Cns Antiparkinson Drugs PDF

Antiparkinson’s Drugs DR. SHAHNAZ MEMON ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY OBJECTIVES What is Parkinson’s disease? What are different classes of drugs used to treat it? How they act and what are their uses and side effects?  Parkinson’s Disease A chronic, pro...

Antiparkinson’s Drugs DR. SHAHNAZ MEMON ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY OBJECTIVES What is Parkinson’s disease? What are different classes of drugs used to treat it? How they act and what are their uses and side effects?  Parkinson’s Disease A chronic, progressive, degenerative disorder of the CNS characterized by tremors, bradykinesia, joint and muscular rigidity and postural instability Results from destruction or degenerative changes in dopamine-producing nerve cells in the substantia nigra & corpus striatum parts of the brain’s basal ganglia system that are involved in motor control  Parkinson’s Disease Basal ganglia normally contain balance of dopamine and acetylcholine. Balance is necessary to regulate posture, muscle tone and voluntary movement. Normally; cell bodies from substantia nigra to the neostriatum release DA which inhibit GABAergic neurons. In Parkinson’s disease, Loss of DA neurons in this tract leads to excessive acetylcholine(ACH) activity resulting in extra pyramidal dysfunction. Parkinson’s Disease Cause is unclear Occurs equally in men and women between 50- 80 years Early onset parkinsonism is felt to have genetic component (in those less than 45yr) Phenothiazines can cause drug-induced parkinsonism (secondary) Consequences of dopamine reductions Tremors – hands and head develop involuntary movements when at rest; pin- rolling sign (finger and thumb). Muscle rigidity – arthritis-like stiffness, difficulty in bending or moving limbs; poker face Brandykinesia – problems chewing, swallowing or speaking; difficulty in initiating movements and controlling fine movements; walking becomes difficult (shuffle feet) Postural instability – humped over appearance, prone to falls Additional symptomology Anxiety Depression Sleep disturbance Dementia Disturbance of ANS (difficulty in urinating) Clinical Presentation  Altered body image  Excessive sweating (depression) (impaired thermoregulation)  Poor balance  Festinating gait  Bradykinesia (slow  Hullucinations (visual) movement)  Postural hypotension  Bradyphrenia (slowness of thought)  Restless leg syndrome (leg  Constipation aches, tingle, or burn)  Dribbling/drooling  Rigidity  Dyskinesias (involuntary  Sleep disturbance movements)  Slurring/slowing of speech  Dysphagia (difficulty  Tremor swallowing  Dystonia (pain spasms) Anti-Parkinson drugs Drugs used in treatment either increase levels of dopamine or inhibit the actions of acetylcholine in the brain Drugs used in Parkinsonism Source: Adams et al (2006). Pharmacology for Nurses – A Pathophysiologic Approach. Prentice Hall Publishers DOPAMINERGIC DRUGS LEVODOPA Mechanism of Action: Precursor to Dopamine: Levodopa is a direct precursor to dopamine.  In patients with Parkinson's disease, dopamine-producing neurons in the brain degenerate, leading to decreased dopamine levels. Levodopa is converted to dopamine in the brain, helping to replenish the depleted supply. Crossing the Blood-Brain Barrier: Unlike dopamine, levodopa can cross the blood-brain barrier. Once it enters the central nervous system, it is converted into dopamine by the enzyme aromatic L-amino acid decarboxylase.  LEVADOPA Dopamine Receptor Activation: The newly synthesized dopamine then binds to dopamine receptors in the brain, particularly in the striatum, which helps improve motor control and alleviate the symptoms of Parkinson's disease, such as rigidity, bradykinesia, and tremors. Combination with Other Medications: Levodopa is often administered with carbidopa, which inhibits the peripheral conversion of levodopa to dopamine. This combination increases the amount of levodopa that reaches the brain and reduces side effects like nausea. Levodopa…. Absorption & Metabolism Drug is absorbed rapidly from small intestine Short half life of 1-2hrs which causes fluctuation in plasma concentration This may produce fluctuation in motor response…. on-off phenomenon Meals may interfere with absorption from gut so it should be taken on empty stomach On-off phenomenon The on-off phenomenon refers to sudden, sometimes unpredictable changes in a PD patient’s symptoms, varying between mobility (usually with dyskinesia) and immobility due to the return of Parkinson’s symptoms. Thesesudden fluctuations can have no apparent relationship to medication timing.  On-off phenomenon "On" State: During this phase, the patient experiences improved motor function, with reduced symptoms like tremors, rigidity, and bradykinesia. This occurs when levodopa levels are adequately maintained in the bloodstream. "Off" State: In this phase, the medication's effects wane, leading to a return of Parkinsonian symptoms. This can happen when the medication is wearing off before the next dose is taken or due to inconsistent absorption. Duration: The "on" and "off" phases can vary in duration and intensity. Some patients may experience rapid fluctuations throughout the day, while others may have more predictable patterns. Levodopa with Carbidopa Carbidopa decreases the dose of levodopa needed by 4-5 folds “ties up” dopa decarboxylase  Levodopa with Carbidopa Carbidopa prevents the conversion of levodopa to dopamine in the peripheral tissues (outside the brain). This ensures that more levodopa reaches the brain, where it can be converted to dopamine. By inhibiting the peripheral conversion, carbidopa helps minimize side effects associated with dopamine. the combination of levodopa and carbidopa optimizes the treatment of Parkinson's disease by enhancing the efficacy of levodopa while minimizing side effects. Levodopa…. Adverse effects Peripheral Effects ◦Anorexia, nausea & vomiting due to stimulation of emetic centre ◦Tachycardia from actions on heart ◦Postural hypotension ◦Mydriasis ◦Blood dyscrasias ◦Saliva & urine are of brownish color due to melanin pigment produced from catecholamine oxidation Levodopa…. Adverse effects CNS Effects ◦Visual and auditory hallucinations ◦Abnormal involuntary movements due to over activity of dopamine at receptors in basal ganglia ◦Mood changes, depression and anxiety Levodopa…. Interactions With vitamin B6 (pyridoxine) …. Decreased effectiveness With MAO inhibitors like phenelzine….. Hypertensive crisis Levodopa…. Contraindications Levodopa should not be given to psychotic patients because it may exacerbate the mental disturbance It is also contraindicated in patients with glaucoma as it may increase IOP It is best given combined with carbidopa to patients with cardiac disease but the slight risk of cardiac dysrhythmia is always there  Levodopa…. Contraindications Patients with active peptic ulcer must also be managed carefully, since gastrointestinal bleeding has occasionally occurred with levodopa Because levodopa is a precursor of skin melanin and may activate malignant melanoma, its use should be avoided in patients with a history of melanoma or with suspicious undiagnosed skin lesions Dopamine receptor agonists….. Bromocriptine & Apomorphine Bromocriptine and pergolide—ergot derivatives that directly stimulate dopamine receptors in the brain Used with levodopa/carbidopa to prolong the effectiveness Caution in CAD, can cause pulmonary fibrosis Bromocriptine also decreases prolactin release so used as treatment of hyperprolactinemia Apomorphine Clinical use: ◦ Patient with on-off phenomenon for treatment of off period. Pharmacokinetics: Incompletely abosrbed need extensive first-pass metabolism (biotransformed in liver) Pergolide & Ropinirole have higher bioavailability (distribution) Short to medium half life (Potency) Adverse effects: Use gradual dose titration N + V (particularly Apomorphine) Dyskinesia Hallucinations and confusion Peripheral vasospasm (Raynaunds) Respiratory depression (Apomorphine Selegiline & Rasagiline Selegiline also called deprenyl selectively inhibits MAO Type B (which metabolizes dopamine) Does not inhibit MAO Type A (which metabolizes norepinephrine and serotonin) Selegiline…. Increase dopamine levels in the brain Enhances the actions of levodopa and reduces its required dose when these drugs are administered together At recommended doses little potential for causing hypertensive crises At high doses, the selectivity of the drug is lost, and the patient is at risk for severe hypertension Selegiline…. Selegiline is metabolized to methamphetamine and amphetamine ◦ Stimulating properties may produce insomnia if the drug is administered later than mid afternoon Rasagiline an irreversible and selective inhibitor of MAO Type B Five times more potent than selegiline Unlike selegiline, it is not metabolized to an amphetamine-like substance  COMT Inhibitors Entacapone and Tolcapone Decrease plasma conc. of COMT Decreased metabolism of levodopa Increased central uptake of levodopa Greater conc. of brain dopamine Tolcapone is associated with hepatic necrosis Diarrhea, anorexia, postural hypotension, nausea, hallucinations and sleep disorders are other side effects Amantadine An antiviral (influenza) agent found to be effective against parkinsonism ◦ Accidentally discovered ◦ Apparently acts by increasing dopamine release from intact dopaminergic neurons ◦ Also used to control dyskinesias occurring with L- dopa therapy late in progression of disease Adverse effects – mild and reversible: ◦ Hallucinations, confusion, insomnia, dizziness, lethargy & slurred speech Anticholinergics Used as adjunct to levodopa therapy Examples: Benztropine and Trihexyphenidyl Pharmacological properties – these agents block the unopposed cholinergic effects in the basal ganglia of parkinsonism patients ◦ Decrease tremor ◦ Little effect on rigidity and bradykinesia Anticholinergics… All of these drugs can induce mood changes and produce xerostomia, visual problems & interfere with GI peristalsis Adverse effects are similar to those caused by high doses of atropine i.e., pupillary dilation, confusion, hallucination, sinus tachycardia, urinary retention, constipation, and dry mouth Contraindicated in patients with glaucoma, prostatic hyperplasia, or pyloric stenosis Other Therapies… Surgical procedures ◦ Thalamotomy & electrode implantation Neuroprotective therapy ◦ Antioxodants & antiapoptotic agents Gene therapy ◦ Viral vectors ◦ Genes for glutamic acid decarboxylase which facilitates GABA synthesis----Inhibitory effects Summary Thank You ANY QUESTION???