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Clinical PK
| Question | Answer |
|---|---|
| What is Pharmacokinetics? | " What the drug does to the body" - ADME |
| What is Pharmacodynamics? | "What the body does to the drug" - relationship between drug concentration at the site of action and the resulting effect |
| Describe Absorption | Passage of drug through physiological barriers before reaching vascular system |
| Describe Volume of Distribution | hypothetical volume that relates drug serum concentrations to amount of drug in body |
| What is Large Vd | penetrate to tissue/organs |
| What is Small Vd | contained in blood |
| What is Metabolism | chemical conversion of drug molecule |
| What is Excretion | irreversible removal of drug from body |
| What is Clearance | volume of serum or blood cleared of the drug per unit of time |
| What is Steady-state concentration | rate of drug administration equals the rate of drug removal |
| What is Linear Pharmacokinetics | steady-state concentration changes proportionally with dose changes |
| What is Non-linear Pharmacokinetics | aka Michaelis-Menten kinetics; steady-state concentration increases more than proportionally to dose changes |
| What is Half-life (T1/2) | time it takes for serum drug concentrations to decrease by one-half |
| What is Elimination rate constant (ke) | rate a drug is eliminated from the body per unit of time C2 = C1 x e^-ke*t |
| What are PD interactions | Occurs when 2 or more drugs are given together and their end effects impact each other |
| What are Additive effects | Agonist medications acting on same receptor and/or drugs with similar end effects that act on different receptors |
| What are Synergistic Effects | When 2 drugs have a great effect when taken in bombination that that obtained by adding the two individualized effects together |
| What is a PK interaction | Drug interactions altering the absorption, distribution, metabolism or excretion of a drug |
| What are Reduced absorption by chelation | when a drug binds to cations in other products- chelated complexes cannot dissolve in gut fluids--> stool |
| List Examples of reduced absorption by chelation | Quinolone antibiotics, oral bisphosphonates, tetracycline antibiotics, levothyroxine + polyvalent cation-containing products/foods |
| What is Reduced absorption due to high GI pH | some drugs require an acidic environment for absorption so will have decreased absorption with used with antiacids |
| List Example of reduced absorption due to high GI PH | PPIs or H2RAs + itraconazole reduced itraconazole absorption |
| What are Metabolism interactions | induction or inhibition (majority of DDIs) |
| What are Excretion Interactions | renal excretion is enhanced or blocked |
| What are CYP Inhibitors | will decrease rate of substance metabolism and increase serum drug concentrations; fast acting |
| What will happen with prodrugs and CYP inhibitors? | an inhibitor will decrease conversion to the active form which will DECREASE serum drug concentrations (reducing therapeutic effect) |
| List of CYP enzyme inhibitors | GPACMAN = Grapefruit, protease inhibitors, azole antifungals, cyclosporine/cobistat, Macrolides, Amiodarone, Non-DHP CCBs (diltiazem, verapamil) |
| What are CYP Inducers? | will increase rate of substance metabolism and DECREASE serum drug levels (slow acting ~4 weeks) |
| What will happen with prodrugs and CYP inducers? | an inducer will INCREASE conversion to the active form which will increase serum drug concentrations |
| List CYP enzyme inducers | PSPORCS = Phenytoin, smoking, phenobarbital, oxcarbazepine, rifampin, carbamazepine, St. Johns Wort |
| What are p-glycoprotein efflux pumps? | pumps GI tract substrates out of body and into gut to be excreted |
| What are P-gp inhibitors | will increase drug absorption (less drug pumped into gut) --> increased concentrations |
| What are P-gp inducers | will decrease drug absorption (more drug pumped into gut) --> decreased concentrations |
| List some common P-gp substrates | DOACS, CV drugs (diltiazem, digoxin, verapamil), Immunosuppressants ( cyclosporine, olimus), Colchicine |
| List some common P-gp inducers | Carbamazepine, phenobarbital, phenytoin, rifampin, st. johns wort |
| List some common P-gp inhibitors | amiodarone, diltiazem, verapamil, cobicistat, ritonavir, cyclosporine |
| When should you obtain a steady-state trough level? | 30 minutes before 4th dose |
| What is the PK impact of decreased renal function? | increased serum drug concentrations for meds that are renally excreted |
| What will happen if CrCl is calculated early in the course of an AKI? | Scr will be FASELY LOW and will OVERESTIMATE actual kidney function |
| What will happen if CrCl is calculated later in the course of an AKI? | Scr will be falsely HIGH and will UNDERESTIMATE actual kidney function |
| What PK drug properties would increase its dialyzability? | molecular weight < 10,000 Daltons, high water solubility, low lipid solubility, decreased ionization, small Vd, low protein binding |
| What would happen to a medication that is highly dialyzable? | it would be removed from body during dialysis. It should be dosed after dialysis |
| IF a drug is not dialyzable... | it can be dosed regardless of dialysis timing. |
| Describe the First pass effect | When a drug is metabolized in the liver after oral administration which leads to a reduction in the concentration of the Active drug before it reaches the site of action or systemic circulation |
| What is Hepatic extraction ratio (Eh) | Fraction of drug presented to the liver that is eliminated during a single pass ( measures the liver's efficiency in eliminating drug from the blood) |
| High extraction ration | Eh > 0.7 or 70% |
| Intermediate extraction ratio | Eh= 0.3-0.7 |
| Low extraction ratio | Eh < 0.3 or 30% |
| Child Pugh Classification A | 5-6 points, well compensated |
| Child Pugh Classification B | 7-9 points, significant functional compromise |
| Child Pugh Classification C | 10-15 points, decompensated disease |
| Aspartate transaminase (AST) | 12-39 U/L |
| Alanine transaminase (ALT) | 7-52 U/L |
| Alkaline Phosphatase (ALP or Alk Phos) | 39-117 U/L |
| Total Bilirubin | 0.1-1.3 mg/dL |
| Albumin | 3.5-5.7 g/dL |
| Geriatrics have an increased sensitivity to medications because... | they have change in receptor numbers, change in receptor affinity, post-reception alteration, and alterations in cellular response. |
| Infant Age | 29 days to < 12 months |
| Child age | 1-12 years |
| Adolescent | 13-17 years |
| Digoxin Mechanism of Action | Heart Failure - inhibition of sodium/potassium ATPase pump (positive inotrope- increased contractility) & Afib- increased parasympathetic activity by vagal nerve stimulation (Negative chronotrope= decreased heartrate) |
| When changing digoxin PO dose to IV you should... | decrease dose by 20-25% |
| Explain digoxin distribution | goes into lean organ tissues and not impacted by obesity, phase lasts 6-8 hours, and has large Vd |
| Explain digoxin metabolism and excretion phase | Digoxin is renally dose adjusted, active metabolites may contribute to therapeutic and toxic effects, and is a P-gp substrate |
| The half-life of digoxin | achieves steady state in 5-7 days , and is increased in renal failure (2-3 weeks) |
| Amiodarone Mechanism of Action | Class III antiarrhythmic- potassium channel blocker, for afib and ventricular arrhythmias |
| Amiodarone metabolism | Hepatic via CYP 2c9 and 3A4, undergoes enterohepatic recirculation |
| Does Digoxin require a loading dose, and what is the regimen? | yes, for Afib, Initial dose 0.25-0.5mg then 0.25 mg q 6 hours for total loading dose 0.75 mg-1.5 mg (3 total doses typically with absolute max dose 1.5 mg)- because it exhibits a 2 compartment PK model. |
| What are the loading dose Adjustments for Digoxin? | CrCl < 20 mL/min, Hypokalemia (3.5-5.1), Hypomagnesemia (ref 1.6-2.5), and Hypercalcemia (Ref: 8.6-10.3) |
| What is the maintenance dosing for Digoxin in A-fib? | 0.125-25 mg PO daily |
| When should you draw digoxin levels? | once patient is in steady state, and wait 8 hours for distribution phase to end after a dose has been given. |
| What are the therapeutic ranges for Digoxin? | Systolic HF= 0.5-0.9 mcg/L ; A-fib= 0.5-2 mcg/L |
| What are signs and symptoms of Digoxin Toxicity? | N/V/D, confusion, vertigo, dizziness, yellow/green halos, ventricular tachycardia, hyperkalemia |
| What are the risk factors for digoxin toxicity? | Elderly, impaired renal function,. hypokalemia, hypomagnesemia |
| What is the treatment for digoxin toxicity? | DigiFab- Digoxin Immune Fab is >10 ng/mL after distribution phase or >15 ng/mL at any time, and acute ingestion >10mg for adults |
| What are some Digoxin DDI that increase digoxin concentrations? | Non-DHP CCB, macrolides and tetracyclines, NSAIDS, Amiodarone, Loop diuretics |
| What DDI with digoxin will decrease concentrations? | cholestyramine, and aluminum containing products |
| What weight do you use for digoxin dosing? | Ideal Body weight |
| Does amiodarone require therapeutic drug monitoring? | No |
| What dose adjustments are there for amiodarone? | not renally dose adjusted, discontinue if AST or ALT are 3x ULN |
| What are some BBW for amiodarone? | pulmonary fibrosis, hepatotoxicity, pro-arrhythmogenic |
| What are some contraindications for amiodarone? | Iodine sensitivity, 2nd or 3rd degree heart block, bradycardia without syncope, and cardiogenic shock |
| What are we monitoring with amiodarone? | Liver functions tests, pulmonary function tests, chest x-rays, eye exam, thyroid stimulating hormone, and EKG (baseline) |
| What are some DDI with amiodarone? | drugs that are affected by Cyp inhibitors, drugs with additive effects that decrease heart rate, and other drugs that cause QTc prolongation |
| What is the mechanism of action of Lithium? | influences reuptake or serotonin or NE moderations glutamate in brain, indicated for bipolar disorder |
| Is lithium renally dose adjusted? | yes |
| When can we get Lithium levels? | trough levels 30 minutes before 4th dose (after 5 days) |
| What are the lithium levels in acute mania? | 0.8-1.5 mEq/L |
| What are the lithium maintenance levels? | 0.6-1 mEq/L |
| What are signs and symptoms of mild lithium toxicity? | 1.2-2 mEq/L= nausea, diarrhea, tremors |
| What are signs and symptoms of moderate lithium toxicity? | 2-2.5 meQ/L = confusion, somnolence |
| What are signs and symptoms of severe lithium toxicity? | >2.5 mEq/L = seizures, delirium, death |
| Which DDI cause increase in lithium concentrations? | Thiazide, ACEI, ARB, ARNI, dehydration, NSAIDS ( only Sulindac can be used with lithium) |
| Which DDI cause decrease in lithium concentrations? | Loop diuretics, theophylline, increase salt or caffeine intake |
| What is the mechanism of action of theophylline? | Blocks phosphodiesterase which increases cAMP, that increases Epinephrine, and causes bronchodilation. Indicated for Asthma and COPD |
| What weight do we use to dose theophylline? | Ideal body weight |
| Is theophylline renally eliminated? | no, does not require dose adjustments |
| What is the half-life of theophylline and how long does it take to reach steady state? | t 1/2 = 8 hours; SS = 1-2 days |
| What is saturable kinetics in theophylline? | at the higher end of the dosing range, small dose increases will lead to large increases in serum concentrations |
| Which CYP 1A2 and 3A4 inhibitors will increase theophylline concentrations? | ciprofloxacin, Zileuton, Clarithromycin |
| Which CYP 1A2 and 3A4 inducers will decrease theophylline concentrations? | carbamazepine, phenytoin, phenobarbital,. rifampin |
| What are theophylline levels? | 5-15 mcg/mL, measure PEAK levels after steady state (2 days) |
| What are signs of theophylline toxicity? | N/V, tachycardia and palpitations, tremor, anything > 80 mcg/mL leads to fatal arrhythmias, seizures |
| Explain the absorption property in Phenytoin. | Oral absorption is variable and slow, where peak concentrations are delayed for several hours after an oral dose. |
| Is phenytoin protein bound? | Yes, ~90% to albumin |
| What is the metabolism and excretion of phenytoin? | Cleared by hepatic metabolism via CYP2C9 where metabolism is capacity limited because the elimination kinetics is dose dependent (Michaelis-Menten) = EVEN small dose increases above max liver metabolism can lead to toxic concentrations |
| Does Phenytoin have a constant half-life? | No, because it depends on the drugs serum concentrations. as phenytoin concentration increases, the half-life increases (DOES NOT REACH STEADY STATE IN 3-5 HALF-LIVES) |
| What happens to phenytoin level at high concentrations? | It starts following non-linear kinetics (Zero order) = constant amount milligrams of drug is eliminated per unit time. |
| What is the excretion properties of carbamazapine? | it is an autoinducer= induces own metabolism (starts 3-5 days after start of therapy and can take ~3-5 weeks to complete) |
| What are the ADME properties of valproate? | different formulations alter rate of absorption; protein binding is saturable, where serum concentrations < 75 mg/L is highly bound (90%) and concentrations 100-150 mg/L have more unbound drug available. It is hepatically metabolized (No renal adj) |
| what is the loading dose for phenytoin? | 20 mg/kg IV or PO (separate PO doses by 2 hours) |
| What is the maintenance dose for phenytoin? | 4-7mg/kg/day, with typical initial doses 300-400mg PO in 203 divided doses |
| What weight do you use for phenytoin dosing? | TBW; but if obese then use AdjBW |
| what is the therapeutic level in phenytoin? | 10--20 mg/L of total phenytoin concentrations |
| When can you draw phenytoin levels? | IV load dose= at least 2 hours after end of infusion; Oral load dose= at least 24 hours after last dose After starting maintenance dose=trough level every 3-4 days, when there is a change in status, stable ambulatory patients = trough level q 3-12 months |
| What factors can alter phenytoin protein binding? | Hypoalbuminemia (Liver disease, severe burns, trauma, malnourishment, elderly); Displacement by Endogenous compounds (hyperbilirubinemia, ESRD), Displacement by exogenous compounds (warfarin, valproic acid) |
| WHEN do we correct for hypoalbuminemia- | when serum albumin is < 3.5g/dL and for is used for normalizing total phenytoin concentration so that it can be compared to usual phenytoin therapeutic range |
| What happens when phenytoin levels reach >20mg/L? | Nystagmus, diplopia |
| What happens when phenytoin levels reach >30mg/L? | Ataxia, N/V, slurred speech, impaired motor function |
| What happens when phenytoin levels reach >40mg/L? | mental status changes and CNS depression, lethargy, severe confusion, and coma |
| When should you obtain a free phenytoin level? | if a patient has altered protein binding (factors that affect PB), when total phenytoin level does not match with their clinical status, and in critically ill patients with suspected altered pb (AKI, elevated LFTs or bilirubin) |
| What is the DDI with valproate and phenytoin? | competes for albumin binding sites, and will increase phenytoin concentrations |
| What is the DDI with oral contraceptives and Phenytoin? | Decreases OC concentration, and is recommended to use alternative contraception method |
| What is the DDI with carbamazepine and phenytoin? | may either increase or decrease phenytoin levels, and will decrease carbamazepine levels |
| What is the DDI with warfarin and phenytoin? | may either increase or decrease anticoagulation effect ( INR monitor) , and increase phenytoin levels |
| What is the DDI with lamotrigine and phenytoin? | it will decrease lamotrigine concentration |
| What genetic testing must be done for carbamazepine? | HLA-B*1502, if (+) avoid giving carbamazepine |
| What risks are associated in patients with a + HLA-B*1502 allele? | At increased risk for developing serious cutaneous adverse reactions (SCAR) with carbamazepine. |
| True/False: Carbamazepine has a loading dose | False, it does not, doses slowly increase over time, and must increase the doing every week. because of autoinduction |
| What are the therapeutic levels for carbamezapine? | 4-12 mg/L |
| When do you draw carbamazepine levels? | Get trough level (before next dose) Within 3-5 days after starting the drug, before autoinduction begins, check again after autoinduction ends (in 3-5 weeks), and when there is a status change. In ambulatory stable pts- trough q 3-4 months |
| What side effects are seen in carbamazepine levels 8-12mg/L? | drowsiness, headache, dizziness, N/V |
| What toxicity levels in carbamazepine will cause ataxia, nystagmus, and somnolence? | 12-15 mg/L |
| What toxicity levels in carbamazepine will cause combativeness, hallucinations, chorea? | > 15 mg/L |
| What toxic effect will occur in carbamazepine levels > 25 mg/L? | seizures, coma |
| What DDI are there with carbamazepine? | Valproate ( increase carbamazepine conc active metabolite); oral Contrac (decreases OC); Phenytoin (decreases carbamazepine levels); Warfarin (decreases INR); Lamotrigine (decrease lamo conc) |
| What is the loading dose of valproate in status epilepticus | 20-40 mg/kg (max 3 grams) |
| what is the typical PO dose initially? | 10-15 mg/kg/day |
| What weight do we use for valproate? | Total body weight |
| What is the maintenance dose and how long does it take to reach steady state | 60 mg/kg/day, takes 4-6 weeks . dose titrations increase weekly |
| What is the therapeutic level for valproate? | 50-100 mg/L |
| When do we draw valproate levels? | trough levels 2-4 days after maintenance dose achieved, when there is a status change, or in ambulatory stable pts q 3-12 months |
| Does valproate have similar factors that affect protein binding as phenytoin? | Yes, if they have altered PB, the would be expected to have a higher free concentration and now at risk for toxicity with normal total concentrations |
| What are the side effects for valproate at 75-100 mg/L | ataxia, sedation, lethargy, drowsiness |
| What toxic levels are there for valproate and what are the symtoms | 100-175 mg/L = tremor, >175 mg/L= stupor, coma |
| What are DDI with valproate? | lamotrigine= Increases lamotrigine conc; warfarin= increases INR; Estrogen-containing contraceptives= decrease VPA concentrations |
| What is the mechanism of action of warfarin? | competitively inhibits vitamin K epoxide reductase, (Vit. K antagonist), and actions on impairing clotting factors (2,7,9,10) and anticoagulant proteins (C & S) |
| What are the ADME properties of warfarin? | 100% completely po absorbed, 99% protein bound to albumin, extensively metabolized by CYP2C9, 1A2, 3A4 to inactive metabolites, excreted renally but DOES NOT REQUIRE RENAL ADJUSTMENTS |
| What is warfarin's anticoagulant effect/ | based on the Half-life of VIT. K DEPENDENT COAGULATION FACTORS (2,7,9,10, C and S) |
| How long is the half-life of factor II? | 5-7 days until patient fully anticoagulated |
| True/False : Patients are hypercoagulable within 24 hours after starting warfarin | True |
| What should you check at baseline before starting warfarin? | CBC, pregnancy test in women of child-bearing age (CI with warfarin), INR |
| What are some indications for warfarin and what are the INR goals? | A-fib & VTE (2.5); Mitral mechanical valve & aortic + mitral mechanical valve (2) |
| When do you want to bridge before starting warfarin? | History of ischemic stroke or TIA, Acute VTE, mechanical heart valves |
| What is the bridging dose of enoxaparin (Lovenox) and for how long? | 1mg/kg SQ q 12 hours, or if CrCl <30mL/min 1mg/kg SQ q 24 hours for at least 5 days and until 2 consecutive therapeutic INRs are achieved (24 hrs apart) |
| What are the syringe sizes for enoxaparin? | 30, 40, 60,80,100,120,150 mg/mL |
| Why is there no loading dose for warfarin? | warfarin is not dependent on drug's half-life; |
| What is the initial dose of warfarin? | 5mg or 2.5 mg if: > 75 yo, liver disease, CHF exacerbation, High bleeding risk, concomitant CYP inhibiting medications, TBW < 50kg, malnourished or NPO x 3 days |
| What do you do in patients with decreased warfarin sensitivity? | start on higher dose 7.5-10mg if concomitant strong CYP inducing meds and/or young <40 healthy ambulatory patients |
| How often should you monitor warfarin after initiating inpatient? | baseline (48 hours before 1st dose), day 3 (5mg) or day 2 (2.5mg) , and daily until at least 2 consecutive values are in range, then 2x week while in hospital and stable |
| How often should you monitor warfarin after initiating outpatient? | every 2-4 days until INR is at target range, then once per week for 2 weeks, and may extend duration between INR checks if stable. (4-6 weeks) |
| What are the 4 Ds in warfarin dose adjustments? | Diet, Drugs, Dose, Disease |
| How often should you monitor warfarin during maintenance therapy? | If INR is stable and in within INR goal for at least 3 months, can monitor q 6-8 weeks. Mostly check q 4 weeks. |
| What should you consider during warfarin dose adjustments? | use the patients current tablet strength to alter regimen, tablets can be halved, round dose to nearest half tablet or whole tablet, spread out doses as evenly as possible throughout the week. |
| What should you do if an interacting drug must be used with warfarin? | check INR 3-5 days after starting the interacting drug |
| What are some exceptions to amiodarone and warfarin use? | DECREASE warfarin weekly maintenance dose by 30-50% after 7-14 days of concomitant therapy |
| What are some exceptions to rifampin and warfarin use? | INCREASE warfarin weekly maintenance dose by 30-50% after 7-14 days of concomitant therapy |
| What are some rare side effects of warfarin | purple toe syndrome, and skin necrosis |
| what is procedural bridging? | when a patient is on warfarin and has a procedure coming up, sometimes they need to have a parenteral bridging before and/or after the procedure |
| What is the purpose of procedural bridging? | to reduce their risk of clotting while off warfarin and decrease bleeding during the procedure |
| What should you do if INR is 5-9 but no significant bleeding? | Omit 1-2 doses of warfarin, reduce the dose by 10-20%, and monitor frequently |
| What if INR > 9 and still not significant bleeding? what do you do? | hold warfarin therapy, give vitamin K (phytonadione) 2.5-5 mg PO once, monitor daily until INR therapeutic, and resume at lower dose |
| What do you do if patient has life-threatening or serious bleeding? | hold warfarin, give vitamin K 5-10 mg IV over 30 min. may repeat every 12-24 hours as needed, can give Kcentra |
| What is Kcentra? | Prothrombin complex concentrate (PCC) that gives clotting factors back ( 2,7,9,10, and protein S) |
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