1. 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:

2. ANTIDEPRESSANTS
Drugs which can Elevate Mood (Mood Elevators)

3. 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

4. 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

5. 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

6. 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

7. Mechanism of Antidepressants

8. 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

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

10. Antianxiety Drugs

11. 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

12. Antianxiety Drugs – contd.

13. 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.

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

15. 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

17. 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

18. 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.

19. Anti-epileptic / anti-convulsant Drugs

20. 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

21. 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.

22. 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

23. 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.

24. 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

25. Thank you