Dr. Laila M. Matalqah Ph.D. Pharmacology PHARMACOLOGY OF CNS part 1 General Pharmacology M212

CNS drugs Classification: I. Central Stimulants Drugs which increase the activating functions of CNS II. Central Depressants Drugs that decrease the activation of CNS Most commonly use in therapy

CNS pharmacology Neurodegenerative disorders : Parkinson disease Alzheimer disease Anxiolytics and hypnotics: Drugs that induce sleep Antidepressants Opioid analgesics: relieve pain and sleep Anticonvulsant: Drugs used to treat epilipsy Antipsychotic drugs Anesthetics

A. Excitatory pathways 1. Stimulation of an excitatory neuron causes the release of neurotransmitter molecules, such as glutamate or acetylcholine, 2. The influx of Na+ causes a weak depolarization effect 3. If the number of stimulated excitatory neurons increases, more excitatory neurotransmitter is released Neurotransmission in CNS

B. Inhibitory pathways 1. Stimulation of inhibitory neurons releases neurotransmitter molecules, such as γ -aminobutyric acid (GABA), glycine or dopamine 2. The influx of Cl– and efflux of K+ cause a weak hyperpolarization. This diminishes the generation of action potentials

Excitatory pathwaysInhibitory pathways

1. Parkinson Disease Parkinsonism is a progressive neurological disorder of muscle movement, characterized: 1. Tremors, 2. Muscular rigidity, 3. Bradykinesia (slowness in initiating and carrying out voluntary movements) 4. postural abnormalities. Etiology: 1. Reduction of activity of dopaminergic (inhibitory pathway in the based ganglia and substania nigra 2. Increased activity of cholinergic (excitatory) fibers in the based ganglia

Drugs Used In Parkinson Disease A. Increase dopaminergic activity: Levodopa and carbidopa Levodopa is a metabolic precursor of dopamine Dopamine itself does not cross the blood-brain barrier, but levodopa, is actively transported into the CNS and is converted to dopamine in the brain Levodopa is decarboxylated to dopamine in the periphery, resulting in side effects that include nausea, vomiting, cardiac arrhythmias, and hypotension. So?

Carbidopa: Carbidopa, a dopa decarboxylase inhibitor Inhibit the metabolism of levodopa in the GIT and peripheral tissues increasing the availability of levodopa to the CNS decrease the dose of levodopa needed by 4-5 times decreases side effects. Actions: levodopa–carbidopa (Sinemet®) decreases the rigidity, tremors, and other symptoms of parkinsonism Drugs Used In Parkinson Disease

Adverse effects: Peripheral effects: 1. Anorexia, nausea, and vomiting: CTZ stimulation 2. Tachycardia: dopaminergic action 3. Mydriasis: Adrenergic action 4. Saliva and urine are a brownish color CNS effects: 1. Visual and auditory hallucinations and abnormal 2. involuntary movements (dyskinesias) 3. Mood change Drugs Used In Parkinson Disease

Ph/KDrug interaction Levodopa has an extremely short half-life (1 to 2 hours) levodopa should be taken on an empty stomach, typically 45 minutes before a meal. Withdrawal from the drug must be gradual. The vitamin pyridoxine (B6) increases the peripheral breakdown of levodopa and diminishes its effectiveness Drugs Used In Parkinson Disease

B. Dopamine-receptor agonists 1. Bromocriptine 2. Apomorphine 3. Rotigotine S/e : same like levodopa C. Anticholinergic agents Benztropine and Benzhexol an adjuvant role in antiparkinsonism therapy. S/e: pupillary dilation, confusion, sinus tachycardia, urinary retention, constipation, and dry mouth Drugs Used In Parkinson Disease

D. Selegiline MOA: inhibits MAO Type B (which metabolizes dopamine) at low to moderate doses S/E: insomnia E. Amantadine antiviral drug in the treatment of influenza MOA: increase the release of dopamine, blocking cholinergic receptors The drug has little effect on tremor, but it is more effective than the anticholinergics against rigidity and bradykinesia Drugs Used In Parkinson Disease

2. Anxiolytics and Hypnotic Drugs Anxiety: is a state of tension, apprehension, or uneasiness (a fear that seems to arise from a unknown source). The physical symptoms of severe anxiety are similar to those of fear (such as tachycardia, sweating, trembling, and palpitations) and involve sympathetic activation. Anxiolytics Drugs I. Benzodiazepines II. Barbiturates III. Others: Chloral Hydrate

Benzodiazepines MOA: Activate (GABA A ) receptors (inhibitory NT) Binding of GABA to its receptor triggers an open ing of a chloride channel Therapeutic Actions 1. Reduction of anxiety: at low doses, the benzodiazepines are anxiolytic ( α2-GABA) E.g., clonazepam, lorazepam and diazepam 2. Sedative and hypnotic actions at higher doses. ( α1-GABA) Temazepam and Flurazepam 3. Anticonvulsant: to treat epilepsy e.g.,, lorazepam and diazepam ( α1- GABA) 4. Muscle relaxant: At high doses: e.x: Diazepam for multiple sclerosis

Benzodiazepines Long-acting: Clonazepam Diazepam Flurazepam Intermediate acting: Alprazolam Lorazepam Temazepam Short-acting: Oxazepam Triazolam

Benzodiazepines Adverse effect 1. Drowsiness and confusion 2. Psychological and physical dependence on benzodiazepines can develop if high doses of the drugs are given over a prolonged period 3. Abrupt discontinuation of the benzodiazepines results in withdrawal symptoms, including confusion, anxiety, agitation, restlessness, insomnia. Overdoses toxicity: Flumazenil is a GABA-receptor antagonist that can rapidly reverse the effects of benzodiazepines

2. Barbiturates MOA: Bind GABA A receptors, which enhances GABAergic transmission Therapeutic Actions 1. Anticonvulsant: Phenobarbital is used in long-term management of seizures 2. Anesthesia: thiopental, are used intravenously to induce anesthesia. which acts within seconds and has a duration of action of about 30 minutes, is used in the 3. sedative and hypnotic: Pentobarbital, secobarbital and amobarbital are short-acting barbiturates, suppress REM sleep 2. Hypnotic and anxiolytics Drugs

Pharmacokinetics: Enzyme induction: Barbiturates induce CYP450 in the liver. Side effects: 1. CNS: Drowsiness 2. Drug hangover 3. Addiction 4. Respiratory depression 5. Physical dependence: Withdrawal symptoms: tremor, seizures, cardiac arrest…. Barbiturates

3. Alcohol Ethanol is an important drug of dependence Acute effect:  CNS: decrease learning ability and attention  GIT: diluted- stimulate gastric secretion. Conc- decrease gastric secretion  CVS: increase HR and CO  Metabolism: Hypoglycemia and metabolic acidosis Chronic effect:  GIT: cirrhosis of liver, gastritis  CNS: acohol withdrwal  Myopathy 2. Hypnotic and anxiolytics Drugs

3. Alcohol Drugs to treat alcohol dependence 1. Disulfiram: blocks the oxidation of acetaldehyde to acetic acid by inhibiting aldehyde dehydrogenase (accumulation of acetaldehyde in the blood, causing flushing, tachycardia, hyperventilation, and nausea) 2. Naltrexone is better tolerated than disulfi ram 2. Hypnotic and anxiolytics Drugs