Pharmacology: Lecture 3 Flashcards
Bioavailability
- amount of drug reaching systemic circulation
- 100% for IV drugs, usually less in other routes
Volume of Distribution
theoretical volume that represents an individual drugs propensity to either remain in the plasma or distribute to other tissue compartments
Charactristics of large Vd
small size, lipophilic, tissue protein bound; likely to leave the plasma and enter extravascular spaces and tissues
Characteristics of small Vd
large size, charged, plasma protein bound; propensity to remain in the plasma
Liner or First Order PK
serum concentration changes are proportional to drug dosing changes; constant PROPORTION of drug (% per hour) is eliminated
Nonlinear or zero order PK
constant amount of drug (mg per hour) is eliminated; more dose dependent
Michaelis-Menten kinetics
- below a given serum concentration, elimination follows 1st order kinetics
- above the given serum concentration, elimination follows zero order kinetics
- ex) phenytoin
Protein-binding non-linear PK
-unbound drug is what exerts pharmacological effect through receptor binding
binding of drugs to plasm proteins is capacity-limited
-total drug concentration increases less than proportionally to dose increases
-more unbound free drugs results in greater rate of elimination–> total concentration is less than proportional to dose increases
Therapeutic Window/Index
- range between desired therapeutic effect and toxic adverse effects
- drugs with narrow therapeutic windows often require therapeutic drug monitoring because its easy to fall out of target levels
Therapeutic Drug Monitoring is important for:
- optimizing clinical response
- avoiding toxicities
- assessing patient adherence
Peak of AUC curve
Cmax=maximum drug concentration
measured 30-60 minutes after a dose for most drugs-allows time for tissue distribution
Trough of AUC curve
- Cmin=minimum drug concentration
- measured immediately (within 30 mins) prior to next dose
- to determine of drug is high enough at lowest point
Phenytoin/Fosphenytoin Basics
- anticonvulsant in CNS
- treatment and prevention of seizures
- follows Michaelis-menten kinetics
- requires therapeutic drug monitoring
- has many drug interactions
Phenytoin Mechanism of Action
blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and slowing its rate of recovery
Phenytoin Dosage Forms
- IV injection: max of 50 mg/min
- oral: immediate release or extended release, chewable tablet, suspension
Fosphenytoin Dosage Forms
- IV or IM injection: max IV dose of 150 mg PE/min
- prodrug of that is rapidly converted to phenytoin in the blood within minutes
Phenytoin Absorption/Bioavilability
Oral Bioavailability: 80-95%
IV: always 100%
Decreased bioavailability for IR oral product in neonates and for oral suspension when given to patients receiving enteral tube feedings(separate enteral feedings by 1-2 hours from phenytoin)
Phenytoin Distribution
- Lipid Soluble: Vd: .6/.7 L/kg in adults and obese patients have larger Vd
- larger Vd may increase half-life so longer time to reach steady state so longer for drug to be eliminated - Highly protein bound: 90-95% in adults; assays measure total phenytoin(bound/unbound)
- adjustments necessary in hypoalbuminemia (<3.5 g/dL)
Phenytoin Metabolism/Excretion
- Renal excretion=negligible, mostly metabolites
- Cleared primarily by capacity-limited (saturable) hepatic metabolism
- Demonstrates Michaelis-menten (nonlinear kinetics)-small increases in the daily dose, can produce large increases in plasma concentration resulting in drug induced toxicity
Phenytoin Dosing
- weight based (initial dosing)
- loading doses given to reach target serum concentrations faster to stop the seizure
Fosphenytoin Dosing
- based on phenytoin equivalents (PE)
- 1 mg PE=1 mg phenytoin sodium
- adjust maintenance dose based on serum concentration
Phenytoin Drug Monitoring
- Trough levels are obtained for routine monitoring
1. within 2-3 days after therapy initiation which is time to reach steady state
2. 2nd level within 5-8 days of initiation
3. q week in acute clinical settings
4. q 3-12 months for long term therapy - Trough levels after dose adjustments or addition/removal of interacting drugs
Phenytoin/Fosphenytoin Toxicites and therapeutic levels
arrhythmia and hypotension can occur with rapid infusion
TL= 10-20 mg/L
Toxic above 30 mg/L
Lethal above 100 mg/L
Side effects of concentration -related Phenytoin
Nystagmus, ataxia and impaired motor function, CNS depression
Phenytoin effects on enzymes
strong inducer of CYP enzymes-2B6, 2C9, 2C19, 3A4
decreases levels of drugs that are metabolized by these enzymes
Phenytoin drug interactions
drug disease interactions: hepatic disease or renal failure
highly protein bound drug so in liver disease, less albumin made my liver
Gentamicin/Tobramycin Basics/Category
- aminoglycoside antibiotics
- variety of dosing formulations
- therapeutic drug monitoring
Gentamicin/Tobramycin Mechanism of Action
binds irreversibly to the 30S ribosomal subunit, inhibiting bacterial protein synthesis
Gentamicin Dosage Forms
- injection, IM or IV
- topical cream and ointment
- ophthalmic solution and ointment
Tobramycin Dosage Forms
- Injections
- nebulizer solution for cystic fibrosis
- ophthalmic solution and ointment
Gentamicin/Tobramycin Absorption
Oral: poorly absorbed, not used
IM/IV: 100% bioavailability
Gentamicin/Tobramycin Distribution
- Highly hydrophilic, primarily extracellular fluid
- high concentration on renal cortex
- poor CNS penetration
- smaller Vd but larger Vd in neonates due to greater water concentration
- protein binding < 30%
Gentamicin/Tobramycin Metabolism/excretion
No metabolism Excreted renally ( greater than 70% as unchanged drug) Normal renal function: 90-95% eliminated in 24 hours poor renal function-->drug accumulates-->toxic levels
Gentamicin/Tobramycin Toxicities
Ototoxicity: IRREVERSIBLE; vestibular and cochlear; hearing loss, tinnitus, loss of balance; related to sustained high concentrations
Nephrotoxicity: REVERSIBLE; acute kidney injury due to acute tubular necrosis; can occur with usual dosing (high troughs increase risk)
Risk factors: prolonged duration of therapy, advanced age, sepsis, decreased renal perfusion, other nephrotoxic drugs
Gentamicin/tobramycin dosing based on:
concentration dependent activity- peak concentration correlates with efficacy
the greater the concentration, the greater the killing of bacteria and post antibiotic effect-effects prolonged even at sub therapeutic levels
-because of this, high dose-extended interval is utilized to reduce risk of nephrotoxicity (large dose, longer intervals)
-traditionally, smaller doses, shorter intervals
What populations are not recommended to take gentamicin/tobramycin?
pregnancy, cystic fibrosis, gram positive bacteria-synergistic with other antibiotics, pediatric patients
Bayesian calculations of gentamicin/tobramycin
computer model of normal population parameters
dosing based on clinical circumstances
Nomogram dosing of gentamicin/tobramicin
dosing based on weight
adjustments based on chart
individualized calculations preferred because not all patients fit the parameters
Gentamicin/tobramycin drug monitoring: peaks and troughs
Peaks-30 minute after dose administered
correlates with efficacy, usually monitored with traditional dosing
Troughs-right before next dose
monitor for toxicity with both dosing strategies
after 2-3 doses (steady state)
can draw after first dose if patient unlikely to exhibit predictable kinetics like in unstable renal function
Vancomycin Basics/category
glycopeptide antibiotic
reserved for resistant infections, most commonly MRSA:gram positive only
Need antimicrobial stewardship and therapeutic drug monitoring
Vancomycin MOA
inhibition of cell wall biosynthesis by inhibition of phospholipids and peptidoglycans
Vanco dosage forms/absorption
injection for MRSA infections
oral capsules/solution: only for Cdiff because of poor tissue penetration and concentrates in lower GI tract
Vanco Distribution
Vd: .4-1 L/kg
wide distribution via IV but not to the CNS
protein binding=50%
Vanco metabolism/excretion
no metabolism!
excreted by urine with IV dose (80-90% as unchanged drug)
excreted by feces with oral dose
Vanco dosing
weight-based dosing for IV
loading doses usually given to acutely ill patients like in sepsis
dosing interval based on renal function (creatinine clearance)
adjust dose based on trough levels-more time based esp in patients with renal impairment or patients on other nephrotoxic meds or in severe infections
Vanco Nephrotoxicity
acute kidney injury
Risk factors: prolonged duration of therapy, high doses, advance age, sepsis/decreased renal perfusion, other nephrotoxic drugs like ahminoglycosides
Vanco Ototoxicity
Rare, unless given with other ototoxic drugs or at excessive doses
-tinnitus, hearing loss, dizziness, vertigo
Vanco Infusion Reactions
often due to infusing vanco too fast (should be infused over > 60 mins)
-pruritus, erythematous rash “red man syndrome”
-hypotension and angioedema less common
not considered an allergic reaction
Vanco Dosing-AUC dependent activity
Area under concentration time curve correlates with efficacy
- overall serum concentration over a period of time
- peak and trough drawn once hit steady state
Vanco drug monitoring via AUC
- new standard of care
- 2 random levels ( peak and 1 half life later)
- Requires inputting patient-specific info into Vanco dosing calculator
- decreased risk of nephrotoxicity compared to trough monitoring
Vanco monitoring via trough levels
- traditional standard of care (maybe in unstable renal function)
- immediately prior to next dose once at steady state
- steady state typically achieved by the 4th or 5th dose
- may take longer to reach steady state in obese patients due to longer distribution times
Vanco drug -drug interactions
increased risk of kidney injury when combined with zosyn or aminoglycosides like gentamicin/tobramycin
Warfarin Basics/Category
Anticoagulant and Vitamin K ANTAGONIST
Drug, disease, and diet interactions
Warfarin MOA
Warfarin inhibits vitamin K epoxide reductase which prevents activation of vitamin K which inactivates new formation of factors II, VII, IX, and X, and protein C and S therefore reducing clotting ability. It can take 3-5 days to see full therapeutic effects of warfarin, so one can still clot in the first few days
Two enantiomers of warfarin
S-enantiomer is 2.7-3.8x greater potency than R-enantiomer
Warfarin dosage forms/absorption
Oral tablet and rapid, complete absorption
Warfarin Distribution
Vd=.14 L/kg so small
protein binding=99%
Warfarin Metabolism and half life
Hepatic via CYP2C9
lesser extent by CYP2C8, 2C18, 2C19, 1A2, 3A4
Half life: 40 hours (ranges from 20-60 hrs)
Warfarin Clotting Factors that are inactivated/Half lives
Factor VII=shortest at 5 hours Factor IX=25 hrs Factor X=40 hours Factor II=longest at 65 hours Protein C=6-8 hrs Protein S=42 hours
Warfarin Dosing
Adults Initial dose: 2-5mg daily
doses adjusted based on INR
INR
international normalized ratio
standardized method for comparing prothrombin time (PT) test results=time in seconds to form a fibrin clot
Warfarin prolongs PT because of inhibition of factor VII specifically
INR= PT (patient) / PT ( control)
INR of pt not on warfarin=1
INR goal for most indications= 2-3
Warfarin target range/monitoring
Check INR initially 2 days after therapy
Follow up every 1-2 days until therapeutic then every 2-4 weeks
Goal INR is higher (2.5-3.5) in mechanical mitral heart valves or mechanical aortic valve with additional risk factors
Warfarin CYP-mediated interactions
Inducers= decrease INR=increased risk of clotting
Inhibitors=increase INR=increased risk of bleeding
Warfarin/other anticoagulants interaction
therapeutic duplication causing increased risk of bleeding
Mechanistic interaction with warfarin
Antibiotics disrupt intestinal flora
fewer number of bacteria to produce vitamin K
warfarin concentration is increased
INR levels increase causing risk of bleeding
Food/disease interactions with warfarin
Vitamin K containing foods can decrease INR levels which increases risk of clots
Acutely ill patients tend to have unstable INRs
What are the two main concerns with warfarin?
bleeding and clotting
Warfarin Toxicities: less common side effects
purple toe-can be reversed by stopping warfarin
osteoporosis, rash, taste change, hepatitis, paresthesia
contraindicated in pregnancy!
