Psychiatry Pharmacology

PSYCHIATRY PHARMACOLOGY J. ‘PSYCHIATRY’ Antidepressants - SSRI (selective serotonin reuptake inhibitor; fluoxetine, sertraline) - SNRI (serotonin (and) noradrenaline reuptake inhibitor; venlafaxine) - Tricyclic (amitriptyline) - Monoamine oxidase inhibitor (phenelzine) Antipyschotic - risperidone - olanzapine - quetiapine - haloperidol - flupentixol - chlorpromazine Hypnotic (and reversal) agents - Benzodiazepine (temazepam; diazepam, midazolam (iv); restless legs: - clonazepam) - Cyclopyrrolone (zoplicone) - Reversal (benzodiazepine) agent (flumazenil) Mood stabilizer - Carbamazepine - Lithium (LEVELS)

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Alan McLeod Alan McLeod Alan McLeod Alan McLeod Alan McLeod Alan McLeod Alan McLeod

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Alan McLeod Alan McLeod Alan McLeod

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Antidepressants GENERAL COMMENTS ABOUT ANTI-DEPRESSANTS  ?Increased risk of suicide in first 2 weeks, due to improved motivation but lag in improvement of mood.  Increase dose gradually over 2-3 weeks  Withdraw dose gradually over 2-3 weeks  Recommended 6m treatment for 1st episode, longer for recurrence  Regular follow-up: 2 weeks, then another 1 month, 2 monthly  Symptoms improve 2-6 weeks, change drug after 4 weeks if no improvement  Prescribe in small quantities (e.g. 1 week) especially TCAs NICE Guidelines Classify depression according to number of ICD10 symptoms: Not depressed = 6 mg)

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Postural hypotension Sedation (caution: driving, operating machinery etc) Dizziness Hyperglycemia +/- diabetes Hyperprolactinemia: galactorrhoea, gynaecomastia, amenorrhoea May lengthen QT interval

Contraindications: • Increased risk of stroke in elderly patients with dementia • Breast feeding

Drug ANTI-ARRHYTHMICS ANTIHYPERTENSIVES: ACE inhibitors, Alpha-blockers, Angiotensin-II receptor antagonists alcohol General anesthetic ANTI-EPILEPTICS: Carbamazepine, Phenytoin, valproate, barbiturates TRICYCLICS: all

Cautions: Use with caution in: • Elderly: assess CVS risk factors Hepatic impairment • Renal impairment • Pregnancy • History of epilepsy • CVS disease • Obesity • Parkinson’s • Drugs which prolong QT interval

Effect of interaction increased risk of ventricular arrhythmias when antiarrhythmics that prolong the QT interval given with antipsychotics that prolong the QT interval Increased hypotensive effect Increased sedation Increased hypotensive effect Reduces anti-seizure efficacy: seizure threshold lowered Increased tricyclic plasma concentration: ventricular arrhythmias

Monitoring: symptomatic monitoring, plus weight. Olanzapine by Alan McLeod Indications: • Schizophrenia, • Mania / bipolar disorder • Agitation / disturbed behaviour in schizophrenia / mania Actions: • D2 receptor antagonist • 5HT receptor antagonist Quetiapine by Alan McLeod Indications: • Schizophrenia, • Mania / bipolar disorder Actions: • D1 / D2 receptor antagonist • 5HT1A / 5HT2 receptor antagonist • H1 receptor antagonist (may be responsible for sedative effects) Haloperidol by Alan McLeod Indications:

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By mouth, initially 1.5–3 mg 2–3 times daily or 3–5 mg 2–3 times Schizophrenia daily in severely affected or resistant patients; in resistant Other psychoses schizophrenia up to 30 mg daily may be needed; adjusted Mania according to response to lowest effective maintenance dose (as Short term management: low as 5–10 mg daily); Psychomotor agitation By intramuscular or by intravenous injection, initially 2–10 mg, Excitement then every 4–8 hours according to response to total max. 18 mg daily; severely disturbed patients may require initial dose of up to Violent / dangerously 18 mg; impulsive behaviour Severe anxiety (Short-term adjunctive management): by mouth, 500 micrograms BD Intractable hiccup: by mouth, 1.5 mg 3 times daily adjusted according to response; Nausea and vomiting: by mouth, 1 mg daily By IM or IV injection, 0.5–2 mg

Action: As with all antipsychotics, it acts through blockage of dopamine receptors. It is approximately 50 times more potent than chlorpromazine on a weight basis (50mg chlorpromazine are equivalent to 1mg haloperidol). Haloperidol possesses a strong activity against delusions and hallucinations, most likely due to an effective dopaminergic receptor blockage in the mesocortex and the limbic system of the brain. The peripheral antidopaminergic effects of haloperidol account for its strong antiemetic activity. There, it acts at the chemoreceptor trigger zone (CTZ). Haloperidol is useful to treat severe forms of nausea/emesis such as those resulting from chemotherapy. The peripheral effects lead also to a relaxation of the gastric sphincter muscle and an increased release of the hormone prolactin, with the possible emergence of breast enlargement and secretion of milk (lactation) in both sexes. Cautions: As above plus • subarachnoid haemorrhage • metabolic disturbances such as hypokalaemia, hypocalcaemia, or hypomagnesaemia Side effects • pigmentation and photosensitivity reactions rare; • extrapyramidal symptoms, particularly dystonic reactions and akathisia especially in thyrotoxic patients; • rarely weight loss; • hypoglycaemia; • inappropriate antidiuretic hormone secretion Flupentixol by Alan McLeod Action • D1 / D2 receptor antagonist; also antagonises 5HT receptors • In decanoate ester form it can be given IM as a depot and lasts up to 4 weeks Indications: • schizophrenia and other psychoses, particularly with apathy and withdrawal but not mania or psychomotor hyperactivity (zuclopentixol may be used with mania / hyperactivity) • depression • Where a depot preparation is required to improve compliance Chlorpromazine by Alan McLeod ‘Typical’ antipsychotic (in fact the first to be marketed!) Indications & Dose • Schizophrenia • Other psychoses • Mania • Short term management: - Severe anxiety - Psychomotor agitation - Excitement - Violent / dangerously impulsive behaviour

By mouth, initially 25 mg 3 times daily (or 75 mg at night), adjusted according to response, to usual maintenance dose of 75–300 mg daily (but up to 1 g daily may be required in psychoses); By intramuscular or by intravenous injection, 25–50 mg every 6–8 hours; By rectum in suppositories as chlorpromazine base 100 mg every 6–8 hours [unlicensed]

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Intractable hiccup: by mouth, 25–50 mg 3–4 times daily

Mode of action: Central Chlorpromazine acts as an antagonist of various postsynaptic receptors: • Dopaminergic (subtypes D1, D2, D3 and D4, different antipsychotic properties on productive and unproductive symptoms), • Serotonergic (5-HT1 and 5-HT2, with anxiolytic, antidepressive and antiaggressive properties as well as an attenuation of extrapyramidal side effects, but also leading to weight gain, fall in blood pressure, sedation and ejaculation difficulties), • histaminergic (H1-receptors, sedation, antiemesis, vertigo, fall in blood pressure and weight gain), • alpha1/alpha2 (antisympathomimetic properties, lowering of blood pressure, reflex tachycardia, vertigo, sedation, hypersalivation and incontinence as well as sexual dysfunction, but may also attenuate pseudoparkinsonism— controversial) • muscarinic (cholinergic) M1/M2 (causing anticholinergic symptoms like dry mouth, blurred vision, constipation, difficulty/inability to urinate, sinus tachycardia, ECG-changes and loss of memory, but the anticholinergic action may attenuate extrapyramidal side effects). • Additionally, chlorpromazine is a presynaptic inhibitor of dopamine reuptake, which may lead to (mild) antidepressive and antiparkinsonian effects. This action could also account for psychomotor agitation and amplification of psychosis (very rarely noted in clinical use). Mode of action: Peripheral • Antagonist to H1 receptors (antiallergic effects), H2 receptors (reduction of forming of gastric juice), M1/M2receptors (dry mouth, reduction in forming of gastric juice) and some 5-HT receptors (different antiallergic/gastrointestinal actions). • Because it acts on so many receptors, chlorpromazine is often referred to as a "dirty drug" Side effects: As above (antipsychotics) Hypnotics and their reversal agents

The pharmacological action of temazepam is thought to be the result of its facilitating the action of gamma aminobutyric acid (GABA), an inhibitor neurotransmitter.

Diazepam is a benzodiazepine that binds to a specific subunit on the GABAA receptor at a site that is distinct from the endogenous GABA molecule.[5][6]The GABAA receptor is an inhibitory channel which, when activated, decreases neurologic activity. Due to the role of diazepam as a positive allosteric modulator of GABA, when it binds to benzodiazepine receptors it causes inhibitory effects. This arises from the hyperpolarization of the postsynaptic membrane, due to the control exerted over negative chloride ions by GABAA receptors.[5][7] Diazepam appears to act on areas of the limbic system, thalamus and hypothalamus, inducing anxiolytic effects. Its actions are due to the enhancement of GABA activity.[2][5]

Mood Stabilisers

Carbamazepine (Tegretol) by Ali Black Voltage gated Na+ channels enable neurons to generate action potentials. After these channels open to start the action potential, they inactivate, essentially closing the channel. Carbamazepine stabilizes the inactivated state of sodium channels, meaning that fewer channels are available to open, making brain cells less excitable. A tricyclic-related compound, carbamazepine has a moderate anticholinergic action which is responsible for some of its adverse effects. A tolerance may develop to the action of carbamazepine after a few months Indications: (see also: epilepsy drugs) • Prophylaxis mania in manic depression where unresponsive to Lithium (may be used alone or with Lithium) • Treatment rapid cycling (>4 /yr) manic depression • Trigeminal neuralgia Dose: Prophylaxis of bipolar disorder: initially 100 mg daily in divided doses increased until symptoms controlled; usual range 400–600 mg daily; max. 1.6 g daily Serum levels: Aim for serum levels of 2-10mg/l: MEASURE until established dose, then monitor. Side effects: • NEURO: Drowsiness (start at low dose & gradually increase), dizzy, ataxia, confusion, agitation, nystagmus, diplopia • SKIN: stevens-Johnson (erythema multiforme; very severe), rash • GI: anorexia and constipation, nausea, hepatotoxicity • OTHER: water intoxication - this can occur with high plasma levels and may cause hyponatraemia, confusion and exacerbation of seizures (when treating epilepsy).

CAUTIONS: Pregnancy / breast-feeding: weigh up potential harm: benefit ratio • May be teratogenic!!! Spina bifida association. • Carbamazepine passes into breast milk in concentrations of about 25 to 60% of the plasma level. Affects of this have not been studied. Use with caution. Other contra-indications: • Previous bone marrow depression • hypersensitivity to the drug, or known sensitivity to any of the tricyclic compounds • Recent (14 days) monoamine oxidase inhibitors use • APLASTIC ANEMIA AND AGRANULOCYTOSIS HAVE BEEN REPORTED but are very rare. Routinely check FBC Long-term toxicity studies in rats indicated a potential carcinogenic risk Lithium Carbonate (Camcolit, Priadel) by Ali Black Indications: Treatment and prophylaxis of mania. Can be used with Carbamazepine. Agression, self-harm, recurrent depression. Mechanism: Unclear. Probably increases serotonin transmission. Current hypotheses include the interference with the phosphoinositide signalling pathway by either reducing the synthesis of second messengers involved in the pathway or inhibiting inositol monophosphatase activities; its neuroprotection against excitotoxicity caused by glutamate hyperactivity; the suppression of intracellular calcium mobilization; its stimulatory effect on ATPdependent dopamine uptake; its regulation of gene expression in long-term treatment; and the selective effect in G-protein subunit expressions in brain cells. Levels Required

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Adjust to serum conc. to 0.4-1.0 mmol/l Measure 12 hours post dose Measure days 4-7 of first week treatment Weekly till levelshave been acceptable and constant for 4 weeks 3 monthly thereafter.

Also check thyroid function (can cause hypothyroidism but impairing thyroxine release). May require thyroxine