Pharmacology RHPT-365

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MMajid ajid AAhmad hmad GGanaie anaie MM. Pharm., . Pharm., PPh.D.h.D.Assistant ProfessorAssistant ProfessorDepartment of Pharmacology Department of Pharmacology E mail: E mail: majidsays@gmail.commajidsays@gmail.com

ChapterChapter 6: 6:

Drugs used in CNS disordersDrugs used in CNS disorders

ANTIDEPRESSANTS

Drugs which can Elevate Mood (Mood Elevators)

ANTIDEPRESSANTS

1. MAO inhibitors:– Irreversible: Isocarboxazid, Iproniazid, Phenelzine and Tranylcypromine– Reversible: Moclobemide and Clorgyline

2. Tricyclic antidepressants (TCAs) NA and 5 HT reuptake inhibitors – Imipramine, Amitryptiline, Doxepin,

Dothiepin and Clomipramine NA reuptake inhibitors – Desimipramine, Nortryptyline, Amoxapine

3. Selective Serotonin reuptake inhibitors: – Fluoxetine, Fluvoxamine, Sertraline and Citalopram

4. 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

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

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

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

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.

LamotriginePharmacological 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 Antiepileptics1. Improper diagnosis of the type of seizures

2. Incorrrect choice of drug

3. Inadequate or excessive dosage

4. 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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