the monoamine hypothesis of gene expression - deficiency in molecular functioning hypothesised problem within the molecular events distal to

the receptor.

Monamine oxidase inhibitors With additonal actions(TCAs) Pure(SNRIs)

Non- selective noradrenalin and serotonin Noradrenaline (NARIs)

Serotonin( SSRIs)

Selective noradrenaline or serotonin Monoamine uptake inhibiotrs Other drugs

(e.g. mirtazepine) Antidepressants

Theory 4 – “neurokinin hypothesis of emotional dysfunction”. Observation that substance P – an antagonist to neurokinins may have an antidepressant action

Selective serotonin reuptake inhibitors – First line nowadays due to improved safety profile

First line treatment for moderate to severe depression Fluoxetine, citalopram, paroxetine

Citalopram most selective, paroxetine most potent may interact with extrapyramidal dopaminergic system.

PK - almost completely absorbed from gut. Long elimination T1/2 metabolised in liver.

Side effects and toxicity

-Common – anorexia, nausea, diarrhoea

Rare – precipitation mania, ↑ suicidal ideation and neurological SE such as tremor, extrapyramidal syndromes

NB – safe in overdose if taken on own Tricyclic antidepressants

First generation antidepressants. Still used amitryptiline, imipramine, clomipramine

Block re-uptake of serotonin, NA Other effects

1. Inhibition of NA uptake, enhancing NA Neurotransmission (sympathomimetic effect)

2. Muscarinic cholinoceptor blockade – ↓cholinergic neurotransmission (anticholinergic effect)

3. Alpha 1- adrenoceptor blockade – suppression of NA neurotransmission (sympatholytic effect)

PK – lipid soluble, absorbed from gut, long half lives, metabolised in liver

SE and toxicity = CNS – sedation and impairment of psychomotor performance, lowering of seizure threshold. ANS, reduction in glandular secretions, eye

accommodation block.

CVS – tachycardia, postural hypotension, impaired myocardial contractility GI – constipation

Overdose

‘PURE’ non-selective monoamine uptake inhibitors

Developed as SSRIS with property of NA uptake inhibition grafted on. E.g.

venlafaxine a second line drug. Dose dependent – lower doses serotonin action, higher doses NA

SE and toxicity- as with SSRIs, also sleep disturbance, ↑BP, dry mouth,

hyponatraemia, relatively short T1/2 therefore may be a withdrawal syndrome on discontinuation

Schizophrenia – Psychosis

Schizophrenia is an example of a mental illness with psychotic symptoms. 1% of UK population

Other illnesses are mania, psychotic depression, and organic syndromes Symptoms of schizophrenia

• Positive symptoms: hallucinations, delusions, thought disorders, abnormal behaviour

• Negative symptoms – blunted affect, social withdrawal, poverty of thought and speech

• Cognitive symptoms – selective attention, poor memory reduced abstract thought

• Affective symptoms – anxiety and depression

Schizophrenia – its symptoms are numerous, its presentations are diverse, its cause is unknown and its response to treatment is unsatisfactory

Genetic (strong familial component) + biological (e.g. maternal gestational hypertension) + upbringing schizophrenia 

Dopamine theory of schizophrenia

Amphetamine causes symptoms very similar to positive symptoms of

schizophrenia. Dopamine antagonists are the best treatment for schizophrenia.

Some evidence of ↑ dopamine function in schizophrenics

But amphetamine does not cause negative symptoms. Dopamine antagonists do not treat negative symptoms; changes in dopamine function may be a response to long term drug treatment

Main dopamine pathways

• Mesolimbic – important in emotional response and behaviour, and connect to the hippocampal and amygdala areas.

• Meso-cortical – important in arousal and mood

• Nigrostriatal – 75% of brain dopaminergic pathways. Neurones span from the substantia nigra to the corpus striatum and is the key pathway

damaged in Parkinson’s disease. Dopamine antagonism can thus induce

‘extra-pyramidal’ movement disorders and are relevant to SE of anti-psychotic drugs key pathway damaged in Parkinson’s disease

• Tuber-hypophyseal in hypothalamus and pituitary gland

Is schizophrenia associated with ↑ 5HT FUNCTION?

5HT has been implicated in a number of behaviours which are disturbed in schizophrenia (e.g. perception, attention, mood, aggression, sexual drive, appetite, motor behaviour, sleep)

Many of the most effective antipsychotic drugs are antagonists at 5HT-2A receptors

Lysergic acid diethylamine (LSD), a 5HT-2A agonist is psychotogenic. Precursors of 5HT exacerbate schizophrenia. Chronic Fluoxetine (Prozac) ↑ 5HT activity and

↑ both +ve & –ve symptoms

BUT LSD produces mainly visual hallucinations: other psychotic symptoms (conceptual disorganisation and cognitive impairments) are generally absent No strong evidence for changes in 5HT function

Is schizophrenia associated with ↓ cortical glutamate function?

Glutamate is the predominant excitatory NT in the brain

Phencyclidine (PCP: non-competitive antagonist at NMDA-type glutamate receptors) induces symptoms very similar to schizophrenia

Post mortem studies have shown:

• ↑ cortical glutamate receptors

• ↑ binding of glutamate receptor ligands in cortex, basal ganglia and hippocampal formation

• BUT both ↑ and ↓ in glutamate binding in temporal lobe have been reported

• Glutamate systems are important, mechanism unclear DRUGS

First generation typical antipsychotics haloperidol, chlorpromazine (increased  dopamine antagonism)

Atypical antipsychotics olanzapine, risperidone, quetiapine, Clozapine (most  effective but serious ADRs)

Action of all antipsychotics

• Sedation – within hours

• Tranquilisation – within hours

• Antipsychotic – several days or weeks

• Activating effect within weeks – negative symptoms

• Production of extrapyramidal side effects – hours or days advantage of atypical

Atypical advantages

Less SE so more acceptable to patient, different preparations e.g. dissolvable some once daily dosage. Differing SE profiles can be matched to patient characteristics, 1st line treatment in schizophrenia

Typical antipsychotics

Haloperidol safe in emergencies, more sedating, well known SE

Wide range of pharmacological action, DA receptor blockade, anticholinergic effects, α-adrenergic blockade, antihistamine effect, allergic reactions

SE – extrapyramidal SE – Parkinsonism, acute dystonia, akathisia (inner restlessness), tardive dyskinesia

Neuroleptic malignant syndrome - severe rigidity, hyperthermia, ↑ CPK,  autonomic lability

Postural hypotension, weight gain, endocrine changes e.g prolactinaemia, pigmentation

Toxicity – CNS depression, cardiac toxicity, risk of sudden death with high dose Anxiety

Fears out of proportion to situation avoidance fear of dying, going crazy  Physical symptoms – light headedness, SOB, hot and cold flushes, palpitations, numbness

Treatment – non-pharmacological approaches first line. Treat any coexistent disorder

Drugs – antidepressants, anxiolytics, occasionally antipsychotics

Principle NT systems – GABA, 5-HT, NA, many of drugs prescribed however have very specific pharmacological effects

Benzodiazepines e.g. diazepam, lorazepam

Exerts effects through structure known as GABA-BDZ receptor complex. BDZ only bind to BDZ receptor of which there are 2 main groups – high and low affinity High affinity group – important in anxiolytic, hypnotic and anticonvulsant effects of BDZ. Inhibitory effects in brain

They act as full agonist at these receptor sites, lead to enhancement of GABA. BA following oral admin – almost complete-maximum concentration 30-90 mins, highly lipid soluble – CNS diffusion rapid. Renal excretion, long t1/2

Tolerance can occur; dependence-on discontinuation of Rx can get withdrawal effects such as insomnia, agitation, anxiety

SE –

• Common – drowsiness, dizziness, psychomotor impairment

• Occasional – dry mouth, blurred vision, GI upset, ataxia, headache, ↓BP

• Rare – amnesia, restlessness, skin rash

Toxicity – cleft lip and palate if used in pregnancy. If taken late in pregnancy may cause resp depression and feeding difficulties in baby

Treatment of overdose – deaths are rare – support

Flumazenil and antagonist/partial inverse agonist at BDZ receptors may be useful in reversing effects

Bipolar disorder Depression and hypomania/mania

Feeling unusually excited, happy, optimistic or feeling irritable

Overactive – poor concentration and short attention span, poor sleep, rapid speech, jump from one idea to another, poor judgement, ↑interest in sex Psychotic symptoms – hallucinations, grandiose delusions

Mood stabilisers – Lithium, sodium valproate, carbamazepine, olanzapine Lithium

Theories

1. Electrolytes and channels – may compete with Mg and Ca ions 2. NT – acute Li ↑5HT, chronic Li may ↓5-HT receptor sites

3. Second messenger systems – Li attenuates the effects of certain NT on their receptors without altering receptor density

Clinical pharmacology – renal excretion, slow release preparations can be given once daily. Li levels need to be monitored (at least 3 monthly) and taken 12 hours after last oral dose. Need to check renal function and thyroid function before starting

Side effects:

• Memory problems – 52%

• Thirst – 42%

• Polyuria – 38%

• Tremor – 34%

• Drowsiness – 24%

• Weight gain – 18%

Other effects – kidneys, hypothyroidism, hair loss, rashes

Toxic effects – need to monitor V&D, coarse tremor, Dysarthria, cognitive  impairment, restlessness, agitation

Rx of toxicity – supportive measure, anticonvulsants, ↑fluid intake, haemodialysis may be necessary

In document Clinical Pharmacology for LUSUMA Notes (Page 98-103)