Pharmacology Flashcards
What is the primary toxicity of anthracyclines and what drug should be given to prevent this?
Doxorubin / daunorubicin
Dilated cardiomyopathy with increased use
Drug given to prevent: Dexrazoxane -> iron chelating agent
List the type 3 anti-arrhythmics and their mechanism of action.
- Sotalol
- Amiodarone
- Dofetilide / Ibutilide (“Till I Die” for -tilide in Sketchy)
Inhibit potassium K+ channels, slowing repolarization, prolonging the QT interval
How does hyperthyroidism as in Graves’ disease produce most of its symptoms? What major symptom is not accounted for by this?
T3 upregulates beta-adrenoceptors, and increased the body’s responses to catecholamines.
Exophthalmos is actually due to infiltration of retroorbital space by T lymphocytes -> increased fibroblast secretion and muscle inflammation. Most other symptoms can be blocked by beta-blockers.
For a train-of-four neurological stimulation tests, measuring muscle response after four repeat stimulations, what will be seen in the Phase I and Phase II response of succinylcholine?
These are phase I and phase II of the depolarizing blockade
Phase I - Equal reduction in each twitch -> muscles are already relatively depolarized, repeat stimulations will not produce a greater response with greater acetylcholine released into the synapse. Will be equal for the train of four.
Phase II - Membrane has repolarized, ACh receptors are available but desensitized. Not well understood, but this block functions more like a non-depolarizing blockade seen in rocuronium / tubocurarine. Each stimulation will have a reduction in response from the previous -> less acetylcholine available with each stimulation to stimulate the neuromuscular junction.
If still confused, see UWorld 1212
What patient will be particularly response to succinylcholine and can last a long time?
Patients with a plasma cholinesterase deficiency -> will need to give blood transfusion to deactivate, which contains the enzyme required.
What agent should you use in PCP pneumonia prophylaxis if CD4<200 and patient is allergic to TMP/SMX? What is the side effect of risk?
Dapsone - similar mechanism of action
Side effect: Hemolysis, especially if patient has a G6PDH deficiency
What drug is contraindicated in C1 esterase inhibitor deficiency, and what labs will be associated? Why?
C1 esterase inhibitor also inhibits kallikrein. Deficiency will lead to increased complement activation (decreased C4 levels) and increased bradykinin levels (kallikrein converts HMW kininogen to bradykinin)
-> ACE inhibitors are contraindicated in hereditary angioedema since ACE functions to degrade bradykinin.
What is the mechanism of action of leflunomide?
Inhibits pyrimidine synthesis via inhibition of dihydroorotate dehydrogenase
What is the mechanism of action of hydroxyurea?
Inhibits ribonucleotide reductase
- > inhibiting the reductase waitress
- > prevents formation of dUDP
also upregulates fetal hemoglobin levels for sickle cell treatment
What is the mechanism of action of mycophenolate?
Inhibits IMP dehydrogenase
- > inhibits guanine synthesis pathway
- > increased AMP (IMP rerouted to AMP synthesis) and decreased GMP prevents cellular proliferation
What is the mechanism of action of ouabain?
Inhibits the Na+/K+ ATPase by binding the K+ site site
Can be used as a cardiac glycoside with mechanism of action similar to digoxin
What is the treatment for cyanide poisoning?
Poisoning is mediated via binding of cytochrome c iron in the Fe+3 state
-> give sodium nitrite or amyl nitrite to cause methemoglobinemia which will compete for the cyanide
-> also give hydroxycobalamin (B12) and sodium thiosulfate as antidotes
UWorld #1415
What can happen to your nutritional state if you have excess mineral oil intake?
Used as a laxative can cause fat soluble vitamin deficiency
-> will transport fat soluble vitamins into stool by dissolving them
What is the mechanism of action of phencyclidine?
NMDA antagonist
-> dissociative agent like ketamine
Give two sympathomimetics used for uterine relaxation and their mechanism of action?
Beta 2 agonists
Terbutaline - do not disTURB
Ritodrine - I DREAM of bandcamp
What is the effect of adenosine on the heart and lungs?
It is basically parasympathetic in action overall
Heart -> increases coronary vasodilation and induces hyperpolarization of pacemaker cells by increasing K+ release
Lungs -> induces bronchospasm / bronchoconstriction. Think of this being released whenever a section of the lung is being overworked (ATP used)
Give a couple adenosine antagonists and their effects.
Theophylline and caffeine -> sympathomimetic effect
Heart -> coronary artery vasoconstriction and depolarization -> increased heart rate
Lungs -> bronchodilation
What are the side effects of concern for fibrates?
Myopathy (especially gemfibrozil in combination with statins)
Cholesterol gallstones** -> remember, fibrates are the PPARalpha modulator, so they are most likely to cause enzyme changes (unlikely cholestyramine).
Blockade of 7alpha reductase leads to decreased usage of cholesterol for bile acid synthesis (which solubilize cholesterol), and inadvertently increased excretion of pure cholesterol in bile (not used to make bile acids, thereby increasing chance of stones)
-> think of the seagull on the stack of stones.
How does cholestyramine modify your risk of gallstones?
Bile acid resin -> prevents intestinal reabsorption of bile acids. This lack of bile acids increases liver bile acid synthesis (drops your LDL by using cholesterol), but contributes to slightly increased risk of gallstones. However, it also increases gallbladder motility (decreasing risk).
-> overall, no change in the risk of gallstones #11739
What antihypertensive medication and DNA-gyrase blocking antibiotic are associated with theophylline toxicity?
Antihypertensives - calcium channel blockers (i.e. verapamil)
Antibiotic - Ciprofloxacin - think CYProfloxacin #11752
What is the name of the proteasome inhibitor used in multiple myeloma and why does it work?
Bortezomib
Used to treat cancers which produce lots of protein, especially MULTIPLE MYELOMA
- > lack of ability of cells to break down pro-apoptotic proteins which are produced in excess when they are churning out lots of proteins
- > induces apoptosis
What is a major side effect of milrinone and why? Why might it be used over dobutamine?
hypotension - more than dobutamine. This is caused by increased cAMP in arteries, causing relaxation (similar to a beta-2 effect)
Used as an inotrope when patient is on beta-blockers so dobutamine won’t work. Increases cardiac contractility by increasing cAMP via being a PDE inhibitor.
Which RNA polymerase does amatoxin inhibit? What’s the consequence?
Inhibits RNA Polymerase II -> inhibits mRNA transcription
-> consequence is severe hepatotoxicity and bloody diarrhea
What is the most important initial treatment of C. diphtheria?
Passive immunization via antitoxin -> largest effect on prognosis #1388
How does the train of four stimulation ratio results differ between phase I and phase II of succinylcholine?
1212
Phase I - depolarizing blockade. TOF ratio is 1:1. Last stimulation is = response to first stimulation, but reduced by a constant amount overall(stimulation of nerve is not highly dependent on amount of ACh in the synapse)
Phase II - non-depolarizing blockade TOF ratio is i.e. 0.3:1 (maybe 4th twitch is 30% of first twitch). (i.e. similar to vecuronium) -> muscle contractions become highly dependent on the amount of ACh required, which is reduced with each rapid contraction.
How does the y-intercept of the Lineweaver Burk plot change with increasing Vmax?
Intercept decreases (gets closer to 0)
Y axis = 1/Vmax
X axis = 1/-Km
What is the slope of the Lineweaver Burk plot?
Rise = 1/Vmax Run = 1/Km Slope = Km/Vmax
What does a rightward shift of the x axis point on a Lineweaver Burk plot mean about enzyme affinity?
1/Km is getting smaller -> Km is increasing -> affinity is decreased
How would you pharmacologically describe a drug which leads to a small maximum effect, but very little drug is required to reach this effect?
Low efficacy (similar to Vmax), high potency
Potency is inversely proportional to Km
-> competitive inhibitors decrease the potency of drugs
How do you calculate volume of distribution?
Vd = amount of drug in the body / plasma drug concentration
amount / (amount / volume) = volume
What types of drugs have the lowest volume of distribution (5-10L)?
Large / charged molecules, ones that are highly protein bound
-> stay intravascular
What types of drugs have medium Vd (20-40L)?
Small hydrophilic molecules -> stay in ECF (outside cells, do not diffuse across plasma membranes)
What effect does protein binding have on Vd?
Increasing protein binding -> decreases Vd
What is clearance equal to?
CDE
CL = Vd * ke
ke = 0.7 / t1/2
importantly: CL*Css = rate of elimination of drug
Css is plasma drug concentration
What is the full steady state equation for dosage calculations?
f(D/T) = Css*CL input = output
f = bioavailability. Aka, if bioavailability is 70%, input is only 0.7 * the dose / dosing interval
How do you calculate loading dose? Include bioavailability in your formula.
(Vd * Css) / bioavailability
You divide by bioavailability cuz obv you need to put in more if the drug is not absorbed 100%
What will the elimination graph look like in first order elimination?
Linear decrease in the amount (not concentration-dependent)
What type of enzymes carry out phase 1 drug metabolism?
Cytochrome P450 mono-oxygenases
Reduction, oxidation, and hydrolysis
What are the phase 2 reactions? Are the products more or less polar than phase 1 reactions?
More polar than phase 1 reactions -> easily renally excreted
Geriatric patients have More GAS
Methylation
Glucuronidation
Acetylation
Sulfation
How will the potency and efficacy of a drug change when a competitive vs noncompetitive antagonist is given?
Competitive - decreases Potency (Km increases, Vmax unaffected)
Noncompetitive - decreases efficacy (Vmax changes, Km unaffected)
What is the calculation for the therapeutic index?
TD50 = median toxic dose ED50 = median effective dose
TI = TD50/ED50. Safer drugs have a higher TI.
How does the sympathetic nervous system innervate the renal vasculature smooth muscle? What receptor subtype is it?
Post-ganglionic nerve has dopamine release -> Gs receptor leads to renal vascular smooth muscle relaxation.
How do amphetamines increase NE in the synapse?
Utilize the VMAT transporter to release stored catecholamines into the end of nerve axoplasm
When [NE] in the cytoplasm is high enough relative to the synapse, NET is reversed -> norepinephrine is dumped into the synapse.
How does angiotensin 2 increase sympathetic outflow?
Angiotensin 2 receptor on presynaptic nerve terminal leads to direct stimulation of NE release from sympathetic nerves
What is the mechanism of action of tropicamide?
Just like atropine -> muscarinic antagonist
Used to produce mydriasis / cycloplegia in ophthalmology
What drugs are the mainstay for antispasmodic treatment for IBS-D? Side effects?
Hyoscyamine, dicyclomine
- > antimuscarinic medications which predominately block Ach release in smooth muscle GI tract
- > side effects include dry mouth, dry skin, and urinary retention
What is the mechanism of action of glycopyrrolate?
Antimuscarinic - used to reduce airway secretions pre-op, before intubation
What is the mechanism of action of midodrine and its used?
Alpha1 agonist, used in the treatment of autonomic insufficiency leading to orthostatic hypotension
What drug is a beta-3 agonist which results in bladder relaxation (treatment of overactive bladder / urge incontinence)?
Mirabegron
What sympathomimetic can directly dilate the pupil?
Phenylephrine - alpha1 effect is Gq -> direct pupillary dilator contraction in the eye
What effect does norepinephrine vs phenylephrine have on pulse pressure and why?
Norepinephrine -> Increases pulse pressure, due to B1 effects on heart, increasing contractility / SV. Stroke volume / contractility correlate quite well with pulse pressure.
Pulse pressure = SBP - DBP.
Phenylephrine -> decreases pulse pressure, due to increasing SBP and DBP, but DBP moreso. Pulse pressure decreases because of reflex bradycardia induced by increased systemic blood pressure -> vagal tone decreases stroke volume.
Will isoproterenol or epinephrine result in a more rapid heart rate?
Isoproterenol. Isoproterenol lacks any alpha1 constricting effects -> will actually drop the blood pressure (Beta2), leading to a reflex tachycardia which is much stronger than epinephrine.
How will NE / E affect heart rate?
NE -> alpha1 effects predominate -> reflex bradycardia, despite increased SV / contractility from B1 effects
E -> beta2 effects predominate -> reflex tachycardia
Which one is the alpha1-selective blocker which cannot be used for the systemic treatment of hypertension?
Tamsulosin -> selective for alpha1a receptors in the smooth muscle of blood vessels in the GU system.
What beta blockers are used in the treatment of portal hypertension?
Nadolol, propranolol
-> induce portal vasoconstriction to decrease bleeds (block beta2 effect)
Note:
Vasopressin and octreotide can also be used for this
What are the nonselective beta blockers? One is a partial agonist, and one is used in glaucoma.
Nadolol, propranolol, pindolol (also partial agonist), timolol
What is the mechanism of action of nebivolol?
B1 selective blocker + B3 agonist -> activates nitric oxide synthase -> relaxes vasculature / decreases systemic vascular resistance
What is the cardioselective beta blocker with intrinsic sympathetic activity? When is this contraindicated?
Acebutolol (alpha1-selective, ABEAM)
- > heart failure / angina contraindicated
- > less likely to have bradycardia
What toxin is found in reef fish like barracuda, snapper, and moray eel? What is its mechanism of action?
Ciguatoxin - opens Na+ channels, causing depolarization
What are the symptoms of ciguatoxin poisoning?
GI side effects
Perioral numbness
Reversal of hot/cold sensations
Bradycardia, heart block
What are the symptoms of tetrodotoxin poisoning?
Blockade of Na+ from pufferfish, remember
Cardiac / neural loss of function: Weakness, dizziness, loss of reflexes, paresthesias, conscious but paralyzed
What does anaphylaxis with normal serum tryptase effect?
Non-mast cell mediated histamine release
- > Scombroid poisoning
- > Spoiled dark-meat fish i.e. tuna, mahi-mahi, or mackerel)
What is the mechanism of histamine release in scombroid poisoning and what is the treatment?
Bacterial histidine decarboxylase (spoiled food) converts histidine to histamine
-> eat tons of histamine in fish
Treatment is same as anaphylaxis: antihistamines, albuterol, and epinephrine
What is the Beers criteria?
A list of 53 medications or classes which should be taken into consideration before prescribing to elderly
What medication classes make the list:
- Anticholinergics
- Antihistamines
- Antidepressants
- Benzodiazepines
- Opioids
- > increased risk of delirium, sedation, falls, constipation / urinary retention
alpha-blockers -> falls due to orthostatic hypotension
PPIs -> C. difficile infection
NSAIDs -> GI bleeding
What is the treatment for Arsenic poisoning?
Dimercaprol
What is the treatment for carbon monoxide poisoning?
Hyperbaric oxygen, nothing else. Don’t get confused.
What is the treatment for cyanide poisoning?
Amyl / sodium nitrite -> oxidize hemoglobin
Hydroxocobalamin -> binds cyanide
Thiosulfate -> serves as a sulfate donor for rhodanese, the body’s natural cyanide-clearing enzyme
What is the treatment of lead poisoning?
EDTA > dimercaprol (normally used for arsenic) > succimer
Use succimer in children -> It “Sucks” to be a kid who eats lead
What is the treatment for methanol or ethylene glycol ingestion?
Fomepizole (inhibits alcohol dehydrogenase) > ethanol
Then:
Dialysis
What is the treatment for Methemoglobinemia? What anesthetic drug is most likely to cause this?
Methylene blue, vitamin C (Reducing agents)
Most likely to be caused by benzocaine
Give three drug causes of SIADH.
Carbamazepine, Cyclophosphamide, SSRIs (think of the water cooler in the sketch)
What antibiotic can likely cause acute cholestatic hepatitis or jaundice?
Erythromycin
What drugs have a caustic effect like bisphosphonates and should be taken with water?
Ferrous sulfate, NSAIDs, potassium chloride, tetracyclines
What chemical is associated with aplastic anemia?
Benzene
What are the key symptoms of DRESS syndrome and give the treatment?
Fever, facial edema, and morbilliform skin rash, systemic eosinophilia
Treatment: Withdrawal of offending agent, corticosteroids
What hematologic side effect can TMP/SMX and hydroxyurea have?
Think of the fireworks in the background -> megaloblastic anemia! Since SMX inhibits dihydropterate synthase (PABA analog) and TMP inhibits dihydrofolate reductase.
Hydroxyurea -> marrow suppression can be megaloblastic
Give three unrelated drugs associated with gingival hyperplasia?
Phenytoin, verapamil, cyclosporin
What CNS side effect can isoniazid cause?
Due to B6 deficiency -> seizures (think of the shaking cowboy in the background)
What inhaled anesthetic is associated with seizures?
Enflurane = epilepsy
How can reserpine cause a Parkinson-like syndrome?
Inhibits VMAT, depleting dopamine release by depletion of neurotransmitter stores
What drugs are associated with Fanconi syndrome?
Cisplatin, ifosfamide (cyclophosphamide derivative), expired tetracyclines, tenofovir
-> all toxic to proximal tubule
What are two key side effects of nitrofurantoin?
- Pulmonary fibrosis
2. Hemolysis in G6PD deficiency
What association should you make with procarbazine?
Disulfiram-like reaction
You don’t know this drug. It’s an antineoplastic of some sort.
What is a key side effect you should associate with griseofulvin, other than CYP induction?
Disulfiram-like reaction
-> not in sketchy, but think of the tin man with greasy alcohol being poured down his throat
What is the antidote for cisplatin toxicity?
Amifostine
What effect do nevirapine and chronic alcohol use have on CYP? What about ACUTE alcohol use?
Both are CYP inducers
Remember that nevirapine is a NNRTI
Acutely -> alcohol is a CYP inhibitor
What NSAID, gout medication, and diabetes treatments are sulfa drugs and can produce the wide range of sulfa drug allergies from SJS to thrombocytopenia to agranulocytosis to interstitial nephritis???
NSAID - Celecoxib
Gout medication - Probenecid
Diabetes - Sulfonylureas (but NOT meglitinides, remember!)
Is it more important to administer atropine or pralidoxime first in a patient with organophosphate poisoning?
Atropine - because all of the life-threatening consequences of organophosphates are mediated by the muscarinic effects
-> give atropine for complete reversal of bronchoconstriction / bradycardia
Obv you should still give pralidoxime pretty early cuz you don’t want an aged adduct, but it’s not as important
Does erythropoietin stimulate bone marrow stem cells or erythroid precursors?
Erythroid precursors -> stimulates erythroblasts
Bone marrow precursors (precursors to both lymphoid and myeloid lines) can be stimulated by IL-2 (aldesleukin) and other early cytokines.
