Download Psychiatric Meds and Opiates

Pharmacology Review:
Psychiatric Meds
& Opiates
Presented by:
A Nelson Avery, MD
Board Certified in Toxicology, Preventive Medicine and Internal Medicine
Clinical Professor and Director
Preventive Medicine Residency Program
[email protected]
Neuroleptics
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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
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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
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Neuroleptics: Parkinsonism
► Because the dopaminergic neurons in the basal
ganglia act to inhibit cholinergic neurons, blockage
ACh
of the dopamine receptors results in excess
central cholinergic stimulation, which can
cause acute dystonia, akathisia,
or Parkinson’s-like presentation dopamine
substantia nigra
dopamine
corpus striatum
(–)
NEUROLEPTICS
(+)
bradykinesia,
tremor, rigidity
acetylcholine
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Sequence of Extrapyramidal Effects
1-5 days
acute dystonia
(oculogyric
crisis)
5-60 days
akathisia
(restless,
inability to sit)
5-30 days
months-years
pseudoparkinsonism
neuroleptic
malignant syn.
tardive
dyskinesia
perioral tremor
(rabbit syn.)
T R E A T M E N T:
▪ diphenhydramine
▪ benztropine
▪  dose of med.
▪ antiparkinson
▪ benzodiazepine
▪  dose of med.
▪  dose of med.
▪ antimuscarinic
▪  dose
▪ cholinergic drug
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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 chemoreceptor 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)
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Neuroleptics: Hypothalamic Effects
► Block of dopamine’s tonic
inhibitory effect on prolactin
release from the pituitary 
 prolactin 
Hypothalamic
Hormones
Ant. Pituitary
Hormones
Dopamine (─)
Prolactin
• amenorrhea/ infertility
• Impotence and  libido
• galactorrhea, gynecomastia
► Thermoregulatory problems:
• hypothermia with haloperidol
• hyperthermia with phenothiazines
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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
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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)
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Lithium &
Antidepressants
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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
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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
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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
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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
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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
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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)
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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
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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
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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
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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
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MAOIs: Interactions
► 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
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Benzodiazepines &
Barbiturates
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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
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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
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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.
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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
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Barbiturates
Ultrashort acting: thiopental (for
anesthesia induction)
Short acting: pentobarbital,
secobarbital
Intermediary: amobarbital, butalbital
Long acting: phenobarbital
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Barbiturates
► Agonists at GABAA receptor   GABA
responses by prolonging the duration that
chloride channels remain open (hyperpolarized).
► Thus they facilitate inhibitory neurotransmission in CNS with a subsequent 
in cGMP and cAMP.
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Barbiturates
► Side effects: sedation, coma; rash, StevensJohnson 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).
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Opioids
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Opioids: Side Effects
► Sphincter spasticity (e.g., gallbladder)
► Euphoria, sedation, drowsiness
► Cough suppression, respiratory
depression (mostly mu)
► Miosis (except meperidine)
► Emesis, constipation
► Urine retention
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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)
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Opioids
Heroin (diacetylmorphine)
► Metabolism to 6-acetylmorphine (6-AM)
 then to morphine
Morphine
► Metabolism to morphine-6-glucuronide
Codeine (methylmorphine)
► Metabolism to morphine, codeine-6glucuronide
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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
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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
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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
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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
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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 20-60 minutes.
Naltrexone used in alcoholism and drug
dependence; 2-9 times greater antagonist
than naloxone.
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Study Questions: Psych
1. In using bupropion (Zyban®) to quit smoking, what is the
neurological concern? [seizures]
2. 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]
3. 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]
4. What are the symptoms seen with neuroleptic malignant
syndrome. [fever, lead pipe rigidity, autonomic dysfunction,
change in mental status]
5. What are the diagnostic criteria for serotonin syndrome. [altered
mental state, agitation, myoclonus, hyperreflexia, hyperthermia,
hypertension, diaphoresis, tremor, diarrhea, incoordination]
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Study Questions: Psych
6. What is the potential effect on water balance with lithium therapy
and why? [nephrogenic diabetes insipidus, lose free water and
raises serum Na+]
7. What is the effect of giving NSAIDs to a person on lithium
therapy? [ level of lithium  toxicity]
8. Name a narcotic that should not be given with MAO inhibitors.
[meperidine]
9. Name a cough medicine not to give with MAO inhibitors.
[dextromethorphan]
10.What effect would adding phenobarbital have on the pro-time of a
person on warfarin (Coumadin)? [ P450   warfarin  
PT]
11.What effect would phenobarbital have on oral contraceptives? [
P450   BCP level]
12.What is the antidote for benzodiazepine overdose? [flumazenil]
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Study Questions: Opioids
1. What is the classic triad of opioid overdose? [coma,
respiratory distress, miosis]
2. 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]
3. What is the main toxic effect that we worry about with
meperidine’s metabolite? [normeperidine, seizures]
4. Name a type of reaction of meperidine + MAOI. [serotonin
syndrome]
5. What is the main toxic effect that we worry about with
propoxyphene’s metabolite? [norpropoxyphene, cardiac
toxicity]
6. Which narcotic can cause rigidity of the chest wall? [fentanyl]
7. Which opioid, that is not an analgesic, can cause a serotonin
syndrome? [dextromethorphan, cough med]
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