1. & Opiates Pharmacology Review: Psychiatric Meds Presented by:
A Nelson Avery, MD
Board Certified in Toxicology, Preventive Medicine and Internal Medicine
Clinical Professor and Director
Preventive Medicine Residency Program

2. Neuroleptics
A Nelson Avery, MD

3. Neuroleptic Classification
Phenothiazines: chlorpromazine, prochlorperazine, thioridazine (most cardiotoxic and most frequent cause of death)
Butyrophenones: haloperidol (tardive dyskinesia in 30%)
Thioxanthenes: thiothixene
Dihydroindolones: molindone
Dibenzodiazepines: clozapine, loxapine
A Nelson Avery, MD

4. Neuroleptics
► Neuroleptics are used for the treatment of schizophrenia, organic mental disorders, anxiety disorders, mixed anxiety depressive illness, and anxiety-agitation accompanying dementia.
► They are dopamine antagonists to varying degrees:
most neuroleptics efficacy related to affinity for the D2 receptor in mesolimbic system and basal ganglia
2nd generation also work at serotonin receptor 5-HT2A
► Excess dopamine associated with psychiatric problems; if decrease dopamine with meds  Parkinson’s syndrome
A Nelson Avery, MD

5. Neuroleptics: Parkinsonism
► Because the dopaminergic neurons in the basal ganglia act to inhibit cholinergic neurons, blockage of the dopamine receptors results in excess central cholinergic stimulation, which can cause acute dystonia, akathisia, or Parkinson’s-like presentation
ACh
dopamine
substantia nigra corpus striatum
dopamine
( – )
neuroleptics ( + )
acetylcholine
bradykinesia, tremor, rigidity
A Nelson Avery, MD

6. Sequence of Extrapyramidal Effects
1-5 days
5-60 days
5-30 days
months-years
acute dystonia (oculogyric crisis)
akathisia (restless,
inability to sit)
pseudo-parkinsonism
tardive dyskinesia
neuroleptic malignant syn.
perioral tremor (rabbit syn.)
T R E A T M E N T:
▪ diphenhydramine
▪ benztropine
▪  dose of med.
▪ antiparkinson
▪ benzodiazepine
▪ antimuscarinic
▪  dose
▪ cholinergic drug
A Nelson Avery, MD

7. Neuroleptics: Side Effects
► Anti-cholinergic effect (block peripheral muscarinic receptor)  blurred vision, dry mouth, urine retention, constipation,  BP, increased heart rate, mydriasis
► Antihistamine effect (block H1 histamine receptors) sedation
► Antiemetic effect (central depression of chemo-receptor trigger zone)
► Block α-adrenergic effect  light headed, orthostatic hypotension (most common side effect),  HR
► Membrane stabilizing effect  quinidine-like action (wide QRS, right axis)
A Nelson Avery, MD

8. Neuroleptics: Hypothalamic Effects
► Block of dopamine’s tonic inhibitory effect on prolactin release from the pituitary   prolactin 
amenorrhea/ infertility
Impotence and  libido
galactorrhea, gynecomastia
► Thermoregulatory problems:
hypothermia with haloperidol
hyperthermia with phenothiazines
Hypothalamic Hormones
Ant. Pituitary Hormones
Dopamine (─)
Prolactin
A Nelson Avery, MD

9. Neuroleptic Toxicity ► Cataracts, pigmentary retinopathy
► Agranulocytosis (esp. with clozapine)
► Cholestatic jaundice
► Neuroleptic malignant syndrome [see next slide]
► Most serious long-term consequences are tardive dyskinesia and parkinsonism from blocking dopamine receptors
A Nelson Avery, MD

10. Neuroleptic Malignant Syndrome
Most common agents: haloperidol, phenothiazines, thioxanthenes
NMS criteria: started neuroleptic within 7 days of onset:
Fever >40oC
Rigidity (“lead pipe”)
Change in mental status (catatonia, stupor)
Autonomic dysfunction ( BP, HR, diaphoresis, incontinence)
A Nelson Avery, MD

11. Lithium & Antidepressants
A Nelson Avery, MD

12. Lithium
► Drug of choice for manic depressive illness (prevents manic episodes in bipolar disorder)
► Direct serotonin 5HT1A agonist
►  Activity of Na+,K+ -ATPase
► Elimination half-life up to 24 hours; crosses cell boundaries at relatively slow rate  delay of 6-10 days to achieve full therapeutic response
A Nelson Avery, MD

13. Lithium: Toxicity
► Has a low therapeutic index (must carefully follow drug level); caution with severe dehydration, diuretic therapy
► Can cause nephrogenic diabetes insipidus from ADH antagonism  thirst, polyuria
► Neuro: incoordination, dysarthria, ataxia, nystagmus, slow reaction time, tremor, weak, confused
► Hypothyroid goiter ( production and release of T4,  TSH)
► High lithium levels cause  anion gap
A Nelson Avery, MD

14. Cyclic Antidepressants
► Metabolites of tertiary amines are active as secondary amines:
imipramine  desipramine
amitriptyline  nortriptyline
► Tricyclics have half-life >24 hrs, so given once a day.
► Reduce seizure thresholds and can cause arrhythmias  high frequency of death in overdose
► Highly lipophilic (have large Vd) and highly protein bound—so cannot dialyze if overdose
A Nelson Avery, MD

15. Tricyclics: Side Effects
Mechanisms of toxicity/side effects:
► Membrane stabilization (quinidine-like effect)  wide QRS,  QT
► Anticholinergic   HR, dry mouth, urine retention
► α-adrenergic block  orthostatic hypotension
► Antihistamine (H1 & H2)  sedation
A Nelson Avery, MD

16. Tricyclics: Second Generation
Amoxapine
► Potent dopamine blocking agent  movement disorders; also have ARF, arrhythmias
Maprotiline
►  Incidence of seizures
Trazodone
► Overdose: hypotension (α-block), CNS depression
Bupropion
► Used to treat depression /  cigarette smoking
► Concern about seizures
A Nelson Avery, MD

17. Pathway of serotonin production:
SSRIs
Pathway of serotonin production:
L-tryptophan 
5HTP (5-OH tryptophan) 
5HT (5-hydroxy tryptamine = serotonin)
Selective serotonin reuptake inhibitors: fluoxetine, fluvoxamine, paroxetine, sertraline
► Used as antidepressants and for premenstrual dysphoric syndrome (PMDS)
A Nelson Avery, MD

18. SSRIs: Side Effects
► Anxiety (they are stimulating rather than sedating like the tricyclic antidepressants)
► Insomnia
► GI distress (nausea)
► Tremor, dizziness
► Sexual dysfunction ( libido, impaired ejaculation)
► Inhibition of P-450 enzymes
A Nelson Avery, MD

19. Serotonin Syndrome ► From excess stimulation of 5HT1A receptors
► Common cause is MAO inhibitor plus
serotonergic agents (SSRIs, tricyclics), or
meperidine or dextromethorphan (found in cough meds)
► Occurs ~2 hours after second agent given
► Signs/symptoms:
Change in mental status (agitated, restless, confused, delirium), coma, seizures
Altered muscle tone (myoclonus, rigidity,  DTRs)
Shivering, fever, autonomic instability (+/- BP)
Diarrhea
Rhabdomyolysis and DIC  acute renal failure
A Nelson Avery, MD

20. MAOIs Irreversible and non-selective (MAO A & B) phenelzine
isocarboxazide
tranylcypromine
pargyline for hypertension
Selective (for MAO-B)
selegiline
► Used for Parkinson’s (  levels of dopamine)
► Metabolism to amphetamine  (+) drug test
A Nelson Avery, MD

21. MAOIs
► MAOIs inactivate monoamine oxidase (MAO), which   levels of monoamines  antidepressant effect.
► Common side effects: HA, insomnia, drowsiness, weight gain,  libido & interference with orgasm, orthostatic hypotension
A Nelson Avery, MD

22. MAOIs: Interactions ► Life threatening  BP (hypertensive crisis)
► Food and drug interactions:
1) Foods that contain tyramine (  dopamine) (Ex: aged cheese), or
2) Medications: dextromethorphan, meperidine, tricyclic antidepressants, pseudoephedrine, phenylpropanolamine
► Life threatening  BP (hypertensive crisis)
► Motor uneasiness, agitation, moan, grimace, hallucinations
► Profuse sweating, fever
A Nelson Avery, MD

23. Benzodiazepines & Barbiturates
A Nelson Avery, MD

24. Benzodiazepines Short acting (3-8 hrs): oxazepam, triazolam
Intermediate (12-24 hrs): alprazolam, lorazepam, quazepam, temazepam
Long acting (1-3 days): chlorazepate, chlordiazepoxide, diazepam, flurazepam
A Nelson Avery, MD

25. Benzodiazepines
► Benzodiazepines bind the GABAA receptor; binding enhances the ability of GABA to open the chloride channel (increasing the frequency of openings)  inhibitory hyperpolarization of neurons.
► Indications: skeletal muscle relaxation, sleep induction, situational anxiety, status epilepticus, acute alcohol withdrawal, preoperative sedation
A Nelson Avery, MD

26. Benzodiazepines
► Benzodiazepines potentiate the effects of other CNS depressants (e.g., alcohol, barbiturates)  can lead to fatal respiratory depression.
► They do not activate liver microsomal enzymes (do not stimulate P-450 system).
► Can develop tolerance and dependence.
A Nelson Avery, MD

27. Flumazenil for Benzodiazepine OD
► Flumazenil is a competitive antagonist to benzodiazepine receptor site (binds to GABAA receptor)—used for overdoses and to reverse midazolam at end of procedure (e.g., colonoscopy)
► Risk of reversing an overdose:
Seizures (contraindicated with prior history)
Arrhythmias (avoid if person took both benzodiazepine + TCA in overdose)
Precipitate withdrawal if addicted
A Nelson Avery, MD

28. Barbiturates Ultrashort acting: thiopental (for anesthesia induction)
Short acting: pentobarbital, secobarbital
Intermediary: amobarbital, butalbital
Long acting: phenobarbital
A Nelson Avery, MD

29. Barbiturates
► Agonists at GABAA receptor   GABA responses by prolonging the duration that chloride channels remain open (hyper-polarized).
► Thus they facilitate inhibitory neuro-transmission in CNS with a subsequent  in cGMP and cAMP.
A Nelson Avery, MD

30. Barbiturates
► Side effects: sedation, coma; rash, Stevens-Johnson syn.; can have skin blebs in overdose
► Treat overdose of phenobarbital with alkalinization of urine (with NaHCO3) to increase excretion (it is a weak acid and will ionize in urine).
► Cause rapid increase in smooth endoplasmic reticulum in hepatic parenchymal cells   P450 (i.e., it stimulates microsomal enzymes in liver)  accelerated metabolism of other drugs (e.g., BCPs, theophylline, coumadin).
A Nelson Avery, MD

31. Opioids
A Nelson Avery, MD

32. Opioids: Side Effects ► Sphincter spasticity (e.g., gallbladder)
► Euphoria, sedation, drowsiness
► Cough suppression, respiratory depression (mostly mu)
► Miosis (except meperidine)
► Emesis, constipation
► Urine retention
A Nelson Avery, MD

33. Opioids: Toxicity ► Acute toxicity/overdose (classic triad):
Unconsciousness
Pinpoint pupils
Respiratory depression is the chief cause of most opioid overdose fatalities
Also emesis, truncal rigidity, non-cardiogenic pulmonary edema (esp. with heroin, methadone)
► Treated with naloxone or naltrexone (opioid receptor antagonists)
A Nelson Avery, MD

34. Opioids Heroin (diacetylmorphine)
► Metabolism to 6-acetylmorphine (6-AM)  then to morphine
Morphine
► Metabolism to morphine-6-glucuronide
Codeine (methylmorphine)
► Metabolism to morphine, codeine-6-glucuronide
A Nelson Avery, MD

35. Opioids
Synthetic opiates used for pain control: hydrocodone, hydromorphone, dihydrocodeine, oxycodone, levorphanol
Fentanyl
► 100 times more potent than morphine; given IV for anesthesia
► Causes rigidity of chest wall  respiratory arrest
A Nelson Avery, MD

36. Opioids Meperidine ► Metabolite normeperidine is a convulsant
► Strong anticholinergic effect  dilated or mid-position pupils instead of miosis
► Will cause a crisis if given to person taking MAOIs
Propoxyphene
► Metabolite norproxyphene is cardiotoxic
A Nelson Avery, MD

37. Opioids Methadone ► Has a long half-life: 48-72 hours
► Used for treatment of heroin addiction
Mixed agonists / antagonists: pentazocine, nalbuphine, butorphanol, buprenorphine, dezocine
► Can cause partial withdrawal if given to person addicted to morphine, codeine or heroin
A Nelson Avery, MD

38. Opioids Dextromethorphan (DM in cough medicine)
► Antitussive, but not an analgesic
► Will cause a crisis if given to person taking MAOIs
Diphenoxylate and loperamide
► Antidiarrheal, but not analgesics
A Nelson Avery, MD

39. Opioid Antagonists
Displace opioids from all receptors and will counteract opioid overdose.
Naloxone pure opioid antagonist ( withdrawal in addict); 2 mg IV; onset in 1-2 minutes; duration minutes.
Naltrexone used in alcoholism and drug dependence; 2-9 times greater antagonist than naloxone.
A Nelson Avery, MD

40. Study Questions: Psych
In using bupropion (Zyban®) to quit smoking, what is the neurological concern? [seizures]
What is the name for the neurological reaction to phenothiazines that would occur after several weeks and the person would not be able to sit still? What is the treatment? [akathisia / RX: antiparkinson drug, benzodiazepine,  dose]
What is the name for the neurological reaction to phenothiazines that would occur after years of therapy, associated with lip smacking, tongue protruding, facial grimacing? What is the treatment? [tardive dyskinesia /  dose + cholinergic drug]
What are the symptoms seen with neuroleptic malignant syndrome. [fever, lead pipe rigidity, autonomic dysfunction, change in mental status]
What are the diagnostic criteria for serotonin syndrome. [altered mental state, agitation, myoclonus, hyperreflexia, hyperthermia, hypertension, diaphoresis, tremor, diarrhea, incoordination]
A Nelson Avery, MD

41. Study Questions: Psych
What is the potential effect on water balance with lithium therapy and why? [nephrogenic diabetes insipidus, lose free water and raises serum Na+]
What is the effect of giving NSAIDs to a person on lithium therapy? [ level of lithium  toxicity]
Name a narcotic that should not be given with MAO inhibitors. [meperidine]
Name a cough medicine not to give with MAO inhibitors. [dextromethorphan]
What effect would adding phenobarbital have on the pro-time of a person on warfarin (Coumadin)? [ P450   warfarin   PT]
What effect would phenobarbital have on oral contraceptives? [ P450   BCP level]
What is the antidote for benzodiazepine overdose? [flumazenil]
A Nelson Avery, MD

42. Study Questions: Opioids
What is the classic triad of opioid overdose? [coma, respiratory distress, miosis]
List 3 things to give to a person with drug overdose, who is in coma and not responding to conservative care. [naloxone, glucose D50W, and thiamine given IV, plus oxygen]
What is the main toxic effect that we worry about with meperidine’s metabolite? [normeperidine, seizures]
Name a type of reaction of meperidine + MAOI. [serotonin syndrome]
What is the main toxic effect that we worry about with propoxyphene’s metabolite? [norpropoxyphene, cardiac toxicity]
Which narcotic can cause rigidity of the chest wall? [fentanyl]
Which opioid, that is not an analgesic, can cause a serotonin syndrome? [dextromethorphan, cough med]
A Nelson Avery, MD