Anixolytics, antidepressants and antipsycotics

Anxiolytics used to treat anxiety. Anxiety is characterized by psychological symptoms such as nervousness and feelings of forbooding, accompanied by variety of physical symptoms such as agitation, palpitations, sweating, sleeplessness, gastrointestinal disturbances. It can be a normal appropriate reaction to disturbing events but can in some circumstances be pathological and disabling, particularly if associated with panic attacks, phobic states or obsessive compulsive disorders. Hypnotics Used to treat insomnia. Insomnia is difficulty in sleeping and it may result from anxiety. Both anxiety and insomnia can be treated with CNS depressant drugs which act as anixolytics at low doses and hypnotics at higher concentrations, to anaesthesia and in toxic doses may result in coma and respiratory depression.

Anixolytics and hypnotics

Drug Mechanism of Action
Bind to brain benzodiazepine receptor in complex with GABAA and barbiturate receptors around common Cl- ion channel. Enhance GABAA mediated inhibition via increased frequency of Cl- channel openings (barbiturates increase duration). Overall action of benzodiazepines on CNS is to produce a general enhancement of the neuroinhibitory actions of GABA. Affinity of benzodiazepines for benzodiazepine receptor correlated with clinical potency. Benzodiazepines cause reduce in anxiety, sedative effect, induction of sleep, reduced muscle tone, anticonvulsant effect. Shorter acting agents preferred as hypnotics to prevent sedative actions throughout the day -

Side Effects
Unwanted sedation Drowsiness, confusion. Lack of motor control risk of accident. Dangerous synergism with alcohol Muscle relaxation (therapy in spasticity) Respiratory, CVS, CNS depression. Tolerance Dependence can develop. Reduced REM sleep, rebound (withdrawal) increase in REM sleep. Withdrawal reaction rebound anxiety and insomnia and convulsions must be a GRADUAL WITHDRAWAL process.

Benzodiazepines

Pharmacokinetics - Diazepam (T = 30hr) N- desmethyldiazepam (T = 65hr *active metabolite) Oxazepam (T =8hr *active metabolite) Glucuronide conjugation excretion - Tamazepam (T = 8hr) Glucuronide conjugation excretion.

NonBenzodiazepines

Zolpidem: Non-benzodiazepine hypnotic acting at benzodiazepine receptor (BZR) not anticonvulsant BZR1>BZR2 Midazolam: Very short life (2-3 hrs) anaesthesia induced can result in amnesia. Flumazenil: Benzodiazepine receptor antagonist to terminate benzodiazepine actions after a surgery overdose precipitates withdrawal in dependant patients.

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Depression is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and loss of interest or pleasure in normally enjoyable activities- Also associated with it are sadness, worthlessness, hopelessness, guilt and suicidal feelings. Monoamine theory depression is a functional deficit of the transmitters NA and 5-HT in the forebrain and in mania there is a functional excess. MAO is a substance that metabolized Na and 5-HT inhibition of MAO results in antidepressant effects!!

Antidepressant drugs
Drug Mechanism of Action Inhibition of monoamine reuptake of NA and 5-H. Acute potentiation of 5-HT and NA actions Delayed therapeutic effect 2-3 weeks. Receptor antagonists of M, 1/2, and H1 these do not result antidepressant activity but results in Side effects!
Potentiation Imipramine Amitriptyline NA ++ + 5-HT +++ ++ DA -

Tricyclicantidepressents (TCA) Imipramine Amitriptyline

Antagonism Imipramine Amitriptyline

M ++ +++

1/2 ++ +++

H1 + ++++

Side Effects Anticholinergics (M block) Impaired alertness, sedation (H1 block) Cardiovascular hypotension 1 block At higher doses conductance changes arrhythmias Major suicide risk Drug interactions with anticholinergics, antihypertensives and sedatives.

Selective Serotonin reuptake inhibitors (SSRIs) Fluoxetine Paroxetine Selective serotoninnoradreneline reuptake inhibitors (SNRIs) Venlafaxine Selective NA reuptake Inhibitor Reboxetine

Stops serotonin reuptake potentiating serotonin actions. However NO receptor antagonism to M, 1/2, and H1 Efficacy similar to tricyclics, however it has less side effects.

Selective serotonin and noradreneline inhibitors potentiate serotonin and noradreneline. Efficacy similar to tricyclics and SSRIs less severe TCA-like problems

Prevents NA reuptake, potentiating noradrenalin effects.

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Drug

Monoamine oxidase inhibitors Phenelzine

Mechanism of Action -Irreversible inhibition of MAO A/B hence potentiation of NA and 5HT. - 2nd line agents for atypical depression. -MAOIs act by inhibiting the activity of monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters and thereby increasing their availability. MAO-A preferentially deaminates serotonin and norepinephrine, thus the inhibitors of MAO-A must prolong 5-HT and NA. PROBLEM inhibition of reuptake of MAO is acute but therapeutic effect is delayed. - Secondary changes over long term treatment Subsensitivity of brain and 5-HT2 receptor induced only over weeks of antidepressant treatment.

Side Effects Potentiation of endogenous and exogenous sympathomimetics to give hypertensive crises, arrhythmias, headache, CVAs. Interaction with tricyclics, LDopa, -methyldopa and opiates. Agitation, insomnia, hyperyrexia the problems can be reduced by careful patient selection, dietary advice and checking drug interactions. OR use:-

Reversible Inhibitor of MAO-A Moclobemide - Has fewer side effects

Antipsychotic drugs used for treatment of schizophrenia.

-Positive symptoms of schizophrenia: delusions, hallucinations and thought disorders. -Negative symptoms of schizophrenia: social withdrawal, emotional flattening, reduced drive, inability to feel pleasure, poverty of speech. Pathophysiology most likely due to malfunction of dopaminergic transmission. Abnormalities in the mesolimbic and mesocortical dopaminergic pathways are most likely since psychotic symptoms develop after injury or lesions in these areas. Also possibly effected by5-HT and glutamate transmitter systems. Antipsychotic drugs alleviate the positive symptoms of schizophrenia but have little effect on the negative symptoms.

Antipsychotic Drugs
Drug Mechanism of Action Side Effects
- Tremor - GIT problems - Renal problems leading thirst, polyuria, comma, convulsions.

1) Mood stabilizers Lithium

-Most mood stabilizers are purely

antimanic agents, meaning that they are effective at treating mania and mood cycling and shifting (not depression) - Lithium limits increases in inositol triphosphate production

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via reduced inositol availability. -Prophylactic against mood swings. - Results seen after 4-5 days. - Therapeutic level 0.8-1.2 mEq/L - Maintainence 0.6-0.8 mEq/L

2) First generation typical antipsychotic drugs

Chlorpromazine (CPZ) D1-5, M, 1, H1 Haloperidol (HAL) D2-4

Dopamine receptor antagonist Antipsychotic effect delayed 24 weeks. Protects against future relapse in long term. Act mostly on reliving the positive symptoms.

3) Second generation atypical antipsychotic drugs Clozapine Risperidone Olanzapine

Clozapine - Weak D2 (+ D1, D3-5) and marked 5-HT2, M, 1, H1 antagonist. - Only antipsychotic more effective than other agents. - Fewer extrapyramidal side effects. - Not only acts on the positive symptoms but are also more effective aginst the negative sym

Extrapyramidal side effects due to basal ganglias D2 antagonism. Parkinsonism - Dystoniai responds to anticholinergics - Akathisiaii responds to blockers. - Neurological tardive dyskinesia (TD) involuntary movements emerging in 20-40% following years of treatment. - Anticholinergic (CPZ>HAL) - Hypotension 1 (CPZ>HAL) - Increase prolactin (CPZ=HAL) - Neuroleptic malignant syndrome: rare but potentially fatal rigidity, hyperpyrexia, autonomic lability. increased CPK (creative phosphokinase) is a biological marker for this. Clozapine S/E - Increased risk of agranulocytosis - Mandatory weekly blood counts must be done monitor WBC weekly and patient only given 1 week of medicine supply. - Hypotension - Seizures - Sedation - Weight gain due to glucose dysregulation. ONLY USED when patients unresponsive to other antipsychotics or has serious EPS.

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Risperidone and Olanzapine -High affinity for D2 and 5-HT2 antagonist. - Broading spectrum of efficacy than the typical agents. - Less effective BUT more EPS compared to clozapine. - Risperidone long acting, i.m, recently available.

Fewer side effects than clozapine but greater weight gain especially olanzapine.

Dystonia- spasms of the face and neck muscles, which can be reliveved with antimuscarinics. Akathisia-motor restlessness, an uncontrolled drive to move about, count ered by blockers or benzodiazepines.

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