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)

Ali Black Ali Black Ali Black Ali Black Alan McLeod Alan McLeod Alan McLeod Alan McLeod Alan McLeod Alan McLeod Alan McLeod Alan McLeod Alan McLeod Alan McLeod -

Ali Black Ali Black

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 = <4 Mild = 4 Moderate = 5-6 Severe = 7 or more Severe with psychotic symptoms Symptoms should be present for a month or more, for most of the day. Consider whether it is: 1st presentation

Recurrent depression Treatment resistant depression. See NICE guidelines: www.nice.org.uk/page.aspx?o=cg023niceguideline SSRIs E.g Fluoxetine (Prozac) Sertraline Selective seratonin re-uptake inhibitors. Fluoxetine Indications: Can be used in under 18s (the only SSRI that can) 1st line for depressive illness, 20mg to start, increase at 3 week intervals by 20mg to max 60mg OCD, 20mg to start, increase at 2 week intervals to max 60mg OD Bulimia nervosa, 60mg OD, can increase to 80mg Sertraline Indications: depressive illness, PTSD in women, OCD Contra-indications of all SSRIs: Manic phase, MAOIs within 2 weeks (dangerous seratonin reaction: CVS collapse, muscle rigidity, hyperthermia) Simultaneous TCA use (inhibits TCA hepatic metabolism) Side effects of SSRIs: less sedative, fewer antimuscarinic and cardiotoxic than TCAs GI: nausea and vomiting, dyspepsia, diarrhoea, constipation, appetite change Skin: rash, photosensitivity Insomnia Headache Dry mouth Loss libido, anorgasmia Venlafaxine by Ali Black SNRI (seratonin and noradrenaline reuptake inhibitor) Potent inhibitors of neuronal serotonin and noradrenaline reuptake and weak inhibitors of dopamine reuptake. Venlafaxine has less affinity for muscarinic, histaminergic, and alpha1-adrenergic receptors in vitro than other psychiatric drugs. This may explain lesser side effect profile seen with Venlafaxine, compared to the various anticholinergic, sedative, and cardiovascular effects seen with other psychotropic drugs. Indications: Severe depressive illness/treatment resistant Generalised anxiety disorder Dose: Depression, initially 75mg in 2 divided doses, then 150mg after 2-3 weeks in divided dose. If in hospital & very severe, may start 150mg, up to 375mg, then gradually reduce. Not for under 18 yrs age. GAD, 75mg divided, daily. Contra-indications: Breast feeding

Pregnancy Hepatic impairment Renal impairment Hypertension Cardiac disease Warnings: Careful monitoring of BP as may cause hypertension ECG prior to commencement

Common s/e: nausea and vomiting diarrhoea, headache, insomnia, agitation, abnormal ejaculation/orgasm and impotence in men cardiotoxicity Interactions: MAOI (within 2 weeks), CBZ, Phenytoin, benzos, Li, ?Warfarin

NICE Guidelines: Baseline ECG and BP, plus regular BP monitoring Use only by secondary care specialists, or GP with mental health special interest. Not used as 1st line in depression, more for treatment resistant Amitriptyline by Ali Black Tricyclic antidepressant TCAs competitively block neuronal re-uptake of noradrenaline and/or seratonin into the presynaptic neurone, increasing the longevity of transmitter in the synapse. Eventually there is down-regulation of receptors in the brain. Amitriptyline indications and dosage: Depression, initially 75mg as divided dose, or in one dose nocte. Increase gradually to 150-200mg. Do not use for depression in under 16yrs age. Especially useful where there is insomnia, due to sedative effects. Bedwetting in children, 7-10yrs 10-20mg nocte, 11-16yrs 25-50mg nocte, max 3 months. Gradual withdrawal. Neuropathic pain (.g. phantom limb, postherpetic neuralgia, peripheral neuopathy, TMJ joint pain etc) initially 10-25mg nocte, max 75mg. Contra-indications: Recent MI Arrhythmias (especially heart block) Severe liver disease Drowsiness (give at night, avoid driving, machinery etc) Anticholinergic: dry mouth, constipation, blurred vision Poor concentration (drowsiness) Postural hypotension and syncope ECG changes and arhhythmia Confusion (esp. elderly) Agranulocytosis Movement disorder Testicular enlargement, gynaecomastia, galactorrhoea Abnormal LFT & jaundice

Side effects (many):

Interference sexual function Increased appetite and weight gain Therepeutic effect takes 3 weeks approx. Suicide by OD is a high risk as motivation improves, but mood may still be low- careful monitoring advised, and prescribe few tablets at a time. Drowsiness may be dangerous depending on job, e.g long distance driving. Tricyclic Overdose Management Symptoms and signs: Arrhthymia Coma Hypotension Hypothermia Hyper-reflexia & upgoing plantars Respiratory failure Convulsions Pupil dilation Metabolic acidosis Delirium and confusion Agitation Urinary retention ITU if severe Supportive: ventilation to correct hypoxia Activated charcoal IV diazepam if convulsing, oral if agitation only

Management:

Antiarrhythmics not used: treating acidosis and hypoxia should correct. Phenelzine by Ali Black Monoamine Oxidase Inhibitor Monoamine oxidase acts in the synapses, and breaks down noradrenaline and seratonin. Thus MAO inhibitors increase noradrenaline and seratonin levels. MAOIS are irreversible, non-competitive antagonists of monoamine oxidase (MAO) type A, in the brain, peripheral neurones, enterocytes of the gut, and platelets. Indications: Rarely used now due to s/e, and newer better drugs, but indicated in: Failure of other antidepressants Phobic states Agitated depression Side effects: due to widespread enzyme inhibition: Postural hypotension Headache Anticholinergic s/e Drug-induced hepatitis (esp. phenelzine) Hypertensive crisis Problems: Diet restriction Affects continue 2-3 weeks after stopping drug: this is because it takes this long to synthesise new MAO.

Hypertensive crisis: Following ingestion of amine-containing foods and drinks and drugs, MAO normally metabolises tyramine to harmless products during absorption. When MAOIs are used, Tyramine is taken up by peripheral sympathetic nerve endings, where it displaces stored endogenous noradrenaline (sympathomimetic effect: stimulates the sympathetic system) hypertension, tachycardia and headache. If severe, may cause CVA. AVOID cheese, meat, yeast, red wine. There are new reversible MAOIs which may be of more use as they are safer (moclobomide). Antipsychotics Drug Risperidone Risperdal Dose 4-16 mg daily As low as 1 or 2 may be useful Side effects Hyperglycaemia Possible diabetes Increased risk of stroke in the elderly Insomnia, agitation, drowsiness Increased risk of stroke in the elderly Drowsiness Speech difficulties Drowsiness Anxiety Notes May soon be recategorised as a typical. typical side effect profile seen with increasing doses esp over 6 mg. Not licensed for acute psychoses Also for mania different dose

Olanzapine Zyprexa Quetipine Seroquil

5-20 mg daily

Flupentixol

25 mg bds day 1 50 mg bds day 2 100 mg bds day 3 150 mg bds day 4 Max 750 mg daily 3-9 mg bd Max 18 mg daily 20-40 mg every 2-4 weeks depot* 1-3 mg bds/tds 5-5 mg bds/tds in resistant symptoms up to max of 30 50-300 mg every 4 weeks as depot*

Less sedating. More extrapyramidal.

Haloperidol

Less sedating. Fewer antimuscarinic or hypotensive symptoms. More extrapyramidal.

Esp with withdrawal & apathy; not mania. Less sedative. Extrapyramidal sympt. more common. Most effective drug for positive symptoms. Also for motor tics and hiccups.

*Depot agents are administered by deep intramuscular injection. They may be used in patients who are poorly compliant but may give rise to a higher incidence of extrapyramidal side effects than with oral medication this occurs less with an atypical depot such as risperidone. Extrapyramidal side effects (mnemonic ADAPT) Effect Seen in Description Acute Dystonia Days Abnormal face and body movements, most common in children and young adults. Akathisia Weeks Restlessness, with limbs in constant movement. May be concealed by activity such as walking. Very poorly tolerated by patients. May be suppressed by antimuscarinic drugs Rhythmic, involuntary movements of tongue, face and jaw.

Parkinsonism Tardive

Weeks Years

dyskinesia

May decrease upon drug cessation but may not very socially disabling. Dry mouth Antimuscarinic Effects Blurred vision Constipation Urinary retention

Drowsiness

General cautions for Antipsychotics Elderly, Hepatic impairment Renal impairment Cardiovascular disease, Parkinsons disease (may be exacerbated by antipsychotics), Epilepsy (and conditions predisposing to epilepsy), Depression, Myasthenia gravis, Prostatic hypertrophy, Susceptibility to angle-closure glaucoma. Severe respiratory disease Patients with a history of jaundice or who have blood dyscrasias

General contraindications Comatose states, CNS depression Phaeochromocytoma. Most antipsychotics are best avoided during pregnancy, unless essential. It is advisable to discontinue breastfeeding during treatment

Risperidone by Alan McLeod Indications: Psychoses: 2 mg in 12 divided doses on first day then 4 mg in 12 divided doses on second day (slower titration appropriate in some patients); usual dose range 46 mg daily; doses above 10 mg daily only if benefit considered to outweigh risk (max. 16 mg daily); Mania, initially 2 mg once daily, increased if necessary in steps of 1 mg daily; usual dose range 16 mg daily; Mode of operation: D2 receptor dopamine antagonist Also blocks 5-HT receptors Side effects: Weight gain Extrapyramidal s/e at high doses (>6 mg) 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 Cautions: Use with caution in: Elderly: assess CVS risk factors Hepatic impairment Renal impairment Pregnancy History of epilepsy CVS disease Obesity Parkinsons

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

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: By mouth, initially 1.53 mg 23 times daily or 35 mg 23 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 510 mg daily); - Psychomotor agitation By intramuscular or by intravenous injection, initially 210 mg, - Excitement then every 48 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, 0.52 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 75300 mg daily (but up to 1 g daily may be required in psychoses); By intramuscular or by intravenous injection, 2550 mg every 68 hours; By rectum in suppositories as chlorpromazine base 100 mg every 68 hours [unlicensed]

Intractable hiccup: by mouth, 2550 mg 34 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 pseudoparkinsonismcontroversial) 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/M2-receptors (dry mouth, reduction in forming of gastric juice) and some 5-HT receptors (different anti-allergic/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 400600 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 ATP-dependent 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

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