PSYCHOPHARMACOLOGICS, ANTIDEPRESSANTS, ANTIPSYCHOTICS, ANTIPARKSONIANS

1. PSYCHOPHARMACOLOGICS, ANTIDEPRESSANTS, ANTIPSYCHOTICS, ANTIPARKSONIANS ANESTHESIOLOGY NURSING PROGRAM FLORIDA INTERNATIONAL NURSING PROGRAM LINDA WUNDER MSN,CRNA

2. NEUROTRANSMISSION DISEASES • Treatable neurotransmission diseases fall into two categories: those caused by too much neurotransmission and those caused by too little neurotransmission • “Too much” neurotransmission may be do to: • A focus of hyperexcitable neurons that fire in the absence of appropriate stimuli ( e. g., seizure disorders). Therapy is directed toward reducing the automaticity of those cells • Too much neurotransmitter molecules binding to postsynaptic receptors (possible explanation for psychosis). Therapy includes administration of antagonist which block post synaptic receptors

3. Neurotransmission diseases • “Too little” neurotransmission may be due to: • Too few neurotransmitter molecules binding to postsynaptic receptors (e.g., depression, Parkinson’s disease). Several treatment strategies increase neurotransmission, including • 1) drugs that cause release of neurotransmitter stores from the presynaptic terminal. • 2) neurotransmitter precursors that are taken-up into presynaptic neurons and metabolized into active neurotransmitter molecules. • 3) drugs which inhibit enzymes that degrade neurotransmitters. • 4) agonist that act at post synaptic receptors.

4. Neurotransmitters of the brain • Norepinehrine—a leading hypothesis suggests that depression is causes by impaired monoamine (e.g., norepinephrine, dopamine, serontonin) neurotransmission. • Dopamine—D1 and D2 activation inhibits the rate of neural firing. Particularly important dopaminergic pathways include: • 1) The nigrostriatal pathway ( from substancia nigra to striatum). • 2) Neurons from the chemotrigger zone of the medulla, which controls vomiting. • 3)Projections from the hypothalamus to the intermediate lobe of the pituitary, which are thought to regulate prolactin release • Antipsychotic drugs inhibit dopamine-stimulated adenyl cyclase (usually associated with D1 receptor activation) and block D2 receptors, suggesting psychoses may result from over stimulation of dopamine receptors • Parkinson’s disease is causes by too little dopaminergic input from the substantia nigra into the striam

5. Neurotransmitters of the brain • 5-Hydroxytryptamine (5-HT, Serotonin • The amino acid typtophan is hydroxylated and decarboxylated to form 5-HT. In the neurons, 5-HT is stored (in vessicles), released, taken up into presynaptic neurons and either recycled or metabolized. • 5-HT is released from the inhibitory neurons originating in the raphe nuclei of the pons and midbrain. LSD is a potent agonist for 5-HT1 and 5-HT2. • 5-HT increases small intestine motility and modulates vasodilatation. 90% of the body’s 5-HT is stored in the enterochromaffin cells of the small intestine. • Depression, attention deficit disorder and headaches have been attributed to serotonergic imbalances

6. Neurotransmitters of the brain • Acetylcholine • Gamma-amino butyric acid (GABA) • Excitatory amino acids (EAA)-glutamate is excitatory neurotransmitter important for learning and memory. Pathogenesis of Alzheimer’s, Huntington's stroke epilepsy and amyotrophic lateral sclerosis (ALS) • Opioids

8. PSYCHOPHARMOCOLOGICS • Antidepressants and anxiolytics are primary care treatment for depression and anxiety disorders. • Lithium and antipsychotics are treatment for bipolar and psychotic disorders including schizophrenia • There is no need to discontinue antidepressant medication preoperatively, just be aware of the interaction with anesthesia

9. ANTIDEPRESSANTS • Appear to work by increasing the amount of norepinephrine and/or serontonin in synapses. • Neurobiologically, reuptake blockade or MAO inhibition occurs promptly after initiation of antidepressant therapy, but clinical improvement typically does not occur for 2-4 weeks • Perhaps adaptive changes including down-regulation of neurotransmitter receptors are necessary before evidence of clinical improvement occurs.

10. ANTIDEPRESSANTS • CLINICAL USES FOR ANTIDEPRSSANT DRUGS • Unipolar and bipolar depression • Panic disorder • Neuropathic pain • Migraine prophylaxis • Obsessive-compulsive disorder • Bulimia • Childhood attention-deficit hyperactivity disorder

11. Selective serontonin reuptake inhibitors Treatment for mild to moderate depression Have little effect on norepinephrine reuptake Lack anticholinergic properties, do not cause postural hypotension or delayed conduction of cardiac impulses Common side effects include insomnia, agitation, headache, nausea, diarrhea, and sexual dysfunction

12. SSRIs-FLUOXETINE • First SSRI 1988 • ½ time 1-3 days acute administration and 4-6 days chronic administration • Active metabolite norfluoxetine has elimination ½ time of 4-16 days • Fluoxetine (prozac) needs to be discontinued 5 weeks before MAO inhibitor treatment is begun • Drug interactions; potent inhibitor of P-450, may increase plasma concentration of drugs that depend on hepatic metabolism for clearance. • Potentiation of certain antidysrhythmic and beta-agonist if depend on hepatic metabolism • MAO inhibitors combined with fluoxetine may cause the development of a serotonin syndrome characterized by anxiety, chills, ataxia, and insomnia • Fluoxetine and lithium or carbamazepine may provoke a fatal syndrome (serotogenic syndrome)

13. SSRIs • Sertraline (zoloft)—shorter ½ life than prozac, cause more GI symptoms • Paroxetine (paxil)—shorter ½ life than prozac, increasd sedative effects, enhancement of the anticoagulant effect of warfarin • Fluvoxamine (luvox)—effective usede for obsessive-compulsive disorders

14. Second generation antidepressants • Bupropion(wellbutrin)—stucturally related to amphetamine, greater incidence of seizures. No anticholinergic effects, does not cause postural hypotension, lacks effects on cardiac conduction. Should not be administered with a MAO inhibitor. • Venlafaxine(effexor)—efficacy similar to tricyclic antidepressants, inhibits the reuptake of serotonin and norepinephrine, not used with MAO inhibitors. • Trazodone(desyrel)—inhibits serotonin reuptake, side effects- sedation, orthostatic hypotension, nausea, vomiting. Should not be administered with a MAO inhibitor. • Nefazodone(serzone)—inhibits serotonin reuptake and acts as an antagonist at 5-HT2 receptors, side effects-nausea, dry mouth, sedation, orthostatic hypotension. May decrease the clearance of triazolam, alprazolam, and the antihistamines terfenadine and astemizole. Not to be administered with a MAO inhibitor

15. Tricyclic and related anti depressants • Used for depression and in smaller doses used for chronic neuropathetic pain • These drugs have measured plasma concentrations and need to be tapered off slowly to avoid withdrawal symptoms-chills , coryza, muscle aches • Structurally resembles phenothiazides

16. Tricyclic and related antidepressants • Tricyclic antidepressants potentiate the actions of biogenic amines (especially norepinephrine and/or serotonin) in the CNS and interfering with the uptake (reuptake) of these amines into the postganglionic sympathetic nervous system nerve endings. Despite the prompt onset, the antidepressant effects take 2-3 weeks . This is associated with (a) decreased sensitivity of postsynaptic beta1 and serotonin2 receptors and of and of presynaptic alpha2 receptors, and (b) increased sensitivity of postsynaptic alpha1 receptors.

17. Tricyclic and related antidepressants • Highly lipid solubility • Large volume of distribution • Long elimination ½ time 17-30 hours • Metabolized in the liver—oxidized by microsomal enzymes in the liver with subsequent conjugation with glucuronic acid.

18. Tricyclic and related antidepressants • SIDE EFFECTS: • Anticholinergic-dry mouth, tachycardia, urinary retention, slowed gastric emptying, ileus • Cardiovascular-prolonged P-R interval, wide QRS, flat or inverted T waves, slow NA influx into the cells results in altered repolarization • CNS-sedation, lower seizure threshold, enflurane CNS stimulating effects may be enhanced

19. Tricyclic and related antidepressants • DRUG INTERACTIONS: • Sympathomimetics-unpredictable response. Indirect acting may have a more pronounced response. Smaller than usual dose (1/3 of the dose) of a direct acting should be used . • Inhaled anesthetics- halothane and pancuronium pretreated with imipramine in anesthetized dogs, increased the incidence of cardiac dysrhythmias including sinus tachycardia, ventricular tachycardia, and ventricular fibrillation. There is a potential interaction between pancuronium and ketamine with tricyclic antidepressants, increasing the anticolinergic and sympathetic stimulating effects. Increase risk of cardiac dysrhythmias with exogenous epinephrine especially with halothane. However, theoretically the increased availability of noepinephrine in the CNS could result in increased anesthetic requirements for inhaled anesthetics

20. Tricyclics and related antidepressants • Anticholinergics- best to use glycopyrrolate, because centrally acting could cause delirium and confusion postoperatively with patients who are taking tricyclic antidepressants. • Antihypertensives- more pronounced rebound hypertension after discontinuation of clonodine. • Opioids-tricyclic augment analgesic and ventilatory effects of opioids and sedative effects of barbiturates, doses may need to be decreased.

21. Tricyclics and related antidepressants • Tolerance –to anticholinergic effects and orthostatic hypotension. Abrupt discontinuation: malase, chills, coryza, skeletal muscle aching are symptoms of withdrawal syndrome. • Overdose-LIFE THREATENING-intractable myocardial depression or ventricular cardiac dysrhythmias are the most frequent terminal events. • Agitation, seizures, coma, respiratory depression, hypotension, hypothermia, tachycardia, wide QRS, are symptoms of overdose. Comatose phase last for 24-72 hours and cardiac dysrhythmias can last up to 10 days.

22. Tricyclics and related antidepressants • Treatment of overdose of tricyclic • Airway • Physostigmine 0.5 to2mg IV for anticholinergic psychosis • Diazepam for seizures (which may precede cardiac arrest) then phenytoin • Correct acidosis/alkalosis • Lidocaine-dysrhythmias • Gastric lavage/activatied charcoal

23. MAO inhibitors • Prevent oxidative deamination of naturally occurring monoamines in the CNS and peripheral autonomic nervous system. • MAO-A deaminates serotonin, norepinephrine, and epinephrine. MAO-B deaminates phenylethylamine. • Platelets contains exclusively MAO-A and the placenta contains MAO-B. • About 60% of the human brain is MAO-A subtype

24. MAO inhibitors • Mechanism of action-form a stable irreversible complex with MAO enzyme, especially with cerebral MAO. • As a result, the amount neurotransmitter (norepinephrine) available for release from the CNS neurons and in the sympathetic nervous system increases.

25. MAO inhibitors • SIDE EFFECTS • Orthostatic hypotension • Anticholinergic • Impotence • Sedation • Weight gain • Hepatits (rare)

26. MAO inhibitors • MAO enzyme is found in the liver, GI tract, kidneys, and lungs. • When taking MAO inhibitors , are unable to metabolize dietary tyramine and other monoamine. If taken results in a hyperadrenergic crisis: hypertension, hyperpyrexia, and CVA. Symptoms may include: headache, N/V, or chest pain and need to be reported. Treatment –nipride, lidocaine and beta-adrenergic antagonist

27. MAO inhibitors Prohibited foods • cheese • Liver • Fava beans • Avocados • Chianti wine • Prohibited drugs • Cyclic antidepressants • Fluoxetine • Cold and allergy medicine • Nasal decongestants • Sympathomimetics • Opioids (meperidine)

28. MAO inhibitors • Opioid reaction with MAO inhibitors • Excitatory-agitation, headache, skeletal muscle rigidity, hyperpyrexia. • Depressive type-hypotension, depression of ventilation, and coma • Meperidine toxicity is increased only when both MAO-A and MAO-B are inhibited. • Fentanyl, sufentanil, alfentanil have all been associated with adverse reaction with MAO inhibitors. • Morphine does not inhibit uptake of serontonin, but its opioid effects may be potentiated in the presence of MAO inhibitors

29. MAO inhibitors Sympathomimetics-exaggerated response with indirect acting --use direct acting 1/3 the dose OVERDOSE-tachycardia, hyperthermia, mydriasis seizures, coma Treatment --gastric lavage, possible dantrolene

30. MAO inhibitors • Management of anesthesia • Continue medication • Consider drug interactions • Regional -no epinephrine added, no need for opioids • No halothane • Etomidate and thiopental have no adverse reaction • Nondepolarizing neuromuscular-blocking drugs can be administered

31. Lithium • Treatment for bipolar disorders • Antimania –prevention of dopamine receptor supersensitivity, increase activity of inhibitory of the neurotransmitter GABA, and enhanced responsiveness to acetylcholine. • Antidepressant—effects are consistent with the increased brain serotonin function and the beta-adrenergic receptor stimulation of adenyl cyclase. Higher doses has antagonism of ADH and has thyrotoxic properties.

32. Lithium • Excreted by the kidneys, filter by the glomeruls and reabsorbed by the proximal renal tubules. SIDE EFFECTS—polydipsia, polyuria, T wave flattening or inversion, hypothyriodism, acne, sedation (may require less anesthetics), responses to depolarizing and Nondepolarizing muscle relaxants may be prolonged.

33. Lithium--interactions • Thiazide diuretics-increase plasma concentration of lithium • Lasix—no change in plasma concentration of lithium • NSAIDs—increase plasma concentration of lithium • Aminophylline—decrease plasma concentration of lithium • ACE inhibitors—increase plasma concentration of lithium • Neuroleptic drugs—may exacerbate extrapyramidal symptoms or increase the risk of neuroleptic malignant syndrome • Anticonvulsant– additive neurotoxicity • Beta-adrenergic—decrease lithium induced tremor • Neuromucular blocking drugs—lithium may prolong the duration

34. Lithium toxicity • Narrow therapeutic index • Sedation, nausea, weakness, ecg changes, wide QRS, AV block, hypotension, dysrhythmias, seizures at lithium levels >2mEq/liter. • Treatment—hemodialysis , osmotic diuretics, sodium bicarbonate

35. Antipsychotic drugs • PHENTHIAZIDES, THIOXANTHENES, BUTYROPHENONES—used for the treatment of schizophrenia, depression with psychotic features and certain organic psychoses. • Blockade of dopamine receptors (D2) in the basal ganglia and the limbic portions of the forebrain. Blockade of the dopamine receptors in the chemotrigger zone of the medulla is responsible for the antiemetic effect of these drugs. • Highly lipid soluble and pass to brain and placenta. Bind to protein not effective to b removed be hemodialysis

36. ANTIPSYCHOTICS • SIDE EFFECTS • Tardive dyskinesia • Acute dystonic reactions • Respiratory distress (laryngospsm-laryngeal dyskinesia) • Chlorpromazine IV-decrease in systemic B/P • Thioridazine and pimozide are potent calcium channel blockers prolong Q-T interval- cardio-toxicity • Increased prolactin levels-galactorrhea, gynecomastia • Sedation • Antiemetic • Obstructive jaundice • Chloropromazine-hypothermia • Decrease seisure threshold

37. Antipsychotics • DRUG INTERACTIONS • Ventilatory depressant effects ,miotic, sedative and analgesic effects of opioids are enhanced. • Interfere with exogenously administered dopamine • Effects of alcohol are enhanced

38. ANTIPSYCHOTIC • NEUROLEPTIC MALIGNANT SYNDROME • Occurs in 0.5% to 1.05 of all patients treated with antipsychotic drugs. • Risk factors are dehydration and intercurrent illness. • SYNDROME • a) 24-72 hrs young men • b) generalized hypertonicity of skeletal muscles-decrease chest wall expansion may need intubation and mechanical ventilation. Myonecrosis, increased creatine phosphate levels, myoglobinuria, renal failure. • c) unstable autonomic nervous system, alterations in B/P, tachycardia, cardiac dysrhythmias, • d) fluctuation of levels of consciousness • Mortality is 20% to 30% with the common causes being ventilatory failure and cardiac failure and/or dysrhythmias, renal failure, and thromboembolism.

39. Other anti-psychotics/mood stabilizers • A new class of drugs being marketed are called serotonin-dopamine stabilizers. • These drugs are antidepressants that work on both dopamine and serotonin receptors. • Often used as combination therapy for patients on conventional anti-depressants. • They have some of the same side effects as anti-depressants

40. Quetiapine (Seroquel) • Works by antagonizing D2 and 5-HT2 receptors in the brain. • It has some H1 antagonistic properties therefore it can cause drowsiness. • It can aggravate suicidal thoughts in susceptible patients. • Not for use in patients with dementia. • It can cause orthostatic hypotension due to antagonistic effect at α1.

41. Aripripazole (Abilify) • Works by multiple neurotransmitter receptor modulation, D2 and D3 it also shows activity at 5-HT1A and 5-HT2A it also shows moderate activity for other dopamine receptors. • Has antagonistic activity at α1which accounts for the orthostatic hypotension. Some activity at H1 receptors.

42. Neuroleptic malignant syndrome • Cause is not fully understood, thought to involve central dopamine system • Treatment • Supportive measures • Dantolene • Dopamine agonist bromocriptine or amantadine • May mimic malignant hyperthermia or central anticholinergic crisis • Nondepolarizing muscle relaxants will produce flaccid paralysis in neuroleptic malignant syndrome not in malignant hyperthermia

43. Clozapine • Antipsychotic without tardive dyskinesia or extrapyrimidal side effects • Common side effects are N/V, sedation, mild sinus tachycardia, agranulocytosis, seizures (treat with valporic acid) • Can use with lithium and antidepressant drugs • Benzodiazepine have increase sedative effects when given with clozapine

44. Butyrophenones • Droperidol and Haloperidol • Pharmacological effects similar to those of phenothiazides and thioxanthenes. • Haloperidol is longer acting. • Droperidol is used for neuroleptanalgesia which is characterized by trance-like state (cataleptic) immobility in an outwardly tranquil patient who is dissociated and indifferent to the external surroundings. • Analgesia is intense able to perform diagnostic and minor procedures such as bronchoscopy and cystoscopy. • Disadvantage is prolonged CNS depression and failure to depress sympathetic nervous system responses predictably to painful stimulation.

45. Butyrophenones • With N2O and fentanyl, droperidol elimination ½ time is 104 mins • Metabolized in the liver and is dependent on hepatic blood flow • Side effects similar to phenothiazide and thioxanthines. • Other effects • CNS-akathisia-restless legs, extapyramidal(give benadryl) • DO NOT GIVE TO PATIENTS BEING TREATED FOR PARKINSONS DISEASE • Laryngospasm • Cerebral vasoconstrictor-decrease blood flow, does not alter cerebral metabolic rate, this could be undesirable with patients with cerebral vascular disease • Dose not produce amnesia and is not an anticonvulsant

46. Butyrophenones • CV • Hypotension-alpha blockade • Hypertension in the presence of pheochromocytoma • Droperidol is a cardiac antidysrhythmic and protects against epinephrine-induced dysrhythmias • Ventilation-resting ventilation and the response to carbon dioxide are not altered by droperidol-good for COPD patients • Droperidol is a powerful antiemetic-inhibition of dopaminergic receptors in the chemotrigger zone • 0.625-2.5mg IV • Innovar- fentanyl/droperidol

47. Antiepileptic drugs • Epilepsy-term used to designate a group of central nervous system disorders characterized by the onset o sudden disturbance of sensory, moter, autonomic, or psychic origin • Medications that compete for protein-binding sites of the highly bound antiepileptic drugs (phenytoin, valproate, carbamazepine) can displace the bound drug and lead to increases in the plasma concentration of the antiepileptic drug • Also hypoalbuminemia can increase plasma concentration

48. Antiepileptic • Mechanism of action varies depending on the drug, the end result is a decrease in the spread of excitation from a seizure focus to normal neurons. • Phenobarbital-long acting barbituate that through modulation of GABA and of the excitatory postsynaptic actions of glutamate-prolong chloride channel opening an limit the spread of the seizure increasing the seizure threshold • Side effects-depression, megalblastic anemia, osteomalacia, nystagmus, ataxia, dupuytren’s contracture, not given in pregnancy, enzyme induction

49. Antiepileptic • Phenytoin • Alters Na+, K+ and Ca2+ conductance and membrane potentials. It also affects GABA concentrations. • Carbamazepine-iminostilbene derivative, structurally related to tricyclic antidepressants • Side effects-sedation N/V, vertigo, diarrhea, ADH secretion, aplastic anemia, hypertension, cardiac dysrhythmias

50. Antiepileptic • Valproic acid • Acts by limiting sustained repetitive neuronal firing through voltage-dependent sodium channels • Side effects • N/V, anorexia, weight gain, distal tremor, thrombocytopenia, hepatotoxicity, hyperammonemia, sedation, ataxia • Valproic acid is a enzyme inhibitor-metabolism of phenytoin is slowed, causes phenobarbital plasma concentration increase by 50%