Comprehensive Pharmacology of Neurodegenerative and CNS Disorders

Comprehensive Pharmacology of Neurodegenerative and CNS Disorders

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  PREPARED BY Prof. ASHISHN. UMALE M. PHARM IN PHARMACOLOGY ASSISTANT PROFESSOR SHRADDHA INSTITUTE OF PHARMACY, WASHIM- 444505 PHARMACOLOGY-I
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  Drugs Used inParkinson’s Disease Introduction Parkinson's disease is a chronic and progressive neurodegenerative disorder that mainly affects movement and muscular control. The disease occurs due to degeneration of dopaminergic neurons present in the substantia nigra region of the brain. Because of this degeneration, the level of dopamine decreases in the basal ganglia. Dopamine normally helps in smooth and coordinated muscular activity. Reduction in dopamine leads to imbalance between dopamine and acetylcholine neurotransmitters, resulting in abnormal motor functions. The disease usually affects elderly individuals, although younger patients may also develop the condition. The symptoms gradually worsen with time.
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  Major Symptoms ofParkinson’s Disease Resting tremors, usually beginning in the hands Muscular rigidity or stiffness Bradykinesia, which means slowness of movement Postural instability and difficulty in balancing Difficulty in speech and swallowing Therapeutic Goals Increase dopamine activity in the brain Restore balance between dopamine and acetylcholine Improve motor function and daily activities Reduce tremors and rigidity Improve quality of life
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  Drug Class Examples Dopamineprecursor Levodopa Peripheral dopa decarboxylase inhibitors Carbidopa, Benserazide Dopamine receptor agonists Pramipexole, Ropinirole, Bromocriptine MAO-B inhibitors Selegiline, Rasagiline COMT inhibitors Entacapone, Tolcapone Anticholinergic drugs Trihexyphenidyl Dopamine releaser Amantadine
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  1. Levodopa Introduction Levodopa isconsidered the most effective drug for the symptomatic treatment of Parkinson’s disease. Dopamine itself cannot cross the blood-brain barrier, therefore dopamine cannot be administered directly. Levodopa acts as a precursor of dopamine and can cross the blood-brain barrier. Mechanism of Action After entering the brain, levodopa is converted into dopamine by the enzyme dopa decarboxylase. The formed dopamine replenishes depleted dopamine stores in the basal ganglia and improves motor activity. Pharmacological Actions Levodopa improves: Bradykinesia, Muscular rigidity, Tremors, Difficulty in walking and speaking The improvement is usually significant during the early stages of treatment.
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  Pharmacokinetics Administered orally, Absorbedfrom the small intestine, Competes with dietary amino acids for absorption, Crosses the blood-brain barrier, Metabolized both in peripheral tissues and brain Combination with Carbidopa Carbidopa is usually administered with levodopa because it inhibits peripheral metabolism of levodopa. This increases the amount of levodopa reaching the brain and reduces peripheral side effects such as nausea and vomiting. Uses Idiopathic Parkinson’s disease Post-encephalitic Parkinsonism Adverse Effects Gastrointestinal Effect:- Nausea, Vomiting, Loss of appetite Cardiovascular Effects:- Postural hypotension, Palpitations CNS Effects :- Dyskinesia, Hallucinations, Confusion, Mood changes
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  2. Dopamine Agonists Examples:Pramipexole, Ropinirole, Bromocriptine Mechanism of Action These drugs directly stimulate dopamine receptors in the brain without requiring conversion into dopamine. Advantages Longer duration of action than levodopa Lower risk of motor fluctuations Useful in younger patients Uses Early-stage Parkinson’s disease Combination therapy with levodopa Adverse Effects:- Hallucinations, Confusion, Drowsiness, Orthostatic hypotension, Edema, Impulse control disorders
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  3. MAO-B Inhibitors Examples:Selegiline, Rasagiline Mechanism of Action Monoamine oxidase-B enzyme is responsible for degradation of dopamine in the brain. These drugs inhibit MAO-B enzyme and therefore increase dopamine concentration Therapeutic Effects Mild improvement in symptoms Delays progression of symptoms Reduces levodopa requirement Side Effects:- Insomnia, Headache, Hypertension, Dyskinesia 4. COMT Inhibitors Examples: Entacapone, Tolcapone Mechanism of Action Catechol-O-methyl transferase enzyme metabolizes levodopa in peripheral tissues. COMT inhibitors block this metabolism and prolong levodopa action. Clinical Importance These drugs are mainly used as adjunct therapy with levodopa. Side Effects:- Diarrhea, Nausea, Dyskinesia, Hepatotoxicity
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  5. Anticholinergic Drugs Example:Trihexyphenidyl Mechanism of Action These drugs block muscarinic receptors and reduce cholinergic overactivity in the basal ganglia. Effects Particularly useful for reducing tremors and rigidity. Side Effects:- Dry mouth, Blurred vision , Constipation , Urinary retention, 6. Amantadine Mechanism of Action Amantadine increases dopamine release and inhibits dopamine reuptake. It also blocks NMDA receptors. Uses Mild Parkinson’s disease Drug-induced Parkinsonism Adjunct with levodopa Side Effects:- Ankle edema, Insomnia, Confusion, Livedo reticularis
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  Drugs Used inAlzheimer’s Disease Introduction Alzheimer's disease is a progressive neurodegenerative disorder associated with gradual loss of memory, cognitive function, and learning ability. It mainly affects elderly individuals. The disease is characterized by degeneration of cholinergic neurons and accumulation of amyloid plaques and neurofibrillary tangles in the brain. Symptoms Progressive memory loss Confusion Behavioral changes Impaired judgment Difficulty in communication Personality changes Drug Class Examples Cholinesterase inhibitors Donepezil, Rivastigmine, Galantamine NMDA receptor antagonist Memantine
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  1. Cholinesterase Inhibitors Mechanismof Action These drugs inhibit acetylcholinesterase enzyme, thereby preventing breakdown of acetylcholine and increasing cholinergic transmission in the brain. Clinical Effects Improve memory Improve attention span Enhance cognitive function Slow progression of symptoms temporarily Donepezil Donepezil is a selective and long-acting acetylcholinesterase inhibitor. Uses: Mild to severe Alzheimer’s disease Side Effects: Nausea, Diarrhea, Insomnia, Bradycardia
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  Rivastigmine Rivastigmine inhibits bothacetylcholinesterase and butyrylcholinesterase enzymes. Special Feature:- Available as transdermal patch. Side Effects:- Vomiting, Weight loss, Dizziness 2. Memantine Mechanism of Action Memantine blocks NMDA glutamate receptors and protects neurons from excitotoxic damage caused by excessive glutamate activity. Uses:- Moderate to severe Alzheimer’s disease Side Effects:- Dizziness, Headache, Confusion, Constipation
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  Drug Class Examples PsychostimulantsAmphetamine, Methylphenidate Methylxanthines Caffeine Wakefulness-promoting drugs Modafinil CNS Stimulants Introduction CNS stimulants are drugs that increase mental alertness, wakefulness, concentration, and motor activity. They stimulate different regions of the central nervous system. 1. Amphetamine Mechanism of Action Amphetamine increases release of dopamine and norepinephrine from presynaptic nerve terminals. Pharmacological Effects Increased alertness & concentration Reduced fatigue Uses: ADHD, Narcolepsy Adverse Effects:- Insomnia, Hypertension, Tachycardia, Dependence, Anxiety
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  2. Caffeine Mechanism Caffeine blocksadenosine receptors leading to CNS stimulation. Effects Increased alertness Reduced fatigue Improved concentration Side Effects: Anxiety, Tremors, Gastric irritation, Palpitations 3. Modafinil Mechanism Modafinil stimulates hypothalamic wakefulness centers. Uses Narcolepsy Shift work sleep disorder Side Effects: Headache, Anxiety, Insomnia
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   Nootropics Introduction Nootropics aredrugs that improve cognitive functions such as memory, concentration, learning, and mental performance. Examples:- Piracetam, Citicoline 1. Piracetam Mechanism Improves neuronal metabolism and enhances neurotransmission. Uses Memory disorders Cognitive dysfunction Vertigo Side Effects :- Nervousness, Weight gain, Sleep disturbances
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  Opioid Analgesics andAntagonists Introduction Opioid analgesics are drugs that relieve moderate to severe pain by acting on opioid receptors in the central nervous system and peripheral tissues. μ-Opioid receptor activation→Analgesia These drugs produce powerful analgesia but may also cause respiratory depression, tolerance, and dependence. Opioid Receptors:- μ (Mu), κ (Kappa), δ (Delta) Drug Class Examples Strong agonists Morphine, Fentanyl Moderate agonists Codeine Partial agonists Buprenorphine Antagonists Naloxone, Naltrexone
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  1. Morphine Mechanism ofAction Morphine mainly acts on μ-opioid receptors and inhibits transmission of pain signals in the CNS. Pharmacological Actions:- Powerful analgesia, Sedation, Respiratory depression, Constipation Pharmacokinetics:- Can be administered orally, intravenously, or intramuscularly, Undergoes hepatic metabolism, Excreted by kidneys Uses :- Severe postoperative pain, Cancer pain, Myocardial infarction pain, Pulmonary edema Adverse Effects:- Respiratory depression, Constipation, Nausea and vomiting, Urinary retention, Dependence and tolerance, Miosis 2. Codeine Uses:- Codeine is mainly used for mild to moderate pain and as an antitussive agent. Side Effects:- Drowsiness, Constipation, Nausea
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  Opioid Antagonists 1. Naloxone Mechanism Naloxonecompetitively blocks opioid receptors and rapidly reverses opioid effects. Uses:- Opioid overdose, Respiratory depression caused by opioids Features:- Rapid onset, Short duration of action Side Effects:- Withdrawal symptoms in dependent individuals 2. Naltrexone Uses:- Naltrexone is used in maintenance therapy for opioid and alcohol dependence. Advantages:- Longer duration of action than naloxone Side Effects:- Nausea, Anxiety, Hepatotoxicity