11 Anxiolytics and antidepressants Flashcards
Anxiolytics and antidepressants
Physiology
Organisation of the brain
Chemical messengers
- the monoamine transmitters - GABA - the most common inhibitory transmitter
Sleep and arousal
Anxiolytics and antidepressants Pharmacology
Antidepressants = MAOIs
= tricylic drugs
= SSRIs
= lithium
Anxiolytics = sedative-hypnotics
= benzodiazepines
= Second generation non- benzodiazepines
Antipsychotics = neuroleptics
= atypical drugs
The limbic system: brain regions involved in mood
An ascending arousal system modulates activity throughout the brain. Different types of messenger (known as transmitter) are produced by nerve cells (known as neurones). Groups of neurones are grouped together in clusters, called nuclei, throughout the brainstem.
Our moods and emotions are controlled by a loose grouping of different regions of the brain, which collectively are often known as the limbic system.
The hypothalamus maintains homeostasis and motivational drives
The amygdala recognises and responds to emotions.
The hippocampusallows long-term storage of experiences and memory.
The nucleus accumbens is involved in reward and pleasure.
The cingulate cortex registers pleasant and painful stimuli. It is also involved in aggression.
The prefrontal cortex deals with decision making and the expression of mood.
Synaptic transmission
The connections between neurones are called synapses.
Neurotransmitters are stored in vesicles within the terminal of the presynaptic neurone.
With the arrival of a nerve impulse, the vesicles bind to the membrane and release their transmitters, which travel across the synaptic cleft. The transmitter binds to selective receptors on the postsynaptic neurone, but can also have an autoregulatory action through presynaptic receptors.
Transmission by monoamines is curtailed by uptake by specific transporters. The monoamines tend to be re-packaged in vesicles, or may be broken down. For example, the enzyme monoamine oxidase, which breaks down monoamines, is found on the membrane of mitochondria.
Serotonergic pathways in the rat brain
Most serotonin in the body is found in mast cells and platelets in the blood.
Serotonin neurones and pathways were first visualised in the rat brain by Dahlström and Fuxe in the 1960s.
They described nine main clusters or nuclei of cells, denoted B1 to B9, which lie in or near the midline of the brainstem. These are sometimes called the raphé nuclei.
The axons of individual serotonergic neurones can split to give rise to collateral projections to functionally related target in the brain.
Serotonin immunostaining in the midline raphé
Immunofluorescent histochemical staining for serotonin in a coronal section of the rat midbrain showing serotonergic neurones in one of the midline raphé nuclei. Right-hand panel, higher magnification of a single neurone. The chemical name for serotonin is 5-hydoxytryptamine (5-HT).
Structure of 5-hydroxytryptamine
Serotonin (5-hydroxytryptamine, 5-HT), noradrenaline and dopamine are called monoamine transmitters because they are derived from amino acids. 5-HT is a derivative of the amino acid, tryptophan, found in our diet.
Synthesis and metabolism
The first step in synthesis of 5-HT is the hydroxylation of tryptophan to form 5-hydroxytryptophan. The enzyme responsible for this is tryptophan hydroxylase. Once synthesised, 5-hydroxytryptophan is immediately decarboxylated to yield the active transmitter 5-hydroxytryptamine or serotonin. The enzyme responsible for this conversion is aromatic amino acid decarboxylase.
5-HT can be inactivated by the enzyme called monoamine oxidase.
Putative structure of the rat serotonin transporter (SERT)
The serotonin reuptake transporter is a member of a large family comprised of other monoamine transporters. This is a schematic diagram showing the amino acid structure of the serotonin transporter. The amino acids in the transmembrane domains are similar to those in the noradrenaline and dopamine reuptake transporters. The serotonin reuptake transporter takes serotonin out of the synaptic cleft and back into the presynaptic terminal to end its “transmission.” The serotonin can be re-packaged in vesicles and used again.
Some drugs act by inhibiting reuptake transporters, which means the transmitter stay in the synaptic cleft and have a prolonged actions. Cocaine is a non-selective inhibitor of monoamine transporters.
SERT inhibitors
Tricyclic antidepressants (also affect NA reuptake):
Desipramine
Imipramine
Selective serotonin-reuptake inhibitors:
Sertraline
Citalopram
Fluoxetine (Prozac)
SERT inhibitors/5-HT releasers:
Fenfluramine
Methylenedioxymethamphetamine (MDMA, “E”)
The classic tricyclic antidepressant drugs inhibit both serotonin and noradrenaline reuptake into nerve terminals. Later antidepressants were designed to be more selective inhibitors of serotonin reuptake.
Their action of these drugs is to maintain higher levels of monoamines in the synaptic cleft.
The transporters can sometimes function in the opposite direction to release transmitters from the terminal. Fenfluramine and MDMA act on the serotonin transporter and not only inhibit the transport of serotonin into the cell but also facilitate its outward transport.
Seven transmembrane, G protein-coupled receptors
The seven trans-membrane spanning, G protein-coupled receptors are superfamily of receptors. They have an external amino terminal which contains the ligand binding site, and an internal carboxy terminal linked to GTP-binding proteins. When the receptor is activated by 5-HT, the G-proteins bind GTP which causes dissociation of the α subunit, which can then activate different intracellular messenger systems.
Receptor families
Decrease cAMP - 5-HT1A 5-HT1B 5-HT1D 5-HT1E 5-HT1F
Increase cAMP 5-HT4 5-HT6 5-HT7 5-HT5A 5-HT5B
Increase inositol phosphates and calcium 5-HT2A 5-HT2B 5-HT2C
Ligand-gated ionic channel
5-HT3
The metabotropic receptors are linked via G proteins to intracellular pathways that involve either adenylate cyclase (and the production of cAMP) or phospholipase C (to increase inositol phosphates and calcium).
The exception is the 5-HT3 receptor, which is a ligand-gated ion channel.
Ligand-gated 5-HT receptor
The ligand-gated family of channels includes the NMDA glutamate receptors and GABAA receptors. Rather than being called metabotropic, these are ionotropic receptors. The 5-HT3 receptor forms a channel which is non-selective for positively-charged ions (e.g. Na+, Ca2+ and K+).
Dopamine deficiency
in Parkinson’s disease
Dopamine and noradrenaline are catecholamines, that are both derived from the amino acid tyrosine, rather than tryptophan. Parkinson’s Disease is caused by the loss of dopamine from neurones in the substantia nigra of the midbrain.
Mesocorticolimbic and nigro-striatal dopamine systems
The substantia nigra projects to parts of the brain, the basal ganglia and dorsal striatum, involved in voluntary movement. However, there is another group of dopaminergic neurones in the ventral tegmental area that give rise to the mesocorticolimbic system. These are the dopaminergic neurones which are involved in mood, reward, etc.
The synthesis of catecholamines
The rate limiting step in catecholamine synthesis is the hydration of tyrosine to L-3,4-dihydroxyphenylalanine (L-DOPA), by the enzyme tyrosine hydroxylase. L-DOPA is then decarboxylated to dopamine the same enzyme that produces serotonin from 5-hydroxytryptophan, though it is often referred to as dopa decarboxylase. In some neurones, dopamine is further processed by dopamine β-hydroxylase to make noradrenaline. In other neurones and in the adrenal medulla it is further modified to produce adrenaline.
The degradation of dopamine
Transmission by dopamine, like the other monoamines, is terminated by reuptake via the dopamine transporter. Dopamine that is not broken down by enzymes is repackaged into vesicles for reuse. If not, enzymatic breakdown is produced by monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT).
Monoamine oxidase is not selective and will break down all the monoamine transmitters.
Dopamine receptors
Dopamine receptors mediate all known pharmacological actions of dopamine
Classic seven transmembrane domain, G protein-coupled receptors
Fall into two major groups D1-like (increase cAMP) and D2-like (decrease cAMP)
D1 and D5 like D1
D2, D3 and D4 like D2
The D1 and D5 receptors are members of the D1-like family of dopamine receptors. Activation of D1-like family receptors is coupled to adenylate cyclase which increases intracellular concentrations of cAMP. The D2, D3 and D4 receptors are members of the D2-like family. D2-like receptors are coupled to phosphodiesterase activity. Phosphodiesterases break down cAMP, producing an inhibitory effect in neurones, and thus the two receptor families tend to have opposing functional effects.
The ascending noradrenergic system
Noradrenergic neurones exert effects on large areas of the brain to cause alertness and arousal, and to influence the reward system. Anatomically, the noradrenergic neurons of the ascending arousal system originate both in the locus coeruleus and the adjacent lateral tegmental field.
Adrenergic receptors
Adrenalin/noradrenaline
a1 phospholipase
a2 adenylatecyclase
B adenylatecyclase
Adrenergic receptors bind both adrenaline and noradrenaline, but α receptors have a higher affinity for noradrenaline. α1-adrenergic receptors are linked to phospholipase C and α2-adrenergic receptors block adenylate cyclase. β receptors are linked positively to adenylate cyclase.
Summary of monoamine transmitter systems
Monoamine neurones are located in discrete nuclei
within the brainstem and midbrain
The neurones project widely throughout the forebrain
They affect broad functional states, such as arousal
and mood
Drugs that alter levels of monoamines are likely to
have profound effects on behaviour
Mood disorders
Major (unipolar) depression Bipolar disorder (manic-depressive illness)
Depression has a triad of symptoms:
low or depressed mood (dysphoria)
anhedonia
low energy or fatigue
Symptoms of mania:
elation
talkativeness, creativity
fullness of energy and confidence
Major (unipolar) depression is a diagnostic category within the mood disorders.
Bipolar disorder – previously known as manic-depressive illness.
Depression is characterised by a triad of symptoms. There is a strong incidence of co-morbidity between depression and anxiety.
It has a consistently high prevalence worldwide, calculated as being between 10% and 20% of the population of most countries.
Mania can lead to creativity and impulsiveness. The incidence is approximately 1%.
Concordance rates for different mood disorders
If an identical (monozygotic) twin has a mood disorder, the likelihood of its identical twin having the same trait is 65%. This is called the concordance rate. The concordance rate for a non-identical fraternal (dizygotic) twin is 20%, and the difference between the two rates is an indication of the extent to which genetics contributes to the disorder. This shows that there is a strong genetic component. If genetics was the only determining factor, the concordance rate for identical twins would be 100%. This shows the importance also of environmental factors in the development of mood disorders, such as depression.
General adaptation syndrome: “fight or flight”
Stress causes the hypothalamus to produce corticotropin-releasing hormone (CRH).
CRH activates the sympathetic nervous system (SNS) and acts as a signal to the pituitary gland to produce adrenocorticotrophic hormone (ACTH), which in turn signals the adrenal gland to secrete cortisol.
These cause the physiological changes necessary for a heightened response to stress.
Cortisol also feeds back on glucocorticoid receptors in the hypothalamus and hippocampus.
Fearful or threatening events are perceived by the amygdala, which initiates the “fight-or-flight response”.
The amygdala drives the hypothalamus to produce the messenger corticotrophin-releasing hormone. CRH activates the sympathetic nervous system (SNS) which is mostly responsible for the release of adrenaline, and increased heart rate and blood pressure. CRH also acts as a signal to the pituitary gland to produce adrenocorticotrophic hormone (ACTH), which in turn signals the adrenal gland to secrete cortisol.
Sympathetic activation and cortisol release cause the physiological changes necessary for a heightened response to stress.
Normally a feedback mechanism inhibits further activation of the hypothalamo-pituitary-adrenal axis.
Depressed patients have an overactive HPA axis
Patients with depression have abnormally high cortisol levels and a dampening of the normal diurnal rhythm. The cortisol feedback on glucocorticoid receptors in the hypothalamus and hippocampus becomes ineffective, so that the HPA axis is not turned off. In this situation, the synthetic glucocorticoid, dexamethasone, fails to suppress cortisol secretion.
Depression involves over- and under-activity in the brain
Depression is characterised by over-activity in some areas of the brain, such as in the amygdala and hypothalamus, and under-activity in other areas, such as the hippocampus, nucleus accumbens and prefrontal cortex.
Treatments for depression
Counselling
Psychotherapy
e.g. cognitive-behavioural
or interpersonal modes
Monoamine oxidase inhibitors Tricyclic drugs Selective serotonin reuptake inhibitors Third generation antidepressants Mood stabilisers
Electroconvulsive therapy (ECT)
Patients with sub-threshold symptoms of depression should be offered counselling. Psychoanalysis has never been proven scientifically. However, very structured types of psychosocial intervention, such as cognitive behavioural therapy or interpersonal therapy can be used in mild cases of depression.
The first antidepressant drugs were discovered by accident. It became apparent that these drugs affect levels of monoamines in the brain. Thus, the monoamine hypothesis of depression postulates that depression is caused by a deficiency or imbalance of noradrenaline and/or serotonin.
Short electroconvulsive shock therapy every two days for a period of a couple weeks is the most clinically effective treatment for severe, life-threatening depression.
Monoamine oxidase inhibitors
Drug name - Phenelzine
Trade name - Nardil Treatment of depression and bipolar disorder
Drug name - Tranylcypromine Trade name - Parnate Treatment of severe depression
Monoamine oxidase inhibitors (MAOIs) are non-selective blockers of the metabolism of all monoamines.
They are still used commonly for severe depression in patients who have failed to respond to other treatments, but are often thought of as a last line for pharmacological intervention.
MAOIs: adverse effects
Hypertensive crisis, especially due to interactions with
other drugs which produce increases in blood pressure.
Foods high in tyramine. “Cheese effect.”
Inhibition of cytochrome P450.
Tryptophan supplements or other psychoactive drugs should be
avoided or there is risk of “serotonin syndrome.”
Other adverse effects include weight gain, oedema, sexual
dysfunction and sedation.
Contraindications: impaired renal or hepatic function,
hypertension. Pregnant or lactating women.
MAOIs inhibit noradrenaline breakdown in the peripheral sympathetic system; they can increase blood pressure, and therefore they should never be prescribed with other drugs that can have the same effect.
MAO in the liver deaminates tyramine; elevated tyramine levels release the higher-than-normal stores of noradrenaline at nerve endings, causing a dramatic increase in blood pressure (often known as the “cheese effect” as cheese is a major source). Tryptophan supplements or drugs that enhance serotonin, e.g. SSRIs, should be avoided or there is danger of “serotonin syndrome.” Care needs to be taken if swapping drug treatments.
MAOIs also inhibit other liver enzymes such as cytochrome P450 which normally degrades other drugs.
An adverse effect of many antidepressants is weight gain.
Tricyclic antidepressants
Drug - Imipramine
Trade - Tofranil
Treatment of depression
Drug - Amitriptyline
Trade - Elavil
Treatment of depression
Drug - Doxepin
Trade - Sinequan
Treatment of depression and anxiety
Tricyclic antidepressants are most useful for treating major depressive episodes, though they can be prescribed for panic disorder and for obsessive-compulsive behaviour.
They work by non-selectively blocking the reuptake of noradrenaline and serotonin, leading to increase in the availability of these transmitters at their respective receptors.
Tricyclic antidepressants: adverse effects
Weight gain, sexual dysfunction, inhibition of cytochrome P450.
Adrenergic effects. Contraindicated for patients with myocardial infarction, with coronary artery disease or any coronary instability.
Antihistaminergic effects. Sedation. Avoid other CNS depressants or anti-histamines, e.g. cimetidine
Anticholinergic effects. Dry mouth, blurred vision, dizziness,
headache and constipation
Some side effects are similar to those seen with MAOIs.
Due to the adrenergic side effects, TCAs are contraindicated for patients with cardiovascular problems.
Anti-histaminergic effects can cause sedation. Patients should be monitored for suicidal thoughts or behaviour.
Anti-cholinergic effects are due to inhibition of muscarinic receptors in the parasympathetic nervous system.
The delay to effectiveness, along with the anti-cholinergic side effects, means there is a problem with patient compliance to take TCAs.
Selective serotonin-reuptake inhibitors
Drug - Fluoxetine
Trade - Prozac Treatment of depression and
obsessive-compulsive disorder
Drug - Paroxetine
Trade - Paxil
Treatment of depression and panic disorders
Drug - Sertraline
Trade - Zoloft
Treatment of depression and panic disorders
Drug - Citalopram
Trade - Celexa
Treatment of depression
The second generation of anti-depressants, including selective serotonin-reuptake inhibitors, were developed to cause fewer side effects, particularly to reduce the anti-cholinergic and cardiovascular side effects. SSRIs are the most widely prescribed class of antidepressants. The delay to therapeutic effect is 2-4 weeks, even though the effect on serotonin levels is almost immediate. There are some suggestions that the delay is needed to allow a down regulation in the expression of autoregulatory serotonin receptors.
SSRIs: adverse effects
Sexual dysfunction.
Dependence and withdrawal.
MAOIs (serotonin syndrome)
Cimetidine; warfarin
Contraindications: Patients with a history of mania or anxiety
Because of their selectivity, SSRIs produce fewer anti-cholinergic, histaminergic and adrenergic adverse effects. The common adverse effects of SSRIs, such as sexual dysfunction, are there but they are usually mild and dissipate within 4-6 weeks. Unlike most other anti-depressants, SSRIs cause weight loss, but also possible dependence.
Due to the long periods required to clear both classes of drugs from the system, caution should be taken if a patient is changing therapies between MAOIs and SSRIs. Concurrent use can cause serotonin syndrome and even death. Serotonin syndrome is characterised by severe agitation, disorientation, ataxia, muscle spasms and exaggerated autonomic function.
Cimetidine decreases SSRI breakdown
SSRIs are not useful for patients with bipolar disorder because they can exacerbate mania or anxiety in patients who already have a history of these problems.
Miscellaneous next generation antidepressants
Drug - Bupropion
Trade - Wellbutrin
Treatment of depression
Drug - Venlafaxine
Trade - Effexor
Treatment of depression
Third generation?
Bupropion is an aminoketone that inhibits the reuptake of serotonin, noradrealine and dopamine. Venlafaxine is a strong inhibitor of serotonin and noradrenaline reuptake, but a weak blocker of dopamine reuptake.
Third generation antidepressants under development include CRH receptor antagonists.
Mood stabilisers
Drug - Lithium carbonate
Trade - Eskalith, Lithobid
Prophylaxis and treatment of acute mania
Drug - Lithium citrate
Trade - Cibalith-S
Prophylaxis and treatment of acute mania
Drug - Carbamazepine
Trade - Tegretol
Mania, epilepsy.
Drug - Valproate
Trade - Depacon
Mania, epilepsy
Patients with bipolar affective disorder need specific drugs for the stabilisation of acute mania.
Anticonvulsants can be used for treating both epilepsy and mania.
Mood stabilisers: adverse effects
Contraindicated for patients with renal dysfunction, leukaemia,
dehydration or sodium depletion.
Sodium bicarbonate.
Other antipsychotic drugs, diuretics and non-steroidal
anti-inflammatory drugs.
Dizziness, headache, confusion, hair loss, oedema,
cardiac dysrhythmias and nephrotoxicity.
Toxicity and withdrawal.
(Anti-convulsants. Birth deformaties).
Lithium drugs are alkali metal salts that change biochemical, electrolyte and endocrine functions in the body, and can therefore have various side effects. Therefore, lithium is contraindicated for patients with renal dysfunction, leukaemia, dehydration or sodium depletion.
Sodium bicarbonate should be avoided as it can increase excretion of lithium, while other drugs can increase its effects. The safe and effective range of lithium is relatively narrow and it is important to avoid toxicity.
The side effects of the anticonvulsants are dizziness and weight loss. They can be toxic to unborn babies.
The sleep-wake circuitry
Ascending arousal system:
Serotonin from dorsal and median raphé nuclei
Noradrenaline from locus coeruleus (LC)
Dopamine from ventral tegmental area (A10)
Histamine from tuberomammillary nuclei (TMN)
Cholinergic neurones of the pedunculopontine
and laterodorsal tegmental nuclei
Reciprocal connections with GABAergic
neurones in the ventrolateral preoptic nucleus
(VLPO)
Serotonergic arousal neurones ascend from the dorsal and median raphe nuclei, noradrenergic neurones ascend from the locus coeruleus, dopaminergic neurones from the ventral tegmental area, histaminergic neurones from the tuberomammillary nuclei, and cholinergic cells from the pedunculopontine and laterodorsal tegmental nuclei.
These make reciprocal connections with GABAergic neurones that reside in the ventrolateral preoptic area.
The switch model of sleep-wake cycles
The sleep-promoting GABAergic neurones of the ventrolateral preoptic area are inhibited by monoaminergic and orexigenic neurones during waking.
At the onset of sleep, which is brought about by homeostatic and circadian mechanisms, there is a shift in the balance.
Typical GABAA receptor
The GABAA receptor consists of five subunits, which form a pentameric ring with the chloride channel between them. GABAA receptors display allosteric regulation. Effectors that enhance the receptor’s activity are referred to as allosteric activators. These include ethanol, neurosteroids, barbiturates and the benzodiazepines, which increase inhibitory signalling through GABA receptors to cause sedation. Effectors that decrease the receptor’s activity are called allosteric inhibitors. The inhibitory drug, picrotoxin binds inside the channel and blocks it.
Anxiety disorders
Generalised anxiety disorder Panic disorder Phobias Post-traumatic stress disorder Obsessive-compulsive disorder
Anxiety and fear are components of the generalised adaptation syndrome or “stress.”
Generalised anxiety disorder is characterised by long-lasting anxiety that is not focused on any particular object or situation.
In panic disorder, a person suffers sudden attacks of intense terror and apprehension accompanied by strong activation of the sympathetic system.
Phobias involve a strong, irrational fear and avoidance of an object or situation.
Post-traumatic stress disorder can result from an extremely stressful situations, e.g. warfare.
Obsessive-compulsive disorder, or OCD, is a type of anxiety disorder primarily characterized by obsessions and/or compulsions.
Statistics of anxiety
In 2003/4, over half a million individuals in Britain believed that they were experiencing work-related stress at a level that was making them ill
Accounted for an estimated thirteen million reported lost working days per year in Britain
Over 20 million American adults ages 18 to 54, or about 13.3 percent of people in this age group in a given year, have an anxiety disorder
Anxiolytics
Sedative-hypnotics
Benzodiazepines
Second generation non-benzodiazepines
Anti-anxiety drugs, or anxiolytics, are non-specific CNS depressants that include barbiturates, benzodiazepines and alcohol. They alleviate symptoms of distress but do not affect the underlying factors that cause anxiety. CNS depressant medications are dose dependent, with increasing doses resulting in sedation and then hypnosis.
The first barbiturate was sodium amytal. The barbiturates all have a similar molecular ring structure with distinct side chains that affect their lipid solubility.
Sedative-hypnotics
Drug - Thiopental
Trade - Pentothal
Preparation for surgery
Drug - Secobarbital
Trade - Seconal
Treatment of insomnia anxiety and acute agitation
Drug - Phenobarbital
Trade - Luminal
Treatment of insomnia, anxiety and seizures
Drug - Zolpidem
Trade - Ambien
Treatment of insomnia
Ultrashort-acting barbiturates, such as Thiopental, produce unconsciousness within less than a minute of intravenous injection, and are used to prepare patients for surgery.
The short to intermediate-acting barbiturates are moderately lipid soluble and take longer to reach significant brain levels. They are likely to produce relaxation and sleep in about 20 to 40 mins and last about 5 to 8 hours. Example are Amytal and Secobarbital that are prescribed for insomnia.
The long-acting drugs have poor lipid penetration, so their onset takes an hour or more, but their slow metabolism produces prolonged action for 10 to 12 hours. These characteristics are optimal for treating seizure disorders because a stable blood level can be maintained.
Sedative-hypnotics: adverse effects
Avoid other CNS depressants.
Check for suicidal tendencies.
Drowsiness or hangover.
Dependence and tolerance. Possible seizure on
withdrawal.
Contraindications: Children under 18 years of age,
pregnant or nursing mothers.
Barbiturates should not be administered with other depressants, such as alcohol, because of risk of respiratory failure. Patients who have a history of suicidal ideation or behaviour must be closely monitored.
Rapid termination of treatment should be avoided.
Benzodiazepines
Diazepam
Valium
Treatment of anxiety and seizures
Alprazolam
Xanax
Treatment of anxiety and panic disorders
Temazepam
Restoril
Short-term treatment of insomnia
Lorazepam
Ativan
Treatment of anxiety, status epilepticus, preoperative sedation, amnesia
The major advantages of benzodiazepines over barbiturates is that they are effective anxiolytics, but do not cause over sedation, have a low incidence of tolerance and a very safe therapeutic index.
BZDs work quickly to reduce anxiety symptoms, with the most improvement occurring within the first week of treatment. The efficacy of BZD therapy decreases after 3-4 months of continuous use.
As well as for the treatment of mild to severe anxiety and panic disorders, some BZDs can be used for seizure control (notably in acute alcohol withdrawal) and sleep induction for insomniacs. The can be used for pre-operative relaxation, but not for anaesthesia.
Benzodiazepines: adverse effects
Contraindications: Renal and hepatic dysfunction;
glaucoma; pregnancy and lactation.
Avoid other CNS depressants.
Accumulation of metabolites leads to over sedation and CNS
depression and ataxia.
Anticholinergic effects (headache, dry mouth, blurred vision,
dizziness, memory loss, hypotension and GI disturbances).
“Date rape.”
Although overdose with BZDs is unusual, combined use with other CNS depressants (e.g. barbiturates, opioids, alcohol, sedatives and anti-histamines) is dangerous.
Over relaxation and ataxia are the most common adverse effects, with older patients being the most susceptible, particularly to falls and subsequent injury. Thus, for older or debilitated patients, BZDs with a short-acting half life that do not accumulate are preferrred, such as Temezepam or Lorazepam.
Side effects from BZD are mainly due to the fact that they can have off target actions to inhibit cholinergic receptors.
“Date rape” drugs, e.g. Flunitrazepam (Rohypnol), are potent when combined with alcohol. They impair judgement and cause amnesia along with significant sedation.
Non-benzodiazepine anxiolytic
Buspirone
BuSpar
Short-term treatment of anxiety,
depression.
The family of azapirone drugs can be used for the short-term treatment of anxiety disorders. There is only really one that is marketed called buspirone.
It has a gradual onset to efficacy of approximately one to four weeks and is often used as a co-therapy when a patient is coming off BZDs or in treating depression that often accompanies anxiety.
It is thought to act as a partial agonist on postsynaptic 5-HT1A serotonin receptors, rather than on GABA receptors.
Non-benzodiazepine anxiolytics: adverse effects
Avoid other CNS depressants.
Never with MAOIs.
Anticholinergic effects (dizziness, headache, insomnia, nausea, dry mouth and blurred vision, mood changes and palpitations).
Buspirone can increase the effects of other CNS depressants and sedatives. It should never be co-adminsitered with monoamine oxidase inhibitors as this can lead to potentially lethal elevation of blood pressure.
Schizophrenia
1% of population. 48% concordance in monozygotic twins.
“Positive” symptoms – hallucinations, delusions, bizarre thoughts
“Negative” symptoms – social withdrawal, flattened mood, apathy
Schizophrenia affects about 1% of the population. There is a genetic influence, but no functional correlations have been found between specific genes and the disease. Positive symptoms include hallucinations, delusions and bizarre thoughts. Negative symptoms include social withdrawal, lowered mood and poor motivation.
Schizophrenia
Patients are unable to separate real from unreal experiences. Behaviour is often inappropriate or bizarre.
Patients with disorganised schizophrenia Disorganised, thought disorder; flattened mood.
Difficult to understand - speech may be incomprehensible
Patients with paranoid schizophrenia
Experience hallucinations and delusions, but not the other symptoms.
Patients with catatonic schizophrenia
Psychmotor disturbances, e.g. catatonic stupor and waxy flexibility.
There are different categories of schizophrenia.
Typical antipsychotics / neuroleptics
Chlorpromazine Thorazine Management of psychosis and
schizophrenia; behavioural
problems in children
Fluphenazine Prolixin Management of psychosis and
schizophrenia
Haloperidol
Haldol
Management of psychosis and
severe behavioural problems
Loxapine
loxitane
Management of mood disorders
and schizophrenia
Two classes: phenothiazines and butyropenones. Neurolpetics are dopamine D2 receptor antagonists. Amphetamines, which act by releasing dopamine, accentuate schizophrenic symptoms. The “dopamine hypothesis” explains the aetiology of schizophrenia. There is thought to be excessive dopamine release in the prefrontal cortex, leading to the positive symptoms of schizophrenia. Thus, the great majority of neuroleptics relieve only the positive symptoms.
Typical antipsychotics/neuroleptics: adverse effects
Parkinsonism. Tardive dyskinesia.
Sedation and hypotension, impaired thermoregulation
and lactation.
Neuroleptic malignant syndrome.
CNS depressants, anticonvulsants or antihypertensives.
Antacids.
Contraindications: Cardiovascular disease, bone marrow
depression, renal, liver or thyroid dysfunction, or
Parkinson’s disease.
Neuroleptics produce motor effects, including tremors, akinesia (a slowing or loss of voluntary movements) and muscle rigidity. these side effects are the equivalent of parkinsonism. Tardive dyskinesia: stereotyped involuntary movements.
Some neuroleptics also cause sedation and hypotension, impaired thermoregulation and lactation.
The rare but potentially fatal condition of neuroleptic malignant syndrome involves altered mental status, high fever, tachycardia, muscle rigidity, seizures, respiratory and renal failure, and coma.
Atypical antipsychotics
Clozapine
Clozaril
Management of schizophrenia
Amisulpride
Solian
Management of schizophrenia
Risperidone
Risperdal
Management of schizophrenia
Olanzepine
Zyprexa
Management of schizophrenia
The efficacy of clozapine seems to reside in the fact that it has an even greater affinity for 5-HT receptors than for dopamine D2 receptors.
Atypical antipsychotics are antagonists are effective in managing psychoses and schizophrenia; importantly treating both the positive and the negative symptoms of schizophrenia.
Atypical antipsychotics: adverse effects
Risk of neuroleptic malignancy syndrome are low.
Avoid CNS depressants. Antihypertensives.
Headache, blurred vision, photosensitivity, insomnia,
nervousness, dizziness and GI distress.
Glaucoma, peptic ulcer disease or urinary retention.
Dysrhythmias or hepatic dysfunction.
Weight gain.
Risk of neuroleptic malignancy syndrome are low. Should avoid depressants and anti-hypertensives, because of risk of excessive hypotension. Anti-cholinergic effects. The major problem with atypical anti-psychotics is that they can cause rapid and excessive body-weight gain.
