation - Confusion - Hallucinations

Adverse Effects ( cont.) 5- Fluctuations in response  6- Miscellaneous  Mydriasis ( an attack of acute glaucoma)  Hemolysis ( +v Coombs test )  Gout  Abnormal of smell or taste  Brownish discoloration of saliva, urine or vaginal secretions Priapism

Levodopa- Drug Interactions 1. Pyridoxine- Enhances peripheral metabolism of levodopa 2.Non selective MOAI –Hypertensive crises

Contraindications  Psychotic patients  Glaucoma  Cardiac patients  Peptic ulcer  In patients with history of melanoma or undiagnosed skin lesions. 

Advantages for the use of dopamine agonist in parkinsonism  1-They do not require metabolic conversion to an active product.  2- Circulating plasma amino acids do not compete with dopa agonist for absorption or transportation.  3-They have long plasma half-life as compared to levodopa

 4- They do not undergo oxidative metabolism & no generation of free radicals & the associated oxidative stress.

BROMOCRIPTINE A synthetic ergot derivative A synthetic ergot derivative directly stimulate D 2 receptors directly stimulate D 2 receptors Used in hyperprolactinemia Used in hyperprolactinemia Best for patients Best for patients Who show akinesia Who show akinesia With “ON” and “OFF” phenomenon With “ON” and “OFF” phenomenon Who are refractory to levodopa Who are refractory to levodopa Can be combined with Can be combined with Levodopa Levodopa Amantadine Amantadine Anticholinergics Anticholinergics

Pharmacokinetics of Bromocriptine  Given orally  The dose must be built up slowly  Plasma ½ life =12-16 hrs  Excreted in bile & feces  Clinical Considerations - Produces less dyskinesia than levodopa - Produces less dyskinesia than levodopa - It has more psychiatric adverse effects - It has more psychiatric adverse effects -

Adverse effects of Bromocriptine  G.I.T: nausea, vomiting and anorexia, G.I.T bleeding  Cardiovascular: - Postural hypotension - Cardiac arrhythmias - Painless digital vasospasm  CNS: Dyskinesia, Confusion,hallucination and psychiatric disturbances  Headache.  Miscellenious :Nasal congestion, erythromelalgia  Rarely pulmonary fibrosis.

Contraindications to Bromocriptine  History of psychiatric disease  Myocardial infarction  History of peptic ulcer  Peripheral vascular disease

PERGOLIDE Stimulates both D1 & D2 receptors. More potent than bromocriptine Dose must be built up slowly Has the same side effects & contraindications of bromocriptine

NON ERGOT DOPAMINE AGONISTS  1) PRAMIPEXOLE Widely used now Widely used now Ha a high affinity for the D3 receptors. Is effective as monotherapy in mild case of Parkinson’s disease Is effective as monotherapy in mild case of Parkinson’s disease

 In advanced cases is given with levodopa ( reducing the dose & fluctuation response of levodopa).  Has a neuroprotective effect ( antioxident activity).  Rapidly absorbed & excreted mostly unchanged by the kidneys. Renal insufficiency may necessitate dosage adjustment. Renal insufficiency may necessitate dosage adjustment.

2. Ropinirole:  D2 receptor agonist  Effective as monotherapy in patients with mild disease  Can be combined with levodopa to smooth its response and prevent fluctuations in advanced diseases  It is metabolized by CYP1A2 hepatic enzymes

Adverse Effects of Pramipexole and Ropinirole  Anorexia,n ausea,vomiting and constipation  Excessive day time somnolence has been reported ( uncontrollable tendency to fall asleep that can result in car accident  Postural hypotension  Cardiac arrhythmias  Peripheral edema

 Dyskinesias  Mental Disturbance  Are more common & severe than with levodopa

AMANTADINE  Mode of action: 1. Releases DA from CNS neurons 2. Inhibits the re-uptake of DA 3. Anticholinergic effect 4. It affects the bradykinesia more than tremors.  Pharmacokinetics: - t ½ = 2-4 hrs - t ½ = 2-4 hrs - excreted unchanged in urine - absorbed orally - absorbed orally

Clinical considerations 1. less potent than levodopa 2. effective only for a few weeks 3. can not be used alone  Adverse effects: - Depression, Agitation, Confusion - Insomnia - Psychosis,Convulsions, C.H.F, urinary retention, Postural hypotension - Ankle edema - Ankle edema - Livedo reticularis - Livedo reticularis  Contraindications: - History of seizures - History of C.H.F - History of C.H.F - With antimuscarinic drugs - With antimuscarinic drugs

DEPRENYL (SELEGILINE)  Used in patients who do not respond well to carbidopa-levodopa combination  Mechanism of action  A) it traps free radicals and other toxins that degrade the neurons.  B) As a MAO- B inhibitor,it may retard the break-down and destruction of dopamine by MAO-B,thus freeing more DA to interact with its receptors in substantia nigra.

MAO-B INHIBITORS (SELEGILINE)  Lacks the cheese reaction( dietary amines)  Reduces “ON” -“OFF” phenomena  Enhances & prolongs the antiparkinsonism effect of levodopa.  Reduces Neuronal damage by toxic free radicals  It retards DA metabolism allowing for reduction of levodopa dosage  Can be combined with other drugs 1. 1.

Adverse effects of Selegiline  Dependence upon chronic use (due to methamphetamine metabolite )  Nausea  Sedation  Skin rashes  G.I.T irritation  Insomnia

Contraindications  Should not be taken with:  Meperidine  Tricyclic antidepressants  Serotonin reuptake inhibitors  ( Risk of acute toxic interactions)

ANTIMUSCARINIC AGENTS  Benztropine  Trihexyphenidyl Procyclidine  Centrally acting antimuscarinic drugs.  Block CNS muscarinic receptors and reduce cholinergic transmission in Corpus Striatum

CLINICAL CONSIDERATIONS  Starts with small doses- gradually increase.  Improve best tremor and rigidity with little effect on bradykinesia.  Can be combined with : levodopa to Rx severe forms

 *Withdrawal should be gradually to prevent acute exacerbation of parkinsonism.  *Benztropine is used mainly in reserpine induced parkinsonism.

Side effects of antimuscarinic agents  Peripheral: Dry mouth, constipation, tachycardia, increased intraocular pressure, blurred vision, urinary retention,increased skin temperature  CNS: Drowsiness, mental slowness, delusions, mood changes, confusion.

Side Effects ( cont.)  Prolonged use of trihexyphenidyl produces involuntary movements & dependence

Contra-indications of antimuscarinic agents  Prostatic Hypertrophy  Obstructive G.I.T disease( paralytic ileus)  Glaucoma  Combination with TCA or certain antihistamines