Drugs Used For Psychopharmacology(1) (1).pdf

DRUGS USED FOR PSYCHOPHARMACOLOGIC THERAPY Rick Schumacher, Pharm.D., BCPS Keiser University Naples [email protected] 1 Psychotropic Agents: Classification Antipsychotic Agents 1. Typical Antipsychotic Agents (First Generation) Phenothiazine & butyrophenone classes are particularly im...

DRUGS USED FOR PSYCHOPHARMACOLOGIC THERAPY Rick Schumacher, Pharm.D., BCPS Keiser University Naples [email protected] 1 Psychotropic Agents: Classification Antipsychotic Agents 1. Typical Antipsychotic Agents (First Generation) Phenothiazine & butyrophenone classes are particularly important to anesthesia providers 2. Atypical Antipsychotic Agents (Second Generation) Tricyclic Antidepressants (TCA’s) Monoamine Oxidase Inhibitors (MAOI’s) Selective Serotonin Reuptake Inhibitors (SSRI’s) Serotonin Norepinephrine Reuptake Inhibitors (SNRI’s) Miscellaneous Agents Lithium Anticonvulsants 2 Psychotropic Agents & Anesthesia Practice It is now accepted that anesthesia can be safely administered to patients being treated with drugs used to treat mental illness The problem of drug interactions between psychopharmacologic drugs and drugs administered in the perioperative period is less than previously perceived and that the past recommendations for discontinuation of these agents are not justified Nevertheless, it still remains important to remain alert for the potential of drug interactions to occur, especially in the elderly population 3 Antipsychotic Agents 4 Antipsychotic Agents Antipsychotic agents are a chemically diverse group of compounds that are divided into two categories based on differences in their mechanism of action and not chemical structure: Typical or First Generation Agents 2. Atypical or Second Generation Agents 1. Typical and atypical antipsychotics can belong to the SAME chemical structure class depending on the agent 5 Antipsychotic Agents: Clinical Uses Prevention of emesis (anti-emetic use) – Anesthesia use! Not very useful, however, for motion sickness Treatment of schizophrenia, mood disorders (mania or major depression) with psychotic features, dementia with psychotic features, delirium with psychotic features Anxiety Disorders Bipolar Disorder Acute Mania and Maintenance Tourette’s Syndrome Obsessive Compulsive Disorder Temporary psychoses from other illness 6 Site of Actions of Antipsychotic Agents 7 Typical Antipsychotic Agents: Chemical Structure Classification 1. Phenothiazines Chlorpromazine, Prochlorperazine, Thioridazine, trifluoperazine, perphenazine, fluphenazine, mesoridazine 2. Butyrophenones Droperidol, Haloperidol 3. Thioxanthene Thiothixene 4. Diphenylbutylpiperidone Pimozide 5. Indole/Dihydroindolone Molindone 6. Dibenzoxazepine Loxapine 8 Typical Antipsychotic Agents: Mechanism of Actions Typical antipsychotic agents are dopamine receptor antagonists, primarily dopamine2 receptor antagonists, that inactivate dopamine neurotransmission Block dopamine transmission in the mesolimbic tract of the brain Blockade of dopamine2 receptors located in the chemoreceptor trigger zone (CTZ) of the medulla is responsible for the antiemetic effects of antipsychotics This is the clinical use that is most important to the anesthesia provider! 9 Typical Antipsychotic Agents: Mechanism of Actions (cont.) In addition to dopamine antagonism, ALL TYPICAL antipsychotic agents also have anticholinergic (M), antihistaminic (H1), and alpha1-adrenergic blocking properties, all of which contributes to these agents adverse effect profile! Hence, typical antipsychotic agents are not just dopamine antagonists. 10 Atypical Antipsychotic Agents The atypical agents were developed to reduce the extrapyramidal system side effects (EPS) and tardive dyskinesia (TD) side effects that is observed with the typical antipsychotics Generally, ALL atypical antipsychotic agents share the following characteristics: 1. The risk of extrapyramidal system side effects and tardive dyskinesia is LOWER than with typical antipsychotics Clozapine & Quetiapine are said to have NO extrapyramidal or tardive dyskinesia side effects 11 Atypical Antipsychotic Agents (cont.) Most new atypical antipsychotic agents have low to very low muscarinic affinity and few, if any, anticholinergic side effects with the exception of clozapine Atypical antipsychotic agents offer a better neurological side effect profile than typical antipsychotic agents Clinical uses Schizophrenia Bipolar Depression Major depressive disorder with or without psychosis Acute agitation in schizophrenic patients Treatment of delirium in critically ill patients 12 Atypical Antipsychotic Agents (cont.) 1. Clozapine (Clozaril®) – the first atypical agent 2. Risperidone (Risperdal®) 3. Olanzapine (Zyprexa®) 4. Quetiapine (Seroquel®) 5. Ziprasidone (Geodon®) Available in oral and IM injection formulations, used as an alternative to haloperidol in the treatment of delirium 6. Aripiprazole (Abilify®) 7. Paliperidone (Invega®, Invega® Sustenna®) An active metabolite of risperidone 8. Asenapine (Saphris®) 9. Iloperidone (Fanapt®) 10. Lurasidone (Latuda®) 13 Atypical Antipsychotic Agents: Mechanism of action Atypical antipsychotic agents are potent 5-HT2 antagonists AND weak dopmaine2 receptor antagonists Since atypical agents do block dopamine2 receptors, they will have anti-emetic effects but they are NEVER the drugs of choice to prevent/treat nausea & vomiting Depending on the atypical agent, they also have affects at numerous other receptors in the body such as a1-& a2adrenergic antagonism, H1 antagonism, muscarinic antagonism, and antagonism or agonism at various other 5-HT receptors The various affinities at all of these receptors contributes to the particular agents adverse effect profile! Clozapine is considered to be the atypical agent with the MOST anticholinergic, sedative, & orthostatic hypotensive properties 14 Antipsychotic Agents: Pharmacokinetics Most antipsychotics drugs are: Highly lipophilic, highly membrane or protein bound, and accumulate in well-perfused tissues such as the brain Enter the fetal circulation and breast milk Antipsychotics have half-lives that range from short to long and despite the agents that have short half-lives, the biological effects of SINGLE doses of most antipsychotics usually persist for at least 24 hours 15 Antipsychotic Agents: Pharmacokinetics (cont.) With a few exceptions, most antipsychotic agents undergo extensive metabolism in the liver followed by conjugation. This occurs primarily via CYP 450 oxidative metabolism, but non-CYP 450 enzymes are also involved in the metabolism of some antipsychotic agents Most oxidative metabolites are pharmacologically inactive and appear primarily in the urine and to a lesser extent in the bile 16 Neurological Side Effects of Antipsychotics A variety of neurological syndromes, involving particularly the extrapyramidal system, occur following the use of almost ALL antipsychotic drugs Extrapyramidal system & tardive dyskinesia side effects correlates with the dopamine2 antagonism potency of the antipsychotic agent, meaning the more potent dopamine2 antagonism the agent posses’, the higher the incidence of EPS and TD side effects the agent has There is a lower risk of EPS & TD with atypical antipsychotic agents compared with typical antipsychotic agents, since atypical agents are more selective for 5-HT2 receptors and are weaker dopamine2 antagonists 17 Neurological Side Effects of Antipsychotics (cont.) Neurological syndromes that can occur from antipsychotic agents include: Extrapyramidal system side effects – Acute dystonia, Akathisia, Parkinsonism Tardive dyskinesia (TD) Neuroleptic malignant syndrome (NMS) 18 Extrapyramidal System Side Effects Parkinsonism Is manifested by symptoms such as bradykinesia, rigidity, tremor or akinesia, mask facies, postural instability, gait shuffling Occurs when dopamine2 potency is high Occurs within 5-30 days, elderly patients at greatest risk Usually responds to agents such as diphenhydramine and benztropine 19 Extrapyramidal System Side Effects (cont.) Acute dystonia (aka: acute dystonic reactions) Is a movement disorder that causes the muscles to contract and spasm involuntarily. The involuntary muscle contractions force the body into uncontrollable repetitive and often twisting movements as well as awkward, irregular posture Spasms of muscles of the tongue, face, neck, back usually The movements may be painful More likely to occur in the first 1-5 days of therapy (early in therapy!) and can occur after 1 dose More common in males, younger patients (10-19 y/o) especially antipsychotic naïve individuals, and with the use of high dopamine2 potency antipsychotic agents 20 Extrapyramidal System Side Effects (cont.) Acute dystonia (aka: acute dystonic reactions) Laryngospasms, Torticollis, and Oculogyric crisis are all examples of acute dystonic reactions Treated with anticholinergics such as Diphenhydramine (25-50 mg IV) or Benztropine 1-2 mg IM 21 Extrapyramidal System Side Effects (cont.) Akathisia Is fundamentally a subjective disorder characterized by a desire to be in constant motion resulting in an inability to sit still and a compulsion to move Treatment Does not really respond well to anticholinergic agents such as diphenhydramine and benztropine More responsive to nonselective beta-blockers with good CNS penetration (i.e.: Propranolol) and high potency benzodiazepines such as clonazepam 22 Tardive Dyskinesia Side Effect Tardive dyskinesia is an involuntary movement disorder characterized by rhythmical, stereotyped, abnormal, repetitive, painless, involuntary, quick choreiform (tic-like) movements of the face, eyelids, (blinks or spasms), mouth (grimaces), tongue, extremities or trunk. There are varying degrees of slower twisting movements Occasionally, the skeletal muscle groups involved in breathing and swallowing are affected Occurs more frequently in elderly patients & women Risk of tardive dyskinesia development is greatest with potent dopamine2 antipsychotic agents 23 Tardive Dyskinesia Side Effect (cont.) Results from long-term therapy with antipsychotic agents (months to years of treatment) and is potentially irreversible and there is no known treatment Clozapine & Quetiapine have not been associated with tardive dyskinesia and changing to these agents is the intervention of choice Bucco-lingual masticatory (BLM) syndrome is an example of a type of tardive dyskinesia 24 Neuroleptic Malignant Syndrome Is a serious and potentially fatal complication of antipsychotic agents and can occur with ANY antipsychotic agent but appears more common with high doses of high dopamine2 antagonist potent agents, especially when they are administered parenterally There is a lower risk with atypical antipsychotic agents causing this compared with typical antipsychotic agents Risk factors also include dehydration incurrent illness Occurs in 0.5 - 1.5% of all patient’s treated with antipsychotic agents and most likely occurs in the first few weeks of therapy, especially in young med, but can occur months after initiation Is thought to be due to excessive, rapid blockade/antagonism of dopamine receptors but the exact cause is unknown 25 Neuroleptic Malignant Syndrome (cont.) At its most severe, may persist for more than a week after the offending agent has been discontinued and can cause brain injury and death Malignant hyperthermia associated with anesthesia as well as central anticholinergic syndrome may mimic the neuroleptic malignant syndrome, so it can be difficult to differentiate between these conditions A distinguishing feature is the ability of nondepolarizing neuromuscular blockers to produce flaccid paralysis in patients experiencing NMS but not in those experiencing malignant hyperthermia 26 Neuroleptic Malignant Syndrome (cont.) Clinical Manifestations (“FALTERM” Mnemonic) F – Fever/Hyperthermia A – Autonomic nervous system instability (unstable blood pressure and unstable HR, tachycardia, diaphoresis, cardiac dysrhythmias) L – Leukocytosis T – Tremor E – Elevated enzymes (liver transaminase, myoglobinuria, elevated CPK levels) R – Hypertonicity/Rigidity of skeletal muscles (“Lead-pipe” rigidity) M – Mental status changes, fluctuating levels of consciousness Mortality is due typically to ventilatory failure, cardiac failure and/or dysrhythmias, renal failure, and thromboembolism 27 Neuroleptic Malignant Syndrome (cont.) Treatment is empiric and primarily supportive Administer lots of volume Cooling the patient Administration of certain medications Dantrolene – is direct-acting muscle relaxant Dopamine agonists – Bromocriptine, amantadine Benzodiazepines such as diazepam or paralytics can also be used 28 Other Side Effects from Antipsychotic Agents Adverse Cardiac Effects Hypotension – primarily from a1-adrenergic antagonism but also due to depression of vasomotor reflexes mediated by the hypothalamus or brainstem, direct relaxant effects on vascular smooth muscle, and direct cardiac depression The a1-adrenergic antagonism can be sufficient enough to blunt or prevent the pressor effects of epinephrine ALL antipsychotics can cause QTc prolongation, which increases the risk of sudden cardiac death Ventricular arrhythmias and sudden cardiac death (rare) Torsades de Pointes – most prominent with IV Haloperidol, IM Droperidol, Thioridazine Tachycardia and hypertension can also occur 29 Other Side Effects from Antipsychotic Agents (cont.) Sedation occurs due to antagonism of a1-adrenergic, muscarinic, and histamine1 receptors Anti-emetic Properties occurs due to blockade of dopamine2 receptors located in the chemoreceptor trigger zone (CTZ) of the medulla Adverse Metabolic Abnormalities/Changes Weight gain, dyslipidemia (particularly hypertriglyceridemia), and hyperglycemia (new onset type 2 DM and diabetic ketoacidosis from newer atypical agents) 30 Other Side Effects from Antipsychotic Agents (cont.) Decreased seizure threshold All antipsychotics carry a class effect label warning regarding their ability to decrease seizure threshold and increase the risk of seizure development Avoid using these agents in patient’s who have a seizure disorder! Hypothalamic Effects Increased appetite, weight gain, autonomic instability (can’t regulate body temperature) Chlorpromazine has a poikilothermic effect and has been used in the past to facilitate the production of surgical hypothermia 31 Other Side Effects from Antipsychotics Agents (cont.) Prolactin Effects Prolactin levels are increased (hyperprolactinemia) due to blockade of dopamine receptors and the loss of normal inhibition of prolactin secretion Galactorrhea, gynecomastia, amenorrhea may also be associated elevated prolactin levels Can lead to sexual dysfunction (men and women) Agranulocytosis (defined as ANC < 500/mm3), leukopenia & neutropenia Agranulocytosis is associated primarily with clozapine only (incidence < 1.3%), and can be life threatening Patients MUST BE enrolled in a monitoring program (monitors the patient’s WBC counts and ANC) in order to take clozapine 32 Other Side Effects from Antipsychotics Agents (cont.) Fever’s Venous Thromboembolism (VTE) Obstructive jaundice – primarily with the phenothiazine agents and is considered to be an allergic reaction to the agent Headache Somnolence 33 34 Comparative Pharmacology of Atypical Antipsychotic Agents Adverse Reaction Risk Anticholinergic Sedation EPS Orthostatic hypotension Clozapine 4 4 0 4 Risperidone 1 2 2-3 3 Olanzapine 3 3 1 1 Quetiapine 1 3 0 3 Ziprasidone 1 1 1 1 Aripiprazole 1 1 1 1 Paliperidone 1 1 2-3 1 Asenapine 2 4 1 4 Iloperidone 1 1 1 4 Lurasidone 1 1 1 1 0=none, 1=none to minimal, 4=high EPS = Extrapyramidal symptoms 35 Butyrophenone Agents Droperidol (Inapsine®) and Haloperidol (Haldol®) belong to the typical antipsychotic chemical class butyrophenones Droperidol is the butyrophenone most often used in the perioperative period as an antiemetic agent Haloperidol has a longer duration of action than droperidol and has less alpha-adrenergic antagonistic activity and thus has little effect on decreasing systemic blood pressure Haloperidol is not routinely used as an anesthetic antiemetic and is primarily used to treat agitation & delirium in critical care patients and as a long-acting antipsychotic agent Haloperidol has been associated with laryngospasms, bronchospasm, and increased depth of respiration 36 Droperidol (Inapsine®) Clinical Uses Indicated to reduce the incidence of nausea and vomiting associated with surgical & diagnostic procedures Also used as an adjunct in neuroleptic anesthesia Dose: 0.625 – 2.5mg IV/IM for post-op nausea/vomiting Monitor EKG x 2-3 hours, possible prolonged QT interval and/or tachycardia Onset of action: 3-10 minutes Peak effect: up to 30 minutes Duration of the tranquilizing and sedative effects: 2-4 hours, although alteration of alertness may persist for as long as 12 hours 37 Droperidol (Inapsine®) Absorption Usually given IV but can be rapidly absorbed if given IM Distribution Crosses the blood-brain-barrier, extensively protein bound Metabolism occurs in liver t1/2 = ~2 hours Excretion < 1 % of unchanged drug is found in the urine Droperidol’s total body clearance is primarily dependent on hepatic blood flow (perfusion dependent), so droperidol’s clearance is reduced when hepatic blood flow is decreased Think what would happen to the plasma concentrations of droperidol if you give a drug such as propranolol or during profound hypotension? 38 Droperidol (Inapsine®) Actions Is a powerful antiemetic agent as a result of blocking dopamine2 receptors in the chemoreceptor trigger zone of the medulla Produces marked tranquilization and sedation Does not produce amnesia!!!!!!!! Produces mild alpha-adrenergic blockade, peripheral vascular dilatation and reduction of the pressor effect of epinephrine It can produce hypotension, decreased peripheral vascular resistance and may decrease pulmonary arterial pressure (particularly if it is abnormally high) Causes cerebral vasoconstriction that causes a decrease in cerebral blood flow 39 Droperidol (Inapsine®) Actions (cont.) Resting ventilation and the ventilatory response to CO2 are not altered by droperidol Droperidol, when given IV, augments the ventilatory response evoked by arterial hypoxemia, presumably by blocking the action of the inhibitory neurotransmitter dopamine at the carotid body For this reason, droperidol may be an acceptable preoperative medication in patients with COPD who depend on carotid body drive to prevent hypoventilation 40 Droperidol (Inapsine®) Drug-Drug Interactions Other CNS depressant drugs (e.g., barbiturates, tranquilizers, opioids and general anesthetics) have additive or potentiating effects with droperidol Neuroleptanalgesia Fentanyl combined with droperidol is administered for the production of neuroleptanalgesia Innovar® is a commercially available combination of droperidol and fentanyl in a ratio of 50:1 This fixed combination is not associated with enhanced ventilatory depression as compared with either drug alone Droperidol prolongs fentanyl’s duration of action but does not enhance analgesia produced by fentanyl 41 Droperidol (Inapsine®) Adverse effects Most common behavioral adverse effects include dysphoria, postoperative drowsiness, restlessness, hyperactivity and anxiety Mild to moderate hypotension and tachycardia Elevated blood pressure, with or without pre-existing hypertension, has been reported following administration of droperidol combined with fentanyl citrate or other parenteral analgesics Hypertension has been reported when given to pheochromocytoma patient’s Postoperative hallucinatory episodes have been reported 42 Droperidol (Inapsine®) Adverse effects (cont.) Extrapyramidal symptoms can rarely occur (Akathisia, oculogyric crisis, laryngospasms or other dystonic reactions) Bronchospasm, chills and/or shivering QT interval prolongation and/or torsade de pointes (Black-box warning), cardiac arrest, and ventricular tachycardia are very rare but can occur at low or high doses. Therefore, droperidol is contraindicated in patient’s with prolonged QTc interval (QTc interval greater than 440 msec in men and 450 msec for females) Do not use droperidol with other agents that also prolong the QTc interval Should not be administered to patients with parkinson’s disease 43 Phenothiazines: Drug-Drug Interactions CNS depressant drugs (i.e., barbiturates, tranquilizers, opioids and general anesthetics) are enhanced by the concomitant administration of phenothiazines Ventilatory effects of opioids are exaggerated Miotic (pupillary constriction) and sedative effects of opioids are increased Analgesic effects of opioids are potentiated 44 Anesthetic implications for the patient taking Phenothiazines Avoid use in patient’s with parkinson’s disease Antipsychotics are dopamine antagonists and parkinson’s disease is a disease of decreased dopamine in the CNS Do not co-administer agents which cause dopaminergic blockade (droperidol, metoclopramide) Avoid the use of ketamine & meperidine Decreases overall opioid use when combined with opiods Use glycopyrrolate if anticholinergic agent is needed Use direct-acting vasopressors for hypotension In general, phenothiazine agents are not used as anti-emetic agents due to their higher incidence of adverse effects (hypotension) compared to the butyrophenones 45 Antidepressant Agents 46 Antidepressant Agents The exact mechanism of action of antidepressants is unknown Neurotransmitters such as serotonin (5-HT) and norepinephrine (NE) play an important role in normal brain neurochemistry It is hypothesized that the inhibition of the reuptake transporters in the presynaptic neuron will increase the amounts of neurotransmitters in the synaptic cleft and increase serotonergic & noradrenergic neurotransmission With chronic administration, this increase of neurotransmitter in the synaptic cleft causes the down regulation or desensitization of the autoreceptors on neurons. This down regulation of autoreceptors is how antidepressants exert their clinical effect 47 Classes of Antidepressant Agents Monoamine Oxidase Inhibitors (MAOIs) Tricyclic antidepressants (TCAs) Selective Serotonin Reuptake Inhibitors (SSRIs) Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) Miscellaneous Agents Following initiation of antidepressant drug treatment there is generally a “therapeutic lag” lasting 3-4 weeks before a measurable therapeutic antidepressant response becomes evident 48 Sites of actions of Antidepressants TCAs Noradrenergic neuron α2AR 49 These 4 are not selective serotoninuptake inhibitors 50 Tricyclic Antidepressants (TCAs) 51 Tricyclic Antidepressants (TCAs) Older antidepressant agents with high incidence of adverse effects Think cardiovascular, CNS and anticholinergic toxicities! Seldom used as first-line agents for depression anymore due to high incidence of adverse effects with TCAs and newer agents being available with a more tolerable adverse effect profile, but TCAs are effective antidepressant agents TCAs were the mainstay of drug treatment of depression until the development of SSRIs 52 Tricyclic Antidepressants (TCAs): Clinical Uses Depression Chronic neuropathic pain syndromes Trigeminal Neuralgia Shingles Migraine prophylaxis Anxiety disorders Enuresis Imipramine primarily used in children 53 Tricyclic Antidepressants (TCAs): Classification Tertiary Amine Tricyclic's Secondary Amine Tricyclic's Amitriptyline (Elavil®) Amoxapine (Asendin®) Clomipramine (Anafranil®) Desipramine (Norpramin®) Doxepin (Sinequan®) Maprotiline (Ludiomil®) Imipramine (Tofranil®) Nortriptyline (Pamelor®) Trimipramine (Surmontil®) Protriptyline (Vivactil®) 54 Tricyclic Antidepressants (TCAs): Mechanism of action TCAs block the reuptake of both NE and 5-HT into the presynaptic nerve terminal via inhibiting NET and SERT and thus enhance noradrenergic and serotonergic transmission TCA’s ALSO block/antagonize other types of receptors to varying degrees which contributes to the different adverse effect profile of the individiual agent a1-adrenergic antagonism H1 antagonism – antihistamine effects Muscarinic antagonism – anticholinergic effects Block Na+ channels – leads to cardiac conduction abnormalities Secondary Amines Primarily inhibit the reuptake of NE Tertiary Amines Inhibit reuptake of both NE & 5-HT 55 Tricyclic Antidepressants (TCAs): Pharmacokinetics Absorption Effectively absorbed from GI tract but have extensive first-pass hepatic effect Protein binding (>90%) Strongly bound to plasma and tissue proteins High volumes of distribution TCAs are highly lipophilic t1/2 Long elimination half-lives (8-80 hours) 56 Tricyclic Antidepressants (TCAs): Pharmacokinetics (cont.) Metabolism Occurs in the liver via multiple CYP 450 enzyme systems TCAs can also INHIBIT several CYP 450 enzyme systems Tertiary amines are metabolized into active secondary amines 57 Tricyclic Antidepressants (TCAs): Adverse Effects Similar side effects to phenothiazines (typical antipsychotic agents) due to structural similarity As a general rule, tertiary amines have a greater tendency to cause adverse reactions 58 Tricyclic Antidepressants (TCAs): Adverse Effects (cont.) Cardiovascular effects Orthostatic hypotension (due to a1 blockade) & tachycardia are the most common cardiovascular effects Cardiac conduction abnormalities occur primarily in overdose situations TCAs have a “Quinidine-Like effect” (Na+ channel blockade) this can be life threatening with overdose and limits TCA use in patient’s with cardiac disease Ventricular dysrhythmias Prolongation of P-R interval Widening of QRS complex, prolonged QT interval Flattening or inversion of T waves Atropine is useful if TCAs slow AV conduction of impulses 59 Tricyclic Antidepressants (TCAs): Adverse Effects (cont.) CNS Sedation, confusion, memory difficulty, hallucinations INCREASED risk of seizures (TCAs decrease seizure threshold) EPS side effects are rare; can see a fine tremor Antimuscarinic actions – prominent, especially at high doses Dry mouth, constipation, tachycardia, blurred vision, urinary retention, increased intraocular pressure, mydriasis, delayed gastric emptying Delirium in elderly Sexual dysfunction Antihistamine actions (H1 blockade) Sedation, weight gain 60 Tricyclic Antidepressants (TCAs): Withdrawal Syndrome Withdrawal Symptoms After prolonged administration, abrupt cessation of treatment may produce nausea, headache, malaise, and chills Other signs & symptoms include irritability, restlessness, and dream and sleep disturbance These symptoms are not indicative of addiction 61 Tricyclic Antidepressants (TCAs): Drug-Drug Interactions Drug interactions may be prominent and include: Any drug that inhibits CYP 2D6 may increase the plasma exposure of TCAs Sympathomimetics Inhaled anesthetics MAOIs – NEVER GIVE AT THE SAME TIME!!! Anticholinergics (Antimuscarinics) Antihypertensives Opioids & Barbiturates Phenothiazine antipsychotic agents Class 1A & 1C Anti-arrhythmic agents Giving TCAs with other drugs that are also highly protein bound agents 62 TCAs and Sympathomimetics TCAs can potentiate sympathomimetic agents The systemic BP effects of administration of sympathomimetics in patient’s treated with TCAs are complex and unpredictable For patients recently started on a TCA, an exaggerated pressor response should be anticipated from direct-acting or indirectacting sympathomimetics. Although pressor responses may be more pronounced with an indirect-acting agent such as ephedrine Smaller than usual doses of direct-acting sympathomimetics are recommended For patients on TCA >6 weeks, the administration of either a direct-acting or indirect-acting sympathomimetic is acceptable, but it may be prudent to decrease the initial dose to 1/3rd the usual dose 63 TCAs and Sympathomimetics (cont.) Conversely, conventional sympathomimetics may not be effective in restoring systemic BP in patients chronically treated with TCAs Adrenergic receptors may be desensitized/down-regulated or catecholamine stores are depleted in patient’s who have been on TCAs chronically. In these patients, a potent direct-acting agent such as norepinephrine may be the only effective management of hypotension 64 TCAs and Anesthetics Induction of anesthesia may be associated with an increase risk of cardiac arrhythmias in patient’s treated with TCAs The dose of exogenous epinephrine necessary to produce cardiac dysrhythmias during anesthesia with a volatile anesthetic is decreased by TCAs A potential for an increase in cardiac arrhythmias may be observed in patients treated with halothane, pancuronium and TCAs 65 TCAs and Anticholinergics Because the anticholinergic (antimuscarinic) effects of drugs are additive, the use of centrally acting anticholinergic (antimuscarinic) agents for preoperative medication of patients treated with TCAs may be associated with increased risk of postoperative delirium and confusion Scopolamine, atropine sulfate Glycopyrrolate – theoretically is less likely to have this drug interaction in patients being treated with TCAs Glycopyrrolate is chemically a quaternary ammonium compound; hence, its passage across lipid membranes, such as the blood-brain barrier, is limited in contrast to atropine sulfate and scopolamine 66 TCAs and Opioids Doses of opioids and barbiturates should be decreased in the presence of TCAs to avoid the exaggerated or prolonged depressant effects (analgesic and ventilatory depressant effects) 67 TCAs and Antihypertensives TCAs given in conjunction with a1 adrenergic antagonists Increased risk of hypotension Theoretically, plasma concentrations of catecholamines can persist for longer periods of time in patient’s treated with TCAs since they prevent the uptake of NE back into the adrenergic nerve ending thus increasing risk of hypertension Rebound hypertension after abrupt discontinuation of clonidine may be accentuated and prolonged by concomitant TCA use 68 TCA Overdose TCA overdose can be life-threatening and can progress rapidly CNS and cardiotoxicity can be life-threatening! Critical manifestations include Severe hypotension and cardiac depressant “quinidine-like” effect Þ cardiac conduction abnormalities CNS depression Þ respiratory depression, coma and seizures/convulsions Other signs of overdose may include Agitation, impaired myocardial contractility, confusion, disturbed concentration, transient visual hallucinations, dilated pupils, disorders of ocular motility, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia 69 TCA Overdose Management Obtain an ECG and immediately initiate cardiac monitoring Protect the patient’s airway, establish an intravenous line GI Decontamination Large volume gastric lavage followed by activated charcoal EMESIS is contraindicated! Hyperventilation OR serum alkalinization with intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55 Reduces risk of dysrhythmias Dysrhythmias unresponsive to sodium bicarbonate therapy may respond to lidocaine or phenytoin Type 1A and 1C antiarrhythmics are generally contraindicated Seizures Control with benzodiazepines (i.e., diazepam), or if these are ineffective, other anticonvulsants (i.e., phenobarbital, phenytoin) 70 Pharmacologic Treatment of TCA Overdose Symptom Treatment Seizures Diazepam Sodium bicarbonate Phenytoin Ventricular cardiac dysrhythmias Sodium bicarbonate Lidocaine Phenytoin Heart block Isoproterenol Hypotension Crystalloid or colloid solutions Sodium bicarbonate Sympathomimetics Inotropics Stoelting & Hillier, 2006, Table 19-3 pg 404 71 Selective Serotonin Reuptake Inhibitors (SSRIs) 72 Selective Serotonin Reuptake Inhibitors (SSRIs): Clinical Uses Major Depressive Disorder (aka: Depression) Generalized anxiety disorder, panic disorder, social anxiety disorder Obsessive-Compulsive disorder Posttraumatic stress disorder Premenstrual dysphoric syndrome 73 Selective Serotonin Reuptake Inhibitors (SSRIs): Available agents 1. Fluoxetine (Prozac®) 2. Paroxetine (Paxil®) 3. Sertraline (Zoloft®) 4. Citalopram (Celexa®) 5. Escitalopram (Lexapro®) Is the S-enantiomer of citalopram 6. Fluvoxamine (Luvox®) 74 Selective Serotonin Reuptake Inhibitors (SSRIs): Mechanism of Action SSRIs selectively inhibit the reuptake of serotonin (5-HT) into the pre-synaptic nerve terminal by inhibiting SERT Inhibition of serotonin (5-HT) reuptake results in an increase in synaptic serotonin (5-HT) levels and enhanced & prolonged serotonergic neurotransmission 75 Selective Serotonin Reuptake Inhibitors (SSRIs): Adverse Effects Fewer side effects than TCAs and not as lethal in cases of overdose as are TCAs Generally, SSRIs: Do not cause major cardiovascular adverse effects such as postural hypotension or delayed conduction of cardiac impulses Lack antimuscarinic adverse effects (dry mouth, urinary retention) Do not block histamine receptors Do not block alpha-adrenergic receptors Cause very minimal sedation Have a very low risk of decreasing seizure threshold 76 Selective Serotonin Reuptake Inhibitors (SSRIs): Adverse Effects (cont.) Most Common Nausea, diarrhea, insomnia, sexual dysfunction and agitation Less Common Increased risk of bleeding, hyponatremia and are rarely associated with extrapyramidal side effects (akathisia, dystonia), bradykinesia and tardive dyskinesia Withdrawal Syndrome (Serotonin Discontinuation Syndrome) Has been observed, especially for the drugs with shorter half-lives, so a gradual dose reduction (i.e.: over 2-4 weeks) may be indicated Symptoms include GI complaints, dizziness, impaired concentration, flu-like symptoms, anxiety, insomnia and electric-shock sensations Least common with fluoxetine due to the long half-life of both fluoxetine and its active metabolite, norfluoxetine 77 Selective Serotonin Reuptake Inhibitors (SSRIs): Suicidal Ideation SSRIs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders Any antidepressant agent on the market has this warning, not exclusive to just the SSRI class 78 Selective Serotonin Reuptake Inhibitors (SSRIs): Drug-Drug Interactions Metabolism of SSRIs is mediated by hepatic CYP450 enzyme systems CYP 2D6 is involved in MOST but others are also involved such as CYP 2C9 and CYP 2C19 SSRIs are also inhibitors of many CYP450 enzyme systems (Fluoxetine is considered the most potent CYP450 inhibitor of all SSRIs) 79 Selective Serotonin Reuptake Inhibitors (SSRIs): Drug-Drug Interactions Monoamine Oxidase Inhibitors Do not use any SSRI within 14 days of stopping an MAOI Allow 14 days after stopping SSRIs before starting an MAOI Exception: Must wait at least 5 weeks after stopping fluoxetine before starting any MAOI Combined use with SSRIs is contraindicated SSRIs may increase risk of bleeding Monitor patient’s closely who are on any antiplatelet or anticoagulant agent as this increases bleeding risk Linezolid Has weak reversible non-selective MAOI properties Combined use increases risk of serotonin syndrome development 80 Serotonin Syndrome Serotonin syndrome is a rare but severe, potentially life threatening condition that can occur with the use of any SSRI or any other serotonergic anti-depressant but occurs particularly with concomitant use of other serotonergic agents like TCA’s, SNRIs and triptan’s, with MAOIs, with antipsychotics or with dopamine antagonists Symptoms can be mild or severe and may include: Altered mental status changes: Agitation, hallucinations, coma Autonomic instability: Tachycardia, hyperthermia, hypertension Neuromuscular: Hyperreflexia, incoordination, clonus, mydriasis GI: Nausea, vomiting, diarrhea In its most severe form, this syndrome can resemble neuroleptic malignant syndrome (NMS) which includes hyperthermia, muscle rigidity (lead-pipe), myoclonus and coma81 Serotonin Syndrome Differential Diagnosis 82 Fluoxetine (Prozac®) Fluoxetine has a prolonged t1/2 (longest of all SSRIs) Is highly protein bound (>90%) Extensively metabolized in the liver to norfluoxetine and other metabolites Norfluoxetine is an active metabolite that has an even longer t1/2 of 4-16 days compared to fluoxetine 83 Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) 84 Serotonin Norepinephrine Reuptake Inhibitors (SNRIs) Newer antidepressant agents with a NON-Tricyclic structure Have NO significant effects at other receptors (muscarinic cholinergic, H1-histaminergic, or α1-adrenergic receptors) Exception is Duloxetine, which has a slightly higher incidence of anticholinergic symptoms (dry mouth) As efficacious as TCAs and SSRIs in treatment of depression Adverse effect profile is more favorable than TCAs Adverse effect profile, warnings, drug interactions and clinical uses are similar to SSRIs 85 Serotonin Norepinephrine Reuptake Inhibitors (SNRIs): Current Agents 1. Venlafaxine (Effexor®) 2. Duloxetine (Cymbalta®) 3. Desvenlafaxine (Pristiq®) The active metabolite of venlafaxine 4. Levomilnacipran (Fetzima®) Is an enantiomer of milnacipran 5. Milnacipran (Savella®) Is ONLY approved for fibromyalgia and not used to treat depression 86 Serotonin Norepinephrine Reuptake Inhibitors (SNRIs): Mechanism of action Mechanism of Action SNRIs block the reuptake of both NE and 5-HT into the presynaptic nerve terminal (Inhibits both NET and SERT) SNRIs cause enhanced serotonergic and/or noradrenergic neurotransmission 87 Serotonin Norepinephrine Reuptake Inhibitors (SNRIs): Pharmacokinetics Protein binding Duloxetine: High (>90%) Venlafaxine, Desvenlafaxine, & Levomilnacipran: Low ( 2L/day occurs in ~70% of pt’s Lithium-induced nephrogenic diabetes insipidus (rare) Amiloride can be given for treatment if this develops CNS Most common CNS effect is a fine postural hand tremor (dosedependent) – Beta-blockers are used to treat the tremor Sedation Extrapyramidal system side effects may rarely occur 117 Lithium: Adverse Effects Cardiac EKG Changes: T-wave flattening and inversion (U waves) QRS complex prolongation, sinus bradycardia, AV Block can occur when lithium levels are > 2.5 mmol/L GI Nausea, vomiting, diarrhea Endocrine Hypothyroidism can occur at anytime Dermatologic Rash, acne, psoriasis 118 Lithium: Toxicity Toxicity signs & symptoms correlates with lithium plasma concentrations. Levels > 2 mmol/L are considered to be toxic. Lithium Conc < 1.5 mmol/L Fine hand tremor, nausea, vomiting, diarrhea, skeletal muscle weakness, mild polyuria and polydipsia Lithium Conc: 1.5 - 2.5 mmol/L Muscle twitching & course tremor, sedation, nystagmus, confusion, hyperreflexia, slurred speech, drowsiness Lithium Conc > 2.5 mmol/L Seizures, coma, stupor, delirium, cardiovascular collapse, AV block or other cardiac dysrhythmias, extrapyramidal symptoms, irreversible brain damage, even death May require hemodialysis 119 Anesthesia Implications & Lithium Responses to nondepolarizing and depolarizing NMB medications may be prolonged in the presence of lithium Lithium associated sedation suggests that anesthetic requirements for injected and inhaled anesthetics could be decreased High plasma concentrations of lithium may delay recovery from the CNS depressant effects of barbiturates 120 Navy beats Army, 17-10, for 13th straight time! 121