First Pass Miss Exam 3 Flashcards
What is biased agonism?
Activation of the receptor via one ligand mediates different effects than activation by another opioid (slightly different signalling pathways and cascades carried out by binding the same receptor)
How does morphine-mediated respiratory depression occur? Who is this important in?
Morphine decreases the response to CO2 via brain stem, which is important in patients with COPD on other CNS depressants
Why should morphine be avoided in head trauma?
Increased pCO2 can cause to cerebrovascular dilation and subsequent increased intracranial pressure
What are the cardiovascular effects of morphine usage? How does this relate to one of its usages?
Peripheral vasodilation / reduced peripheral resistance. This can cause orthostatic hypotension and thus
fainting upon standing
Used for patients with dyspnea due to acute pulmonary edema associated with LV heart failure. Good in a palliative care setting.
What can increase and decrease the plasma levels of fentanyl?
Increase - CYP3A4 inhibitors like macrolides, azole antifungals, and grapefruit juice
Decrease - CYP3A4 inducers like carbamazepine, phenytoin
What are the best described effects mediated by opioid signal transduction at the cellular level?
- Closing of voltage gated Ca channels on presynaptic nerves -> prevent release of NT
- Opening of K channels on postsynaptic neurons -> hyperpolarize
What is the oral bioavailability and action of codeine alone?
It has good oral bioavailability because it is not glucuronidated as easily as morphine
Before any metabolism, it is a weak agonist of opioid receptors and does have some modest analgesic effect + antitussive activity (think of codeine barcode)
After CYP2D6 metabolism, it is made into morphine
- > rapid metabolizers at risk for OD, do not give to children
- > CYP2D6 inhibitors like fluoxetine can also interfere
What are the contraindications for tramodol?
Other CYP2D6 / CYP3A4 inhibitors - increase seizure risk by limiting metabolism and increasing SNRI activity
Other antidepressants - serotonin syndrome
Patients with seizure history
Children - same reason as codeine
Tramodol, Codeine, and Fentanyl all rely on CYPs to some degree
What is naloxegol and what is it used for?
Pegylated naloxone metabolite used for treatment of opioid-induced constipation in chronic pain patients
What is the PD profile of dextromethorphan?
Very strange
- > NDMA antagonist - NMDA camel
- > Sigma-1 receptor antagonist
- > SNRI
Why are opioids of concern in the elderly?
Polypharmacy, poor clearance via kidneys, and many surgeries to merit their use -> constipation, balance issues (fainting upon standing), impaired cognition
How are benzodiazepines metabolized?
The majority must first be oxidized in the liver by CYP450, and then ALL will be conjugated with glutathione and excreted in the urine
What drug is a partial agonist of 5-HT1A receptors and what is its primary indication? How long is its effect?
Buspirone
Takes weeks to manifest the effects -> used for long-term anxiety treatment, especially generalized anxiety disorder of patients with substance abuse (not dangerous like benzos)
What is one drug which can be used for both sleep onset and sleep maintenance insomnia? Does it have abuse potential? What are its side effects?
Suvorexant -> orexin receptor antagonist
- > no abuse potential
- > daytime drowsiness and suicidal ideation
-> ramelteon CANNOT help with sleep maintenance, causes increased prolactin, decreased testosterone, and doing things will asleep
How can benzos have varying specificities, aside from their halflife?
Each has two alpha, two beta, and 1 gamma subunit, each with different isoforms -> different areas of the brain will have different receptor isoforms depending on gene expression
-> some alpha subunits of receptors are only expressed in the basal ganglia, for instance, and thus would be targeted in muscle relaxants
What is the most common side effect of benzos/barbs and who is at greatest risk? What should be done to mitigate risk?
Psychomotor dysfunction - including cognitive impairment, decreased psychomotor skills, and unwanted daytime sedation. Worse in drugs with long-lived active metabolites
Greatest risk: elderly patients, dose should be reduced by at least 50% since it increases the risk of falls and fractures. This is due to changes in brain function with aging (not liver)
What are the two primary indications for carbamazepine?
Trigeminal neuralgia and bipolar disorder
- > can also treat focal seizures or generalized tonic clonic
- > make absence and myoclonic seizures worse
What are the most common and most severe toxicities of carbamazepine? what should be done to limit toxicity?
Most common: Ataxia (pancake stack falling) and diplopia (crossed headlights of car)
Most severe - Steven-Johnsons syndrome - predicted by presence of a certain HLA-B allele most often seen in Asian patients
Screen for this allele and give with divided doses
What a final broad spectrum AED which can be used against all seizures? What is its mechanism of action?
What are the common adverse effects of levetiracetam and why is it used over the others?
Levetiracetam (think elevator)
Mechanism of action - binds SV2A glycoprotein in synaptic vesicles, modifying neurotransmitter release
Other than the typical ataxia and diplopia: causes somnolence
Used over the others for its clean PK profile - secreted unchanged by the kidney or nonhepatic metabolism to inactive metabolite (does not interact with CYP450).
What is the primary side effect of ethosuximide? When would you want to use the second line drug and what is it?
Dose-related GI stress
Second line drug: Valproic acid -> used when they may also have generalized seizures of different types, or focal seizures (ethosuximide only good for absence)
What benzo might be good to give in an ambulence for status epilepticus and why?
IM midazolam -> IM injection easier to give than IV lorazepam (or IV diazepam, followed by phenytoin or phenobarbital)
What is Lennox-Gastaut syndrome and what is the best treatment?
Multiple seizures of different types, coupled with some mental disability.
Best treatment is ketogenic diet -> high fat, low carb, medium protein.
Secondary treatments include lamotrigine, levetiracetam, and valproate
What is RNS and how does it work?
Response neurostimulator device - electrical stimulation in brain foci for drug-refractory seizures -> works about as well as vagal stimulation
Vagal stimulation also used in treatment of anxiety / depression
What is one broad spectrum anticonvulsant most commonly used for offlabel treatment of refractory migraine and bipolar disorder? How does it work?
Topiramate! - Toupee -rimate from sketchy
Works by inactivation of Na+ , agonism to GABA-A allosteric site, and inhibition of carbonic anhydrase
What are the two clinically important MAO inhibitors? What is their mechanism of action?
- Tranylcypromine - try a sip of wine
- Phenelzine - funnel leading into bottle of wine
They nonselectively bind and irreversibly inhibit MAO-A and MAO-B
What is the mechanism of action of TCA’s? What other receptors do they inactivate?
Imipramine, Desipramine, Clomipramine (OC!!D)
Primary:
Blockage of NE and 5-HT reuptake, and blockade of 5-HT2 subtypes
Secondary: "Dirty drugs" - blockade of: H1 receptor - swatting bee dodgeball alpha1 receptor - alpha1 cupcake candle M1 receptor - anticholinergic tea party Na channels - peanut stand, heart effects
What are the contraindications of TCA’s and why?
Prostatism / narrow angle glaucoma - anticholinergic effects
Post-MI and heart block - anticholinergic effects
Bipolar disorder -> can lead to a switch syndrome (mania after depressive episode)
What are the features of TCA overdose?
Other than craziness from anticholinergic effect:
3 C’s
Coma
Convulsions - seizures, antagonist to GABA-A receptor?
Cardiotoxicity - Na channel interference can cause prolonged QRS and QT -> leads to TdP arrhythmia
What are the adverse effects of TCA’s not in overdose?
- Weight gain
- Anticholinergic effects
- Cardiovascular effects - tachycardia (M1), orthostatic hypotension (alpha 1), conduction delay and arrhythmias (Na channel)
- CNS - drowsiness / lethargy (H1), lowers seizure threshold - shaking kid
What are the clinical indications of TCA’s?
Major depressive disorder - second line due to toxicity
Chronic pain syndromes - i.e. migraine bell, diabetic neuropathy diasweeties
OCD - kid compulsively sorting marbles
Other than depression, what are SNRI’s good for treating?
Neuropathic pain (diasweeties machine with broken cord) as well as fibromyalgia (fiber bars)
What are the adverse effects of bupropion? How does this relate to contraindication?
Can cause insomnia, nightmares, anxiety, and seizures
Contraindicated (seizure risk) for patients with history of CNS tumor, seizures, head trauma, or eating disorders - think of girls having a seizure with their eating disorders on the basketball court in sketchy
What drug class is trazodone in? Mechanism of action?
Trazodone trombone
In the SARI class - Seratonin antagonist / Reuptake Inhibitor
Antagonizes the 5-HT-2 receptors in specific (basketball number 52), also the alpha 1 receptor (burnt out alpha1 lighter) and H1 receptor (bee being swatted on head of player)
Low dose hypnotic, high dose antidepressant
-> augmentation therapy for insomnia
What is the mechanism of action of Mirtazapine?
Alpha-2 antagonist -> increases NE and serotonin in the synapse
H1 antagonist: relieves insomnia at night but possible daytime sleepiness
Antagonizes 5-HT-2 and 5-HT-3: Less nausea, GI, insomnia, and anxiety
Net effect is boosted 5-HT to 5-HT-1 receptor: decreased depression
What class of drugs is Nefazodone in and what does it share all its characteristics with?
SARI - like trazodone
What are the clinical features of serotonin syndrome? When does this most often occur?
Hyperpyrexia (high temp), hyperreflexia, hypertension, agitation, tremor, tachycardia, and myoclonus
Any serotonin reuptake blocking agent (including drugs of abuse like cocaine, and dextromethorphan / linezolid) + a MAO-Inhibitor
What SSRI’s are safest and most dangerous in pregnancy?
Safest - Fluoxetine and citalopram
Dangerous - Paroxetine, particularly ASDs and VSDs of the heart
How long does it take for lithium action to be seen? What should be done to treat acute episodes of mania in light of this?
Halflife is 24 hours -> onset of action is around 10-14 days
Thus, in acute episodes, start lithium and acutely treat with an antipsychotic or benzodiazepine (i.e. valium)
What are the most common dose-related effects of lithium toxicity and when are these worse?
Worse 1-2 hours after oral dosing, when plasma levels are highest
Include: GI distress, fine hand tremor, and polyuria-polydipsia
Why does lithium cause polyuria and lithium-induced diabetes insipidus (LINDI)?
Polyuria - due to inhibitory effect on vasopressin -> increase in urine volume and thirst
LINDI - due to loss of responsiveness to antidiuretic hormone in the kidney (lithium is brought in principle cells and reduces the expression of aquaporin-2)
-> treated with amiloride or HCTZ
What factors predispose to lithium toxicity?
Sodium restriction / loss, dehydration, vomiting / diarrhea, and drug interaction which reduces lithium clearance
-> maintain adequate sodium and fluid intake
What three drug interactions are most likely to cause lithium toxicity and why?
- NSAIDs - reduction of GFR increases Na / Li resorption in PCT
- Thiazide diuretics - reduce GFR
- ACE inhibitors - reduce GFR
What are two drugs which decrease lithium levels?
- Caffeine / theophylline - increase diuresis and lithium clearance
- Sodium -> high dietary sodium intake promotes renal clearance of lithium
Should lithium be used in pregnancy and why?
Probably not, especially in first trimister due to two conditions.
- Ebstein’s anomaly - downward displacement of tricuspid valve into right ventricle (think of the snowmen in sketchy)
- Floppy infant syndrome - low apgar scores, hypotonia, lethargy, shallow respiration, hypothyroidism, and goiter
What is the treatment of lithium toxicity?
Gastric lavage + IV fluids, with monitoring of electrolyte status.
Hemodialysis may be required at very high levels
What is an important physical sign / risk factor for falling? What can induce it?
Orthostatic hypertension -> diuretics, nitrates, psychoactive drugs
What are the distribution changes that occur with age? (think of body composition changes) How does this influence halflife?
- Decreased lean body mass -> increase plasma concentration of water soluble drugs (decreased half life)
- Increased body fat -> higher Vd for lipophilic drugs (higher halflife)
- Total body water decreases -> increased plasma concentration of water soluble drugs
- Decreased serum albumin concentration -> decreased protein binding, can lead to toxicity if extra drug is given
What is the Cockroft-Gault equation?
Formula for adjusting drug doses for renal function, based on body weight parameters and creatinine concentration (Age > 75)
Creatinine Clearance = ((140-age) * wt / (Scr * 72))
Multiply by 0.85 only in women
Most of the bisphosphonates are given orally. Which is not? What do these serve to do?
Zoledronic acid is given once yearly via IV, or once every two years to prevent osteoporosis
Reduce the risk of vertebral and non-vertebral fractures
