Leche 4 ANTIDEPRESSANTS OBJECTIVES Define the following terms: Endogenous depression * Tricyclic antidepressant ‘+ Monoamine oxidase (MAO) inhibitor * Bipolar affective disorder * Second generation antidepressant You should be able to: ‘* Describe the probable mechanisms and the majof pharmacodynamic properties of tricyclic antidepressants. + List the toxic effects that occur during chronic therapy with tricyclic antidepressants. * Describe the therapeutic use and toxic effects of MAO inhibitors * Identify the major drug interactions associated with the use of antidepressant drugs.DRUGS USED IN AFFECTIVE DISORDERS ‘THE NATURE OF DEPRESSION ‘+ The symptoms of depression include emotional and biological components: > emotional symptoms: * misery, apathy and pessimism * low self-esteem: feelings of guilt, inadequacy and ugliness * indecisiveness, loss of motivation > biological symptoms * retardation of thought and action * loss of libido * sleep disturbance and loss of appetite * There are two distinct types of depressive syndrome, > unipolar depression, in which the mood swings are always in the same direction > bipolar affective disorder, in which depression alternates with mania. (excessive exuberance, enthusiasm and self-confidence, accompanied by impulsive actions) MONOAMINE THEORY OF DEPRESSION * The monoamine theory, proposed in 1965, suggests that depression results from functionally deficient monoaminergic (noradrenalin and/ot 5-HT) transmission in the CNS. * The theory was based on the ability of known antidepressant drugs (tricyclic antidepressants and monoamine oxidase inhibitors) to facilitate monoaminergic transmission, and of drugs such as reserpine to cause depression. ‘* Biochemical studies on depressed patients do not clearly support the monoamine hypothesis in its simple form. ‘* An abnormally weak response of plasma cortisol to exogenous steroid (dexamethasone suppression test) is common in depression and may reflect defective monoamine transmission in the hypothalamus. ‘Though the monoamine hypothesis in its simple form is insufficient as an explanation of depression, pharmacological manipulation of monoamine transmission remains the most successful therapeutic approach. ‘* Current approaches focus on other mediators (¢.g. corticotrophin-releasing hormone), signal transduction pathways, growth factors, ete, but theories remain imprecise. ‘TYPES OF ANTIDEPRESSANT DRUGS © Main types are: > monoamine uptake inhibitors (tricyclic antidepressants —TCA, selective S-HT reuptake inhibitors — SSRI and others) > monoamine oxidase inhibitors (MAOND miscellaneous (‘atypical’) antidepressants, mainly non-selective receptor antagonists (e.g. bupropion, trazodone, mirtazepine) * TCA and SSRI act by inhibiting uptake of noradrenaline and/or S-HT by monoaminergic nerve terminals, thus acutely facilitating transmission. ‘© MAOIs inhibit one or both forms of brain MAQ, thus increasing the cytosolic stores of noradrenaline and S-HT in nerve terminals. Inhibition of MAO-A correlates with antidepressant activity. Most are non-selective; moclobemide is specific for MAO-A.. ‘+ Mode of action of ‘atypical’ antidepressants is poorly understood.* All types of antidepressant drug take at least 2 weeks to produce any beneficial effects, even though their pharmacological effects are produced immediately, indicating that secondary adaptive changes are important, * The most consistent adaptive change seen with different types of antidepressant drug is downregulation of B and a2 adrenoceptors, as well as S-HT2 receptors. How this is related to therapeutic effect is not clear. ‘TESTING OF ANTIDEPRESSANT DRUGS ‘+ Animal models of depression include > leamed helplessness model, > reversal of reserpine-induced behavioural syndrome > mother-infant separation in primates. + None is a good model for human depressive illness, but they are the best available for testing new drugs * Biochemical and pharmacological measures include inhibition of monoamine uptake, receptor-blocking activity, enhancement of peripheral noradrenergic transmission, * Clinical testing of antidepressant drugs necessitates allowance for large placebo effects, TRICYCLIC ANTIDEPRESSANTS (TCA) * TCA are chemically related to phenothiazine, and some have similar non-selective receptor blocking actions. ‘+ Important examples are imipramine, amitriptylline and clomipramine. Widely used as antidepressants. ‘Most are long acting, and they are often converted to active metabolites, Important side-effects: sedation (HI-block), postural hypotension (a-adrenoceptor block(, dry mouth, blurred vision, constipation (muscarinic block), occasionally mania and convulsions. Risk of ventricular dysrhythmias through potassium channel block. TCAs are dangerous in acute overdose, causing confusion and mania, and cardiac dysrhythmias. ‘They are liable to interact with other drugs, e.g. alcohol, anesthetics, hypotensive drugs and non-steroidal anti-inflammatory drugs; TCA should not be given with monoamine oxidase inhibitors. SELECTIVE 5-HT UPTAKE INHIBITORS (SSRI) + Examples include fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram, * Antidepressant actions are similar in efficacy and time course to those of tricyclic antidepressants. * Acute toxicity is less than that of monoamine oxidase inhil overdose risk is reduced. Side-effects include nausea, insomnia, and sexual dysfunction. No food reactions but dangerous ‘serotonin reaction’ (hyperthermia, muscle rigidity cardiovascular collapse) can occur if given with MAOI. Currently the most commonly prescribed antidepressants; also used for some other psychiatric indications. tors (MAOI) or TCA, soOTHER MONOAMINE UPTAI * Inhibit monoamine uptake by a noradrenaline- selective (e.g, maprotilline, reboxetine) or non-selective (e.g. venlafaxine) mechanism. * Generally similar to tricyclic antidepressants pharmacologically but have fewer side-effects, especially with respect to cardiac effects, so safer in overdose. MONOAMINE OXIDASE INHIBITORS (MAON + Main examples are phenelzine, tranyleypromine, isocarboxazid and moclobemide. + For many years superseded by tricyclic antidepressants (TCA), mainly because of drug and food interactions; currently undergoing a revival, ‘+ Action is tong lasting (weeks) because of irreversible inhibition of MAO. Moclobemide has a short duration of action ‘Main side-effects: postural hypotension (sympathetic block); atropine-like effects (as with ‘TCA); weight gain; CNS stimulation, causing restlessness, insomnia; liver damage (rare). * Acute overdose causes CNS stimulation, sometimes convulsions, ‘+ May cause severe hypertensive response to tyramine-containing foods (‘cheese reaction’); this does not occur with moclobemide. MAOI should not be given simultaneously with TCA of S-HT reuptake inhibitors (SSRI) Interact with many drugs (e.g. pethidine, causing hyperpyrexia and hypotension). OTHER ANTIDEPRESSANT DRUGS WaUsnna’ ya fa pena ‘+ Heterogeneous group, including trazodone, mirtazapine and bupropion. + No common mechanism of action. Act mainly as non-selective antagonists at presynaptic receptors, possibly enhancing amine release, * Delay in therapeutic responses is similar to TCA and MAOI. Mirtazapine may act more rapidly, * Unwanted effects and acute toxicity vary but are generally Jess than with TCA. LITHIUM * Inorganic ion taken orally as lithium carbonate. * Mechanism of action is not understood. The main biochemical possibilities are: > Interference with inositol triphosphate formation, > Interference with cAMP formation. © Acts to control mania as well as depression. Lithium is mainly used prophylactically in bipolar depression. ‘+ Long plasma half-life and narrow therapeutic window. ‘+ Hence, side-effects are common, and monitoring of plasma concentration essential, especially in presence of renal disease. Action enhanced by diuretic drugs. + Main unwanted effects: nausea, thirst and polyuria, hypothyroidism, tremor, weakness, mental confusion, convulsions and cardiac dysrhytmias. + Alternative mood-stabilising drugs (e.g. carbamazepine, valproate, gabapentin) are gaining favour because of better side-effect and safety profile,TGonsoas as 9 amp uowuarodsy | cus ryBtow cerewosut mpurg ayqysionoun jo asmeseq | axoass jo ystz J uorsuorody “naogjo-aps ol wonae jo wonanp 'z-1 | -(unudaiss” —sproido ‘ ‘syou)suonse=u surety cao, uonsea1 —asaay9, 2A019956-UON, surzauag uonemp Buoy axvy. spanodusos cal SOV suonesour town | 30 ysu os ‘sarap woneurguioo | zeimo Jo uasyoqerau ase 9q ou ssnus nq J aqua “ouuseAsour ‘ssopioso ur ys mo | Sesewosm “wore “eu “easnen, wonoeos joa eapIRLAL TRS Ho WeGT PARE SST ‘Sr9plosip Aanwe 10j posn OY 2AnWpSS Say WORN Buoy iat [_2audidnsou wy ponanuos tT eee cm somes Young orcs — ee ap) stoaa [somes ton | Surana OPIN TN NOT ue saya opis samay ancy. 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Buyoe vous, YOvW SIOWTY 21)89 oy anus 196g “andai98OPIOID ANALGESICS MODULATION OF PAIN TRANSMISSION + Transmission in the dorsal horn is subject to various modulatory influences, constituting the "gate control’ mechanism. ‘© Descending pathways from the midbrain and brainstem exert a strong inhibitory effect on dorsal horn transmission. Electrical stimulation of the midbrain periaqueductal grey area causes analgesia through this mechanism. * The descending inhibition is mediated mainly by enkephalins, S-HT, noradrenaline and adenosine. Opioids cause analgesia partly by activating these descending pathways, partly by inhibiting transmission in the dorsal horn, and partly by inhibiting excitation of sensory nerve terminals in the periphery. + Repetitive C-fibre activity facilitates transmission through the dorsal horn (‘wind-up’) mechanisms involving activation of NMDA and substance P receptors. MECHANISMS OF PAIN AND NOCICEPTION + Nociception is the mechanism whereby noxious peripheral stimuli are transmitted to the central nervous system. Pain is a subjective experience, not always associated with nociception. * Polymodal nociceptors’ (PMN) are the main type of peripheral sensory neuron that responds to noxious stimuli. The majority are non-myelinated —fibres with endings that respond to thermal, mechanical and chemical stimuli. * Chemical stimuli acting on PMN to cause: include bradykinin, protons, ATP and vanilloids (e.g. capsaicin). PMN are sensitised by prostaglandins, which explains the analgesic effect of aspirin-like drugs, particularly in the presence of inflammation. * The vanilloid receptor VR1 responds to noxious heat as well as capsaicin-like agonists. The lipid mediator anandamide is an agonist at vanilloid receptors, as well as being an endogenous cannabinoid receptor agonist. + Nociceptive fibres terminate in the superficial layers of the dorsal horn, forming synaptic connections with transmission neurons running to the thalamus. * PMN neurons release glutamate (fast transmitter) and various peptides (especially substance P), which act as slow transmitters. Peptides are also released peripherally and contribute to neurogenic inflammation, + Neuropathic pain, associated with damage to neurons of the nociceptive pathway rather than an excessive peripheral stimulus, is frequently a component of chronic pain states and may respond poorly to opioid analgesics. OPIOID ANALGESICS + There are 3 main families of endogenous opioid peptides; these have analgesic activity and have many physiological functions, but they are not used as drugs. * Opioid drugs include: > Phenanthrene derivatives, structurally related to morphine > Synthetic compounds with a variety of dissimilar structures but similar pharmacological effects.* Important morphine-like agonists include diamorphine and codeine; other structurally related compounds are partial agonists (e.g. nalorphine and levallorphan) or antagonists (e.g. naloxone) + The main groups of synthetic analogues are the piperidines (c.g. pethidine and fentanyl), the methadone-like drugs, the benzomorphans (e.g. pentazocine) and the thebaine derivatives (e.g. buprenorphine) * Opioid analgesics may be given orally, by injection, or intrathecally to produce analgesia OPIOID RECEPTORS * The u-receptors are thought to be responsible for most of the analgesic effects of opioids, and for some major unwanted effects (e.g. respiratory depression, euphoria, sedation and dependence). Most of the analgesic opioids are p-receptor agonists. + The 5-receptors are probably more important in the periphery but may also contribute to analgesia, + The x-receptors contribute to analgesia at the spinal level and may elicit sedation and dysphoria; they produce relatively few unwanted effects and do not contribute to dependence. Some analgesics are relatively x-selective. © The c receptors are not true opioid receptors but are the site of action of certain psychotomimetic drugs, to which some opioids also bind, * All opioid receptors are linked through G-proteins to inhibition of adenylate cyclase. They also facilitate opening of potassium channels (causing hyperpolarisation), and inhibit opening of calcium channels (inhibiting transmitter release). These membrane effects are not linked to the decrease in cAMP formation. * Functional heterodimers, formed by combination of different types of opioid receptor, may occur and give rise to further pharmacological diversity. In the table below are listed the functional effects associated with the main types ot opioid receptor, _ 3 ‘Analgesia Supraspinal HH : : Spinal aA ‘e Peripheral ea : + Respiratory depression + as = Pupil constriction 4 - + Reduced GI motility + + + Euphoria He : - Dysphoria : fs Sedation + - an Physical dependence Ht : a Velde. 4Selectivity of opioid drugs and peptides for receptor subtypes # 8 Kk Endogenous peptides B Endorphin +H +H HH Leu-enkephalin : oe 7 Met-enkephalin +H . Dynorphin oa + et Opiate drugs ~ Pure agonists Morphine, codeine, oxymorphone, dextropropoxyphene aay + + Methadone +H : . Meperidine + + + Ethorphine, bremazocine ae vas ann, Fentanyl, sufentanil ans + . Partial mixed agonists Pentazocine, ketocyclazocine * + H Nalbuphine * + Hy Nalorphine - * : +) Buprenorphine ay) - ” Antagonists Naloxone + * ” Naltrexone ~ +18 * oe Note: “+” symbols represent agonist activity; partial agonists in parentheses “*” symbols denote antagonist activity; ‘-' symbols represent weak or no activity. ToeACTIONS OF MORPHINE © The main pharmacological effects are: Analgesia Euphoria and sedation Respiratory depression and suppression of cough Nausea and vomiting Pupillary constriction Reduced gastrointestinal motility, causing constipation Histamine release, causing bronchoconstriction and hypotension + The most troublesome unwanted effects are constipation and respiratory depression Morphine may be given by injection (intravenous of intramuscular) or by mouth, often as slow-release tablets. Acute overdosage with morphine produces coma and respiratory depression. Morphine is metabolised to morphine 6-glucuronide (M6G), which is more potent as an analgesic. ‘* Morphine and M6G, are the active metabolites of diamorphine and codeine. vVvVVvVVY TOLERANCE AND DEPENDENCE, * Tolerance develops rapidly, accompanied by physical withdrawal syndrome. «The mechanism of tolerance is unclear. It is not pharmacokinetic in origin and receptor downregulation is not a major factor, * Dependence is satisfied by p-receptor agonists, and the withdrawal syndrome is precipitated by 1-receptor antagonists. © Dependence comprise 2 components: > Physical dependence, associated with the withdrawal syndrome, lasting for a few days; > Psychological dependence, associated with craving, lasting for months or years Psychological dependence rarely occurs in patients being given opioids as analgesics. © Weak, long acting p-receptor agonists, such as methadone, may be used to relieve withdrawal symptoms. * Certain opioid analgesics, such as codeine, pentazocine and buprenorphine, are much less likely to cause physical or psychological dependence. OPIOID ANTAGONISTS * Pure antagonists include naloxone (short acting) and naltrexone (long acting). They block u-, 5- and k-receptors more-or-less equally. Selective antagonists are available as experimental tools. ‘© Other drugs, such as nalorphine and pentazocine, produce a mixture of agonist and antagonist effects. + Naloxone rapidly reverses opioid-induced analgesia and respiratory depression; it is used mainly to treat opioid overdose or to improve breathing in newborn babies affected by opioids given to the mother. * Naloxone precipitates withdrawal syndrome symptoms in morphine-dependent patients or animals. Pentazocine may also do thisCLINICAL USES OF ANALGESIC DRUGS * Analgesics ate used to treat and prevent pai > Pre- and postoperatively > Common painful conditions including headache, dysmenorthoea, labour, trauma, burns » Many medical and surgical emergencies (myocardial infarction, renal colic) > Terminal disease (especially metastatic cancer). * Opioid analgesics are used in some non-painful conditions, e.g. acute heart failure (because of their haemodynamic effects) and terminal chronic heart failure (to relieve distress). * The choice and route of administration of analgesic drugs depends on the nature and duration of the pain. + A progressive approach is often used, starting with non-steroidal anti-inflammatory drugs (NSAIDs), supplemented first by weak opioid analgesics and then by strong opioids. * In general, severe, acute pain is treated with strong opioids (e.g. morphine, fentanyl) given by injection. Mild inflammatory pain is treated with NSAIDs or by paracetamol supplemented by weak opioids (codeine, dextropropoxyphene). Severe pain (cancer pain) is teated with strong opioid given orally, intrathecally, epidurally or by subcutaneous injection, Patient-controlled infusion systems are useful postoperatively, * Chronic neuropathic pain is often unresponsive to opioids and is treated with tricyclic antidepressants (amitriptylline) or anticonvulsants (carbamazepine, gabapentin) eg CONTRAINDICATIONS AND CAUTIONS IN THERAPY ‘+ Use of pure agonists with mixed agonist-antagonists. * Use in patients with head injuries (carbon dioxide retention caused by respiratory depression results in cerebral vasodilatation; in patients with elevated intracranial pressure this may Jead to lethal alterations in brain function, Use during pregnancy. + Use in patients eith impaired pulmonary function, * Use in patients with impaired hepatic or renal function. © Use in patients with endocrine diseasevwossudep a eee ead PO OS a aso Gur strane soudnedoxtomog aa a ee Jo ag pm ote = ae = ee ae ott She = “atte = ; oe eee = moun as = coon Sree = ae a oe.» naman we SE ey vo tec na ang aU = So tr sotoy 3, Se = “Sine ipsa = nu souejo,"BuyoH! “SuyRWOS suo ee aunydao ba aa wou “Gor BANDE OL paHaAUOD "UER-E Ey PU AINE soy pas KIapLAL weedeat Se - cae SEER ‘sBnup 1s0UL 10} AIsnoauenogns Jo Kpre|nosnweAUL snouaaenur uaAt8 aq Kew suonoafu) sup o1s98 yeu proido urew axp Jo sonsti9}aeIEyC)