PD/PK/PG/DDIs

Question 1

Explain the breakdown of the nervous system and the neurotransmistters that act as signals in each component

Answer 1

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

Question 2

Muscarinic receptor
-Endogenous substrate and its agonist action

-Agonist drugs on this receptor

-Drug antagonists and its antagonist action

Answer 2

Endogenous substrate: acetylcholine (ACh) –> increases SLUDD (salivation, lacrimation, urination, diarrhea/defecation, digestion)

Drug agonists: pilocarpine, bethanechol

Drug antagonists: atropine, oxybutynin –> decrease SLUDD

Question 3

Nicotinic receptor
-Endogenous substrate and its agonist action

-Agonist drugs on this receptor

-Drug antagonists and its antagonist action

Answer 3

Endogenous substrate: acetylcholine (ACh) –> increases HR and BP

Drug agonist: nicotine

Drug antagonists: neuromuscular blockers (ex. rocuronium) –> neuromuscular blockade

Question 4

Alpha-1 receptor
-Endogenous substrate and its agonist action

-Agonist drugs on this receptor

-Drug antagonists and its antagonist action

Answer 4

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

Question 5

Alpha-2 receptor
-Endogenous substrate and its agonist action

-Agonist drugs on this receptor

-Drug antagonists and its antagonist action

Answer 5

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

Question 6

Beta-1 receptor
-Endogenous substrate and its agonist action

-Agonist drugs on this receptor

-Drug antagonists and its antagonist action

Answer 6

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

Question 7

Beta-2 receptor
-Endogenous substrate and its agonist action

-Agonist drugs on this receptor

-Drug antagonists and its antagonist action

Answer 7

Endogenous substrate: EPI –> bronchodilation

Drug agonists: albuterol, terbutaline, isoproterenol

Drug antagonists: non-selective beta-blockers (ex. propranolol, carvedilol) –> bronchoconstriction

Question 8

Acetylcholinesterase:
-Effects of enzyme

-Drugs that act on enzyme and their actions

Answer 8

Enzyme: breaks down acetylcholine, ACh

Drugs: acetylcholinesterase inhibitors (donepezil, galantamine, rivastigamine) –> block acetylcholinesterase to increase ACh levels to treat Alzheimer’s disease

Question 9

Angiotensin-converting enzyme (ACE):
-Effects of enzyme

-Drugs that act on enzyme and their actions

Answer 9

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

Question 10

Catechol-O-methyltransferase (COMT):
-Effects of enzyme

-Drugs that act on enzyme and their actions

Answer 10

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

Question 11

Cyclooxygenase (COX):
-Effects of enzyme

-Drugs that act on enzyme and their actions

Answer 11

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

Question 12

Monoamine oxidase (MAO):
-Effects of enzyme

-Drugs that act on enzyme and their actions

Answer 12

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)

Question 13

Phosphodiesterase (PDE):
-Effects of enzyme

-Drugs that act on enzyme and their actions

Answer 13

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

Question 14

Vitamin K epoxide reductase:
-Effects of enzyme

-Drugs that act on enzyme and their actions

Answer 14

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

Question 15

Xanthine oxidase:
-Effects of enzyme

-Drugs that act on enzyme and their actions

Answer 15

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

Question 16

Oxidation
-What type of reaction
-Visual indicators

Answer 16

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)

Question 17

Prevention of Oxidation

Answer 17

-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)

Question 18

Hydrolysis:
-What type of reaction
-Prevention

Answer 18

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)

Question 19

Photolysis
-What type of reaction
-Prevention

Answer 19

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

Question 20

Common CYP Inhibitors involved in DDIs: G-PACMAN
-Effects on substrates and prodrugs

Answer 20

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)

Question 21

Common CYP Inducers in DDIs: PS PORCS
-Effects on substrates and prodrugs1
-Lag time if inducer is stopped

Answer 21

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

Question 22

P-gp: common substrates

Answer 22

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

Question 23

P-gp: Common inducers

Answer 23

CARBAMAZEPINE, PHENOBARBITAL, PHENYTOIN, RIFAMPIN, ST. JOHN’S WORT

Others: dexamethasone, tipranavir

Question 24

P-gp: Common inhibitors

Answer 24

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

Question 25

CYP450: Common CYP3A4 substrates

Answer 25

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

Question 26

CYP450: Common CYP3A4 inducers

Answer 26

Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, smoking, St. John's Wort

Question 27

CYP450: Common CYP1A2 substrates

Answer 27

Theophylline, R-warfarin

Question 28

CYP450: Common CYP3A4 inhibitors

Answer 28

Anti-infectives: clarithromycin, erythromycin, azole antifungals, isonazid CV drugs: amiodarone, diltiazem, verapamil HIV drugs: cobicistat, ritonavir, protease inhibitors (PIs) Others: cyclosporine, grapefruit juice

Question 29

CYP450: Common CYP2C9 substrates

Answer 29

S-warfarin

Question 30

CYP450: Common CYP1A2 inhibitors

Answer 30

Ciprofloxacin, fluvoxamine

Question 31

CYP450: Common CYP1A2 inducers

Answer 31

Carbamazepine, phenobarbital, phenytoin, rifampin, smoking, St. John's Wort

Question 32

CYP450: Common CYP2C19 substrates

Answer 32

Clopidogrel (prodrug)

Question 33

CYP450: Common CYP2C9 inhibitors

Answer 33

Amiodarone, fluconazole, metronidazole, Bactrim AAA = Azole, Amiodarone, Anti-infectives

Question 34

CYP450: Common CYP2C9 inducers

Answer 34

Carbamazepine, phenytoin, phenobarbital, rifampin, smoking, St. John's wort

Question 35

CYP450: Common CYP2C19 inhibitors

Answer 35

Esomeprazole, omeprazole

Question 36

CYP450: Common CYP2D6 Inhibitors

Answer 36

Amiodarone, duloxetine, fluoxetine, paroxetine

Question 37

CYP450: Common CYP2D6 substrates

Answer 37

Analgesics: codeine, meperidine, tramadol Others: some antipsychotics/antidepressants, tamoxifen "Pain and Psych" drugs: only major CYP enzyme NOT subject to inducers

Question 38

Drugs with additive effects of seroteonergic toxicity

Answer 38

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)

Question 39

Drugs with additive effects of bleeding -These drugs should be avoided together except when?

Answer 39

1. Anticoagulants 2. Antiplatelets 3. NSAIDs 4. SSRIs and SNRIs 5. 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)

Question 40

S/Sx of Sertonin Snydrome and Prevention

Answer 40

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)

Question 41

Drugs with additive effects of hyperkalemia

Answer 41

1. Renin-angiotensin-aldosterone system (RAAS) drugs - ACEIs, ARBs, aliskiren, sacubitril/valsartan (Entresto), spironolactone, eplerenone 2. Potassium-sparing diuretics: amiloride, triamterene 3. Others: salt substitutes (KCl), calcineruin inhibitors (tacrolimus and cyclosporine), Bactrim, canagliflozin, drospirenone-containing oral contraceptives

Question 42

S/Sx of hyperkalemia and recommendations for additive drugs that cause hyperkalemia

Answer 42

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

Question 43

Drugs with additive effects of QTc prolongation

Answer 43

1. Antiarrhythmics - class 1a, 1c, and III 2. Anti-infectives: antimalarials, azole antifungals (except isavuconazonium), lefamulin, macrolides, quinolones 3. Antidepressants: SSRIs (especially citalopram, escitalopram), TCAs, mirtazapine, trazodone, venlafaxine 4. Antipsychotics: first-gen (haloperidol, thioridazine), second-gen (highest risk w/ ziprasidone) 5. Antimetics: 5-HT3 receptor antagonists (-setrons), droperidol, metoclopramide, promethazine 6. Oncology: andogren deprivation therapy (leuprolide), tyrosine kinase inhibitors (nilotinib), arsenic trioxide 7. Others: cilostazol, donepezil, fingolimod, hydroxyzine, loperamide, ranolazine, solifenacin, methadone

Question 44

QTc prolongation: -What are the main concerns and risk factors? -What are recommendations for prevention?

Answer 44

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)

Question 45

Drugs with additive effects of CNS depression

Answer 45

1. Opioids 2. Skeletal muscle relaxants 3. Anticonvulsants 4. Benzodiazepines 5. Barbiturates 6. Hypnotics 7. Antidepressants: mirtazapine, trazodone 8. Anti-HTN: propranolol, clonidine 9. Cannabis-related drugs: dronabinol, nabilone 10. Sedating antihistamines 11. Cough syrups w/ antihistamine or opioid 12. Some NSAIDs HIGHEST RISK: opiods + BZDs or other CNS depressant

Question 46

S/Sx of CNS depression -General pt counseling -Recommendations for opioids

Answer 46

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)

Question 47

Drugs with additive effects of ototoxicity -S/Sx of ototoxicity -Recommendations

Answer 47

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

Question 48

Drugs with additive effects of nephrotoxicity -S/Sx -Recommendations

Answer 48

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

Question 49

Drugs with additive effects of anticholinergic toxicity

Answer 49

1. Antidepressants: paroxetine, TCAs 2. First-gen antipsychotics 3. Sedating antihistamines: Benadryl, brompheniramine, chlorpheniramine, doxylamine, hydroxyzine, cyrpoheptadine, meclizine 4. Centrally-acing anticholinergics: benztropine, trihexyphenidyl 5. Muscle relaxants: baclofen, carisoprodol, cyclobenzaprine 6. Antimuscarinics for urinary incontinence: oxybutynin, darifenacin, tolterodine 7. Others: atropine, belladonna, dicyclomine

Question 50

S/Sx of anticholinergic effects -Who is at highest risk? -Recommendations

Answer 50

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

Question 51

What drugs taken with PDE-5 inhibitors (ex. sildenafil, vardenafil, tadalafil, avanafil) further increase the risk of hypotension/orthostasis? -S/Sx -Recommendations

Answer 51

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

Question 52

Explain the following DDI and recommendations: amiodarone and warfarin

Answer 52

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 (

Question 53

Explain the following DDI and recommendations: amiodarone + digoxin

Answer 53

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)

Question 54

Explain the following DDI and recommendations: digoxin and loop diuretics

Answer 54

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

Question 55

Explain the following DDI and recommendations: statins and strong CYP3A4 inhibitors

Answer 55

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)

Question 56

Explain the following DDI and recommendations: warfarin and CYP2C9 inhibitors or inducers

Answer 56

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)

Question 57

Explain the following DDI and recommendations: opioids and CYP3A4 inhibitors

Answer 57

DDI: CYP3A4 inhibitor increases levels of opioids, increasing risk of sedation and fatality Recommendation: avoid combination, avoid grapefruit juice

Question 58

Explain the following DDI and recommendations: valproate and lamotrigine

Answer 58

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

Question 59

Explain the following DDI and recommendations: anticonvulsants (CYP inducers) and drugs metabolized by CYP enzymes

Answer 59

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

Question 60

Explain the following DDI and recommendations: smoking (CYP1A2 inducer) including marijuana and tobacco with CYP1A2 substrates

Answer 60

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)

Question 61

Prodrug, capecitabine, converts to __________.

Answer 61

Flurouracil (5-FU)

Question 62

Prodrug, clopidogrel, converts to __________ via CYP _________.

Answer 62

Active metabolite via CYP2C19 --> poor metabolizers of this enzyme WILL NOT benefit from this drug

Question 63

Prodrug, codeine, converts to __________ via CYP_______.

Answer 63

Morphine via CYP2D6 --> ultra-metabolizers have risk of toxicity while poor metabolizers will have poor analgesia

Question 64

Prodrug, colistimethate, converts to __________.

Answer 64

Colistin

Question 65

Prodrug, cortisone, converts to __________.

Answer 65

Cortisol

Question 66

Prodrug, famciclovir, converts to __________.

Answer 66

Penciclovir

Question 67

Prodrug, fosphenytoin, converts to __________.

Answer 67

Phenytoin

Question 68

Prodrug, isavuconazonium sulfate, converts to __________.

Answer 68

Isavuconazole

Question 69

Prodrug, levodopa, converts to __________.

Answer 69

Dopamine

Question 70

Prodrug, lisdexamphetamine, converts to __________.

Answer 70

Dextroamphetamine

Question 71

Prodrug, prednisone, converts to __________.

Answer 71

Prednisolone

Question 72

Prodrug, primidone, converts to __________.

Answer 72

Phenobarbital

Question 73

Prodrug, tramadol, converts to __________ via CYP _________.

Answer 73

Active metabolite via CYP2D6 --> ultra-metabolizers have risk of toxicity while poor metabolizers will have poor analgesia

Question 74

Prodrug, valacyclovir, converts to __________.

Answer 74

Acyclovir

Question 75

Prodrug, valganciclovir, converts to __________.

Answer 75

Ganciclovir

Question 76

Once a drug is D/C, will an inducer or inhibitor of enzyme effects go away more quickly?

Answer 76

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.

Question 77

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? 2. Explain the process of an PO drug through the body and the types of absorption processes.

Answer 77

1. Intravenously - goes straight to bloodstream; Extravascularly (PO, SL, buccal, IM, SC, transdermal, inhaled, topical, ocular, intraocular, intrathecal, and rectal) 2. -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)

Question 78

Pharmacokinetics (PK): Absorption 1. What are drug formulations intended for local effects vs. systemic effects? 2. What are the types of absorption: passive diffusion, active diffusion?

Answer 78

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

Question 79

Define disintegration, dissolution, and solubility

Answer 79

-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)

Question 80

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). 2. Rate the dosage forms by fastest to slowest rate of absorption. 3. _____________ 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.

Answer 80

1. Noyes-Whitney equation; inactive ingrdients 2. IV > SL > ODT > IR tablets > XR tablets 3 Enteric-coated; micronized; disolution

Question 81

Define bioavailabilty (F). What is a considered a high vs. low F?

Answer 81

F: the extent of drug absorption into the systemic circulation -High: >70% (100% means IV = PO dose) -Low: <10%

Question 82

Pharmacokinetics (PK): Distribution 1. Define distribution 2. What are factors that contribute to greater drug distrubtion?

Answer 82

1. The process by which drug molecules move from the systemic circulatoin to various tissues and organs 2. High lipophilicity, low molecular weight, unionized, low protein binding

Question 83

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. 2. How to assess bound and unbound drug? What is the consideration with phenytoin? 3. Define volume of distribution (V or Vd)

Answer 83

1. Unbound; ?%; unbound 2. -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 3. 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

Question 84

Pharmacokinetics (PK): Metabolism 1. Define metabolism. What is the primary site of metabolism? 2. Define first-pass metabolism 3. What are the phases of metabolism?

Answer 84

1. 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 2. 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)

Question 85

Pharmacokinetics (PK): Excretion 1. What are the organs that can facilitate excretion? What is the primary organ? 2. 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. 3. Define clearance (Cl) 4. First order vs. zero order kinetics (which one is more common?)

Answer 85

1. Primarily the kidneys (others: gut, liver, lungs, skin via sweat) 2. Acidifying; alkalinizing; P-gp 3. 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

Question 86

Pharmacokinetics (PK): Excretion 1. What is Michealis-Menten kinetics? 2. What are the main considerations with dosing drugs that follow Michealis-Menten kinetics? 3. What are drugs that exhibit Michealis-Menten kinetics?

Answer 86

1. 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 2. 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 3. Phenytoin, theophylline, voriconazole

Question 87

Pharmacokinetics (PK): Excretion 1. Define half-life. How many half-lives does it take to reach steady state? 2. Half-life is __________(dependent/independent) of drug concentration in first-oder kinetics.

Answer 87

1. The time required for the drug concentration to decrease by 50% -Five Half-lives to reach steady state (ss) 2. Independent

Question 88

Define: Pharmacogenomics (PG)

Answer 88

The science of examining inherited variations in genes that determine pt's response to drug ("Personalized Medicine")

Question 89

Define the following terminology related to genomics: deoxyribonucleic acid (DNA), nucleotide, chromosome, gene

Answer 89

-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

Question 90

Define the following terminology related to genomics: allele, genotype, phenotype

Answer 90

-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

Question 91

Define the following terminology related to genomics: haplotype, polymorphism, SNP

Answer 91

-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)

Question 92

Define the different types of metabolizers: -Ultrarapid metabolizer (UM) -Rapid metabolizer (RM) -Normal metabolizer (NM) -Intermediate metabolizer (IM) -Poor metabolizer (PM)

Answer 92

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

Question 93

Abacavir: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:

Answer 93

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

Question 94

Allopurinol: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:

Answer 94

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

Question 95

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:

Answer 95

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)

Question 96

Citalopram: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:

Answer 96

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

Question 97

Clopidogrel: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:

Answer 97

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

Question 98

Codeine: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:

Answer 98

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)

Question 99

Warfarin: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:

Answer 99

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

Question 100

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:

Answer 100

HER2 gene expression -Significance: require overexpression of HER2 for efficacy -Action: if tumor is HER2 negative, do NOT use

Question 101

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:

Answer 101

KRAS mutation -Significance: positive predicts poor response (not effective with colorectal cancer) -Action: if positive for KRAS mutation, do NOT use

Question 102

Azathioprine: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:

Answer 102

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

Question 103

Capecitabine and fluorouracil: explain what might be tested related to pharmacogenomics, the significance/population of consideration and the action that should be taken:

Answer 103

DPD dihydropyrmidine dehydrogenase (DPD) -Significance: DPD deficiency increases risk of severe toxicity (diarrhea, neutropenia, neurotoxicity) -Action: if DPD deficient, do NOT use

Question 104

Among the drugs considered testing for pharmacogenomic implications, which ones have testing required or strongly recommended?

Answer 104

1. Abacavir 2. Azathioprine 3. Carbamazepine 4. Cetuximab, other EGFR inhibitors 5. Trastuzumab, other HER2 inhibitors