Psychopharmacology Flashcards
What is monoamine oxidase?
enzyme found in presynaptic nerve endings, the liver, and the intestinal wall that metabolizes biogenic amines
dopamine
serotonin
epi
norepi
MAO A metabolizes which neurotransmitters?
serotonin
norepi
epi
MAO B metabolizes which neurotransmitters?
phenylethylamine
dopamine
may see these used in parkinson’s because they enhance dopamine levels
MAOI (Monoamine oxidase inhibitors): MOA
MAOIs form a stable irreversible complex with MAO –> increasing availability of these neurotransmitters in the CNS and peripheral autonomic nervous system
MAOIs: Agents
Phenelzine (nardil)
Tranylcypromine (parnate)
Isocarboxazid (marplan)
Selegine (eldepryl) - selective for MAO B, but at higher doses become non selective
MAOIs: Side Effects
Most common: orthostatic hypotension --ESPECIALLY PROMINENT IN ELDERLY anticholinergic like effects impotence/anorgasmy weight gain sedation or mild stimulant effects
MAO A enzyme present in liver, GI, tract, kidneys, lungs
–metabolizes dietary tyramine
Dietary to amino acid to avoid with MAOIs and why?
MAO A enzyme present in liver, GI tract, kidneys, lungs
—metabolizes dietary tyramine
dietary tyramine + certain medications ---massive release of endogenous catecholamines/serotonin --> hypertensive crisis hyperpyrexia CVA
S/S of MAOIs + certain medication interactions
serious headache vomiting chest pain tachycardia HTN hyperthermia CNS excitation delirium seizure death
Foods to avoid with MAOIs (containing tyramine)
cheese fava beans wine avocado liver cured meats
MAOIs: adverse drug interactions
antidepressants (TCAs, SSRI, etc) opioids (NO meperidine) cold - allergy drugs sympathomimetics nasal decongestants (often alpha 1 agonists)
MAOI + meperidine (demerol)
SEROTONIN SYNDROME
Excitatory response (type I) enhanced serotonin activity in the brain
- -agitation
- -skeletal muscle rigidity
- -hyperpyrexia
Depressive response (type II) slowed breakdown of meperidine
- -hypotension
- -resp depression
- -coma
MAOIs: Anesthesia Considerations
may need a higher MAC with volatile agents
MINIMIZE POSSIBILITY OF SYMPATHETIC NERVOUS STIMULATION OR DRUG INDUCED HYPOTENSION (just don’t have many drugs that we can give)
Sympathomimetics
- -may get an exaggerated response from indirect acting drugs, NO EPHEDRINE!!!!!!!!
- -USE DIRECT ACTING ONLY IF NEEDED AT ALL
- -decrease dose by 1/3 and titrate to effect
- -Art line
vigilant about using drugs that are short acting, easily titratable, can easily reverse
Antidepressant discontinuation syndromes
All should be tapered!
- can get dizziness
- myalgias
- parasthesia
- irritability
- insomnia
- visual disturbances
- tremors
- lethargy
- N/V/D
Ketamine IV: MOA
Unclear
- -NMDA antagonist
- -promote synaptic plasticity
- —activation of brain derived neurotrophic factor (BDNF)
- —modulate rapamycin (mTOR) signaling pathways
Ketamine IV: use and dose
sub anesthetic doses used OFF LABEL for treatment-resistant depression with potential suicidal ideation
0.5mg/kg and 1.0mg/kg most effective
Benzodiazepines: MOA and use
Facilitates the action of GABA (major inhibitory neurotransmitter in the CNS)
allosteric agonist - binds between alpha and gamma whereas GABA is between alpha and beta
widely prescribed for anxiety and insomnia
panic disorder
some muscle relaxation (not surgical level obvi)
alprazolam: class, use
benzo, anxiolytic
high potency; short acting
can depress cortisol secretion
clonazepam
longer acting benzo
Buspirone: Class, use, MOA, E 1/2
anxiolytic, non benzo
partial agonist at serotonin receptor
no direct effect on GABA so no cross reactivity with benzo, barbs, ETOH
used for treatment of generalized anxiety disorder but not panic disorder
E1/2t: 2 - 11 hours
Antipsychotics: “typical agents*
FIRST GENERATION - phenothiazines, thioxanthenes (DOPAMINE ANTAGONISTS)
chlorpromazine (low potency) thioridazine perphenazine trifluoperazine thiothixene
SECOND GENERATION - butyrophenone (DOPAMINE ANTAGONISTS)
haloperidol (high potency)
droperidol
1st gen/2nd gen antipsychotics: MOA
dopamine antagonists at D2 receptors (high potency) in the basal ganglia and limbic portions of the forebrain (expect to see parkinson like effects because antagonizing dopamine receptors)
also muscarinic cholinergic, antihistamine, and alpha blocking properties
- -sedation (H1 receptor blockade)
- -anticholinergic effects (dry mouth, constipation, urinary hesitancy)
- -anti adrenergic effects: alpha blocking effect usually seen as orthostatic hypotension
- -interference with dopamine –> extrapyramidal side effects
- -blockade of dopamine receptors in chemoreceptor trigger zone of medulla –> antiemetic effects
1st gen/2nd gen antipsychotics: extrapyramidal symptoms
parkinsoniasm, dyskinesia
ANESTHESIA PERSPECTIVE
- -acute dystonia: acute skeletal muscle rigidity & cramping of muscles of eyes, tongue, face, larynx, neck, and back
- —resp distress from laryngeal dyskinesia (LARYNGOSPASM)
- —responds well to diphenhydramine 25-50 mg IV
- -tardive dyskinesia: involuntary jaw or oral musc movements expanding over time to include muscles in the extrem and trunk
- —results of long term therapy
- —concern for ASPIRATION RISK
Mesolimbic tract in brain
behavior, mood
excessive dopamine signaling –> schizophrenia, psychoses
Antipsychotics: “Atypical agents”
clozapine (clozaril)
1st gen/2nd gen antipsychotics SE: neuroleptic malignant syndrome – ONSET + S/S
develops over 24-72 hours after administration usually in young men
- hyperthermia
- hypertoniciy of skeletal muscles
- –myoglobinuria
- instability of ANS
- fluctuating LOC
4% fatality with early intervention
30% mortality with delayed intervention
related to respiratory failure, CV collapse, dysrhythmias
neuroleptic malignant syndrome: treatment
treatment is supportive and includes:
- dantrolene (will produce flaccid paralysis)
- dopamine agonists
1st gen/2nd gen antipsychotics: other adverse effects
-severe dysrhythmias: QT PROLONGATIONS (rare) leading to torsades & v fib (potentially fatal)
- decreases in BP
- –due to depression of vasomotor reflexes/peripheral alpha adrenergic blockade
- –relaxants on vascular smooth muscle
- –direct cardiac depression
- agranulocytosis: (rare) check WBC
- Pregnancy: 3rd trimester babies may develop w/d symptoms and EPS
- sedation
- –due to antagonism of alpha 1, muscarinic, & histamine receptors
- –tolerance to sedation develops with chronic therapy
-seizure threshold decreased (in people w/ seizure hx) - similar EEG pattern as seen with seizure disorders, and sensory evoked potentials often decreased in amplitude
- skeletal muscle relaxation
- –by CNS action not neuromuscular junction
1st gen/2nd gen antipsychotics: drug interactions - intensification of effect
anticholinergics
CNS depressants
1st gen/2nd gen antipsychotics: drug interactions - reduction of effect
levodopa
dopamine agonists
1st gen/2nd gen antipsychotics: drugs to avoid (QT prolongation)
Many of these antipsychotics are metabolized by CYP450 enzymes, others are inhibitors of CYP450
avoid drugs that prolong the QT interval:
- amiodarone
- erythromycin
- quinidine
Neuroleptanalgesia: INNOVAR
Fentanyl + droperidol
- prolonged action of fentanyl, intense analgesia
- potentiation of opioid side effects (sedative, ventilatory, analgesic)
Droperidol (2nd gen antipsychotic): CNS effects
- extrapyramidal reactions
- cerebral vasoconstrictor (decreased CBF, but not CMRO2)
- dysphoria
Droperidol (2nd gen antipsychotic): Metabolism and clearance
- clearance is PERFUSION DEPENDENT - hepatic metabolism opposed to hepatic enzyme activity
- accumulation of drug with decreased hepatic blood flow
- maximal excretion of metabolites in 1st 24 hrs
Droperidol (2nd gen antipsychotic): CV effects
- dec in systemic BP from alpha blockade - usually minimal
- antidysrhythmic, protects against epi induced dysrhythmia
- large doses dec conduction along accessory pathways responsible for tachy-dysrhythmias helpful in WPW syndrome
- prolonged QT interval
- torsades
- –have occurred at low doses
- –pts with no risk factors
- –no precise cause
- –some have been fatal
Droperidol (2nd gen antipsychotic): BLACK BOX WARNING
- ALL pts get 12 lead prior to administration of droperidol
- must be monitored prior to and continued for 2-3 hrs
- Caution with patients at risk of developing QT syndrome -CHF
- bradycardia
- use of a diuretic
- cardiac hypertrophy
- hypokalemia
- hypomagnesemia
- admin of other drugs known to increase the QT interval
Atypical antipsychotics: MOA
multi receptor antagonists,
- less potent dopamine blocker than typical agents
- potent serotonin receptor antagonist
also blocks receptors for alpha 1, histamine, ach
atypical antipsychotics: CV risk factors
decreased risk of EPS and tardive dyskinesia
increased risk of metabolic disease - ages CV system
weight gain
t2dm
dyslipidemia
myocarditis/pericarditis
ANESTHESIA CONSIDERATIONS:
recent cardiologist report, heavy CV work if they have been on this drug for a while
Clozapine: Class + use
atypical antipsychotic
indicated for schizophrenia - especially high suicide risk and bipolar disorder
clozapine: serious side effects
-agranulocytosis: dec WBCs (clozapine only)
CONTRAINDICATED IN WBC < 3500
- All agents (atypical agents): NMS
- tonic clonic seizures
- myocarditis
clozapine: common side effects
-weight gain - leading to metabolic syndrome, sedation, orthostatic hypotension, anticholinergic side effects
Lithium: Class + MOA
Mood stabilizer
MOA: unknown despite considerable research
- inhibition of glycogen synthase kinase 3 beta?
- promotion of neuronal survival factors and reversal of atrophy?
Lithium: pharmacokinetics
positively charged
distributed throughout total body H20 and excreted by the kidneys
E1/2t: 24 hours
proximal reabsorption of lithium and NA is competitive
—Na depletion can inc plasma concentration of drug by 50%
Lithium: pharmacokinetics
positively charged
distributed throughout total body H20 and excreted by the kidneys
E1/2t: 24 hours
proximal reabsorption of lithium and NA is competitive
—Na depletion can inc plasma concentration of drug by 50%
BE MINDFUL OF HYDRATION STATUS
Lithium: side effects (kidneys)
- evaluate renal function every 6 months
- -polydipsia and polyuria; >3 L/day
- -impaired renal concentrating ability
- —amiloride (potassium sparing diuretic) can dec urine volume
Lithium: side effects (CV)
- EKG - T wave changes, flattening or inversion
- —no related clinical effects and reversible
- heart block (rare)
- —CI in pts with SA node dysfunction
Lithium: side effects (neuro)
- fine tremor
- sedation
- memory disturbances/cognitive slowing
Lithium: side effects (other)
-new onset psoriasis/acne
- hypothyroidism can develop - more common in females
- —-assess for goiter! - THINK AIRWAY - awake intubation
Lithium toxicity: mild
sedation nausea skeletal muscle weakness wide QRS complex AV heart block hypotension dysrhythmia seizure
lithium: significant toxicity
> 2.5 mEq/L
- medical emergency
- aggressive RX
- hemodialysis
- osmotic diuresis and IV Na+ bicarbonate
lithium: anesthesia considerations
- pre op labs and ECG (BMP, creatinine)
- anesthetic requirements may be decreased
- —esp CNS depressants
- action of neuromuscular blocking agents may be PROLONGED - use PNS for sure
AIRWAY ASSESS FOR GOITER
lithium: drug interactions
diuretics - inc lithium levels/risk of tox by dec NA levels
NSAIDs - in lithium levels ~60%
ACE - inhibitors - inc lithium levels
anticholinergics: urinary retention with polyuria can be uncomfortable
Epilepsy pharmacotherapy: mechanisms
- inhibiting voltage activated ion channels (Na, Ca2+)
- promote the efflux of K = hyper-polarization
- antagonize glutamate (primary excitatory neurotransmitter of CNS)
- enhance function of GABA - inhibitory neurotransmitter
Many anti-epileptics are associated with which life threatening side effects
BONE MARROW SUPPRESSION
HEPATOTOXICITY
Consider:
- liver function tests
- hematologic studies
Phenytoin (dilantin): Class + MOA
anti-epileptic
MOA: regulates neuronal excitability and thereby the spread of seizure activity from a seizure focus by regulating Na and Ca ion transport across neuronal membranes
Phenytoin (dilantin): atypical pharmacokinetics
non linear pharmacokinetics; metabolism is saturable
“zero order kinetics” above low doses
narrow therapeutic window; therapeutic drug monitoring
highly protein bound - 90% to plasma protein
Phenytoin: Administration and dosing
- IV formulation: very basic (pH 12), precipitates in solutions with pH < 7.8 - PHLEBITIS (extravasations are concern)
- Not recommended IM - precipitates, poorly absorbed
- Infusion no faster than 50 mg/min in adults to prevent hypotension and cardiac dysrhythmias
Peds: 1 - 3 mg/kg/min or 50 mg/min - whichever is slowe
Phenytoin: side effects
-dose related CNS toxicity
- non dose related
- -allergic reaction –> steven johnson syndrome/toxic epidermal necrolysis
- -gingival hyperplasia
- -hirsutism
- -acne
- -measles like rash
- -hepatotoxicity
- -purple glove syndrome
- -severe congenital malformations (POTENTIAL FOR PREGNANCY)
- GI irritation
- hepatotoxicity
phenytoin: metabolism
induces CYP450 (POTENT, POTENT, POTENT)
increases metabolism of other antiepileptics, BCP (birth control pills), warfarin, corticosteroids
fosphenytoin: MOA, PK, Use, dose
FOS = PRO DRUG
antiepileptic
- acts on on Na ion channel blockade
- highly protein bound
- water soluble phenytoin pro drug
- used in hospitals for status epilepticus and in neurosurgery to prevent/treat seizures
- –10-20 mg/kg IV LOADING DOSE
Carbamezapine (tegretol): Class + MOA
anti epileptic
sodium channel blocker
Carbamezapine (tegretol): drug interactions
enzyme inducer, auto induction
- accelerated metabolism of warfarin and oral contraceptives are of particular concern
- grapefruit juice can inc levels (inhibitor?)
- phenytoin and phenobarb can decrease levels (inc dose)
Carbamezapine (tegretol): Adverse effects
- minimal cognitive impairment: mild CNS
- rash mild –> steven johnson syndrome
- hematological effects: aplastic anemia, thrombocytopenia, anemia, leuokopenia (CBC)
- inappropriate ADH secretion (FLUID/ELECTROLYTE)
- congenial defects (neural tube defects)
lamotrigine (lamictal): Class + MOA
anti epileptic, can also be used as a mood stabilizer
MOA: blocks sodium channels, also:
–decreases glutamate via calcium channel block
lamotrigine (lamictal): side effects
CNS effects
-sedation, visual disturbances, HA, N/V, depression, suicide risk
Rash is a major concern (steven johnson’s sydrome); MUST TITRATE DOSE SLOWLY
lamictal: metabolism
metabolism can be induced by other anti - epileptics that are inducers (phenytoin, phenobarbital, carbamezapine)
Inhibited by valproate!
Inhibited by valproate
lamictal
Phenobarbital: Class + MOA
anti epileptic; long acting barbiturate
MOA: modulation of post synaptic actions of GABA and glutamate; prolong duration of chloride channel opening; limiting spread of SZ
phenobarbital: metabolism
enhances cyp450 system in liver
phenobarbital: side effects
cognitive and behavioral SE limit usefulness - 2nd line drug
sedation in adults; hyperactivity in children
depression
confusion in elderly
Valproate/valproic acid (depakote) Class, MOA, use
anti epileptic; bipolar disorder, migraine prevention
MOA:
- blocks Na channel
- blocks t type calcium currents
- promotes synthesis of GABA
Valproate/valproic acid (depakote): drug interactions
-not metabolized by CYP450
ENZYME INHIBITOR - when administered with topiramate - high levels of ammonia can accumulate and cause CNS toxicity
valproate/valproic acid (depakote): side effects
- MAJOR congenital malformations - category D
- fatal pancreatitis
- fatal hepatotoxicity (esp in peds <2 yo)
- n/v, weight gain, alopecia, thrombocytopenia (CBC)
Topiramate (topamax): MOA + Class
anti epileptic
MOA: multiple modes of action
- blocks sodium channels, enhances GABA
- blocks calcium channels
- glutamate antagonist
Topiramate: drug interactions
- phenytoin and carbamazepine can decrease levels of drug
- topiramate can increase phenytoin levels
Topiramate: adverse effects
drowsiness, impaired cognition, ataxia, weight loss
SERIOUS: psychomotor slowing, renal stones, metabolic acidosis (ABG), glaucoma, congenital malformations
Keppra (levetiracetam):
MOA: unknown
adverse effects much less significant
very few drug interactions, not metabolized by CYP450
pregnancy safety uncear = category C
Pharmacotherapy of Parkinson’s: goals of therapy
Tx is palliative
RESTORE DOPAMINE
- inc dopamine synthesis
- inc dopamine release
- dopamine receptor agonism
- dec dopamine re uptake
- dec dopamine metabolism
Levodopa/carbidopa (sinemet): MOA
dopamine does not cross BBB
immediate precursor levadopa, does via active transport
carbidopa does not cross BBB, but does inhibit peripheral conversion of levodopa to dopamine by blocking peripheral dopamine decarboxylase; therefore, levadopa is available to cross the BBB
Levodopa: side effects
- N/V - dop induced stimulation of the chemoreceptor trigger zone
- CV - alpha and beta responses evoked by higher plasma levels of dop resul in transient flushing of skin, sinus tach, PACs, PVCs, and orthostatic hypotension
- abnormal involuntary movements - tics, grimacing, develops after 1-4 months of therapy in 50% of pts
- psychiatric disturbances
Levodopa: lab measurements
- urinary metabolites can cause false positive tests for ketoacidosis
- transient increase in BUN
- increase in liver enzymes
usually not reflective of any long term effects
Levodopa: drug interactions
butyrophenones and phenothiazines
- ANTAGONIZE EFFECTS OF DOPAMINE - avoid them!
- metoclopramide - worsens effects of disease
- droperidol - skeletal muscle rigidity and pulmonary edema d/t sudeen antagonism of dopamine
MAO inhibitors
-interferes with inactivation of catecholamines including dopamine
Anticholinergics
- act synergistically with levodopa to improve tremor
- levodopa (bringing dopamine level up), anticholinergic (bringing ach level down) –> restoring balance
Catechol - O - Methyl Transferase (COMT) Inhibitors: MOA + Agent
MOA: prevent breakdown of dop - more levodopa to cross BBB; in amount of dop available to CNS (prolongs half life 50-75%)
Agent: Entacapone (prototype) - used with levodopa
Catechol - O - Methyl Transferase (COMT) Inhibitors: adverse effects
- similar to levodopa as it intensifies those effects
- urine discoloration (orange)
- hallucinations
Direct dopamine agonists: MOA, use + agents
MOA: selectively binds to D2 and D3 receptor subtypes: delayed onset of effect 2-3 weeks
used as 1st line monotherapy and then combined with levodopa as disease progresses
Agents: Prototype: pramipexole (mirapex) bromocriptine pergolide ropinirole (requip
Direct dopamine agonists: adverse effects
- n/v
- postural hypotension
- hallucinations
- vivid dreams
- sleepiness
- dyskinesias (less than with levodopa)
- impulsive
- high risk behaviors
Parkinson’s drug therapy, Anticholinergics: MOA + agents
MOA: blunt effects of excitatory neurotransmitter ach correcting balance between dopamine and Ach
Agents:
- trihexyphenidyl (artane)
- benztropine (cogentin)
Parkinson’s drug therapy, Anticholinergics: side effects
- confusion
- hallucination
- urinary retention
think CAS
Parkinson’s drug therapy, Amantadine (symmetrel): MOA, use
- anti viral
- MOA: anti parkinsons action unclear: weak, non competitive antagonist of the NMDA receptor, enhances dop release into the synapse and delays reuptake into the nerve endings
- symptomatic improvement of parkinsonian symptoms
Parkinson’s drug therapy, Selegine (eldepryl): MOA, use
MOA: highly selective irreversible inhibitor of MAO B (selective for MAO B so not quite as worried about serotonin syndrome, but should still treat conservatively)
used as an adjunct to carbidopa - levodopa
Non pharmacologic Rx: Parkinson’s
- deep brain stimulation
- stem cell transplantation and other therapeutic mechanisms are under investigation
Cholinesterase Inhibitors: use, moa, agents
Use: alzheimers
MOA: inhibit acetylcholinesterase; thereby inc Ach concentrations in the synapse
- donepezil (aricept)
- rivastigmine (exelon)
- galantamine (razadyne)
cholinesterase inhibitors: side effects
- nausea
- diarrhea
- dizziness
- HA
- bronchoconstriction
Memantine: Class, Use, MOA
Class: NMDA receptor antagonist
Use: indicated for moderate to severe AD, very modest benefits
MOA: 2 proposed mechanisms
- blocking “leaky” channels to help reduce calcium induced excitotoxicity
- blocking “leaky” channels helps reduce background noise, making signals relatively stronger
Memantine: side effects and considerations
(NMDA receptor antagonist)
- dizziness
- HA
- fatigue
- sedation
- HTN
- rash
- diarrhea
- wt gain
- urinary frequency
- anemia
CBC, HTN, FLUID/ELEC BALANCE
