PD/PK/PG/DDIs Flashcards
Explain the breakdown of the nervous system and the neurotransmistters that act as signals in each component
Central Nervous System (CNS): brain and spinal cord which will send signals to the PNS
Peripheral Nervous System (PNS) is broken into:
-Somatic nervous system (SNS): voluntary, controls muscle movement, primary neurotransmitter is acetylcholine (ACh)
-Autonomic nervous system (ANS): involuntary, controls other bodily functions
Autonomic Nervous System (ANS) is broken into:
-Parasymphathetic Nervous System (PSNS): “rest and digest” system that works when ACh binds to muscarinic receptors throughout the GI tract, bladder, and eyes which creates the response SLUDD (salivation, lacrimation, urination, defacation, digestion)
-Sympathetic Nervous System (SNS): “fight or flight” system that works when EPI and NE act on adrenergic receptors (alpha-1, beta-2, and beta-2) in CV and respiratory systems, increasing HR, BP, glucose production, and bronchodilation
Muscarinic receptor
-Endogenous substrate and its agonist action
-Agonist drugs on this receptor
-Drug antagonists and its antagonist action
Endogenous substrate: acetylcholine (ACh) –> increases SLUDD (salivation, lacrimation, urination, diarrhea/defecation, digestion)
Drug agonists: pilocarpine, bethanechol
Drug antagonists: atropine, oxybutynin –> decrease SLUDD
Nicotinic receptor
-Endogenous substrate and its agonist action
-Agonist drugs on this receptor
-Drug antagonists and its antagonist action
Endogenous substrate: acetylcholine (ACh) –> increases HR and BP
Drug agonist: nicotine
Drug antagonists: neuromuscular blockers (ex. rocuronium) –> neuromuscular blockade
Alpha-1 receptor
-Endogenous substrate and its agonist action
-Agonist drugs on this receptor
-Drug antagonists and its antagonist action
Endogenous substrate: EPI and NE –> smooth muscle vasoconstriction, increased BP
Drug agonists: phenylephrine, dopamine (dose-dependent)
Drug antagonists: alpha-1 blockers (ex. doxazosin, carvedilol, phenotalmine) –> smooth muscle vasodilation, decrease BP
Alpha-2 receptor
-Endogenous substrate and its agonist action
-Agonist drugs on this receptor
-Drug antagonists and its antagonist action
Endogenous substrate: EPI and NE –> decrease release of EPI and NE (negative feedback loop), decrease BP and HR
Drug agonists: clonidine, brimonidine
Drug antagonists: ergot alkaloids, yohimbine –> increase BP and HR
Beta-1 receptor
-Endogenous substrate and its agonist action
-Agonist drugs on this receptor
-Drug antagonists and its antagonist action
Endogenous substrate: EPI and NE –> increase myocardial contractility, CO, and HR
Drug agonists: dobutamine, isoproterenol, dopamine (dose-dependent)
Drug antagonists: beta-1 selective blockers (ex. metoprolol) and non-selective beta-blockers (ex. propranolol, carvedilol) –> decrease CO and HR
Beta-2 receptor
-Endogenous substrate and its agonist action
-Agonist drugs on this receptor
-Drug antagonists and its antagonist action
Endogenous substrate: EPI –> bronchodilation
Drug agonists: albuterol, terbutaline, isoproterenol
Drug antagonists: non-selective beta-blockers (ex. propranolol, carvedilol) –> bronchoconstriction
Acetylcholinesterase:
-Effects of enzyme
-Drugs that act on enzyme and their actions
Enzyme: breaks down acetylcholine, ACh
Drugs: acetylcholinesterase inhibitors (donepezil, galantamine, rivastigamine) –> block acetylcholinesterase to increase ACh levels to treat Alzheimer’s disease
Angiotensin-converting enzyme (ACE):
-Effects of enzyme
-Drugs that act on enzyme and their actions
Enzyme: converts angiotensin I to II, a potent vasoconstrictor
Drugs: ACE inhibitors (ACEis) such as lisinopril and ramipril –> decrease vasoconstriction and aldosterone secretion to treat HTN, HF, and kidney disease
Catechol-O-methyltransferase (COMT):
-Effects of enzyme
-Drugs that act on enzyme and their actions
Enzyme: breaks down levodopa
Drugs: COMT inhibitors (entacapone) to prevent peripheral breakdown of levodopa, resulting in increased duration of action of levodopa to treat Parkinson disease
Cyclooxygenase (COX):
-Effects of enzyme
-Drugs that act on enzyme and their actions
Enzyme: converts arachidonic acid to prostaglandins (causes inflammation) and thromboxane A2 (causes platelet aggregation)
Drugs: NSAIDs (ex. ASA and ibuprofen) to treat pain and inflammation
-ASA specifically decreases platelet aggregation
Monoamine oxidase (MAO):
-Effects of enzyme
-Drugs that act on enzyme and their actions
Enzyme: breaks down catecholamines (ex. DA, NE, EPI, 5-HT)
Drugs: MAO inhibitors (phenelzine, isocarboxazid, tranylcypromine, selegiline, rasagiline) –> increase catecholamines to treat depression
-HTN crisis (from increased DA, NE, and EPI) particularly with foods that contain tyrosine that increases dopamine and other catecholamines (linezolid, amphetamines/stimulants, methylene blue, antidepressants)
-Serotonin syndrome (from increased 5-HT) particularly with other drugs that increase 5-HT (SSRIs, SNRIs, TCAs, mirtazapine, trazodone, triptans, opioids, tramadol, buspirone, lithium, dextromethorphan, St. John’s Wort)
Phosphodiesterase (PDE):
-Effects of enzyme
-Drugs that act on enzyme and their actions
Enzyme: breaks down cyclic guanosine monophosphate (cGMP), a smooth muscle relaxant
Drugs: PDE-5 inhibitors (sildenafil, tadalafil, vardenafil) –> prevents breakdown of cGMP to prolong smooth muscle relaxation for erectile dysfunction
Vitamin K epoxide reductase:
-Effects of enzyme
-Drugs that act on enzyme and their actions
Enzyme: converts vitamin K to active form required for production of select clotting factors
Drug: warfarin –> inhibits enzmye to decrease clotting factors II, VII, IX, and X to treat or prevent blood clots
Xanthine oxidase:
-Effects of enzyme
-Drugs that act on enzyme and their actions
Enzyme: breaks down hypoxanthine into xanthine and xanthine into uric acid
Drug: xanthine oxidase inhibitor (allopurinol) –> blocks enzyme to decrease uric acid production to treat gout attacks
Oxidation
-What type of reaction
-Visual indicators
Compound is oxidized and losses electrons (reduction = gain of electrons)
-Drugs most likely oxidized when it has a hydroxyl (-OH) group attached to an aromatic ring
Visual indicators: sometimes color changes (EPI becomes amber-colored, others can turn pink/reddish)
Prevention of Oxidation
-Light protection: ambler glass, UV blocking containers (plastic) and light-protective sleeves (bags) for IV bags, lines, and syringes
-Temperature control: store drug according to manufacturer
-Antioxidants (free radical scavengers): inhibit free radicals - ascorbic acid (Vitamin C), tocopherols (vitamin E), ascorbyl palmitate, Na ascorbate, Na bisulfate, Na sulfoxylate, and Na thiosulfate
-Chelating agents: chelate metal ions that have unshared electron in outer shell (free radicals) - edetate disodium (EDTA), EDetate calcium disodium, and EDetic acid
-pH control: maintain with a buffer (ex. acetic acid, sodium acetate)
Hydrolysis:
-What type of reaction
-Prevention
When water cleaves the bond of a molecule
-Most common in structures with an ester, amide, and lactam with the carbonyl component most likely to be subject to the hydrolysis
Prevention:
-Storage of medication: prevent storage in bathbroom and close drug containers tightly
-Adsorbents (desiccants): adsorb any moisture that enters the container
-Lyophilized powders: drug stored as freeze-dried powder that is only recommended to reconstitute into solution shortly before use
-Hygroscopic salt: water-absorbing salt form of drug
-Other methods used to prevent oxidation (light protection, temperature control, chelating agents, pH control)
Photolysis
-What type of reaction
-Prevention
With UV light exposure, covalent bonds can break down and cause drug degredation
Prevention: protect from light (ex. amber vials)
-Compounds typically sensitive to light: ascorbic acid, folic acid, nitroprusside, phytonadione
Common CYP Inhibitors involved in DDIs: G-PACMAN
-Effects on substrates and prodrugs
G: Grapefruit
P: Protease inhibitors (PIs), especially ritonavir
A: Azole antifungals
C: Cyclosporine, cobicistat, cimetidine
M: Macrolides (clarithromycin and erythromycin -NOT azithromycin)
A: Amiodarone (and dronedarone)
N: Non-DHP CCBs (verapamil and diltiazem)
Effect on substates: decreased metabolism, increased serum levels and clinical effects/toxicities
Effects on prodrugs: decreased conversion to active drug (decreased serum levels and clinical effects)
Common CYP Inducers in DDIs: PS PORCS
-Effects on substrates and prodrugs1
-Lag time if inducer is stopped
P: Phenytoin
S: Smoking
P: Phenobarbital and primidone
O: Oxcarbazepine
R: Rifampin > rifabutin, rifapentine
C: Carbamazepine (also auto-inducer)
S: St. John’s Wort
Effect on substrates: increased metabolism, decreased serum levels and clinical effects
Effect on prodrugs: increased conversion to active drug (increased serum levels and clinical effects)
“Lag” time for Enzyme Induction: induction most often requires additional enzyme production which takes time –> when inducer is stopped, it could take 2-4 weeks for induction effects to disappear completely
P-gp: common substrates
Antigoagulants: APIXIBAN, edoxaban, dabigatran, RIVAROXABAN
CV drugs: DIGOXIN, DILTIAZEM, carvedilol, ranolazine, VERAPAMIL
HCV drugs: sofosbuvir
Immunosuppressants: CYCLOSPORINE, sirolimus, TACROLIMUS
Others: atazanavir, COLCHICINE, dolutegravir, posaconazole, raltegravir, saxagliptin
P-gp: Common inducers
CARBAMAZEPINE, PHENOBARBITAL, PHENYTOIN, RIFAMPIN, ST. JOHN’S WORT
Others: dexamethasone, tipranavir
P-gp: Common inhibitors
Anti-infectives: clarithromycin, itraconazole, posaconazole
CV drugs: AMIODARONE, carvedilol, conivaptan, DILTIAZEM, dronedarone, quinidine, VERAPAMIL
HCV drugs: ledipasvir
HIV drugs: COBICISTAT, RITONAVIR
Others: CYCLOSPORINE, flibanserin, ticagrelor
CYP450: Common CYP3A4 substrates
Analgesics: fentanyl, hydrocodone, methadone, oxycodone
Anticoagluants: apixiban, rivaroxaban, R-warfarin
CV drugs: amiodarone, amlodipine, diltiazem, verapamil
Immunosuppressants: cyclosporine, tacrolimus, sirolimus
Statins: atorvastatin, lovastatin, simvastatin
HIV drugs: NNRTIs
PDE-5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil
Others: ethinyl estradiol
CYP450: Common CYP3A4 inducers
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, smoking, St. John’s Wort
CYP450: Common CYP1A2 substrates
Theophylline, R-warfarin
CYP450: Common CYP3A4 inhibitors
Anti-infectives: clarithromycin, erythromycin, azole antifungals, isonazid
CV drugs: amiodarone, diltiazem, verapamil
HIV drugs: cobicistat, ritonavir, protease inhibitors (PIs)
Others: cyclosporine, grapefruit juice
CYP450: Common CYP2C9 substrates
S-warfarin
CYP450: Common CYP1A2 inhibitors
Ciprofloxacin, fluvoxamine
CYP450: Common CYP1A2 inducers
Carbamazepine, phenobarbital, phenytoin, rifampin, smoking, St. John’s Wort
CYP450: Common CYP2C19 substrates
Clopidogrel (prodrug)
CYP450: Common CYP2C9 inhibitors
Amiodarone, fluconazole, metronidazole, Bactrim
AAA = Azole, Amiodarone, Anti-infectives
CYP450: Common CYP2C9 inducers
Carbamazepine, phenytoin, phenobarbital, rifampin, smoking, St. John’s wort
CYP450: Common CYP2C19 inhibitors
Esomeprazole, omeprazole
CYP450: Common CYP2D6 Inhibitors
Amiodarone, duloxetine, fluoxetine, paroxetine
CYP450: Common CYP2D6 substrates
Analgesics: codeine, meperidine, tramadol
Others: some antipsychotics/antidepressants, tamoxifen
“Pain and Psych” drugs: only major CYP enzyme NOT subject to inducers
Drugs with additive effects of seroteonergic toxicity
Antidepressants: SSRIs, SNRIs, TCAs, mirtazapine, trazodone
MOAIs: isocarboxazid, pheneizine, tranylcypromine, selegiline, rasagiline, linezolid, methylene blue
Opioids: fentanyl, meperidine, methadone, tramadol, tapentadol (any risk w/ opioids, but these particularly)
Triptans: occasional PRN triptan may be more safe
Natural products: St. John’s Wort, L-tryptophan
Others: busprione, lithium, dextromethorphan (drug abuse)
Drugs with additive effects of bleeding
-These drugs should be avoided together except when?
- Anticoagulants
- Antiplatelets
- NSAIDs
- SSRIs and SNRIs
- Natural products: the 5 G’s (garlic, ginger, ginkgo biloba, ginseng, glucosamine), vitamin E, willow bark, fish oils (high doses)
Avoid combinations except for when:
-ASA (for cardioprotection) + NSAID PRN
-SSRI/SNRI + NSAID PRN
-Dual antiplatelet therapy (ex. in cardiac stent thrombosis pt)
-Bridging/overlapping treatment (ex. enoxparin + warfarin until INR therapeutic >/=24 hours)
S/Sx of Sertonin Snydrome and Prevention
S/Sx:
-Autonomic dysfunction (diaphoresis, N/V, hyperthermia)
-Altered mental status (akathisia, anxiety, agitation, delirium)
-Neuromuscular excitation (hyperreflexia, tremor, rigidity, tonic-clonic seizures)
Prevention:
-Avoid using serotonogeric drugs together
-Recommend eliminating initial serotongeric drug with at least 2 weeks apart from starting new one (5 weeks or more if longer duration of action such as fluoxetine)
Drugs with additive effects of hyperkalemia
- Renin-angiotensin-aldosterone system (RAAS) drugs - ACEIs, ARBs, aliskiren, sacubitril/valsartan (Entresto), spironolactone, eplerenone
- Potassium-sparing diuretics: amiloride, triamterene
- Others: salt substitutes (KCl), calcineruin inhibitors (tacrolimus and cyclosporine), Bactrim, canagliflozin, drospirenone-containing oral contraceptives
S/Sx of hyperkalemia and recommendations for additive drugs that cause hyperkalemia
S/Sx: weakness, heart palpitations, arryhtmmia
-Higher risk in renal impairment
Recommendations:
-do NOT use ACEIs, ARBs, or sacubitril/valsartan (Entresto) together
-Avoid salt substitutes containing KCl
-Monitor potassium –> if at further risk, consider alternatives especially for canagliflozin, Bactrim, or drospirenone-containing OCs
Drugs with additive effects of QTc prolongation
- Antiarrhythmics - class 1a, 1c, and III
- Anti-infectives: antimalarials, azole antifungals (except isavuconazonium), lefamulin, macrolides, quinolones
- Antidepressants: SSRIs (especially citalopram, escitalopram), TCAs, mirtazapine, trazodone, venlafaxine
- Antipsychotics: first-gen (haloperidol, thioridazine), second-gen (highest risk w/ ziprasidone)
- Antimetics: 5-HT3 receptor antagonists (-setrons), droperidol, metoclopramide, promethazine
- Oncology: andogren deprivation therapy (leuprolide), tyrosine kinase inhibitors (nilotinib), arsenic trioxide
- Others: cilostazol, donepezil, fingolimod, hydroxyzine, loperamide, ranolazine, solifenacin, methadone
QTc prolongation:
-What are the main concerns and risk factors?
-What are recommendations for prevention?
Main Concern: Torsades de Pointes (TdP)
Risk Factors: higher doses, higher drug levels w/ concurrent enzyme inhibitors or reduced clearance (ex. renal or liver disease), multiple QTc-prolonging drugs, elderly >60 yo, pts w/ CVD
Recommendations:
-If possible, avoid multiple QT-prolonging drugs or inhibitors of metabolism of QT-prolonging drug
-Limit use of QT-prolonging drugs especially with arrythymias (except: amiodarone is DOC in arrhythmia in pt w/ HF)
-Citalopram: do NOT exceed 40mg daily (20mg daily in elderly, liver disease, or w/ enyzme inhibitors that decrease clearance)
-Escitalopram: do NOT exceced 20mg daily (10mg daily in elderly)
-Droperidol: do NOT use for inpatient N/V (restricted use)
Drugs with additive effects of CNS depression
- Opioids
- Skeletal muscle relaxants
- Anticonvulsants
- Benzodiazepines
- Barbiturates
- Hypnotics
- Antidepressants: mirtazapine, trazodone
- Anti-HTN: propranolol, clonidine
- Cannabis-related drugs: dronabinol, nabilone
- Sedating antihistamines
- Cough syrups w/ antihistamine or opioid
- Some NSAIDs
HIGHEST RISK: opiods + BZDs or other CNS depressant
S/Sx of CNS depression
-General pt counseling
-Recommendations for opioids
S/Sx: somnolence, dizziness, confusion/cognitive impairement, altered consciousness/delirium, gait instability/imbalances/fall risk, accidents (including motor accidents)
Counseling:
-do NOT use alcohol concurrently
-do NOT operate a car or other machines/vehicles
-Can increase risk of falls and confusion
-Use alternatives when possible
Opioids:
-do NOT use in combination w/ BZDs; use of other CNS depressants including alcohol can increase risk of fatality
-ER formulations: can become shorter acting when taken with alcohol, increasing risk of fatality
-Avoid codeine if pharmacogenomic profile is unknown (high risk w/ CYP2D6 ultrametabolizer to convert to morphine)
-Recommend naloxone for high risk pts (high doses, rapid dose increase, reduced clearance)
Drugs with additive effects of ototoxicity
-S/Sx of ototoxicity
-Recommendations
Drugs: aminoglycosides, cisplatin, loop diuretics (especially as rapid IV administration), salicylates (ASA, magnesium salicylate, etc.), vancomycin
S/Sx: hearing loss, tinnitus, vertigo
Recommendations:
-Consider audiology consult at start of TX for baseline hearing assessment and continue to monitor
-Avoid using multiple ototoxic drugs at the same when possible
Drugs with additive effects of nephrotoxicity
-S/Sx
-Recommendations
Drugs: anti-infectives (aminoglycosides, amphotericin B, polymyxins, vancomycin), cisplatin, calcineurin inhibitors (cyclosporine, tacrolimus), loop diuretics, NSAIDs, radiographic-contrast dye
S/Sx: worsening renal function (increased SCr and BUN), decreased urine output
Recommendations:
-Monitor urine output, BUN, Scr, and drug levels
-D/C offending agent if acute renal failure occurs
-Maintain adequate hydration (dehydration can worsen)
-Cisplatin: use amifostine to protect kidneys
Drugs with additive effects of anticholinergic toxicity
- Antidepressants: paroxetine, TCAs
- First-gen antipsychotics
- Sedating antihistamines: Benadryl, brompheniramine, chlorpheniramine, doxylamine, hydroxyzine, cyrpoheptadine, meclizine
- Centrally-acing anticholinergics: benztropine, trihexyphenidyl
- Muscle relaxants: baclofen, carisoprodol, cyclobenzaprine
- Antimuscarinics for urinary incontinence: oxybutynin, darifenacin, tolterodine
- Others: atropine, belladonna, dicyclomine
S/Sx of anticholinergic effects
-Who is at highest risk?
-Recommendations
S/Sx: CNS depression (sedation), dry mouth/eyes, blurry vision, constipation, urinary retention, heat intolerance
Highest risk: elderly
Recommendations:
-Provide alternatives to sedating antihistamines: loratadine, fexofenadine, cetrizine, or saline nasal spray/drops
-Lifestyle changes for sleep rather than sedating agents
-Laxatives for constipation
What drugs taken with PDE-5 inhibitors (ex. sildenafil, vardenafil, tadalafil, avanafil) further increase the risk of hypotension/orthostasis?
-S/Sx
-Recommendations
Drugs: CYP3A4 inhibitors, nitrates, alpha-1 blockers
S/Sx: HA, dizziness (increased fall risk), flushing
-Nitrates: SEVERE HYPOTENSION –> AVOID
Recommendations:
-Taking CYP3A4 + PDE-5i: start with half the usual starting dose of PDE-5i
-Taking alpha-1 blocker + PDE-5i: start with low dose when adding a drug from either class, do NOT start PDE-5i unless stable (no s/sx of hypotension w/ alpha-1 blocker)
-DO NOT TAKE NITRATES AND PDE-5is TOGETHER
Explain the following DDI and recommendations: amiodarone and warfarin
DDI:
-Amiodarone (or dronedarone): inhibits multiple enzymes, including CYP2C9 that metabolizes the potent warfarin isomer
-Warfarin levels increase and INR/bleeding risk increases
Recommendation: these drugs can be added together for Afib (amiodarone for rhythm control and warfarin for clot risk)
-If adding warfarin to amiodarone: start warfarin at lower doses (</=5mg)
-If adding amiodarone to warfarin: decrease warfarin dose by 30-50% depending on INR
-Taking both currently: monitor INR and adjust PRN
Explain the following DDI and recommendations: amiodarone + digoxin
DDI:
-Amiodarone: inhibits P-gp
-Digoxin: P-gp substrate –> decreased excretion, increased toxicity risk (bradycardia, arrhythmia fatality)
Recommendations: can be taken together for Afib treatment (amiodarone for rhythm control and digoxin for rate control or symptoms in HF)
-Adding digoxin to amiodarone: start oral digoxin at low dose (ex. 0.125mg QD)
-Adding amiodarone to digoxin: decrease oral digoxin dose by 50%
-Taking both currently: counsel pt on s/sx of digoxin toxicity (N/V, vision changes), monitor HR, check for other drugs that lower HR
-Digoxin being used for rate control: inform prescriber of alternatives (beta-blockers, non-DHP CCBs)
Explain the following DDI and recommendations: digoxin and loop diuretics
DDI: Loop diuretics decrease K, Mg, Ca, and Na which can worsen arrhythmias (digoxin toxicity associated w/ decrease K and Mg levels and increased Ca levels)
Recommendation: can be taken together for HF
-Check renal function: renal impairment can go along with HF (digoxin excreted by kidneys) –> in impairment, decrease digoxin dose, frequency, or D/C
-Monitor electrolytes and correct if abnormal
Explain the following DDI and recommendations: statins and strong CYP3A4 inhibitors
DDI: lovastatin, simvastatin, and atorvastatin are particularly increased when CYP3A4 is inhibited which increases the risk of myopathy or even rahambomyolysis w/ AKI
-Strong CYP3A4 inhibitors: protease inhibitors (including ritonavir), cobicistat, clarithromycin, erythromycin, azole antifungals, cyclosporine, grapefruit/grapefruit juice
Recommendations:
-Simvastatin and lovastatin: CI w/ strong CYP3A4 inhibitor –> recommend statin NOT metabolized by CYP450 enzymes (pitavastatin, pravastatin, rosuvastatin)
Explain the following DDI and recommendations: warfarin and CYP2C9 inhibitors or inducers
DDI:
-CYP2C9 inhibitor (azole antifungals, Bactrim, amiodarone, metronidazole): increases levels of warfarin, increasing INR and bleeding risk
-CYP2C9 inducer (rifampin, St. John’s Wort): decrease levels of warfarin, decreasing INR and increasing clotting risk
Recommendation:
-Monitor INR (typical goal of 2-3; 2.5-3.5 for high risk conditions)
Explain the following DDI and recommendations: opioids and CYP3A4 inhibitors
DDI: CYP3A4 inhibitor increases levels of opioids, increasing risk of sedation and fatality
Recommendation: avoid combination, avoid grapefruit juice
Explain the following DDI and recommendations: valproate and lamotrigine
DDI: valproate inhibits lamotrigine metabolism, increasing the risk of skin reactions (SJS/TENs) with lamotrigine
Recommendation:
-Initiate lamotrigine using starter kit that begins with lower latromgine doses, titrating Q2 weeks
-Counsel pts to receive emergency help if rash develops
Explain the following DDI and recommendations: anticonvulsants (CYP inducers) and drugs metabolized by CYP enzymes
DDI: anticonvulsants (phenytoin, phenobarbital, primidone, carbamazepine, oxcarbazepine) decrease drugs levels of CYP enzyme substrates (oral contraceptives, other anticonvulsants and auto-inducers like carbamazepine) which decreases drug effects of anticonvulsants
Recommendation:
-Monitor drug levels (induction can take up to 4 weeks for full effect)
-Consider increasing dose of substrate drug
-If substrate is lamotrigine, use starter kit that begins with HIGHER lamotrigine doses
Explain the following DDI and recommendations: smoking (CYP1A2 inducer) including marijuana and tobacco with CYP1A2 substrates
DDI:
-Current smoker: CYP1A2 substrates (some antipsychotics, antidepressants, hypnotics, anxiolytics, caffeine, theophylline, R-warfarin will have decreased drug levels
-Previous smoker: if quit recently, CYP1A2 substrates will increase causing potential for toxicity
Recommendation:
-Counsel/advocate for smoking cessation: nicotine replacement therapy does NOT induce CYP enzymes
-When pt quits, monitor INR if taking warfarin (R-isomer is less potent, but still narrow therapeutic index drug)
Prodrug, capecitabine, converts to __________.
Flurouracil (5-FU)
Prodrug, clopidogrel, converts to __________ via CYP _________.
Active metabolite via CYP2C19 –> poor metabolizers of this enzyme WILL NOT benefit from this drug
Prodrug, codeine, converts to __________ via CYP_______.
Morphine via CYP2D6 –> ultra-metabolizers have risk of toxicity while poor metabolizers will have poor analgesia
Prodrug, colistimethate, converts to __________.
Colistin
Prodrug, cortisone, converts to __________.
Cortisol
Prodrug, famciclovir, converts to __________.
Penciclovir
Prodrug, fosphenytoin, converts to __________.
Phenytoin
Prodrug, isavuconazonium sulfate, converts to __________.
Isavuconazole
Prodrug, levodopa, converts to __________.
Dopamine
Prodrug, lisdexamphetamine, converts to __________.
Dextroamphetamine
Prodrug, prednisone, converts to __________.
Prednisolone
Prodrug, primidone, converts to __________.
Phenobarbital
Prodrug, tramadol, converts to __________ via CYP _________.
Active metabolite via CYP2D6 –> ultra-metabolizers have risk of toxicity while poor metabolizers will have poor analgesia
Prodrug, valacyclovir, converts to __________.
Acyclovir
Prodrug, valganciclovir, converts to __________.
Ganciclovir
Once a drug is D/C, will an inducer or inhibitor of enzyme effects go away more quickly?
Inhibitor - drug actively binds to enzyme –> once D/C, goes away
However, with inducers, there is a “lag time” because inducers increase transcription of enzymes and do NOT work immediately. The full effect may not be seen for 4 weeks, and could take 2-4 weeks to disappear after D/C.
Pharmacokinetics (PK): Absorption
1. When a drug is given _________, absorption does NOT occur. When a drug is given __________, absorption occurs. What are examples of this?
- Explain the process of an PO drug through the body and the types of absorption processes.
- Intravenously - goes straight to bloodstream; Extravascularly (PO, SL, buccal, IM, SC, transdermal, inhaled, topical, ocular, intraocular, intrathecal, and rectal)
- -Passes from stomach to intestine (small intestine is site of most absorption due to larger surface area and permeable membrane)
-After gut absorption, enters portal vein and travels to the liver (some drugs are extensively metabolized before reaching the systemic circulation called the first-pass metabolism)
-Some drugs are retransported through the bile back to the gut to be reabsorbed (enterohepatic recycling)
-Types of absorption: passive diffusion (the gut to lower concentration in the blood), active transport (via transporter proteins that are normally used to absorb nutrients from food)
Pharmacokinetics (PK): Absorption
1. What are drug formulations intended for local effects vs. systemic effects?
- What are the types of absorption: passive diffusion, active diffusion?
1.
-Local: eye drops, dermal preparations, nasal sprays, topical
-Systemic: PO, certain suppositories
2.
-Passive diffusion: moving from a higher concentration (from the gut) into a lower concentration (the blood)
-Active diffusion: via transporter proteins that typically absorb nutrients from food
Define disintegration, dissolution, and solubility
-Disintegration: when a solid dosage form ingested, it breaks into smaller pieces in the GI tract
-Disolution: smaller pieces from disintegration dissolve, active ingredient is released from dosage form
-Solubility: the rate and extent to which the drug dissolves (only dissolved drug is absorbed)
Pharmacokinetics (PK): Absorption:
1. The rate of disolution is defined by the ____________ equation. The rate of dissolution and disintegration depend on the ____________(active ingredient/inactive ingredients).
- Rate the dosage forms by fastest to slowest rate of absorption.
- _____________ formulation limits drug degradation in the stomach via hydrolysis. __________ formulation can reduce the particle diameter to increase the surface area and therefore increase the ________(disintegration/disolution) rate.
- Noyes-Whitney equation; inactive ingrdients
- IV > SL > ODT > IR tablets > XR tablets
3 Enteric-coated; micronized; disolution
Define bioavailabilty (F). What is a considered a high vs. low F?
F: the extent of drug absorption into the systemic circulation
-High: >70% (100% means IV = PO dose)
-Low: <10%
Pharmacokinetics (PK): Distribution
1. Define distribution
- What are factors that contribute to greater drug distrubtion?
- The process by which drug molecules move from the systemic circulatoin to various tissues and organs
- High lipophilicity, low molecular weight, unionized, low protein binding
Pharmacokinetics (PK): Distribution
1. _________(Bound/unbound) drug interacts with the receptors, exerts therapeutic or toxic effects, and can be cleared from the body. If a drug is highly protein bound (>___%) and has a low serum albumin level, a higher percentage of the drug wil be in the _________(bound/unbound) form.
- How to assess bound and unbound drug? What is the consideration with phenytoin?
- Define volume of distribution (V or Vd)
- Unbound; ?%; unbound
- -Many drug assays cannot differentiate between bound and unbound drug
-When assessing highly protein bound drugs with low serum albumin, use correction formulas
-Phenytoin: free phenytoin and ionized calcium measure unbound portion - no adjustment for hypoalbuminemia
- How large of an area in the patient’s body the drug has distributed into –> relates the amount of drug in body to concentration of drug measured in plasma
-Plasma volume: 0.04L/kg
-Extracellular water volume: 0.23 L/kg
-Total body water: 0.60 L/kg
Pharmacokinetics (PK): Metabolism
1. Define metabolism. What is the primary site of metabolism?
- Define first-pass metabolism
- What are the phases of metabolism?
- Process by which a drug is converted from its original chemical structure into other forms to facilitate elminiation from the body
-Primary sites = gut, liver - Metabolism of drug before it reaches the systemic circulation which can drastrically reduce the bioavailability of the oral formulation (ex. lidocaine so extensively metabolized that it must be given IV or other drugs need to be given at high doses)
3.
-Phase I: provide reactive functional group that can be attacked by phase II enzymes –> oxidation, reduction, hydrolysis
-Phase II: conjugation (ex. glucuronidation)
Pharmacokinetics (PK): Excretion
1. What are the organs that can facilitate excretion? What is the primary organ?
- In the kidneys, excretion can be increased by __________(acidifying/alkalinizing) the urine for a weak base and (acidifying/alkalinizing) the urine for a weak acid. In the gut, _______ failicitates excretion.
- Define clearance (Cl)
- First order vs. zero order kinetics (which one is more common?)
- Primarily the kidneys (others: gut, liver, lungs, skin via sweat)
- Acidifying; alkalinizing; P-gp
- The rate of drug removal in a certain volume of plasma over a certain amount of time
4.
-First order: constant percentage of drug removed per unit of time –> most common among drugs
-Zero order: constant amount of drug removed per unit of time
Pharmacokinetics (PK): Excretion
1. What is Michealis-Menten kinetics?
- What are the main considerations with dosing drugs that follow Michealis-Menten kinetics?
- What are drugs that exhibit Michealis-Menten kinetics?
- Also called “saturable” kientics or “non-linear” kinetics
-At very low concentrartions: rate of metabolism mimics a first-order process
-At most concentratoins approaching and exceeding the Km (Michealis-Menten constant): rate of metabolism becomes mixed
-At high concentrations: rate of metabolism mimics a zero-order process - Increases in doses lead to disproportionate incresasd in drug concentration at steady state whereas typically with first-order kinetics, a dose increase would approximately double the serum concentration
-Doubling dose with this type of kinetics can more than double the serum concentration
-Using a proportion to calculate new dose is NOT appropriate
-Dosing adjustments should be made with caution to avoid toxicity
- Phenytoin, theophylline, voriconazole
Pharmacokinetics (PK): Excretion
1. Define half-life. How many half-lives does it take to reach steady state?
- Half-life is __________(dependent/independent) of drug concentration in first-oder kinetics.
- The time required for the drug concentration to decrease by 50%
-Five Half-lives to reach steady state (ss) - Independent
Define: Pharmacogenomics (PG)
The science of examining inherited variations in genes that determine pt’s response to drug (“Personalized Medicine”)
Define the following terminology related to genomics: deoxyribonucleic acid (DNA), nucleotide, chromosome, gene
-DNA: genetic information inherited from parents in two long chains of nucleotides joined by hydrogen bonds and twisted into a double helix
-Nucleotide: subunits of DNA/RNA that have bases containing two purines (adenine and guanine) and two pyrmidaines (thymine and cytosine)
-Chromosome: tightly packed structure within cel nucleus consisting of DNA and proteins (human cells have 23 pairs)
-Gene: specific sequence of nucleotides that code a single protein
Define the following terminology related to genomics: allele, genotype, phenotype
-Allele: specific form of gene which can be wild-type (most commonly occurring allele) or variant
-Genotype: set of unique genes that determine specific trait (can be homozygous with two identical alleles or heterozygous with two different alleles)
-Phenotype: observable trait of genotype
Define the following terminology related to genomics: haplotype, polymorphism, SNP
-Haplotype: group of genes or DNA variations inherited from single parent that can exist on same chromosome and likely to be inherited together
-Polymorphism: inherited variation in DNA squence
-SNP (Single Nucleotide Polymorphism): inherited variation where there is a single base pair change (most common genetic alteration which accounts for majority of individual variability in response to drug)
Define the different types of metabolizers:
-Ultrarapid metabolizer (UM)
-Rapid metabolizer (RM)
-Normal metabolizer (NM)
-Intermediate metabolizer (IM)
-Poor metabolizer (PM)
UM, RM: have higher enzyme activity compared to NMs
-Can lead to faster metabolism of drug through enzyme, causing drug levels to decrease
-Prodrugs: quicker metabolism to active form and/or eliminated faster than expected
NM: have fully functional enzyme activity, resulting in expected drug response
IM: lower enzyme activity that falls between NM and PM
PM: singificantly reduced or NO enzyme activity
-Drug levels could increase
-Prodrugs: NOT metabolized to active form
Abacavir: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:
HLA-B*5701
-Significance: positive indicates increased risk for hypersensitivity rxn –> test ALL pts prior to starting (serious and fatal rxns have occurred)
-Action: if positive, do NOT use
Allopurinol: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:
HLA-B*5801
-Significance: positive indicates increased risk for SJS –> consider testing high-risk individuals (African, Asian, and Native Hawaiian/Pacifican Islander ancestry)
-Action: D/C at any first site of allergic rxn including skin rash, if test positive for HLA-B*5801 do NOT use
Carbamazepine, oxcarbazepine, phenytoin, and fosphenytoin: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:
HLA-B*1502
-Significance: positive indicates increased risk for SJS and TEN –> test all Asian pts before starting carbamazepine (suggested for oxcarbazepine, optional for phenytoin/fosphenytoin)
-Action: if positive, do NOT use (unless benefit outweights risk)
Citalopram: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:
CYP2C19
-Significance: citalopram is metabolized by 2C19 to inactive metabolites, *2 and *3 alleles indicate reduced metabolism with increased QT prolongation risk
-Action: if *2 or *3 allele present, limit citalopram to 20mg/day
Clopidogrel: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:
CY2C19
-Significance: clopidogrel is a prodrug activated by 2C19, *2 and *3 alleles indicate increased CV event risk
-Action: if *2 or *3 allele present, consider alternative TX
Codeine: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:
CYP2D6
-Significance: codeine is a prodrug metabolized to morphine by 2D6, UM have increased risk of opioid overdose (CNS and respiratory depression), infant deaths have occurred with UM nursing mothers
-Action: if UM, do NOT use; if PM, do NOT use (lack of efficacy)
Warfarin: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:
CYP2C9 and VKORC1
-Significance: warfarin is metabolized by 2C9, increased bleeding risk if reduce allele function (*2 and *3) and VORKC1 G > A variant
-Action: if allele variations are present, start at lower dose
Trastuzumab and other HER2 inhibitors: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:
HER2 gene expression
-Significance: require overexpression of HER2 for efficacy
-Action: if tumor is HER2 negative, do NOT use
Cetuximab and other EGFR inhibitors: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:
KRAS mutation
-Significance: positive predicts poor response (not effective with colorectal cancer)
-Action: if positive for KRAS mutation, do NOT use
Azathioprine: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:
thiopurine methyltransferase (TPMT)
-Significance: low/absent TPMT activity results in less metabolism of azathioprine and increased risk of severe life-threatening myleosuppression, moderate activity is also at some increased risk
-Action: if low/absent TPMT activity, start at very low dose or use alternative
Capecitabine and fluorouracil: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:
DPD dihydropyrmidine dehydrogenase (DPD)
-Significance: DPD deficiency increases risk of severe toxicity (diarrhea, neutropenia, neurotoxicity)
-Action: if DPD deficient, do NOT use
Among the drugs considered testing for pharmacogenomic implications, which ones have testing required or strongly recommended?
- Abacavir
- Azathioprine
- Carbamazepine
- Cetuximab, other EGFR inhibitors
- Trastuzumab, other HER2 inhibitors
