© SPMM Course 1 © S P M M C o u r s e Pharmacodynamics Paper A Syllabic content 4.3 We claim copyright for our own text material, productions and adaptations. We claim no rights to Images/Figures with CC-BY-SA license if they are used in this material.
© SPMM Course 2 1. Introduction The term pharmacodynamics refers to the study of the mechanism of action of drugs (the effect of drugs on the body). Most psychotropics affect neurotransmitters of the brain. This effect can occur at various levels. Level of action in neurotransmission cycle Examples Synthesis L-tryptophan, l-dopa Storage Reserpine depletes NA and DA. Release from storage Amphetamine stimulates release of NA and DA Reuptake SSRI, TCA, cocaine – dopamine reuptake, Bupropion – dopamine & Noradrenaline reuptake Degradation MAO inhibitors, Acetyl cholinesterase inhibitors e.g. donepezil Pre synaptic receptors Clonidine, lofexidine at alpha2. Post synaptic receptors Most antipsychotics at D2 Partial agonism Aripiprazole – D2; Buspirone 5HT1A; Clonazepam – BDZ receptor; Buprenorphine – opioid receptor mu Antagonism Flumazenil for benzodiazepines, antipsychotics at D2 Full agonism Benzodiazepines at GABA-A complex, bromocriptine for dopamine Second messengers Lithium at inositol level. Refer to Neurochemistry SPMM Notes for more details of different neurotransmitters, their structure and receptor actions.
© SPMM Course 3 2. Receptor mechanisms The ‘receptor’ of a drug can be defined generally as the cellular component to which the drug binds and through which the drug initiates the pharmacodynamic effects on the body. There are 2 major superfamilies; Ionotropic or metabotropic receptors. Ionotropic: Theses are ligand-gated ionic channels. Their activation leads to a rapid transient increase in membrane permeability to either positive cations like sodium or calcium or negative anions like chloride. It causes excitation or inhibition of the postsynaptic membrane. Examples are nicotinic acetylcholine receptors, GABA-A receptors, glutamate receptors and serotonin 5HT 3. Metabotropic: These produce slower response involving so-called G-proteins which bind to the intracellular portion of the receptor and activate a second messenger. Altered second messenger levels result in changes in the phosphorylation state of key proteins rendering them active or inactive. Examples are Dopamine (D1-5), Noradrenaline, and Serotonin 5HT1-7 except 5-HT 3, muscarinic acetylcholine receptors and opioid receptors (mu). Ionotropic receptors result in quick response (GABAA, a benzodiazepine); G protein coupling (metabotropic) is a comparatively slower process (most antipsychotics, antidepressants. Kinetics of receptor binding: A drug can be an agonist for a receptor and can stimulate the biological activity of the receptor or could be an antagonist that inhibits the biological activity. Full agonists produce a maximal response. The measure of the degree of response is usually measured against physiological neurotransmitter efficiency for any given receptor. Partial agonists cannot elicit a maximal response and are less effective than full agonists. Examples are Aripiprazole, buspirone and buprenorphine. Partial agonists have a ceiling effect. The degree of response of a partial agonist depends on availability of physiological neurotransmitter in the vicinity; i.e. when maximal dopamine is available, partial agonist aripiprazole can actually inhibit the dopaminergic transmission as a less efficient molecule competes with more efficient molecule. In dopamine deficient states, the same partial agonist can enhance dopaminergic effects. An inverse agonist is an agent that binds to the same receptor but produces the opposite pharmacological effect. No clinical drug acts via this mechanism but several have been researched especially at GABA complex. Antagonists are drugs that interact with receptors to interfere with their activation by neurotransmitter or other agonistic molecules.
© SPMM Course 4 Types of antagonism Competitive antagonism can be reversed completely by increasing the dose of the agonist drug. Competitive antagonists reduce the potency (minimal dose needed to produce an effect) but not the efficacy (maximal response produced) of agonists. Examples of competitive antagonism include atropine at muscarinic receptors and propranolol at betaadrenergic receptors. Noncompetitive antagonists alter the receptor site in some way so increasing the dose of the agonist drug can reverse the effects only partially. Non-competitive antagonism reduces both the potency and the efficacy of agonists. Therefore, non-competitive antagonists not only shift the curve to the right but also reduce the maximum effect. For example, ketamine and phencyclidine are noncompetitive NMDA antagonists. Irreversible antagonists bind irreversibly to the target site e.g. most traditional MAOIs. Pharmacological antagonism refers to the opposing action of two molecules by acting via same receptors. Physiological antagonism refers to the opposing action of two molecules by acting via different receptors e.g. acetylcholine vs. adrenergic actions. Chemical antagonism refers to the opposing action of two molecules by acting via chemical reactions. This is not seen in psychotropics, but heparin and protamine reaction is an example. Most drugs bind reversibly to receptors, and the response is proportional to the fraction of receptors occupied (law of mass action). As the concentration of drug increases, the responses increases until all receptors are occupied giving a dose-response curve. Receptors can be up-regulated or down-regulated by drugs. With therapeutic use, agonists may cause down-regulation (desensitivity) or reduction in receptor numbers while antagonists may have the opposite effect- upregulation (hypersensitivity) or increase in receptor numbers. The potency of a drug with receptor binding action refers to the amount of the drug needed to produce a particular effect compared to another standard drug with similar receptor profile (‘vigor’). The potency of a drug is determined by; a. The proportion of the drug reaching the receptor b. The affinity for the receptor c. Efficacy Affinity refers to the ability of the drug to bind to its appropriate receptor (‘affection’). Drugs that bind readily to a receptor are described as having high affinity for that receptor and, in general, the higher the affinity and the more receptor a drug occupies, the more potent it is.
© SPMM Course 5 Efficacy refers to how well the drug produces the expected response i.e. the maximum clinical response produced by a drug (‘productivity’). Efficacy depends on affinity, potency, duration of receptor action in some cases and kinetic properties such as half-life, among other factors. Haloperidol is more potent than chlorpromazine as approximately 5 mg of haloperidol is required to achieve the same effect as 100 mg of chlorpromazine. These drugs, however, are comparable in the maximal clinical response achievable using them i.e. equally efficacious but not equipotent.
© SPMM Course 6 3. Modes of therapeutic action for psychotropics Antipsychotic drugs In general all antipsychotics act via varying degrees of D2 blockade. Aypical drugs show selectivity for D2 receptors and also show high 5HT2: D2 blocking ratio. Specific actions are listed below. DRUG MECHANISM Amisulpride Both D2 and D3 antagonism. Similar dose-dependent pre & postsynaptic profile to sulpride. Some degree of limbic selectivity and 5HT7 activity also noted. Aripiprazole Partial dopamine agonist at D2. Also 5HT2A antagonist. Exhibits a Goldilocks’ phenomenon -stabilising action wherein anatagonising DA at sites of excessive dopamine such as mesolimbic zones while mimicking DA (agonism) at dopamine deficient zones such as mesocortical areas that are linked negative symptoms. Does not produce much change in tuberoinfundibulum where normal DA levels are expected in schizophrenia. Aripiprazole acts on both postsynaptic D2 receptors and presynaptic autoreceptors. Asenapine D2 antagonist and serotonin 5HT2A blocker (similar to olanzapine). Has potent alpha-2 blockade effect. Sublingual; allegedly weight and prolactin-neutral. Licensed for use in mania. Chlorpromazine, promazine The moderate antimuscarinic effect in addition to D2 blockade. Highly sedative phenothiazine drugs. Clozapine A High ratio of 5HT2 to D2 blockade; also blocks D4 and 5HT6 receptors. Has notable alpha 1 antagonism and anticholinergic and antihistaminic properties. Weak D1 and D2 affinity. Also binds 5HT3. Proposed to have a faster dissociation rate (similar to quetiapine) hence a hit and run profile is noted. Lurasidone D2 antagonist and serotonin 5HT2A blocker (similar to risperidone). Also has a high affinity for serotonin 5HT7; partial agonist at 5HT1A receptors. Has minimal affinity for alpha-1 (less orthostatic effect) and histamine receptors (thus may be weight neutral) Olanzapine Atypical antipsychotic. Has high 5HT2 / D2 blockade ratio. Potent D4 blockade and 5HT6 blockade also noted. It has significant anticholinergic and some antihistaminic effects. Paliperidone A metabolite of risperidone. Similar mechanism of action Quetiapine Similar to clozapine – hit and run profile on D2. Compared to other atypicals it has somewhat lesser 5HT2A blockade. Significant anticholinergic effects similar to olanzapine. Risperidone Serotonin-Dopamine Antagonist - Atypical Antipsychotic. Has high 5HT2A antagonistic property. In higher therapeutic doses can bind to D2 in a similar fashion to typicals and can lead to extrapyramidal and prolactin related side effects. Sulpiride Pure D2 antagonist. At low doses presynaptic receptors blocked (helps negative symptoms?); above 800mg/day doses, affects postsynaptic D2 – reducing positive symptoms. Thioridazine, pericyazine, D2 antagonists. Marked antimuscarinic effect. Less EPSEs than other typicals.
© SPMM Course 7 pipotiazine Thioxanthenes Exhibit stereoisomerism. D2 antagonists – typical antipsychotics. Ziprasidone Atypical antipsychotic with 5-HT2A and D2 blockade. Antagonizes 5-HT1D, 5-HT2C, D3, D4 receptors. Poor affinity for muscarinic effects; some antihistaminic property noted. Agonistic at 5-HT1A; also some serotonin and norepinephrine reuptake inhibition noted. Zotepine Atypical antipsychotic with 5HT2A, 5HT2C, D1, D2, D3, D4 antagonism. Potent noradrenaline reuptake inhibitor. Potent antihistaminic activity and some NMDA antagonism.
© SPMM Course 8 Antidepressant drugs DRUG MECHANISM Agomelatine Agomelatine enhances norepinephrine and dopamine neurotransmission through 5- HT2C antagonism. It is also a direct agonist at melatonin (MT1 and MT2) receptors. GABA interneurons tonically inhibit noradrenergic circuits (from locus coeruleus) and dopaminergic circuits (from ventral tegmentum) projecting to the prefrontal cortex. Serotonin via 5HT2C stimulation drives these GABA interneurons. Thus, norepinephrine and dopamine circuits are inhibited by the normal tonic release of serotonin onto 5-HT2C receptors (Stahl, 2007). Thus agomelatine, through 5HT2C inhibition, acts as norepinephrine and dopamine disinhibitor (NDDI). Antidepressant with possible sedative effects. Amoxapine Tetracyclic with dibenzoxazepine structure. Has both dopamine antagonistic and serotonin-noradrenaline reuptake inhibition effects. So claimed to have significant antipsychotic properties in addition to antidepressant effects. Similarly, extrapyramidal side effects are seen more often than other tricyclic. Bupropion Dopamine and noradrenaline reuptake inhibitor. Used to help quit smoking and in depression. It is noted to increase the efficiency of noradrenergic transmission and reduce total norepinephrine turnover. It has no antimuscarinic activity. Some degree of competitive nicotinic antagonism. Buspirone Partial agonist on serotonin 5-HT1A receptors. At presynaptic levels, it is mostly a full agonist, which inhibits the release of serotonin, with consequent antianxiety effects. Partial agonist action at postsynaptic receptors appears to account for the antidepressant activity. Citalopram SSRI, most selective of all SSRIs for serotonin reuptake. Occurs in a racemic mixture of which s isomer has pharmacological activity. But r- enantiomer inhibits the action of s- enantiomer; hence if escitalopram is used (s- enantiomer) lesser dose is sufficient. Clomipramine Tricyclic – regarded as most potent; higher SRI selectivity than other TCAs but lesser selectivity than SSRIs. Desipramine Tricyclic with least anticholinergic action but lethal on overdose. Duloxetine SNRI similar to venlafaxine. Said to have a better profile for psychosomatic pain and neuropathic pain. Levothyroxine & Liothyronine Levothyroxine is T4; liothyronine is T3 – both are thyroid hormones; suppress TSH and acts as an adjuvant in resistant depression. The exact mechanism of antidepressant effects unknown – possibly via neuroendocrine changes. Lithium Lithium is thought to act via the second messenger system. It putatively enhances serotonin transmission by 1. Increasing tryptophan uptake into neurons 2. Enhancing serotonin release 3. Downregulation of 5HT1A, 1B and 2 receptor subtypes is also noted on chronic administration. 4. Directly inhibiting glycogen synthase kinase-3 (GSK-3) and also 5. Competing with magnesium directly at several important regulatory enzymes such as inositol-monophosphatase (IMPase), which catalyzes inositol second messenger system.
© SPMM Course 9 According to the inositol depletion hypothesis, inhibition of IMPase by lithium reduces myoinositol and phosphoinositide phosphate (PIP-2), leading to therapeutic efficacy. Further, through an increase in intracellular sodium, it may also affect Na+K+ pump and reducing dopamine synthesis in dose-dependent fashion. Milnacipran SNRI similar to venlafaxine. New drug Levomilnacipran also acts similarly Mirtazapine 5HT2A antagonism, alpha 2 antagonism, anti histaminic and anti 5HT3 properties noted. Mianserin has similar profile, but it is not antihistaminic; instead it has anticholinergic properties. Moclobemide Reversible inhibitor of MAO-A selectively. Nefazadone 5HT2 antagonist with some serotonin reuptake inhibition and mild norepinephrine reuptake inhibition. Has some alpha 1 antagonistic effect. Produces mCPP as a metabolite. Paroxetine Selective Serotonin Reuptake Inhibitor – most potent of all SSRIs in serotonin reuptake blockade, but not specific – has significant antimuscarinic action. Phenelzine Monoamine Oxidase Inhibitor – increased availability of monoamines including serotonin and noradrenaline may explain the mechanism of antidepressant action though disputed. Pindolol Beta blocker with intrinsic sympathomimetic activity. Also 5HT1A antagonism – tipped to enhance the onset of action of SSRIs through this mechanism. Reboxetine Noradrenergic specific reuptake inhibitor (NARI) Selegiline Monoamine Oxidase Inhibitors – selective for B at normal therapeutic doses; selectivity lost when a patch is applied at higher doses, leading to some antidepressant action. SSRIs Reuptake inhibition at somatodendritic areas takes place soon after administration – this leads to down regulation of somatic autoreceptors for serotonin and as a consequence inhibitory tone on serotonergic transmission is lost; the serotonergic output is facilitated. (see below) Tranylcypromine Monoamine Oxidase Inhibitors. Irreversible, non-selective. Positive enantiomer better MAOI, negative enantiomer better reuptake inhibitor. Trazodone 5HT2A/2c antagonism and some alpha 2 blockade. Alpha 1 blockade and antihistaminic properties also noted. Feeble reuptake inhibition at serotonin transporters. Tricyclics Monoamine reuptake inhibition (see below). The varying degree of noradrenaline and serotonin reuptake inhibition. Very minimal negligible effect on dopamine. Clomipramine is the most serotonin specific. Secondary amines are more noradrenergic. Venlafaxine SNRI. Serotonin noradrenaline reuptake inhibitor. Acts as an SSRI in lower (<150mg) doses. Vilazodone Mechanism not fully understood but selective serotonin reuptake inhibition and also a partial agonist action at serotonergic 5-HT1A receptors (the chemical structure is close to trazodone and nefazodone) Vortioxetine A structure similar to reboxetine but predominantly an SSRI-like effect. In addition, also shows 5HT3 antagonism and 5HT-1A agonism.
© SPMM Course 10 Selectivity of antidepressants: The ratio of concentration required to produce equivalent inhibitions of serotonin (5-HT) to Noradrenalin is shown below. Amitriptyline 1:1 Clomipramine 1:7 Fluoxetine 150:1 Citalopram >2000:1 Inhibition of nerve terminal NE neuronal uptake system Increase in synaptic concentrations of NE Desensitization of inhibitory Alpha2-adrenoceptors in the terminal Increase in neuronal NE release Further increase in synaptic concentrations of NE Desensitization of postsynaptic Beta adrenoceptors without affecting postsynaptic Alpha1-adrenoceptor sensitivity 5HT Reuptake inhibition at somatodendritic areas Increase in local concentrations of 5HT Desensitisation of inhibitory 5HT1A autoreceptors in the soma Increase in neuronal 5HT release Increase in synaptic concentrations of 5HT Desensitization of presynaptic 5HT1B receptors without affecting postsynaptic 5HT1A sensitivity Mechanism of TCA Action Mechanism of SSRI Action
© SPMM Course 11 Mood stabilizers DRUG MECHANISM Carbamazepine Prolongs sodium channel inactivation. As a consequence, calcium channel inactivation is prolonged. It also reduces glutamate neurotransmission, adenosine A1 receptor antagonism and increase in brain catecholamine activity. It inhibits peripheral benzodiazepine receptors and reduces limbic kindling. It interferes with glial cell steroidogenesis. GABApentin GABA analogue structurally - binds to the α2δ subunit of the voltage-dependent calcium channel in the central nervous system. Acts on l-amino acid transport and thus can increase GABA availability in the brain. It crosses BBB via this l-AA transport. Has a high-affinity site in GABA-A complex; but no benzodiazepine-like actions noted. Lamotrigine Blockade of voltage-sensitive sodium channels leading to modulation of glutamate and aspartate release; some effect on calcium channels. Some inhibition of serotonin reuptake and weak inhibition of 5-HT3 receptors. Levetiracetam Indirectly enhance GABA system. Anticonvulsant with weak evidence against mania. Oxcarbazepine A metabolite of carbamazepine; similar mechanisms proposed. Pregabalin GABA analogue structurally (similar to gabapentin). Like gabapentin, pregabalin binds to the α2δ subunit of the voltage-dependent calcium channel in the central nervous system. This may subtly reduce the release of certain neurotransmitters. It may as well influence GABergic neurotransmission. It has anti-epileptic, analgesic (neuropathic pain) and anxiolytic effects. It is more potent than gabapentin hence has a higher therapeutic index and fewer dose-related side effects. Tiagabine Tiagabine is a potent and selective reuptake inhibitor of GABA. It also has mild antihistaminic effects. Topiramate Topiramate is a fructose derivative; it is a selective inhibitor of Glutamate AMPA receptors, blocks Na+ receptors, and has indirect GABAergic activity by potentiating the action of GABAA receptor. Valproic acid Unknown- speculated to act via increased GABA release, decreased GABA metabolism, increased neuronal responsiveness to GABA and increased GABA receptor density, inhibition of phosphokinase C similar to lithium and functional dopamine antagonism. Vigabatrin VIGABATRIN expands as Vi- GABA- TR-transaminase IN- inhibitor. The name explains the mode of action.
© SPMM Course 12 Sedatives & Hypnotics DRUG MECHANISM Benzodiazepines Act via a particular site called omega site in GABA-A complex. All are agonists except clonazepam, which is a partial agonist. They facilitate GABA action on GABA-A complex – thus facilitating inhibitory neurotransmission via chloride ions. They have no direct agonistic action in the absence of GABA. They do not increase the number but the frequency and duration of chloride channel opening. Chloral hydrate, paraldehyde and meprobamate Barbiturate like agents. Probably potentiate GABAergic neurotransmission. Paraldehyde is cyclic ether. They have a poor safety profile and hence none of these are in clinical use currently. Flumazenil Benzodiazepine antagonist Ramelteon Ramelteon is a melatonin receptor full agonist with high affinity and selectivity for human melatonin receptors MT1 and MT2 over the MT3 receptor. It decreases sleep latency and increases sleep time across all ages; the dose-response curve is flat with no significant difference in efficacy between the 16-mg or 64-mg doses of ramelteon. It may have lower abuse potential than other hypnotics Thiopental Act directly on GABA-A complex and facilitate GABA transmission by opening chloride channels and enhancing hyperpolarisation. At lower doses, barbiturates enhance GABA by decreasing the rate of GABA dissociation and increasing the duration (not a number) of GABA-activated chloride channel opening. At slightly higher concentrations, barbiturates directly activate chloride channel opening even in the absence of GABA, an action that is not shared by benzodiazepines. Zolpidem, Zaleplon, Zopiclone, eszopiclone Z-drugs act via GABA A complex but act differently than benzodiazepines. Benzodiazepines occupy all 3 subunits of the ω receptor, but Z-drugs occupy only certain subunits. e.g,. zolpidem and zopiclone acts on ω1 receptors – hence no muscle relaxant, anxiolytic and anticonvulsant effects noted. Also, slow wave sleep is unaffected. Zaleplon occupies all 3 ω receptors. Zopiclone occurs as a racemic mixture where only s-isomer is active (eszopiclone). Z HYPNOTICS Given their selectivity on BDZ-receptor subunits, Z-drugs are less likely to impact sleep stages and have a lower risk of tolerance and dependence compared with benzodiazepine hypnotics Zopiclone is the least selective of all Z-drugs
© SPMM Course 13 Addiction pharmacology DRUG MECHANISM Alcohol Intercalates into the fluid cell membrane; decreases NMDA sensitivity; increases GABA sensitivity; down-regulates calcium channels; up-regulates nicotine receptor gated sodium channels. Amphetamine Acts via releasing stored monoamines especially noradrenaline and dopamine. Hence a central sympathomimetic. Buprenorphine Partial opioid agonist. Lower doses – mild agonism; higher doses – antagonistic effects. Cannabis Acts via cannabinoid receptors. CB1 is central and activated by 11OH tetra hydro cannabinoid. This inhibits GABA tone in the substantia nigra and other areas. May be related to increased dopamine activity at reward centres. CB2 is peripheral immune-related and seen in spleen and thymus. (Endogenous cannabinoids called anandamides are derived from arachidonic acid; their function is unclear) Clonidine, lofexidine Presynaptic alpha 2 agonist – reduces central sympathetic tone. Opioid receptors on locus coeruleus projections reduce noradrenergic tone on long-term use. The cellular machinery compensates via up-regulation of adenylate cyclase and maintains sympathetic tone in a chronic user. Sudden withdrawal leads to increased adrenergic firing rate (withdrawal symptoms); hence alpha 2 autoreceptor stimulation which reduces central sympathetic tone helps in opioid withdrawal. Dexfenfluramine & Fenfluramine Produce massive serotonin release from nerve endings. [Fen-Phen was an off-label combination of fenfluramine and phentermine used for promoting weight loss but fenfluramine (and dexfenfluramine) was withdrawn due to irreversible serotonergic damage, valvular regurgitation and pulmonary fibrosis]. Disulfiram Inhibits aldehyde dehydrogenase. Leads to accumulation of acetaldehyde if alcohol is consumed producing unpleasant reactions. Levomethadyl acetate (LAAM) Long-acting opioid agonist; potentially similar use as methadone. Withdrawn due to prolonged QT and torsades de pointes. Pure mu agonist. LSD 5HT2A partial agonism producing hallucinogenic effect MDMA Has 2 isomers R(-) isomers produce LSD-like effects and the S(+) isomers have amphetamine-like properties LSD-like action is mediated via serotonin release from presynaptic neurons. In the long term, this can damage serotonergic tracts irreversibly. Methadone Opioid receptor agonist. Longer acting than heroin and orally available. Pure mu agonist. Naloxone Short-acting opioid mu antagonist Naltrexone Longer acting opioid mu antagonist Phencyclidine Noncompetitive NMDA antagonist similar to ketamine; also binds to sigma receptors Varenicline Varenicline (Champix) is a partial agonist at the α4β2 unit of nicotinic acetylcholine receptor. It assists smoking cessation by relieving nicotine withdrawal symptoms and reducing the rewarding properties of nicotine.
© SPMM Course 14 Anti dementia drugs DRUG MECHANISM Donepezil, Galantamine, Rivastigmine Cholinesterase Inhibitors. The act by inhibiting acetyl cholinesterase enzyme that breaks down acetylcholine centrally. Rivastigmine inhibits both the acetyl and butylcholinesterase while donepezil and galantamine are acetyl specific. Galantamine also has nicotine agonistic properties. Memantine Blockade of N-methyl-d-aspartate (NMDA) glutamate receptors. Unlike ketamine, which is a high-affinity noncompetitive blocker, memantine is a non-competitive blocker with low affinity and binds only to actively open NMDA channels. Its receptor dissociation rate is relatively fast, and so it does not accumulate and interfere with normal NMDA activity. Acetylcholine is inactivated by both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Cholinesterase inhibitors increase the amount of ACh available through inhibition of these enzymes. An acetylcholinesterase inhibitor can work at either of two sites on AChE, an ionic subsite or a catalytic esteratic subsite; Tacrine and donepezil act at the ionic while physostigmine and rivastigmine act at the catalytic esteratic subsite. Tacrine, and to some extent rivastigmine are non-selective inhibitors of both AChE and BChE. CNS specific inhibition of AChE can occur with donepezil. Binding to the AChE sites may be either reversible or irreversible, and may be competitive or noncompetitive with acetylcholine. Galantamine is a competitive drug while tacrine is a non-competitive inhibitor. AChE tetramer, G4, is located on the presynaptic membranes while a monomer, G1, is found on postsynaptic membranes. Although G4 is decreased along with the neuronal loss in AD, postsynaptic cholinergic receptor neurons and G1 ACh are not decreased significantly with AD or aging. Rivastigmine and to some extent galantamine are highly selective for the postsynaptic G1 monomer while donepezil is not selective. RILUZOLE It is approved for use in Motor Neuron Disorder. It is unclear whether this would help features of fronto-temporal dementia associated with MND. It prolongs survival by nearly 10% for more than a year of treatment. Riluzole’s mechanism of action is via 1. Sodium channel blockade 2. High-voltage calcium channel blockade 3. NMDA-glutamate receptor antagonism. It preferentially blocks the sodium channels in damaged neurons, reducing calcium flow and indirectly preventing excitotoxic damage.
© SPMM Course 15 Miscellaneous drugs DRUG MECHANISM Amantadine Used in Parkinsonism. It augments dopaminergic neurotransmission through an unknown mechanism. Dextroamphetamine Methylphenidate Methylphenidate, dextroamphetamine, and amphetamine are indirectly acting sympathomimetics – induce the release of dopamine and Noradrenaline from presynaptic neurons. Dextroamphetamine and methylphenidate are also weak inhibitors of catecholamine reuptake and inhibitors of monoamine oxidase. Atomoxetine Tricyclic like structure – phenylpropanolamine derivative. Selective inhibitor of the presynaptic noradrenaline reuptake (NARI) similar to the antidepressant reboxetine. Benztropine, Biperiden, Orphenadrine, Procyclidine Anticholinergic drugs. Used in the treatment of EPSEs induced by antipsychotics. Carbidopa Carbidopa inhibits aromatic-L-amino-acid decarboxylase (DOPA Decarboxylase). Administered together with l-dopa as Sinemet to reduce the peripheral conversion of dopa to dopamine. Carbidopa cannot cross the blood-brain barrier. Dantrolene Directly affects the formation of actin-myosin complexes in skeletal muscle through ryanodine calcium channel inhibition. Diphenhydramine, Hydroxyzine, Promethazine, Cyproheptadine. Antihistaminic drugs against central histamine H1 receptor. Cyproheptadine has both a potent antihistamine and serotonin 5-HT2 receptor antagonist properties. All of these agents have some antimuscarinic properties too. Cyproheptadine was used as anti-anorexic agent, and also to treat delayed ejaculation associated with SSRI use. Levodopa Dopamine precursor used in parkinsonism; is combined with carbidopa to reduce peripheral conversion to dopamine. Modafinil Activates hypocretin-producing neurons possibly through alpha 2 and/or alpha-1 adrenergic agonist properties (alerting effects) or some noradrenaline reuptake blocking effects; the stimulating effect of modafinil can be attenuated by prazosin. Pemoline Indirectly stimulates dopaminergic activity - but it has little actual sympathomimetic activity. A stimulant. Withdrawn due to hepatotoxicity. Reserpine Depletes the stored dopamine and other monoamines from vesicles. Can lead to depression and suicide. Sildenafil Phosphodiesterase-5 Inhibitor. Propranolol . Beta-adrenergic antagonist. Lipophilic and so can pass blood brain barrier and can have central actions. Reduces akathisia and peripheral signs of sympathetic overdrive seen in anxiety Pramipexole, ropinirole, apomorphine Apomorphine, pramipexole, and ropinirole are dopamine agonists - bind about 20 times more selectively to dopamine D3 than D2 receptors. Bromocriptine is less selective 2:1. Pergolide is most selective 5:1. Bromocriptine and pergolide are ergotamine derivatives. Pramipexole is a nonergot dopamine agonist. Apomorphine is structurally related to morphine and other opioids. Sumatriptan 5HT1D and 1F agonist Yohimbine It is an alpha 2 antagonist sometimes used in treating erectile dysfunction.
© SPMM Course 16 Lorcaserin, phentermine-topiramate combination, and naltrexone-bupropion combination are novel FDA approved treatment approaches to tackle obesity. These drugs are promoted as anorectic agents, similar to fenfluramine-phentermine combination ('fen-phen'), rimonabant, and sibutramine (all of the latter 3 which fell out of favour due to various adverse effects). Lorcaserin is a serotonin 2C receptor agonist; it is prescribed twice daily with an instruction to discontinue if 5% weight loss is not achieved by 12 weeks. The commonest side effect is a headache. In diabetic patients, this drug can induce hypoglycaemia. Phentermine is a sympathomimetic amine while topiramate is an antiepileptic drug. This combination is used in an extended-release preparation. Side effects include paraesthesia, dysgeusia and dizziness. Naltrexone is an opioid antagonist while bupropion is an aminoketone antidepressant that promotes weight loss in subjects even as a standalone drug (so a prescription of bupropion is not advised in those with a history of eating disorders).
© SPMM Course 17 4. Neurochemical effects of ECT Repeated subconvulsive electrical stimulation in animals reduces the seizure threshold – this process is called kindling. ECT does NOT produce a kindling effect; in fact it protects against kindling in animal studies. Thus, it can be termed an anti-kindling agent. As a result, dosing may need to be increased over the course of treatment to achieve the same seizure-inducing effect. Hippocampal neuronal loss occurs in kindling. But ECT results in neurogenesis in the rat. This could be mediated by an increased expression of brain-derived neurotrophic factor and its receptor, Blood–brain barrier permeability acutely increases following ECT but returns to baseline within 24 hours Imaging studies show that ECT is not associated with markers of cell loss or damage e.g. there is no change in myelin basic protein immunoreactivity or neuron-specific enolase in serum. Tau protein, neurofilament and S-100 beta protein, markers of neuronal and glial damage, are also unchanged after ECT. EEG shows delta and theta activity after applying ECT. This pattern returns to normal after 3 months of the end of treatment. An increase in 5HT2 receptors are noted in rodents after applying electrical stimulation; this change is opposite to the changes noted after administering antidepressant drugs. But note that using a [18F] setoperone PET scan Yatham et al. (2010) have now demonstrated that unlike in rodents, and similar to antidepressants, ECT reduces brain 5-HT2 receptors in individuals with depression. ECT also reduces β noradrenergic receptors and increases noradrenaline turnover. Further alpha 2 receptors are reduced after ECT, similar to antidepressants. Variables affected by ECT Changes Neurotrophic factors Increase in NGF,BDNF, NF3. Cell growth and synaptic connectivity Increased esp. In hippocampus Hormones Increased cortisol, prolactin, TSH coincides with good response. TRH gene expression increased in animals. Vasopressin, ACTH, oxytocin and opioid endorphins also increase consistently. Neurotransmitters and their receptors 5-HT-, NA-, cholinergic-, glutaminergic- and GABAergic systems, adenosine A1-receptor & 5-HT2A – all decrease in sensitivity. Activation of DA transmission and stimulation of 5-HT in hippocampus and amygdala.
© SPMM Course 18 5. Psychopharmacogenetics Psychopharmacogenetics focuses on how polymorphisms in genes affecting the mechanism of action of a drug’s effect and/or metabolism (both peripheral and central) can influence an individual’s clinical response to the drug, in terms of both therapeutic efficacy and adverse effects. Drug Effect Biological substrate Nicotine replacement Response to nicotine replacement (esp. in women) Dopamine receptor DRD2 variant Clozapine Drug response No association with DRD2 variants DRD3 Ser9Gly polymorphism – controversial DRD4 polymorphisms– no correlation 5HT2A receptor polymorphism – associated 5HT2C receptor polymorphism – associated 5HT transporter linked polymorphic region (5HTTLPR) – associated CYP2D6 variations – overall efficacy not affected Methylphenidate Poor response of ADHD symptoms. Homozygosity for the 10-repeat allele at DAT1 Clozapine Agranulocytosis HLA loci variants Typical antipsychotics No association with DRD2 variants DRD3 Ser9Gly polymorphism – associated DRD4 polymorphisms– no correlation 5HT2A receptor polymorphism - associated Typical antipsychotics Extrapyramidal symptoms, postural hypotension & excess sedation Poor metabolizers of CYP2D6 Typical antipsychotics Acute akathisia Polymorphisms in DRD3 and DRD2 Typical antipsychotics Tardive dyskinesia DAT polymorphism, 5-HTTLPR and the tryptophan hydroxylase (TPH) polymorphism and to some extent CYP1A2 polymorphisms Typical antipsychotics Hyperprolactinaemia & NMS DRD2 polymorphism
© SPMM Course 19 The serotonin transporter (5-HTT) protein acts as the primary mechanism for removing 5-HT from the synaptic cleft. Two polymorphisms have been identified within the human 5-HTT, an insertion/deletion polymorphism in the promoter region (5-HTTLPR) results in a short (s) and a long (l) variant, and a VNTR polymorphism in intron.
© SPMM Course 20 6. Ethnopharmacology Ethnicity is defined as a self-ascribed belongingness to a group with common geographical origins, race, language, religion, etc., which transcends kinship and neighbourhood. Ethnic categories retain a strong racial component. Race on the other hand is largely perceived by appearance and attributed to biological and genetic traits. Culture is a shared system of concepts or mental representations established by convention and reproduced by traditional transmission. Differences exist in the placebo response, compliance, doctor-patient relationship, social stress and health beliefs. The following are differences in the pharmacology of drugs administered. Absorption and availability Caucasians appear to have lower plasma levels of tricyclic antidepressants and attain plasma peaks later when compared with Asians (of Far Eastern ancestry as well as those from the Indian subcontinent). These differences have been attributed to a greater incidence of slow hydroxylation among Asians when compared with Caucasians Maximal haloperidol concentration in plasma after rapid tranquillisation is significantly high for Asians than Caucasians (Lin & Finder, Am J Psychiatry 140:490-491, 1983). Metabolism In the CYP system, variations in CYP2D6 are largely determined by genetic factors. (CYP2D6 metabolizes a number of antidepressants, antipsychotics, beta-adrenoceptor blockers, and antiarrhythmic drugs). The CYP2D6 variation is called debrisoquine/sparteine polymorphism: 4 groups exist – 1. Poor metabolizers: develop side effects quickly. Caucasians - the highest rate of poor metabolizers (nearly 7%). East Asians - lowest – 1%. These 7% Caucasians and 1% East Asians lack this enzyme, and so are poor metabolizers of risperidone and tricyclics 2. Intermediate metabolizers: higher in Asians (most Asians fall into this group – hence have more side effects though good drug efficacy) 3. Extensive metabolizers 4. Ultrarapid metabolizers: need high doses. 33% North Africans have multiple copies of CYP2D6, and so are ultra-rapid metabolizers. They require higher doses of risperidone. Only 5% Caucasians and 1% East Asians are ultra-rapid. 25% Indians may have this variant. CYP2C19 enzyme participates in the metabolism of omeprazole, propranolol and psychotropic drugs such as hexobarbital, diazepam, citalopram, imipramine, clomipramine, sertraline and amitriptyline. The incidence of poor metabolizers of CYP2C19 substrates is
© SPMM Course 21 much higher in Asians (15–30%) than in Caucasians (3–6%). CYP2C19 polymorphism is mephenytoin related. Unlike CYP2D6, the variations in CYP3A4 often influenced by environmental (e.g. diet) factors. Nearly 40% Asians and around 60% South American Native Indians lack Aldehyde dehydrogenase enzyme in sufficient amounts to metabolise alcohol – this serves as a natural deterrent in these communities. Pharmacodynamics The long form serotonin transporter polymorphism in Caucasians is associated with better SSRI response and tolerance while the opposite is true in South East Asians. Low COMT variant is seen in less than 20% of Asians and Africans, but nearly 50% of Caucasians show low variant. Adverse effects A well-known example from general medicine is that of Isoniazid – East Asians are most likely to be rapid acetylators and suffer from hepatotoxicity. But they have lesser peripheral neuropathy seen in slow acetylators. Chinese people had higher levels of extrapyramidal side-effects with haloperidol, and their blood levels were comparably high on equivalent dosages. On the administration of antipsychotics, Asian subjects were reported to produce greater serum prolactin levels than Caucasian subjects. This remains statistically significant after controlling for the difference in haloperidol concentrations, suggesting that the two groups differ in their dopamine receptor-mediated response. A summary of some relevant ethnic effects is given below. African Americans Asians Increased diagnosis of schizophrenia but decreased diagnosis of depression Have more side effects with lithium, tricyclics Higher tardive dyskinesia with antipsychotics. Better, rapid response to tricyclics and lorazepam, but poor response to fluoxetine. More depot medications received by African Americans. It is best to start at half of the standard dosage of all psychiatric medications Clozapine better effect in lower serum range, but higher incidence of agranulocytosis Taiwanese have lower required therapeutic level of lithium. Metabolise TCA slowly. Asians use herbal remedies more often than others.
© SPMM Course 22 Gender differences in psychopharmacology Antipsychotic response is shown to be superior in women In chronically ill population, men are found to require twice as high a dose as women for effective maintenance. Women have higher antipsychotic plasma levels than men after receiving the same dose of the drug. The enzyme CYP1A2 appears to be less active in women than in men, leading to relatively higher blood concentrations of olanzapine and clozapine in women. The volume of distribution of lipophilic drugs, such as antipsychotics, is greater in women than in men In women, the blood volume is smaller, butlipid compartments are larger. This prolongs the half-life of antipsychotics in the body, leading to accumulation over time, a phenomenon that becomes important when administering depotinjections. After a steady state is achieved, dosing intervals for women should be longer than for men. Acute dystonia, long thought to be more prevalent among men, has been shown now to be more frequent in females at equivalent doses. Earlier clinical studies had not taken into account the factthat young male patients were commonly given higher doses than women. Pulmonary embolism (a rare problem seen with drugs that have an affinity for the serotonin 5-HT2A receptor) and tardive dyskinesia appear to be more common in women.
© SPMM Course 23 Notes prepared using excerpts from: Appleby, L. et al (Ed) Postgraduate psychiatry: Clinical and scientific foundations. 2nd ed. Page 65 Bhugra, D & Bhui, K. Ethnic and cultural factors in psychopharmacology. Advances in Psychiatric Treatment (1999), vol. 5, pp. 89-95 http://www.dlc-ma.org/Resources/Health/Ethnic%20Psychopharmacology.html Kaplan & Sadock's Synopsis of Psychiatry: Behavioral Sciences/Clinical Psychiatry, 10th Edition. Lippincott Williams & Wilkins 2007 Poolsup et al. Pharmacogenetics and psychopharmacology. Journal of Clinical Pharmacy and Therapeutics (2000) 25, 197-220 Seeman, M. (2004) Gender differences in the prescribing of antipsychotic drugs. Am J Psychiatry 161:1324-1333. Shiloh, R., Nutt, D. & Weizman, A. (2000). Atlas of psychiatric pharmacotherapy. Martin Dunitz, London. Stahl, S. M. Essential psychopharmacology : neuroscientific basis and practical application 2nd ed Cambridge University Press 2000 Tsapakis, E. M., Basu, A. & Aitchison, K. J. (2004) Clinical relevance of discoveries in psychopharmacogenetics. Adv Psychiatr Treat, 10, 455-465. Yudkin, P. (2004) Effectiveness of nicotine patches in relation to genotype in women versus men: randomised controlled trial. BMJ, 328, 989 -990. Maixner D& Taylor MA. The efficacy and safety of electroconvulsive therapy. In Effective Treatments in Psychiatry. ed. Tyrer P. Cambridge University Press, 2008. Wahlund, B., & von Rosen, D. (2003). ECT of major depressed patients in relation to biological and clinical variables: a brief overview. Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology, 28, S21-6. Yatham, L. N., Liddle, P. F., Lam, R. W., Zis, A. P., Stoessl, A. J., Sossi, V., ... & Ruth, T. J. (2010). Effect of electroconvulsive therapy on brain 5-HT2 receptors in major depression. The British Journal of Psychiatry, 196(6), 474-479. DISCLAIMER: This material is developed from various revision notes assembled while preparing for MRCPsych exams. The content is periodically updated with excerpts from various published sources including peer-reviewed journals, websites, patient information leaflets and books. These sources are cited and acknowledged wherever possible; due to the structure of this material, acknowledgements have not been possible for every passage/fact that is common knowledge in psychiatry. We do not check the accuracy of drug related information using external sources; no part of these notes should be used as prescribing information.
© SPMM Course 1 © SPMM Course Adverse Drug Effects Paper A Syllabic content 4.4 We claim copyright for our own text material, productions and adaptations. We claim no rights to Images/Figures with CC-BY-SA license if they are used in this material.
© SPMM Course 2 1. Types of adverse reactions Type of reaction Mnemonics Features A: dose-related Augmented e.g., Lithium toxicity – ataxia, coarse tremors, vomiting. B: non-dose related Bizarre Idiosyncratic e.g. malignant hyperthermia, or lamotrigine induced Steven Johnson syndrome C: dose and time related Continuous use Related to cumulative drug use—e.g. long term lithium use and renal damage D: delayed effect Delayed Not due to dose per se but due to the length of use of a medication e.g. tardive dyskinesia in some cases. E: Withdrawal End of use Related to abrupt discontinuation e.g. SSRI discontinuation reaction, opioid withdrawal effects, etc. Tolerance is defined as the need to use increased doses of a drug to maintain a clinical effect. Tolerance is seen for both therapeutic effects and side effect. This may be due to decreased sensitivity of the target receptors due to down-regulation (decrease in numbers in case of agonists), up-regulation (increase in number of receptors in case of antagonists), or reduced responsivity without alterations in receptor numbers. Drugs with similar pharmacological actions can exhibit cross-tolerance e.g. benzodiazepines and barbiturates. Sensitization (aka reverse tolerance) manifests when sensitivity to a drug effect increases over time i.e. the same dose typically produces more pronounced effects as treatment progresses. This is reported with the street use of cocaine. Note that up or down-regulation can be a mechanism of therapeutic effect e.g. in case of SSRIs, the 5HT1A autoreceptors in somatodendritic zones undergo downregulation secondary to increased serotonin availability in the vicinity when reuptake is blocked; this in turn leads to an increase in serotonergic tone of the neurons. Withdrawal: When drugs are administered for a reasonable period of time, a physiological adaptation develops which on withdrawal of the drug can get disturbed and leads to withdrawal symptoms. Abrupt withdrawal of treatment especially for an agent with shorter elimination half-life leads to clinically significant withdrawal symptoms. Hypnotics, opiates, barbiturates, SSRIs, Venlafaxine are some of the drugs associated with discontinuation reaction or withdrawal symptoms. The variables influencing withdrawal symptoms are listed below:
© SPMM Course 3 1. Half life Methadone has less withdrawal than heroin as methadone has longer t1/2 2. Range of action Paroxetine has anticholinergic properties; withdrawal causes cholinergic rebound=d symptoms 3. Enzyme interference Paroxetine inhibits its own metabolism via CYP2D6. So withdrawal leads to loss of inhibition Æ excessive paroxetine breakdown Æ sudden steep drop in levels Æ withdrawal symptoms 4. Active metabolites Fluoxetine has active metabolite norfluoxetine with long half-life – hence it produces fewer withdrawal symptoms 5. Rate of withdrawal Slow, gradual tapering is the best. 10% dose reduction every 2 weeks is advocated for benzodiazepines. 6. Co-prescribed drug effects Prescribing an enzyme inducer can reduce the effects of a drug acutely if its metabolism depends on the induced enzyme; Similarly prescribing an antagonist can precipitate withdrawal symptoms. This is the rationale for leaving at least 72 hours before prescribing naltrexone for an opioid detoxified patient. 7. Receptor profile Full agonists on withdrawal produce more discontinuation reactions than partial agonists e.g. clonazepam produces lesser benzodiazepine withdrawal symptoms. Sustained-release preparations influence the absorption kinetics– not elimination kinetics, hence upon withdrawal, the drop in plasma levels occur at same rate in both XL and plain preparations; e.g. venlafaxine XL has similar discontinuation reaction as venlafaxine normal release. But depot preparations have less withdrawal propensity that corresponding oral drugs.
© SPMM Course 4 2. Mechanism of adverse effects Side effect Receptor Agitation α 2 blockade, 5HT2A/2C stimulation, DRI Akathisia D2 blockade, 5HT2A stimulation (hence some data on mirtazapine, 5HT2A antagonist, reducing akathisia) Delirium Anticholinergic effect (antimuscarinic) EPSE D2 blockade reduces with 5HT2A antagonism Hyperthermia Antimuscarinic action, in serotonin syndrome, may be mediated via 5HT2A/2C Insomnia α1 stimulation, 5HT2Astimulation (hence SSRIs cause insomnia) Amnesia (memory defects) Anticholinergic effects, GABAA stimulation Hyperprolactinaemia D2 blockade, 5HT1A stimulation Disrupted slow wave sleep SWS is maintained by 5HT2A inhibition; 5HT2A stimulation disrupts sleep architecture Sweating Cholinergic effect and increases with noradrenaline reuptake inhibition Postural hypotension α 1 antagonism Appetite loss 5HT2A stimulation (antihistaminics can increase appetite) GI discomfort, nausea, vomiting 5HT3 stimulation Weight gain 5HT2C antagonism and antihistaminic effects Anticholinergic effects Blurred vision, exacerbation of narrow-angle glaucoma, delirium, and photophobia due to mydriasis, dry secretions, constipation, tachycardia, decreased sweating, urinary retention and hyperthermia. Anorgasmia α 1 antagonism, 5HT2A/2C stimulation (delayed ejaculation in SSRIs). Retrograde ejaculation due to α 1 block, anticholinergic and antihistaminic effects. Tardive dyskinesia Supersensitivity of dopamine receptors, which develops because of prolonged therapy with dopamine-blocking drugs Impotence α 2 blockade, 5HT2A/2C stimulation. 5HT2A/2c stimulation can also reduce libido. Priapism α 1 blockade Obsessions 5HT1D stimulation can induce obsessions. 5HT1A and 2A stimulation reduce OCD. Pathological gambling Habituation of dopamine receptors on repeated use of dopamine agonists (e.g. levodopa) leading to dopamine dysregulation syndrome (DDS)
© SPMM Course 5 Weight gain: No single mechanism can explain the complex metabolic phenomenon of weight gain. Antihistaminic effects, 5HT2A/2C antagonism, insulin resistance (valproate and olanzapine) are noted. Genetic factors seem to involve 5-HT2C receptor. Drugs with a strong 5-HT2C affinity will have a greater impact on body weight of patients with a specific variant of polymorphism of the 5-HT2C receptor promoter regions. Low-potency antipsychotics (chlorpromazine and thioridazine) produce more weight gain and sedation than high-potency agents (haloperidol and fluphenazine).
© SPMM Course 6 3. Antipsychotics - adverse effects Extrapyramidal effects Acute extrapyramidal syndromes such as acute dystonia, akathisia and parkinsonism are noted with high potency drugs more than low-potency drugs. Tardive dyskinesia and dystonia, perioral tremor (rabbit syndrome) are chronic late side effects. PET studies have indicated that 60%–80% occupation of D2 receptors is associated with antipsychotic efficacy. Higher occupancy levels are associated with an increased risk of acute extrapyramidal symptoms as well as hyperprolactinemia from the blocking of D2 receptors on anterior pituitary mammotrophic cells that normally are tonically inhibited by dopamine produced in the hypothalamic arcuate nucleus. Antipsychotic drugs which have the propensity to induce Parkinsonism (trifluoperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than the endogenous ligand dopamine to D2, while the drugs with low Parkinsonism-inducing propensity (quetiapine, clozapine etc) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the loosely bound ones are weaker in potency and thus require higher doses to be clinically effective, but can be titrated faster. These loosely-bound drugs may also dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than the traditional tightly bound antipsychotic drugs (though ths does not seem to be the case for clozapine). Drug-induced parkinsonism is seen in 15-20% of patients treated with antipsychotics, seen within 90 days of treatment (5 to 90) and is characterized by muscle stiffness, cogwheel rigidity, shuffling gait, stooped posture, and drooling. The pill-rolling tremor of idiopathic Parkinsonism is not seen in drug-induced EPSEs - but a regular coarse tremor is seen. Elderly and female are under higher risk. Low potency drugs and those with higher anticholinergic effects cause less EPSEs. It is thought that higher than 80% receptor occupancy of brain D2 by antipsychotics can cause EPSEs. Atypical drugs cause low EPSEs probably due to anticholinergic effects, HT2A antagonism or less avidity of binding i.e. hit and run profile especially for clozapine and quetiapine. Anticholinergics can be used for short period of up to 6 weeks to treat the parkinsonian symptoms. As tolerance can develop for EPSE, the anticholinergics should be withdrawn after 4 to 6 weeks; also, longer chronic anticholinergic prescription increases the risk of TD. The rabbit syndrome is a tremor affecting the lips and perioral muscles and occurs late in the course of treatment.
© SPMM Course 7 Dystonias are brief or prolonged contractions of specific groups of muscles resulting in symptoms such as oculogyric crises, tongue protrusion, trismus, torticollis, blepharospasm. Rarely pharyngeal dystonia can occur resulting in dysarthria, dysphagia, and even respiratory choking. Dystonias occur early in treatment course and can reduce compliance. It is often seen in younger men receiving a high dose of high-potency medications. It is more common with IM administration. Dopaminergic hyperactivity in the basal ganglia occurring when plasma levels fluctuate may be the mechanism behind dystonias. Dystonias show spontaneous fluctuations, response to reassurance and to anticholinergic drugs. Akathisia includes both subjective and objective - feelings and signs of restlessness. (Possibly due to higher D2 occupancy in striatum). Patients may exhibit inability to relax, jitteriness, pacing, rocking with alternation of sitting and standing. Akathisia can be caused by not only neuroleptics but also antidepressants and sympathomimetics. Dose reduction, changing the drug or adding beta blocker/anticholinergic drugs or benzodiazepines or cyproheptadine are recommended. Akathisia may be associated with an increase in absconsion, suicides and violence if left undiagnosed and untreated in some cases. Tardive dyskinesia is a late side effect occurring in nearly 25% patients usually only after (at least 6 months) 1 – 2 years of treatment. It presents as abnormal, involuntary, irregular choreoathetotic movements of the muscles of the head, limbs, and trunk. Perioral movements are the most common. In some serious cases, patients may have breathing and swallowing muscles involved leading to aerophagia and grunting. TD is exacerbated by stress but is absent during sleep. The absence of insight about the movement disorder is striking in patients. Most cases remit spontaneously. Elderly have a poor spontaneous resolution. Tardive dyskinesia is less likely to remit in elderly patients than in young patients, however. Clozapine can reduce the risk and also treat TD. Dose reduction, withdrawal of the drug, switch to newer atypicals or adding clonazepam can be considered. Neuroleptic Malignant Syndrome Can occur at any time during treatment with neuroleptics RISK FACTORS FOR TARDIVE DYSKINESIA Female gender Elderly Diabetics Previous brain damage Affective illness rather than pure psychotic disorder Children Learning disabled Afro-Caribbean race Long term co-prescription of anticholinergics Frequent drug holidays – will lead to high dose prescription with each relapse
© SPMM Course 8 Consists of the tetrad of extreme hyperthermia, severe muscular rigidity and confusion, and autonomic fluctuations (BP and pulse rate). Patients may be akinetic and mute. Increased WBC count, creatinine phosphokinase, liver enzymes, plasma myoglobin, and myoglobinuria are noted. Subacute onset in 24 to 72 hours, and if untreated lasts 10 to 14 days. More common in young men, after agitation and when using high potency drugs especially in rapid tranquillisation situations. Dopaminergic drugs on withdrawal can produce NMS. The mechanism may be related to dopamine blockade or hypothalamic sympathetic dysregulation. The mortality rate is around 20-30% if untreated and higher if depot is used. Symptomatic management of vital signs instability, fluid replacement and prevention of renal failure secondary to myoglobinuria and prevention of aspiration pneumonia are main treatment methods after immediate stopping of offending psychotropic. Dantrolene, Bromocriptine or amantadine can be used. Low potency or atypical must be used following recovery for an antipsychotic prescription. Agranulocytosis Occurs in around 1 per 100 patients on clozapine. This is 15 to 30 times higher than the risk associated with phenothiazines and olanzapine. The maximum risk is between 4 and 18 weeks, and after a year the risk is same as with phenothiazines. Weekly monitoring of the white cell count is required for 26 weeks in most countries, with the frequency decreasing to biweekly or monthly thereafter. In the UK, yellow, green and red signals are used in WBC monitoring. When a result is red, clozapine must be stopped and never tried again. If yellow, then monitoring frequency must be increased until a green signal is obtained again. Benign neutropenia is common especially in south Asian and Afro-Caribbean race. Lithium can increase WBC count albeit transiently. Some anecdotal evidence supports using lithium in patients with benign ethnic neutropenia in preparation for clozapine use. But lithium and clozapine together can increase the risk of seizures and confusion. Clozapine, when combined with carbamazepine, phenytoin, propylthiouracil, sulfonamides, and captopril, can increase the risk of agranulocytosis further. Paroxetine may precipitate clozapine-associated neutropenia. Many side effects of clozapine such as salivation, sedation, and weight gain, fatigue and lowering of seizure threshold are dose related. But agranulocytosis and myocarditis can occur at any dose.
© SPMM Course 9 Transient leucopenia can occur with typical neuroleptics. But agranulocytosis is the rare effect. Sexual dysfunction: Increased dopaminergic transmission can enhance sexual arousal and penile erection. Hyperprolactinaemia can result in loss of sexual arousal and erectile dysfunction in men; amenorrhoea, reduced sexual desire and hirsutism in women. Antipsychotics reduce sexual performance both directly by reducing dopaminergic transmission and indirectly through inducing hyperprolactinaemia. 43% of those taking antipsychotics report sexual dysfunction at some point, not all of this attributable to the drug. Neuroleptic agents commonly cause ejaculatory problems. Total inhibition of ejaculation (dryejaculation), reduced ejaculatory volume and ‘retrograde’ ejaculation are the various effects associated with conventional neuroleptics and also clozapine, risperidone and olanzapine. Drug-induced priapism is related to simultaneous α1-adrenergic blockade and anticholinergic activity. The most commonly reported associations are with antipsychotic drugs (20% of all reported priapisms) followed by trazodone. Antipsychotics implicated in this problem include risperidone, chlorpromazine clozapine, olanzapine and thioridazine. The risk is doseindependent and can occur at any time during the course of treatment (duration-independent). Priapism is a urological emergency and can lead to permanent impotence if untreated. Dopaminergic agonist bromocriptine is used to treat sexual dysfunction in men that is associated with hyperprolactinaemia. Other side effects Seizure threshold is lowered especially by low potency antipsychotics. Molindone may be the least epileptogenic. This is a dose-dependent effect. Chlorpromazine is the most sedating typical antipsychotic – mediated by H1 antihistaminic action – tolerance usually develops for this effect. Low potency agents can also cause anticholinergic syndrome (see TCAs). Neuroleptics can decrease cardiac contractility, increase circulating levels of catecholamines, and prolong atrial and ventricular conduction time. Low-potency drugs are more cardiotoxic than high-potency drugs. ECG shows QT and PR prolongation, blunting of the T waves, and ST depression. Thioridazine and droperidol, in particular, can cause torsade de pointes. Antipsychotic related sudden death may be due to cardiac arrhythmias or even seizures asphyxiation or malignant hyperthermia. Drugs causing QT prolongation are associated with more sudden deaths (e.g. thioridazine). Postural hypotension is most common with
© SPMM Course 10 low-potency drugs, and tolerance develops soon. Patients should avoid all caffeine and alcohol, drink plenty of fluid and liberal salt in food. Low-potency drugs can cause weight gain but not as much as is atypical drugs. Nearly 50% of men taking antipsychotics report ejaculatory and erectile disturbances. Thioridazine is particularly associated with decreased libido and retrograde ejaculation in men. Allergic dermatitis and photosensitivity can occur with low-potency agents. Long-term chlorpromazine use can cause blue-gray discoloration of skin areas exposed to sunlight. This is reversible. Irreversible retinal pigmentation is associated with the use of high dose thioridazine (above 1000 mg a day). An early symptom of the side effect can sometimes be nocturnal confusion associatd to difficulty with night vision. This pigmentation is irreversible and can progress even after stopping thioridazine. Chlorpromazine related pigmentation of the anterior lens and the posterior cornea is seen as whitish brown stellate granular deposits noted in slit lamp – this is benign and not vision impairing. This can resolve gradually unlike thioridazine related retinal damage. Chlorpromazine is associated with cases of obstructive or cholestatic jaundice especially in the first month of treatment associated with rash and eosinophilia. Immediate discontinuation and avoidance of rechallenge are advised. Haloperidol isone of the safest typical antipsychotics in overdose. After an overdose, the electroencephalogram (EEG) shows diffuse slowing and low voltage. QT prolongation: Prolongation of the QT interval is mediated by blockade of the rapid component of the delayed rectifier potassium current (IKr) responsible for repolarisation of cardiac Purkinje cells and myocardial cells. Many drugs, including certain antipsychotics and antidepressants, bind to this potassium channel and thereby decrease the outward movement of potassium. Some antipsychotics – especially droperidol, pimozide, sertindole and thioridazine – have a greater capacity than others to cause IKr blockade. InAdvertent IntraVascular injection event (IAIV) or postinjection delirium sedation syndrome (PDSS) has been described after olanzapine pamoate (long-acting depot) injections. Within 20 min to 3 hours of injection, patients present with sedation, confusion, dizziness, altered speech/dysarthria, and somnolence, symptoms that are consistent with those reported in the case of oral olanzapine overdose. Rarely deep coma may ensue. Medical hospitalization and supportive medical care are usually sufficient to ensure full recovery (usually within 3–72 hours). This effect is linked to accidental punctures of a vessel or injections into a rich capillary bed during administration, leading to quick dissolution and release of free olanzapine. Eli Lilly has recommended a postinjection
© SPMM Course 11 observation period of at least 1 - 3 hours in a healthcare facility and to avoid driving or operating heavy machinery in the 24 hours after injection. Metabolic syndrome Metabolic syndrome is a cluster of disorders comprising obesity (central and abdominal), dyslipidaemias, glucose intolerance, insulin resistance (or hyperinsulinaemia) and hypertension. It is highly predictive of type 2 diabetes mellitus and cardiovascular disease. Diabetes Mellitus is twice as prevalent among schizophrenia cohorts than in the general population Unaffected first-degree relatives of patients with schizophrenia share a propensity fortype 2 diabetes mellitus (19-30%); this suggests a genetic association between these two disorders Schizophrenia patients have 3 times greater intra-abdominal fat (IAF) than the control group, increasing the risk for metabolic syndrome. In the pre-antipsychotic era over 15% of drug-naïve individuals with first-episode schizophrenia had impaired fasting glucose levels, hyperinsulinaemia and high levels of cortisol. Both typicals and atypicals increase the risk of metabolic syndrome in schizophrenia manifold. But antipsychotics cannot explain all the metabolic dysfunctions noted in schizophrenia. The frequency of metabolic syndrome was 2-4 times higher in a group of people with schizophrenia treated with either typical or atypical antipsychotics. MOST Olanzapine / clozapine quetiapine risperidone ziprasidone aripiprazole/ lurasidone LEAST World Health Organization criteria for metabolic syndrome •Insulin resistance and/or impaired fasting glucose and/or impaired glucose tolerance AND two or more of the following: •Waist - hip ratio >0.90 (men), >0.85 (women) OR body mass index 30 kg/m2; •Triglyceride level 1.7 mmol/l OR high-density lipoprotein <0.9 mml/l (men), <1.0 mmol/l (women); •Blood pressure 140/90 mmHg (or treated hypertension); •Microalbuminuria. (This is not presented in some revised criteria for metabolic syndrome)
© SPMM Course 12 In Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial baseline data (n = 689), the metabolic syndrome was prevalent in 51.6% of female patients and 36.0% of male patients. Females with schizophrenia have a higher risk than males with schizophrenia when compared with a reference population. Mean weight increases during the first year of therapy o 12 to 14lb for clozapine (5 to 6 kg) o 15 to 26lb for olanzapine (7 to 12kg) o 6 to 12lb for quetiapine (2.5 to 5kg) o Up to 5lb for risperidone (2 to 2.5kg) o Less than 2lb for Ziprasidone and aripiprazole For patients with schizophrenia, the best-studied options for weight control include diet and exercise. But controlled behavioral programs for weight reduction in schizophrenia have high dropout rates and are not always accessible. Switch to relatively weight neutral drugs can be considered in resistant cases. CATIE summary CATIE stands for Clinical Antipsychotic Trials of Intervention Effectiveness. The study design was double-blind pragmatic RCT. 1493 patients with chronic schizophrenia (mean duration of illness = 14 years), 57 sites, 2001 to 2004 Olanzapine, quetiapine, Risperidone, ziprasidone (added later in the trial), perphenazine Primary outcome is a ‘real-world’ measure – discontinuation for any reason, either patient-initiated or physician initiated 76% power to detect 12% difference in primary outcome Irrespective of the prescribed drug – 74% discontinued treatment in 18 months (surprisingly high despite naturalistic design). The median time to stop was 4.6 months. Olanzapine had lowest discontinuation rate (still 64%) – but highest side effect burden. 64% discontinued olanzapine; 75%, perphenazine; 82%, quetiapine; 74%, risperidone; and 79%, ziprasidone. Olanzapine caused most weight gain while quetiapine caused most anticholinergic symptoms; perphenazine had highest EPSE related discontinuation. Those who did not respond after 18 months (those who discontinued for the ineffectiveness of therapy) were re-randomised in phase 2 trial (n=99), and Clozapine was compared to other atypical agents (efficacy pathway). Clozapine had lowest discontinuation rate – median at 10 months. This time-to-discontinuation was nearly 3 times longer than time-to-discontinuation with the other SGAs. Quetiapine had comparatively less EPSEs. As a part of the phase 2 CATIE study (tolerance pathway) those who terminated phase 1 for ‘‘intolerable side effects’’ (444 volunteers) were tested with olanzapine, risperidone, quetiapine, or ziprasidone. Of these treatments, olanzapine and risperidone had equivalent effectiveness, and both were better than quetiapine or ziprasidone by significant but modest margins. CATIE Controversies o Quite complicated study design and many outcomes were analysed from the dataset. o Decisions to add ziprasidone to the protocol was made after recruitment began o Perphenazine was used only in one randomized phase (phase 1) of the study generating controversy.
© SPMM Course 13 o The decision to use double-blinded treatments decreased the resemblance of the study procedures to those of routine clinical care The mean doses used remain controversial though it is claimed that the study was designed to be pragmatic and not purely experimental. CUtLASS summary: CUtLASS stands for Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study It is an unblinded randomised controlled trial comparing first-generation v. second-generation antipsychotics The primary outcome was the quality of life at 1 year and symptom measures were the main secondary outcome. 1, 227 people with schizophrenia who were being assessed by their clinical team for medication review because of poor response or adverse effects were randomised. The second-generation drugs were amisulpride, olanzapine, quetiapine or risperidone. The rate of follow-up interview was 81% at 1 year. The results showed no advantage of second-generation drugs in terms of quality of life or symptom burden over 1 year with those on first-generation antipsychotic doing relatively better. Participants reported no clear preference for either class of drug. The second phase - CUtLASS 2 trial was of similar design and compared clozapine with other secondgeneration drugs in 136 patients who had not responded well to two or more previous drugs. Results showed that there was a significant advantage for clozapine in symptom improvements over 1 year; moreover, patients significantly preferred it.
© SPMM Course 14 4. Antidepressants - adverse effects Tricyclic agents Side effects of TCAs are related to anticholinergic, antihistaminic and antiadrenergic properties. Clomipramine is a more selective inhibitor of serotonergic reuptake selective; desipramine is the most noradrenergic selective of TCAs. Amoxapine, nortriptyline, desipramine, and maprotiline have the least anticholinergic activity; doxepin has the most antihistaminic activity. The TCAs are less likely to cause sexual dysfunction and insomnia than the SSRIs. Amitriptyline is associated with weight gain (antihistaminic effect – weight gain can also occur secondary to 5HTc antagonism in other antidepressants). TCAs may cause QT prolongation. Even at therapeutic doses, the TCAs cause tachycardia, flattened T waves, prolonged QT intervals, and depressed ST segment. TCAs are lethal in overdose, causing cardiac arrhythmias and anticholinergic delirium. This may occur 3-4 days after overdose due to the long half-life. No specific antidote available; needs lavage and QRS monitoring. Anticholinergic delirium is characterized by symptoms often described as ‘Mad as a hatter, (confusion, disorientation, visual hallucinations), Hot as a hare (hyperpyrexia), Blind as a bat (loss of visual accommodation), Red as a beet (peripheral vasodilatation) and Dry as a bone (drying of mucous membranes)’. Amoxapine can cause hyperprolactinemia as it has dopamine antagonistic effects. SIADH and hyponatremia can occur with TCAs. Fine rapid tremor and dysarthria are sometimes reported with TCAs. Tricyclic agents such as amitriptyline and imipramine and the nontricyclic agents such as mianserin hydrochloride have been documented to precipitate an attack of angle closure glaucoma. TCA discontinuation: Can cause cholinergic rebound – best to reduce 25 to 50mg per 2-3 days. Discontinuation reaction may occur as early as 48 hours or as late as 2 weeks after discontinuation. Propantheline or reinstitution of withdrawn TCA can reduce cholinergic rebound symptoms.
© SPMM Course 15 NMS vs. serotonin syndrome NMS Serotonin syndrome Dopamine antagonism and suspected hypothalamic mediated sympathetic overdrive. Excess serotonin availability Onset subacute – days to weeks Sudden minutes to hours onset Resolves in 2 weeks - depending on t1/2 of offending drug Resolves as soon as excess serotonin is reduced – in 24 hours generally No myoclonus Myoclonus prominent Hypomania, not a feature Hypomania may be seen Reflexes normal or absent Hyperreflexia seen Rhabdomyolysis, resultant renal failure and acidosis occur commonly Muscle breakdown not common •Serotonin syndrome is a result of excessive serotonergic transmission in brain. Although no single mechanism appears to be responsible for all of the noted effects, most CNS symptoms are possibly mediated via 5HT 2A receptor stimulation. Mechanism of Serotonin Syndrome •It is characterized by diarrhea, myoclonus, diaphoresis, hyperactive reflexes, ataxia, hypomanic or labile mood, tremors and disorientation. • It may mimic NMS or anticholinergic syndrome in those receiving psychotropics. Features of serotonin syndrome •Any serotonergic agent on overdose – including SSRI and TCA antidepressants, fenfluramine, LSD, ecstasy, anti-migraine (e.g. sumatriptan) drugs. •High risk with combinations of SSRI and MAOI or RIMA or SSRI themselves, or TCAs especially serotonergic, or SNRI, lithium or l-tryptophan. TCA and MAOI combinations. Tramadol, pethidine, meperidine can also cause serotonin syndrome on combination with the above agents. •Oxazolidinone antibacterial linezolid (which is a reversible non-selective MAOI), tetrabenazine (acts via dopamine and serotonin depletion at nerve endings), entacapone (COMT inhibitor) and selegiline are also implicated. Drugs with high risk of serotonin syndrome: •Withdraw the offending agent •Supportive care: correction of vital signs •Benzodiazepines •5HT2A antagonists: cyproheptadine, atypical antipsychotics, chlorpromazine (? mirtazapine – controversial reports) •In severe cases neuromuscular paralysis and intubation may be required Treatment of Serotonin syndrome:
© SPMM Course 16 CPK elevation common; WBC also elevated These laboratory abnormalities are less frequent in serotonin syndrome SSRI antidepressants Nausea, vomiting, anorexia, and diarrhea are common side effects of SSRIs – these are somewhat dose-dependent and can be lessened by dose reduction or a slower titration. SSRIs (similar to TCAs, but less frequently) cause weight gain in up to 30% of patients especially in long-term maintenance phase. During initial treatment insomnia and anorexia are often present. Desensitization and down-regulation of receptors may explain the reversal of the initial SSRI appetitesuppressing effects, which can ultimately lead to weight gain late during therapy. Sexual difficulties such as reduced libido, impotence, ejaculatory dysfunction, and anorgasmia are reported with SSRIs. The incidence of sexual dysfunction is nearly every 1 in 3 patients treated. Akathisia like effects, EPSEs and galactorrhea are rarely reported with SSRIs. Also, fluoxetine is associated with a change in the duration of menstrual period – significance of this is unknown. SSRIs can cause functional impairment of platelet aggregation (thrombasthenia), but not a reduction in platelet number. This can cause easy bruising or prolonged bleeding in those with gastric ulcers or bleeding diathesis. SIADH is also reported; this is often troublesome in alcoholics and the elderly causing hyponatremia, hyperkalemia, hypo-osmolality in serum and increased osmolality of urine. Stopping the offending drug, using demeclocycline and fluid restriction can help. Severe sweating especially nocturnally is seen in some patients; Terazosin is effective in counteracting sweating. Nocturnal myoclonus is reported with SSRIs. The repetitive leg movements occur every 20 to 60 seconds, with extensions of the large toe and flexion of the ankle, the knee, and the hips. Benzodiazepines and levodopa may be tried. In restless leg syndrome, patients complain of creeping deep sensations that cause an irresistible urge to move the legs – disturbing sleep. It is associated with SSRIs and treatment is possible using ropinirole or benzodiazepines and levodopa. Duloxetine, venlafaxine, citalopram, fluoxetine and paroxetine can induce acute angleclosure glaucoma. The pathophysiological mechanism of SSRI –precipitated glaucoma remains unclear; anticholinergic effects or increased level of serotonin, which cause partial pupillary dilation have been implicated. SSRI discontinuation syndrome: The abrupt withdrawal of SSRI especially paroxetine (additional cholinergic rebound) or fluvoxamine (shorter half-life), is associated with a discontinuation syndrome. It usually requires at least 4-6 weeks of treatment before
© SPMM Course 17 discontinuation and resolves spontaneously in 3 weeks. Those who have significant SSRI intolerance during treatment onset will have more discontinuation reactions. Fluoxetine is the SSRI least likely to cause withdrawal syndrome as its metabolite has a long half-life (more than 1 week), producing a slow self-tapering effect in plasma. Fluoxetine in some cases can be used to even treat discontinuation syndrome or to prevent it when stopping another SSRI agent. But a delayed withdrawal syndrome has been reported with fluoxetine in some cases. SSRI discontinuation syndrome Criterion A Discontinuation or reduction of dose of SSRI after at least 1 month use Criterion B 2 or more of the following seen within 1-7days of criterion A causing significant functional impairment and not due to a general medical condition: x Dizziness, lightheadedness, shock-like sensations (paresthesias), diarrhea, fatigue, gait instability, headache, insomnia, nausea, tremors, visual disturbances Suicide risk and SSRIs: A link between antidepressant use and suicidal ideation among those up to age 24 in short-term (4 to 16 weeks), placebo-controlled trials of nine antidepressant drugs has been reported. The average risk of suicidal thinking or behavior during the first few months of treatment in those receiving antidepressants was 4 percent while placebo produces a risk of 2 percent. Ecological studies indicate that since the introduction of large scale SSRI prescription for every 10% rise in prescription 3% decline in suicide rates has happened in certain countries. It is also noted that patients were significantly more likely to attempt/commit suicide in the month before they began drug therapy than in the 6 months after starting it. But the issue still remains controversial, and MHRA has advised against certain SSRI prescriptions in children and adolescents. SSRIs increase the risk of upper GI bleeding especially in the elderly and in those using NSAIDs. SSRIs inhibit the uptake of serotonin into platelets; serotonin is crucial for the haemostatic response of promoting platelet aggregation. Further, SSRIs also increase gastric acid secretion thus elevating the risk of gastric erosion, ulcer and bleeding. Alcohol intake and being positive for H.pylori will also increase the risk of GI bleeding when prescribing SSRIs. Antidepressants with low inhibition of serotonin reuptake (e.g. nortriptyline, doxepin, trazodone) are safer in this regard when compared to those with high inhibition of serotonin reuptake (e.g. clomipramine, paroxetine, sertraline, fluoxetine). Increased serotonergic neurotransmission can adversely affect sexual performance; this explains SSRI-induced sexual dysfunction. Some antidepressants (bupropion, mirtazapine, moclobemide, nefazodone and reboxetine) may be associated with a relatively lower incidence of sexual dysfunction. 5-HT2 antagonists, (e.g. cyproheptadine, mirtazapine), 5-HT1a
© SPMM Course 18 agonists, (e.g. buspirone) and bupropion (being a dopamine reuptake inhibitor) can reverse sexual dysfunction related to SSRI use. A nitric oxide-dependent second messenger (cGMP) mediates penile vasodilatation. cGMP is eventually broken down by phosphodiesterase type 5 enzyme. Sildenafil is an inhibitor of phosphodiesterase type 5, an action that enhances penile erection in patients with erectile dysfunction. Sildenafil (Viagra) has been tried successfully in the treatment of SSRI-induced erectile dysfunction. The side effects of sildenafil include headaches (most common), dizziness, blurred vision and a blue tinge to vision. Very rarely, persistent painful erection (priapism) can occur. Sildenafil must be avoided by patients with arrhythmias, unstable angina / uncontrolled hypertension. Other antidepressants Venlafaxine: Sweating is more common than in SSRIs and is treated by terazosin. Significant numbers of patients receiving doses above 300mg/day experience an increase in diastolic blood pressure. This risk is not restricted to those with preexisting hypertension. Mydriasis and exacerbation of angle closure glaucoma are reported with venlafaxine; significant discontinuation reactions are reported due to the shorter half-life of venlafaxine – tapering gradually over 2-4 weeks is recommended. Duloxetine has side effects similar to venlafaxine, but fewer propensities to affect blood pressure. Trazodone is associated with priapism that can be serious if unattended. The first step in the emergency management of priapism is the intracavernosal injection of an alpha1 agonist such as metaraminol or epinephrine. The risk of priapism is greatest during the early phase of treatment. Nefazodone inhibits CYP3A4 and can cause serious hepatic damage and hence not used as often now. Though anticholinergic effects are predominantly absent, alpha1 antiadrenergic effects can produce pseudo-anticholinergic symptoms. Afterimage formation similar to the LSD related tracking phenomenon is reported in up to 12% patients on nefazodone. Both trazodone and nefazodone have a favourable profile for elderly and those with cardiac illness. Bupropion has a very different side-effect profile than the conventional antidepressants. It has no anticholinergic effects, does not cause sedation or weight gain and cause almost negligible sexual side effects compared to other classes of antidepressants. It does not cause orthostatic hypotension or cardiac side effects. It can exacerbate ADHD, eating disorders and tics in those with ADHD. It can enhance sexual activity unlike SSRIs; it increases the risk of seizures in a dose-dependent fashion. Headache, insomnia, dry mouth, tremor, and nausea are the most common side effects of bupropion. Severe anxiety or panic can be exacerbated by bupropion. Due to its effects on dopaminergic neurotransmission bupropion can cause
© SPMM Course 19 psychotic symptoms as well as delirium. Bupropion can cause word-finding difficulties in some patients. Agranulocytosis is reported with mirtazapine use. Hence, signs of infection need to be promptly followed. Buspirone can increase concentrations of haloperidol. Buspirone + MAOI can cause serotonin syndrome; 2-week washout period is recommended. CYP3A4 inhibitors such as erythromycin, itraconazole, nefazodone and grapefruit juice, increase buspirone plasma concentrations. Buspirone does not cause weight gain, sexual dysfunction, discontinuation symptoms, or significant sleep disturbance. It does not produce sedation. Mianserin and mirtazapine produce drowsiness during the first weeks of treatment but has a low propensity to produce orthostatic hypotension or cardiac effects. Increased weight gain and appetite are also noted while sexual side effects are minimal. 5-HT3 blockade is associated with a reduction in nausea and vomiting; hence to treat depression associated with cancer chemotherapy, mirtazapine is a preferred option. Reboxetine is a noradrenaline reuptake inhibitor (NARI) with negligible serotonergic effects. It has a safe cardiovascular profile and can be used in the elderly. Atomoxetine belongs to the same group but not used as an antidepressant; it is used in ADHD. Reboxetine has a specific side-effect profile linked to the noradrenergic system. Urinary hesitancy has been observed in around 10% of male patients taking part in the clinical trials. Relief from this side effect could be achieved by using tamsulosin, a peripheral alpha1-receptor blocker or doxazosin with a similar mechanism of action as tamsulosin. MAOIs such as phenelzine can induce orthostatic hypotension, pedal edema and insomnia. Apart from cheese reaction, MAOIs can also cause serotonin syndrome in combination with serotonergic agents. Tranylcypromine, and phenelzine to some extent can have stimulating effects leading to insomnia – hence the last dose is best given before 6 PM. Weight gain and sexual dysfunction are also reported. Cheese reaction: o MAOIs and tyramine (and other monoamine) rich foods interact to cause cheese reaction or tyramine reaction. o Tyramine has both direct and indirect (via vesicular release) sympathomimetic actions that develop 20 min to 1 h following ingestion of food. o It is characterized by nausea, apprehension, occasional chills, sweating, restlessness and hypotension with occipital headache, palpitations, and vomiting. o Sympathetic overdrive manifests as piloerection dilated pupils and fever. If severe cerebral hemorrhage and death can occur.
© SPMM Course 20 o In terms of the frequency and severity of the hypertensive crisis, the reversible MAOIs are safer. o Food materials to be avoided include any mature cheese such as Stilton, blue cheese, old cheddar and mozzarella. Fish, cured meats, sausage must be avoided together with mature poultry, wild game etc., liqueurs and concentrated yeast extract. o An MAOI-induced hypertensive crisis can be treated with alpha-adrenergic antagonists such as phentolamine or even chlorpromazine, which is immediately available in most psychiatric wards. This can lower blood pressure in few minutes.
© SPMM Course 21 5. Antimanic agents - adverse effects Renal effects Certain side effects including polyuria seems to be associated with peak lithium levels; once daily instead of twice daily dosing can reduce these problems. Nearly 1/3rd of those treated will have this side effect, but tolerance develops in due course; functional antagonism of ADH by lithium ion is considered to be the underlying mechanism. Use of K+ sparing diuretics such as amiloride or spironolactone can control polyuria. Renal damage may occur in severe, prolonged toxicity – but cumulative lithium use rather than toxicity leads more commonly to renal failure in lithium users. Chronic exposure longer than 10 years induces interstitial fibrosis resulting in chronic renal damage. Lithium has a narrow therapeutic index. Lithium toxicity occurs in conditions of overdose or dehydration. Non-specific gastrointestinal symptoms usually precede the more serious neurological symptoms and renal shutdown. Immediate cessation of lithium followed by urgent medical attention is required as some patients may require a hemodialysis if levels exceed 4mEq/L. Topiramate is a weak inhibitor of carbonic anhydrase and can promote the development of renal stones. SIADH may be seen with valproate use though more common with carbamazepine; it is dependent on the dose prescribed. Oxcarbazepine is a 10-keto derivative of CBZ with an identical profile but less enzyme induction and fewer drug–drug interactions. It produces less rash and neurotoxicity but more hyponatremia than CBZ. Cardiac effects ECG effects of therapeutic lithium dose are similar to hypokalemia – with flat T waves, or inverted T. Lithium can depress sinus node activity and so is contraindicated in sick sinus syndrome. Endocrine effects Lithium can cause a variety of thyroid problems – the most common being a benign hypothyroid state. 5% patients may develop goiter, and overt hyperthyroidism is also reported in some cases. Thyroid deficiency is common in those with high risk for preexisting antithyroid antibodies (especially middle-aged women). The risk is 3-4:1 in women and is high in first 2 years of treatment. Rapid cycling patients are at higher risk. High TSH is seen in nearly 1/3rd of chronic lithium-treated patients even in the absence of clinical hypothyroidism. In resistant depression
© SPMM Course 22 and in non-responsive rapid cyclers with bipolar disorder, using thyroxine to treat subclinical hypothyroidism may be beneficial for the mood disorder. Polycystic ovaries (PCO): 25 - 33% UK population of adult females have PCO morphology notable in ultrasound. 5-26% may have actual PCOD, which is defined as having PCO in ultrasound with hyperandrogenism or LH disturbance. 10% woman on valproate have new onset PCOD. The relative risk is 7.5 for PCOD. On stopping most people remit from PCOD. The exact mechanism by which valproate might causes PCOD remains unknown, although several mechanisms are proposed. For example, valproate increases ovarian androgen production. It also can result in weight gain and insulin resistance, both risk factors for PCOD. In the liver, the drug can increase unbound testosterone. Epilepsy, for which valproate is widely used, is tipped to increase PCOD occurrence. Such association has not been established so far for bipolar disorder. Almost all patients who develop oligomenorrhea develop it in first year of treatment with valproate. Haematological effects Lithium can cause leucocytosis that can be therapeutically utilized in some cases of benign neutropenia related to clozapine use. This is not widely practiced. Around 10% of individuals taking carbamazepine will see gradual onset leucopenia in first 3months of treatment. This is reversible on continued treatment or dose reduction. Thrombocytopenia is a dose-related effect of valproate and carbamazepine – a reduction in dose is required if bruising, or bleeding gums is noted. Neurological effects Fine tremor is a common benign side effect of lithium, and coarse tremor is a sign of toxicity. Propranolol can be used in treating lithium-induced fine tremor at therapeutic levels. Lamotrigine is generally well tolerated but can cause dizziness, ataxia, headache, sedation, tremor, and nausea. Topiramate can produce word finding difficulties (anomia) and poor concentration Vigabatrin, an antiepileptic with no significant antimanic efficiency, has been tried in some openlabel trials. It has a peculiar side effect of causing visual field defects.
© SPMM Course 23 Gastrointestinal effects Valproate inhibits hepatic enzymes; in some cases the acute liver injury may occur though this is rare in clinical practice. Of persons taking valproate, 5 to 40 percent experience a persistent but clinically insignificant elevation in liver transaminases up to three times the upper limit of normal, which is usually asymptomatic and resolves after discontinuation of the drug (termed ‘transaminitis’). Liver failure is reported with valproate, lamotrigine, topiramate and carbamazepine. Risk factors include young age and combination therapy. This is caused by 2 mechanisms: 1. Metabolic toxicity e.g. due to 4-en valproate, a metabolite of valproate. 2. Hypersensitivity - doseindependent effect is resulting in fulminant failure. Severe hepatic damage associated with valproate is seen especially in those with learning disability when undiagnosed urea cycle disorders are present (less than 2 years often). Another rare side effect of valproate is acute pancreatitis. This is a hypersensitivity reaction; dose reduction will not be helpful. Hyperammonemia can be associated with coarse tremor and carbamazepine co-prescription; it may respond to L-carnitine administration. Valproate competes with carnitine transport and can induce a state of carnitine depletion especially in children and in epileptics. Teratogenic effects The most common teratogenic effect of lithium involves cardiac valves especially Ebstein's anomaly of the tricuspid valves. The risk of Ebstein's malformation in lithium-exposed fetuses is 1 of 1,000 (20 times the risk in the general population). Lithium’s teratogenic effects are somewhat lower than that caused by the use of valproate or carbamazepine. Lithium is excreted into breast milk, and signs of lithium toxicity in infants include lethargy, cyanosis and sluggish neonatal reflexes. Valproate causes neural tube defects as a teratogenic effect in 1% to 4% mothers. Folate-vitamin B complex supplementation for all young women of childbearing potential may reduce risk though it is best to avoid valproate totally. Learning disability and low IQ in children is the most common teratogenic effect of valproate. Skin effects Exacerbation of acne and psoriasis are associated with lithium therapy. Alopecia / hair loss occurs in 5 to 10 percent. It is not clear if zinc and selenium supplementation can reverse or prevent the latter effect.
© SPMM Course 24 Valproate can cause obesity, hyperandrogenism and PCOD associated with hirsutism. Anticonvulsant hypersensitivity syndrome is seen in 0.1% of patients taking anticonvulsants. Aromatic compounds (lamotrigine, carbamazepine, phenytoin and phenobarbitone) are especially risky. 5 to 20% of those taking aromatic anticonvulsants will experience a rash. Lamotrigine can cause a rash in 10% of patients. Risk factors for rash include rapid initial dose escalation, concurrent VPA, and age less than 16 years. As benign rashes cannot be distinguished from potentially serious ones, any rash requires discontinuation of the drug. Lamotrigine carries a significant risk of Steven Johnson Syndrome (SJS – risk of 1 in 3000) especially if administered together with Valproate as the enzyme inhibiting effects of Valproate may increase lamotrigine levels. SJS starts with a rash, pharyngitis and fever. Systemic involvement follows quickly if the drug is not stopped. Drug Dose-related effects Idiosyncratic reactions Carbamazepine Visual disturbances, GI disturbances, cognitive impairment, vertigo and, dizziness. Hematological reactions including agranulocytosis or aplastic anemia, idiosyncratic Stevens-Johnson syndrome, fulminant hepatic damage, and pancreatitis. SIADH is more common in the elderly Valproate Hyperammonemia, Teratogenicity, Sedation, Thrombocytopenia Hepatotoxicity, pancreatitis, rash and rarely acute dermatitis. Weight related effects Weight gain is common (70% of those taking valproate and 40% of those taking carbamazepine over 12 months will experience weight gain); valproate induced weight gain is considered to be due to impaired beta-oxidation of fatty acids, and thus independent of calorie intake. Lamotrigine is often weight neutral Topiramate is weight neutral and can even cause weight loss. Topiramate can be potentially used to counteract the weight gain caused by many psychotropic drugs.
© SPMM Course 25 6. Other agents - adverse effects Cholinesterase inhibitors: Donepezil causes nausea, diarrhea, insomnia, vomiting, muscle cramps commonly. Rivastigmine causes similar symptoms albeit at a higher frequency of some. Galantamine too has a similar profile. Tacrine is not used anymore in UK due to reports of fatal hepatotoxicity. By increasing central and peripheral cholinergic stimulation cholinesterase inhibitors, can 1. Increase the risk for GI bleeding especially in NSAID users or patients with peptic ulcer. 2. Produce bradycardia, especially in those with supraventricular conduction delay, 3. Exacerbate COPD 4. Cause urinary retention 5. Increase seizure risk 6. Prolong the effects of succinylcholine-type muscle relaxants Rivastigmine’s metabolism does not depend on liver P450 enzymes, and, therefore, no drug interactions related to the P450 system have been observed. Memantine does not inhibit or induce hepatic microsomal enzymes; because it is excreted in the urine predominantly as unchanged drug, it is unlikely to be affected by drugs that affect hepatic enzyme function. Stimulants and other drugs used for ADHD: The most common adverse effects are anxiety, irritability, insomnia, tachycardia, cardiac arrhythmias, and dysphoria with decreased appetite. Tolerance usually develops for appetite loss. Less commonly self-limited exacerbation of movement disorders, such as tics and dyskinesias, may occur. Stimulants are linked to growth suppression. Bruxism and restlessness are also reported. Pemoline is associated with fulminant hepatic failure and is no longer used widely. Dependence can occur with methylphenidate though this is rare at doses used for ADHD. Side effects of atomoxetine are appetite loss, sexual dysfunction and dizziness; severe liver injury in has also been reported. Clonidine is not a popular option for treating tics/ADHD due to high rates of hypotension associated with it. Hypnotics: Overdose of benzodiazepines can produce slurred speech, incoordination, unsteady gait, nystagmus, impairment in attention or memory, stupor or coma and behavioural changes (inappropriate sexual or aggressive behaviour, mood lability, impaired judgment etc.).
© SPMM Course 26 High-potency benzodiazepines such as triazolam can cause anterograde amnesia. Paradoxical disinhibition is seen in a few patients especially when preexisting brain damage is present. Triazolam is banned in UK since 1991 following reports of disinhibition and aggression. Benzodiazepines can produce respiratory impairment especially in those with COPD or sleep apnea. Benzodiazepines are better avoided in those with myasthenia gravis, head injury or porphyria due to this risk. Alprazolam can cause weight gain via appetite stimulation. Cleft palate and lips are teratogenic effects associated with benzodiazepines; withdrawal syndrome is seen in a neonate with third trimester use. Z-hypnotics have more potential to cause upset stomach and diarrhea compared with benzodiazepines. Eszopiclone’s unique temporary side effect is an unpleasant taste. It can also cause dry mouth especially in the elderly in a dose-dependent fashion. The occurrence of benzodiazepine withdrawal syndrome depends on The duration of treatment, The dosage prescribed, The rate of tapering and The half-life of the compound. Benzodiazepine withdrawal is characterized by anxiety, diaphoresis, kinaesthetic hallucinations, restlessness, irritability, light-headedness, tremor, insomnia, autonomic hyperactivity, and weakness. In severe cases, depression, paranoia, delirium, and grand mal seizures are seen. The syndrome can occur after 1 or 2 weeks in long-acting benzodiazepines. Alprazolam and lorazepam are associated with immediate and severe withdrawal syndrome and should be tapered gradually. Using prescribed benzodiazepines for 4 weeks or less rarely results in significant withdrawal symptoms. But if used for 4 months – 5-10% have withdrawals; in 2 years – 25-45% and in 6- 8years – 75% develop withdrawal syndrome and dependence pattern (Law et al. 2004). Slow taper at a rate of 25% per week, use of longer acting agents when tapering, avoiding longterm use of short-acting benzodiazepines, use of carbamazepine to assist discontinuation are the various strategies employed to manage withdrawal symptoms. 7. Psychiatric effects of non-psychiatric drugs
© SPMM Course 27 Non-psychiatric drugs Psychiatric side effects Beta-blockers Sedation, nightmares, dysphoria (nearly 50% in some samples) and depression. Psychiatric effects are seen only with lipophilic compounds e.g. metoprolol and propranolol. Angiotensinconverting enzyme (ACE) inhibitors Increased arousal, anxiety, fatigue, insomnia and increased psychomotor activity (4-8%) Clonidine Sedation or lethargy (35%); anxiety (3%), agitation (3%), depression (1%), and insomnia (1%). Nitrates/nitrites Delirium, psychosis (including delusions), anxiety, restlessness, agitation, and hypomania. Digoxin Depression and delirium (even in therapeutic levels) Statins Uncertain association with depression (evidence inconclusive) Corticosteroids Mood changes (mania more than depression), anxiety, agitation, lethargy. Dose-dependent. 1 in 6 patients has psychiatric side effects if prednisolone is prescribed in doses above 80mg/day. Symptoms start within 2 weeks. More common in females and those with past psychiatric history. Anabolic androgenic steroids Acute paranoia, delirium, mania or hypomania, homicidal rage, aggression, and extreme mood swings, as well as a marked increase in libido, irritability, agitation, and anger. Usually dose-dependent and resolve in 1-4 weeks after stopping the steroids. Gonadotropinreleasing hormone (GnRH) agonists (e.g. leuprolide) Depressive symptoms Interferon-alpha Nearly 40% develop psychiatric side effects; ~20% experience depression. Seen in first 12 weeks of treatment. Penicillin Sedation, anxiety and hallucinations Cephalosporins Delirium Ciprofloxacin and ofloxacin Restlessness, irritability, lethargy, tremors, insomnia, mania, depression, psychosis, delirium, seizures, or catatonia (incidence ≤1%) Isoniazid Delirium, mania, depression, and psychosis. Tetracyclines Depression, insomnia, and irritability at high dosages. Antihistamines and Atropine-like psychosis