Drugs Flashcards
Warfarin
Therapeutic Use, Mechanism of Action, Side Effects, Therapeutic Index, Metabolism, Pharmacogenomics, TDM
Therapeutic Use: Increases clotting time (anticoagulant) to prevent thrombi/stroke
Mechanism of Action: suppresses VKORC1 - reduces vitamin K regeneration - blocks carboxylation of coagulation factors
Side Effect: Increases bleeding if dose is too high
TI: ~1 - very narrow sweet spot
Metabolism: CYP2C9
Pharmacogenomics: CYP2C92/3 have reduced function - poor metabolizers need more days to determine if anticoagulation is stable & TDM via INR (international normalized ratio of patient prothrombin time - how long it takes to clot - adjust dose based on this number)
Pharmacodynamics: VKORC1 haplotype A - more sensitive to drug than wild-type G - higher risk of hemorrhagic activity
Dosage scheme depends on genetics of CYP2C9 and VKORC1
Benzodiazepines [-azepam + -azolam]
Diazepam [Valium]
Midazolam [Versed]
(Therapeutic Use, Mechanism of Action, Side Effect, TI, Metabolism)
Therapeutic Use: sedation, improve sleep, treat anxiety + muscle spasms
Mechanism of Action: allosteric activator of GABA-a receptors (binds b/w b+g subunits) - increase IPSP, increase Cl- current by increasing frequency of channel openings
Side Effect: over-sedation, dizziness, confusion, memory loss
TI: ~100+ (safer)
Metabolism: CYP3A4 hydroxylation [CYP2C19 helps with -azepams] (reduce 90% activity) & Glucuronidation (very water soluble and inactive form)
Sulfonylureas
Mechanism of Action
inhibit K-ATP channels, resulting in depolarized Vrest, allowing V-gated Ca channels to open and cause insulin secretion in pancreas and vasoconstriction in SMC
Minoxidil
Therapeutic Use, Mechanism of Action
Therapeutic Use: Treat HT
Mechanism of action: activates K-ATP receptors in SMC - hyperpolarized Vrest - v-gated Ca channels harder to open - more vasodilatation
Local Anaesthetics (Therapeutic Use, Mechanism of Action, and Special Characteristic)
Therapeutic Use: Localized pain reduction
Mechanism of Action: Block V-gated Na Channels by enhancing inactivation (preferential binding to inactivated state);
Use-Dependent Block: inhibition intensifies with use as more Na channels get inactivated after every AP (good for neurons that fire frequently - pain nerves + epilepsy); weak base than enters channel from cytosolic side through fenestrations
Tetrodotoxin (TTX)
Therapeutic Use, Mechanism of Action
Use: Eating pufferfish, should be just enough to make your fingertips tingle, POISON
Mechanism of Action: Potent Na Channel Blocker; acts like plug on EC side of channel (Pre-synaptic Transmission NMJ), also EC block on nicotinic receptor (Post-synaptic Transmission NMJ)
Drug Class: L-Type Ca++ Channel Blockers (Mechanism of Action, Therapeutic Uses)
Mechanism of Action: shorten cardiac AP plateau (phase II) = shorten AP
Use: treat angina, HT (inhibit SMC VC), Arrythmia
Drug Class: Na+ Channel Blockers (Mechanism of Action, Therapeutic Uses)
Mechanism of Action: Decrease/Attenuate depolarization upstroke (blunts rate of rise) - slows AP conduction through heart - prevents re-entry loops
Therapeutic Uses: local anaesthesia, arrhythmia, epilepsy/migraines
Drug Class: K+ Channel Blockers
Mechanism of Action, Therapeutic Uses, Side Effect
Mechanism of Action: impair repolarization in phase III - longer cardiac AP
Therapeutic Uses: arrhythmia
Side Effect: Drug Induced LQTS, pro-arrhythmic
Ondansetron (Zofran) and -setrons
Mechanism of Action, Therapeutic Use
Mechanism of Action: Competitive Antagonist at 5-HT3 Serotonin Receptors
Therapeutic Uses: Treat nausea + vomiting (that typically occurs because of cancer chemotherapy agents)
Zolpidem (Ambien)
Mechanism of Action, Therapeutic Use, Key Feature
Mechanism of Action: binds selectively to specific B[a]p sites involved in producing sleep
Therapeutic Use: help fall asleep
Allosteric Activator - reduces likelihood of receptor desensitization
Penicillin
Side Effect, Mechanism of Action, Excretion
Major Side Effect: blocks open GABA-a receptor channels - induces seizures!
Mechanism of Action: uncompetitive antagonist to activated GABA-a channels - CONVULSANT
Excretion: Tubular Secretion (through OATs, competing pathway with Probenecid causes prolonged penicillin activity - GOOD)
Strychnine
Mechanism of Action, Effect
Mechanism of Action: Post-synaptic inhibitor, competitive inhibitor of glycine receptors
Effect: causes excessive spasticity
Tetanus Toxin (Mechanism of Action, Effect)
Mechanism of Action: Pre-synaptic inhibitor, blocks glycine release
Effect: causes excessive spasticity
Memanite
Mechanism of Action, Effect
Mechanism of Action: binds to open NMDA channel (uncompetitive antagonist) and inhibits Ca2+ flow
Effect: May be used to treat Alzheimer’s and seizures
Acts like penicillin (uncompetitive antagonist)
Fluticasone [-son- and -one drugs]
Mechanism of Action, Effect
Mechanism of Action: activates glucocorticoid receptors to inhibit inflammatory response
Selective Serotonin Reuptake Inhibitors [SSRIs]
Mechanism of Action, Therapeutic Use
Mechanism of Action: blocks SLC6A4 serotonin reuptake SLC secondary active transporter
Therapeutic Use: anti-depressent (more serotonin lingering in synaptic cleft)
Grapefruit Juice [Furanocoumarins]
Mechanism of Action, Effect, Low vs. High F, Oral vs. IV
Mechanism of Action: Inhibit CYP3A4 + PGP, increasing bioavailability of drugs
Effect: Toxic elevations of drug in systemic circulation
Large effects on drugs with low F - bigger boosts possible
Only affects orally ingested drugs
Cimetidine [-idine]
Mechanism of Action, Key Feature, Metabolism Reaction, Problem
Mechanism of Action: Competitive Inhibitor (complementary shape) for H2 Histamine Receptor
Metabolized by S-oxidation
Inhibits many types of CYPs cause of drug:drug interaction toxic buildup
Desensitization: continual use causes GCPR receptor upregulation, over-inhibition suppresses internalization/degradation
Caffeine
Use, Mechanism of Action, Metabolism Reaction, Family
Use: stimulant
Mechanism of Action: competitive inhibitor (complementary shape to adenosine) of adenosine receptor at low doses (disinhibition of cellular functions)
Minor Mechanism: inhibits phosphodiesterases at higher doses (increase cAMP and signaling through pathway)
Metabolism: N-dealkylation to active metabolite or theophylline
METHYLXANTHINE FAMILY WITH THEOPHYLLINE
Theophylline
Use, Mechanism of Action, Metabolism Reaction, Family
Use: last resort to treat bronchiole disorders
Mechanism of Action: competitive inhibitor (complementary shape to adenosine) of adenosine receptor at low doses (disinhibition of cellular functions)
Minor Mechanism: inhibits phosphodiesterases at higher doses (increase cAMP and signaling through pathway)
Metabolism: N-dealkylation to inactive metabolite
METHYLXANTHINE FAMILY WITH CAFFEINE
Ethanol
Pathway, Problem
Pathway: EtOH - alcohol dehydrogenase oxidizes to - acetaldehyde (TOXIC drunk guy) - aldehyde dehydrogenase oxidizes to - acetate
Problem: Role in Acetaminophen toxicity - high ethanol induces CYP2E1, which can metabolize acetaminophen into toxic NAPQI
Polymorphisms: “Asian Glow” Chinese more likely to have enhanced alcohol DH and reduced aldehyde DH = toxic buildup of aldehyde causes facial flushing
Succinylcholine
Mechanism of Action, Metabolism
Mechanism of Action: prevents ACh excitation of skeletal muscle; depolarizing blocker - fastest known ACh blocker b/c you can overload dose and it’ll be degraded
Metabolism: Degraded twice via ester hydrolysis by pseudocholinesterases
Acetaminophen
Therapeutic Use, Mechanism of Action, Metabolism, Treatment for Metabolism Problems
Therapeutic Use: analgesic & antipyretic
Mechanism of Action: inhibits cyclooxygenases (housekeeping COX1 + painful COX2)
Metabolism: no phase I reaction because already hydroxylated, many possible pathways:
A. Sulfation to nontoxic inactivated form (LOW DOSES)
B. Glucuronidation to nontoxic inactivated form (LOW DOSES)
C. HIGH DOSES: CYP2E1 + CYP3A4 make NAPQI (reactive toxic intermediate electrophile kills hepatocytes) - metabolized again via GLUTATHIONE GSTs - requires glutathione
*If HIGH DOSE AND LOW GLUTATHIONE - NAPQI reacts with nucleophilic macromoleculs, triggering liver cell death
Treatment: N-acetylcysteine - complementary shape to glutathione, but less polar so it can diffuse through lipid bilayer (anti-inflammatory and antioxidant)
Albuterol
Therapeutic Use, Mechanism of Action
Therapeutic Use: rescue inhaler for asthma, treats COPD
Mechanism of action: beta-2 receptor agonist (relax SMC)
Codeine
Therapeutic Use, Metabolism, Key Feature, Pharmacogenomics
Therapeutic Use: Pro-drug analgesic
Metabolism: via O-dealkylation by CYP2D6 (Phase I) to Morphine (activated Drug)
Key Feature: Morphine involved in Enterohepatic Cycle (Antibiotics cause increased half-life)
Pharmacogenomics: Affects Biotransformation, CYP2D6 polymorphisms create poor metabolizers (ineffective doses) and ultra-rapid metabolizers (toxicity)
Hydrocodone
Therapeutic Use, Metabolism
Therapeutic Use: active analgesic, also a pro-drug to become even more active
Metabolism: via O-dealkylation by CYP2D6 (Phase I) to Hydrophorphone (even more activated)
(poor metabolizers need more and rapid metabolizers need less)
Metoprolol
Therapeutic Use, Mechanism of Action, Metabolism
Therapeutic Use: anti-HT, anti-anginal, antiarrhythmic (like propanolol but MORE selective)
Mechanism of Action: Selectively blocks beta-1 receptors (inhibiting causes decrease in HR and contractility) - good beta blockers for asthmatics b/c doesn’t block airway
Metabolism: CYP2D6 inactivates (poor metabolizers need less and rapid metabolizers need more)
Omeprazole (-prazoles)
Therapeutic Use, Mechanism of Action, Metabolism
PROTON PUMP INHIBITOR
Therapeutic Use: treat excess acid secretion disorders (ulcers)
Mechanism of Action: irreversibly blocks proton pump + prevents acid secretion
Metabolism: CYP2C19
Clopidogrel [Plavix]
Therapeutic Use, Metabolism, Pharmacogenomics - KNOW THE VARIANTS
Therapeutic Use: Anti-platelet Activity
Metabolism: Pro-drug activated by twice metabolism through CYP2C19
Pharmacogenomics: CYP2C192/3 variants cause reduced function, impaired anti-platelet effects - high risk of thrombosis/stroke - even in carriers with one of these variants!
Ibuprofen
Family, Therapeutic Use, Mechanism of Action, Metabolism
NSAIDs - non-steroidal anti-inflammatory drugs
Therapeutic Use: pain-reliever + anti-inflammatory
Mechanism of Action: inhibits both housekeeping COX1 and painful COX2 enzymes
Metabolism: CYP2C9 - polymorphic poor metabolizers have reduced clearance
Celecoxib
Family, Therapeutic Use, Mechanism of Action, Metabolism
NSAIDs - non-steroidal anti-inflammatory drugs
Therapeutic Use: pain-reliver + anti-inflammatory - used more than Ibuprofen in treating post-operative pain
Mechanism of Action: Selectively inhibits painful COX2
Metabolism: CYP2C9 - polymorphic poor metabolizers have reduced clearance
Imatinib [Gleevec]
Mechanism of Action, Therapeutic Use
Mechanism of Action: binds to ATP-binding site of constitutively active BCR-ABL Tyrosine Kinase to prevent ATP binding and phosphorylation
Therapeutic Use: Treat specific type of CML
Digoxin
What is it, Complications
Cardiac Medication
Transport: Uses OCT on basolateral side in Tubular Secretion
Competes with: Quinidine (another cardiac medication) - Prolonged half-lives, toxic build-up
Key Drug in Enterohepatic Cycle (Antibiotics kill gut bacteria - decrease drug’s half life)
Estradiol
What is it, Complications
Birth Control
Key Drug in Enterohepatic Cycle (Antibiotics kill gut bacteria - decrease drug’s half life - cause unplanned pregancies)
Statins
Mechanism of Action, Complications
Mechanism of Action: Inhibit HMG CoA Reductase - prevent cholesterol biosynthesis - treat familial hypercholesterolemia
Transport: Biliary Drug Excretion through SLC01B1 (OATP1B1)* polymorphisms cause increased sensitivity and toxicity - myotoxicity + muscle injury
Tacrolimus
Therapeutic Use, TI, F, Metabolism, Pharmacogenomics
Therapeutic Use: Immunosuppressant, prevents organ rejection in transplants, treats inflammatory/autoimmune disorders
TI: NARROW requires TDM
F: Low F due to high first pass metabolism
Metabolism: by CYP3A4 (no polymorphisms) + CYP3A5 (polymorphisms significant!)
Pharmacogenomics: CYP3A5 variants have 1nc change in splice site that makes enzyme NON-functional - extremely common in Caucasians
Poor Metabolizers: Non-functional diplotype - most prevalent in Caucasians - considered norm - use standard dose and monitor with TDM
Intermediate/Extensive Metabolizers: increase starting dose
Thiopurines
Therapeutic Use, Pharmacogenomics
Therapeutic Use: Pro-Drugs require conversion to THIOGUANINES for anti-cancer cytotoxicity
Pathway: Thiopurine - 6-MP - Thioguanine
TPMT: Enzyme that converts intermediate 6-MP into inactive form
Pharmacogenomics: variants have impaired TPMT function
Poor metabolizers: less elimination - increased risk for bone marrow suppression - need to give lower doses for variant carriers
Mg2+ and other polyvalent cations (Mn, Co, La)
Mechanism of Action
Block pre-synaptic Calcium ion entry into nerve terminal at NMJ
Botulinum Toxin Type A
Mechanism of Action, Therapeutic Use
- cleaves SNAP-25 in fusion machinery - inhibits priming of secretion and release of ACh at NMJ
- Therapeutic Use: Treats blepharospasm
-curoniums
Mechanism of Action
- Most popular non-depolarizing competitive inhibitors of nicotinic ACh receptors at NMJ
Neostigmine [-stigmines]
Mechanism of Action, Therapeutic Use
- reversible inhibitor of AChE at NMJ - prolongs effects of ACh
- speeds recovery from -curoniums after surgery, treats Myasthenic Gravus
Atropine
Mechanism of Action, Therapeutic Use
- competitive inhibitor of ACh at mAChR’s in heart (parasympathetic), blocks vagal slowing
- Increases HR during spinal anesthesia
Ipratropium, Tiotropium [-tropiums]
Mechanism of Action, Therapeutic Use
- competitive inhibitor of ACh at mAChR’s in bronchioles (parasympathetic), reduces constriction to open airway
- Treat airway disorders (Asthma, COPD)
Norepinephrine, Epinephrine, Phenylephrine
Mechanism of Action, Therapeutic Use
- a-1 agonist - increase BP through smooth muscle constriction
- phenylephrine also decreases nasal congestion by constricting mucosal layers
Propanolol
Mechanism of Action, Therapeutic Uses, Metabolism
- b-1 + b-2 competitive antagonist of norepinephrine
- anti-arrhythmia, anti-HT, anti-HF
- metabolized by CYP3A4
