Pharmacology RHPT-365 Chapter 6: Drugs used in CNS disorders By Majid Ahmad Ganaie M. Pharm., Ph.D. Assistant Professor Department of Pharmacology E mail: majidsays@gmail.com

ANTIDEPRESSANTS Drugs which can Elevate Mood (Mood Elevators)

ANTIDEPRESSANTS MAO inhibitors: Irreversible: Isocarboxazid, Iproniazid, Phenelzine and Tranylcypromine Reversible: Moclobemide and Clorgyline Tricyclic antidepressants (TCAs) NA and 5 HT reuptake inhibitors – Imipramine, Amitryptiline, Doxepin, Dothiepin and Clomipramine NA reuptake inhibitors – Desimipramine, Nortryptyline, Amoxapine Selective Serotonin reuptake inhibitors: Fluoxetine, Fluvoxamine, Sertraline and Citalopram Atypical antidepressants: Trazodone, Mianserin, Mirtazapine, Venlafaxine, Duloxetine, Bupropion and Tianeptine

Causes of Depression and Mechanism of antidepressants The Monoamine Theory: Adrenaline, Noradrenaline, Dopamine and 5-HT are neurotransmitters (Biogenic amines) Called Noradrenergic, Serotonergic or Dopaminergic etc. neurones Normally NA and 5 HT are in adequate numbers at post synaptic region In DEPRESSION – Deficiency of NA or 5 HT or BOTH

Mechanism of antidepressants – contd. Drugs act by increasing the local availability of NA or 5 HT MAO Inhibitors: MAO is a Mitochondrial Enzyme involved in Oxidative deamination of these amines MAO-A: Peripheral nerve endings, Intestine and Placenta (5-HT and NA) MAO-B: Brain and in Platelets and Mainly Serotonergic (Phenylalanine) Selective MAO-A inhibitors (RIMA) have antidepressant property

Mechanism of antidepressants – contd. TCAs: NA, 5 HT and Dopamine are present in Nerve endings Normally, there are reuptake mechanism and termination of action TCAs inhibit reuptake and make more monoamines available for action SSRIs: Serotonins also reuptaken by Nerve terminals SSRIs inhibit the reuptake mechanism and make more 5 HT available for action NA neruones mostly arise from locus ceruleus (pons) and lateral tegmentum in Midbrain Serotonergic neurones arise from raphe nucleus of pons

Mechanism of Antidepressants

MAO inhibitors Drugs: Irreversible: Isocarboxazid, Iproniazid, Phenelzine and Tranylcypromine, Reversible: Moclobemide and Clorgyline Not popular now except irreversible selective MAO-A inhibitors: Strict dietary restrictions Irreversible action Drug-drug interactions Safer drugs are available now Major drawbacks: Manic state or hypertensive crisis Cheese reactions Other drug interactions MAO degrades some of NA within the neurones even after uptake. Inhibition of this MAO enzyme may accumulate NA in excess and may cause hypertensive crisis and manic state Cheese reactioon – Indirectly acting sympathomimetic amines escape degradation by MAO, reaches systemic circulation and displace large amount of NA from nerve endings leading to hypertensive crisis. Treated with phentolamine and prazosin

Effect of Antidepressants Deficient Drive of MOOD to - Normal Rhythmic Drive on Prolonged Treatment

Antianxiety Drugs

What is anxiety? Anxiety is a normal reaction to stress It helps one deal with a tense situation in the office, study harder for an exam, keep focused on an important speech In general, it helps one cope But when anxiety becomes an excessive, irrational dread of everyday situations, it has become a disabling disorder

Antianxiety Drugs – contd.

What are the Drugs? Benzodiazepines: Alprazolam, Diazepam, Chlordiazepoxide, Oxazepam and Lorazepam Older Drugs: Barbiturates, Chloral hydrate and Meprobamate Azapirones: Buspirone, Gepirone and Isapirone Others: Propranolol, Imipramine Fluoxetine and Zolpidem etc.

Classifications of Benzodiazepines - Short acting: (3-5 hours): triazolam - Intermediate: (6-24 hours) Alprazolam, Lorazepam, Oxazepam Estazolam, Temazepam - Long acting: ( 24-72 hours) Clonazepam , Chlordiazepoxide ,Diazepam Flurazepam

GABA (γ-aminobutyric acid): is an inhibitory neurotransmitter Mechanism of Action Benzodiazepines act by binding to BZ receptors in the brain  enhance GABA action on brain  chloride channels opening   chloride influx to the cell  hyper- polarization  inhibition of brain. GABA (γ-aminobutyric acid): is an inhibitory neurotransmitter

Antianxiety Drugs - Buspirone Partial agonist action on presynaptic auto receptor 5-HT1A – reduces serotonergic activity in dorsal raphe Antagonist of certain 5-HT1A post synaptic receptors Weak D2 action but no antipsychotic effect Adaptive changes after chronic treatment – reduction in 5-HT2 receptors in cortex Given orally, absorbed rapidly – high 1st pass metabolism, active metabolite – urine and faeces Dose: 5-15 mg dose

Antianxiety Drugs - Propranolol Reduces symptoms of anxiety Symptoms: Sympathetic overactivity – palpitation, tachycardia, rise in BP, sweating, tremor, GIT hurrying etc No action on psychological symptoms – fear, tension etc. Useful in examination fear, public appearance etc.

Anti-epileptic / anti-convulsant Drugs

Definition of Epilepsy It is a Chronic medical condition produced by sudden changes in the electrical function of the brain. A group of chronic CNS disorders characterized by recurrent seizures First generation AED Phenytoin, Carbamazepine, Valproic acid Second generation AED Lamotrigine, Gabapentin, Vigabatrin, Topiramate, In general, the newer AEDs have less CNS sedating effects than the classical AEDs

Phenytoin Mechanism of Action: Clinical Uses: Pharmacokinetics Well absorbed when given orally, however, it is also available as iv. (for emergency) Mechanism of Action: Membrane stabilization by blocking Sodium & Calcium influx into the neuronal axon. or inhibits the release of excitatory amino acids via inhibition of Calcium influx Clinical Uses: Used for partial Seizures & generalized tonic-clonic seizures. But not effective for absence Seizures . Also can be used for treatment of ventricular fibrillation.

Lamotrigine Mechanism of Action: Pharmacological effects Resembles phenytoin in its pharmacological effects Well absorbed from GIT Mechanism of Action: Inhibits excitatory amino acid release (glutamate & aspartate ) by blockade of Na channels. Uses: As add-on therapy or as monotherapy

Common Causes of Failure of Antiepileptics Improper diagnosis of the type of seizures Incorrrect choice of drug Inadequate or excessive dosage Poor compliance Antiepeliptics and Pregnancy: Seizure very harmful for pregnant women. Monotherapy usually better than drugs combination. Folic acid is recommended to be given for every pregnant women with epilepsy Phenytoin, sodium valproate are absolutely contraindicated and oxcarbamazepine is better than carbamazepine. Experience with new anticonvulsants still not reliable to say that are better than old ones.

Possible Mechanism of Action 1) By acting on the neuronal membrane action potential: Membrane Stabilization: Phenytoin; Carbamazepine: Phenobarb; Lamotrigine; Topiramate, Zonisamide. Prolong refractory period: e.g: Ethosuximide; Valproate 2) By inhancement of GABA neurotransmissions: Inhibit GABA catabolism (inhibit GABA transaminase) e.g: Valproate; Vigabatrin Inhibit re-uptake of GABA: benzodiazepines Analog of GABA: e.g: Gababentin Increase the activity of GABA: phenobarbitone; Topiramate; Gabapentin 3) By antagonizing the action of Aspartate and Glutamate: e.g: Lamotrigine

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