Psychopharm Flashcards
Presynaptic 5HT: function and targets
- reuptake channels
- TCAs and SSRIs
~ clomipramine
~ fenfluramine
Sumatriptan receptors
- vasoactive
- presynaptic: 1B, 1D
- postsynaptic: 1F; 1B,1D
5HT-3 receptors
- most clinically active
- ondansterone
- 5HT-2C/2A receptor
- active site of atypical antipsychotics and LSD
Mesolimbic pathway
- decreased DA
- increased DA
- increase: antipsychotic, anti-anxiety, anti-agitation
- decrease: inhales pleasure; increases psychosis, mania, agitation
- note: nucleus acumbens is center for addiction and pleasure
Meso-cortical path
- increased DA
- decreased DA
- decrease: negative symptoms of schizophrenia, depression, cog. Impairment, inattention (hypofrontality, ADD)
- increased: opposite of above
Nigro-striatal pathway
- increased DA
- decreased DA
Decreased: 4 extra-pyramidal symptoms
~ dystonia, akinesia, Parkinsonism, NMS (fever, AMS, autonomic instability and increased CK)
Increased: tardive dyskinesia, chorea, Tourette’s
Tuberinfundibular pathway
- decreased DA
- increased DA
- decreased: increased prolactin
~ results in -> galactorrhea, amenorrhea, gynecomastia,
infertility, impotence - increased: decreased prolactin
Chemoreceptive trigger zone for DA
- decreased: antiemetic
- increased: N/V
5HT/NE synthesis
5HT - tryptophan derived - tryptophan hydroxylase - rate limiter NE - Tyrosine derived - tyrosine hydroxylase (first step) - rate limiter
Selective monamine transporters (3)
- 5HTT
- NET
- DAT
VMAT
- recycling of monoamines int vesicles
5HT N2K receptors
- 5HT3 is the only non-G protein receptor
- 5HT1D,1A, 2A, 2C (involved in depression)
5HT1A
- in raphe nuclei and post synaptic cell bodies hippocampus
5HT1D
- auto-inhibitors of 5HT release at axon terminals
alpha adrenergic receptors
- a1, 2 and B1, 2 most relevant
- a2: auto inhibitory
MAO-A, B
- anti depressant is primarily MAO-A
Phenelzine (selegiline): MAOI, use, side effects
- MOA: MAOB inhibitor (Parkinson’s, dermal patch depression)
- SE: result from a-adrenergic blockade
~ orthostatic hypotension
~ weight gain
~ sexual dysfunction
~ potentially lethal drug interaction (carbidopa, meperidine,
linezolide, St. John wort, SSRIs)
Tricyclic antidepressants: effects, examples
- TCAs With secondary amines preferentially affect NE systems
- TCAs With tertiary amines preferentially affect 5HT systems
- don’t effect DA
- can also trt neuropathic pain
- amytriptyline, nortriptyline, desipramine, imipramine
Tricyclics specs
- MOA: non-selective 5HT and NE uptake inhibition
- SE: cardio-conduction delays, first degree blocks
~ also blocks: 5HT, NE, a-1, hist, ACh
Histamine blockade SE
- sedation
- weight gain
- impaired coordination
- orthostatic hypotension
- cognitive impairment
Muscarinic blockade
Anti-parasympathetic
- dry mouth
- constipation
- urinary hesitancy
- decreased visual acuity (loss of accommodation)
- aggravation of glaucoma
- tachycardia
- cognative impairment
- impotence
A adrenergic blockade SE
- orthostatic hypotension
- reflex tachycardia
- ejaculation
- cognitive impairment
5HT blockade SE
- anxiety
- anorexia
- N/V
- insomnia
- sedation
- sexual SE: arousal
- weight gain
- serotonin
NE blockade SE
- anxiety
- tremor
- tachycardia
SSRIs
- first line antidepressants
- also trt OCD, panic disorders, PTSD, Social phobias, GAD
- fluoxetine, paroxetine, sertraline, citalopram
- microsomal interactions
1A 5HT autoreceptors
- desensitize/down regulate in increased concentrations of 5HT
5HT2A
Anxiety, akinesia, myoclonus, sexual dysfunction (orgasm and ejaculation (spinal cord), decreased libido
5HT2C
Anxiety and panic attacks
5HT3
N/V/D
5HT4
Increased bowel motility, cramps and diarrhea
Serotonin syndrome
- excessive 5HT
- agitation, insomnia
- diaphoresis, hyperpyrexia, tachycardia, hypertension
- rigidity, tremor
- can be life threatening, onset may be acute or insidious
SSRI withdrawal
- flu like const. Symp.
- restlessness, confusion
- irritability
- circadian disturbance
- less likely with loner 1/2 life drugs
- moral: for SSRIs taper off.
Venlafaxine, duloxetine
- mixed 5HT/NE (both preferential for 5HT, vel is stronger)
- appears to have increased efficacy due to synergy
- marketed as management if painful effects of depression
Mirtazapine
- MOA: a-2 antagonist
- SE: weight gain, sedation (5HT3 inhibition)
- is also a 5HT2A
Bupropion
- MOA: augments NE release and inhibits DA reuptake (exact mech unknown)
- SE: potential seizure risk: Cind in epileptics or bulimic PTs.
- helpful in smoking cessation
Trazadone
- MOA: 5HT2A antagonism, weak 5HT reuptake inhibition
- associated with priapism
- extremely sedating
- SE make it most useful at very low doses for insomnia
Common SE for all antidepressants
- cardiac effects (esp TCAs)
- allergic rxns (Stevens Johnson’s)
- mania (esp is bipolar or manic predisposition)
- seizures (practically only bupropion, TCAs)
- hepatotoxicity (mostly benign enzyme elevation)
- hematoxic
- agranulocytosis, neutropenia
Overdose: MAOIs, TCAs, SSRIs
- MAOI, TCAs: 7-10 day supply can be lethal
- TCAs: cardiac, seizures
- MAOIs: HTN crisis, hyperpyrexia
- SSRI: safer theraputic index lethal interactions can occur with as little as 25 day supply
Antidepressants and pregnancy
- most are category C (paraxetone: cat D)
- cross placenta DNA breast milk
- increase spontaneous abortion
Lithium
- trt for bipolar disorder
- IP3/DAG blockade via inhibition of PIP2 regeneration
- renal metabolism: GFR makes a big difference (PCT resorb, competes with Na)
- 17-26 hr 1/2life
- carbonate salt in solid form; citrate salt in liquid form
Lithium absorption
- mostly in PCT
- distal tubule diuretics can increase resorption (thiazides, amino ride, spironolactone)
Lithium SE (common)
- weight gain
- N/V
- fine tremor
- polyurea, polydypsia
- skin rxn
- hypothyroidism
- benign leukocytosis
- edema
Lithium SE (uncommon)
- bradycardia
- syncope
- cog/ NPsych symptoms
- nephrogenic diabetes insipidus
- renal insufficiency
- decreased seizure threshold
0.6-1.2 mEqs
Desired lithium lvl
- > 2 mEqs sever toxicity
Elevators of lithium levels
- ACE inhibitors
- NSAIDS
- Distal Tubule Diuretics (DTDs)
Decreasers of lithium levels
- caffiene
- carbonic anhydrase inhibitors
- laxatives
- PTDs
- theophylline
Toxic interactions with lithium
- antipsychotics
- drugs that increase seizure risk
Lithium and pregnancy
- cardiac anomalies (Ebsteins anomaly)
- not particularly hazardous
Bipolar trt: valproic acid
Valproic acid (depakote): GABA agonist (exact unknown) - SE: dyspepsia, weight gain (common), dysphoria, dizziness, hair loss, HA, N/V, (uncommon), hepatotox, pancreatitis (rare)
Bipolar trt: carbamazepine
- Na channel inhibitor (exact unknown)
- rare but serious SE: agranulocytosis, aplastic anemia
- NTDs in preggers
- drowsiness, dizziness, slurred speech, ataxia
Bipolar trt: oxcarbazepine
- similar to CBZ
- less side effects (hyponatremia)
- preferred
Bipolar trt: Lamotrigine
- Na and Ca channel inhibition
- common SE: HA, dizziness, insomnia
- associated with Stevens-Johnson’s syndrome (slow titration to avoid)
Bipolar and women’s health
- contraceptive interactions
- osteoporosis (supplement vitamin D and C)
Brain heart liver blood skin
- common antidepressant SE
Ebsteins anomaly
- cardiac event resultant from Lithium use in pregnancy
5HT2
Responsible for sexual side effects
- NDRIs (bupropion) don’t have sexual side effects because they don’t
- S5HT antagonist: blocks non-depressive 5HT receptors
Buspirone use
Effective in trt of GAD.
Phenylzene side effects
- MAOI
results primarily from a-adrenergic blockade - orthostatic hypotension
- also weight gain, sedation
- Tyramine interactions: lethal (wine, beer, soy sauce, aged cheeses)
Venlafexine (moa, SE)
- mixed (pure) NSRI
- diastolic BP elevation
SSRI withdrawal
- flu like symptoms
- irritability, confusion, restlessness
- circadian disturbance
- risk reduced with longer 1/2 life
Lithium MOA
- PIP2 inhibitor -> results in lack of recharge of IP3/DAG decreasing cell activity
Typical antipsychotics
- 1st generation
- significant side effects
- chlorpromazine, haloperidol, thiothixine, biphenylbutylpiperdine
Atypical antipsychotics
- 2nd generation
- much lower Sx profile
- Clozapine, resperidone, olanzapine, quietapine, aripiprazole
Clozapine: MOA, Use, side effect
- 5HT-2a antagonist
- useful in the trt of drug resistant schizophrenia
- rare but serious: agranulocytosis
- common: weight gain, hypotension, sinus tach, anticholinergia, sedation
Aripiprazole: MOA, use
- partial D2 agonist
- agonism depends on the [DA]: can treat both hyperDA in mesolimbic, and hypofrontality in mesocortex
Early treatment of psychosis
- early is essential
- antipsychotics are neuroprotective
Significant risk of suicidality in psychosis indication
- clonazapine
Acute bipolar mania indication
- all atypicals
Bipolar mania indication
- olanzapine or aripiprazole
Tic disorder indication
- pimozide
Tardive dyskinesia: cause, at risk, treatment
- D2 upregulatory theory
- elderly females at highest risk
- all 1st gen antipsychotics higher risk
- of the 2nd gens, only resperidone significant
- trt with antioxidants, clonazapine(benzo)/naltrexone, high dose branched chain AA
Common antipsychotic side effects (6)
- hypotension
- NMS
- Tardive dyskinesia (quietapine)
- prolonged QT
- sinus tach
- sedation
Dystonia
- hypercholinergic effect
- more common in younger males IM admin
- trt: anticholinergics
Parkinsonism: (non-idiopathi) etiology and trt
- more common in elderly or brain trauma
- trt with amantadine
Metabolic syndrome
- greater risks with second gen antipsychotics
Common benzo SE
- impaired motor effects
- amnesia
- disinhibition (more common in elderly)
- essentially resembles a drunk
Flumazenil
- benzo overdose trt (GABA antagonist)
Benzos vs barbs
- benzos alter NMDA receptors t increase binding affinity
- barbiturates potentiate the kinetics such that they are active longer and can even open Cl- channels directly
Chlorodiazepoxide metabolism
- benzo
- metabolized to multiple intermediates (desmethylchloridiazepoxide, desmethyldiazepam)
Benzos with no clinically active metabolites (3)
- Alprazolam (Xanax)
- triazolam
- lorazepam
Diazepam metabolism
- desmethyldiazepam -> oxazepam
- more highly metabolized benzos have a longer 1/2life (wide variability)
Buspirone: MOA, uses
- 5HT1A
- non-sedating, muscle relaxing, or physical dependance inducing
- used in a med student because it won’t effect her performance
Kava
Interacts with benzos
- rare liver toxicity
Omega (BZ-1) benzos: examples and use
- zolpidem sedating (sleep aid)
- zaleplon (less memory issues, more metabolic interactions)
- Eszopiclone (longer duration)
(ZZE like the letter BZ-1 is for ZZZZs)
Non-selective BZs
- alter stage 2 sleep (which can rebound when off med)
- Temazepam: intermediate duration (little accumulation)
- Trazolam: retrograde amnesia, rebound insomnia/anxiety
(TT- two non selective)
Flurazepam
- long lived -> accumulation
- residual sedation
Anesthetic Barbiturates
- thiopental, thioamylal
~ really short acting makes them useful in this setting
Anticonvulsant barbiturates
- phenobarbital: long duration
Barbiturate effects
- increase stage 2 sleep/decrease rem
- Overdose is extremely dangerous
- Hyoeralgesia is common can cause insomnia
- Lots of interactions including microsomal, ALA synth, and aldehyde dehydrogenase
- porphyriase -> contraindication
Methaqualone
- illegal drug
- “Mickey” date rape
- reacts with EtOH to form sedating compound
Nocturnal myoclonus trt
- Clonazepam
- etiology includes lots of drugs: SSRIs, uremia, TCAs et al
Restless leg trt
- Clonazepam, carbamazepine, quinine
OCT extras: valerian, antihistamines, melatonin, ramelteon
- Antihistamines: sleep aid (drowsiness: may look like delirium in elderly)
- valerian: sleep aid (reqs several days to stack)
- melatonin: great for jet lag
- ramelteon: melatonin receptor agonist
Thiopental/thioamylal
Short acting anesthetic barbiturates
Tramazepam/Trazolam
- sedating barbiturates
~intermediate acting
~ retrograde amnesia, rebound in stag 2 sleep
Xanthine examples
Caffeine (caffeine with ergotamine): vasoactive migraine trt
Theophylline: asthma prophylaxis
Sympathomimetics e.g.
- amphetamines: NE-> DA-> 5HT
- sibutramine
- norepinephrine
- DA
- OTC: St. John’s wort, ma Huang (ephedra)
Sympathomimetics action and effects
- NE>DA>5HT
- increase alertness
- restlessness, insomnia, decreased fatigue and appetite, increased BP
- assoc with use in anorexia nervousa
Clinical use of amphetamines
- limited, primarily to increase satiety
- sibutramine: NE/5HT reuptake inhibition
- narcolepsy treatment: drug holidays are important
~ GHB current trt: obtained in precursor Na Oxybate - methylphenidate: Ritalin phenylpiperdine precursor preferentially releases NE/DA
ADHD trt
- methylphenidate
- atomoxatine: NETi
- pemoline: DA releasing and hypatotoxic
- clonidine: a2 agonist
Atomoxatine
- NETi
- lacks abuse potential
- cardiac and BP SEs
- abdominal cramps
Methylphenidate
- NE/DA release
- ADHD trt
- anorexia side effect -> trt for morbid obesity
Clonadine
- trt ADHD
- can resolve vigilance issues and tics
Bupropion
- NE/DA uptake inhibitor
- along with anti-depressants are also useful
Sibutramine
NE/DA reuptake inhibition
Phenylpiperdine
Active for of methylphenidate
Ritalin
Gamma-hydroxy-butyrate
- trt for narcolepsy
5HT3A
- key to atypicality of 2nd gen antipsychotics
