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Intro to Clinical Medicine > Pharmacology: Lecture 3 > Flashcards

Pharmacology: Lecture 3 Flashcards

1
Q

Bioavailability

A
  • amount of drug reaching systemic circulation

- 100% for IV drugs, usually less in other routes

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2
Q

Volume of Distribution

A

theoretical volume that represents an individual drugs propensity to either remain in the plasma or distribute to other tissue compartments

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3
Q

Charactristics of large Vd

A

small size, lipophilic, tissue protein bound; likely to leave the plasma and enter extravascular spaces and tissues

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4
Q

Characteristics of small Vd

A

large size, charged, plasma protein bound; propensity to remain in the plasma

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5
Q

Liner or First Order PK

A

serum concentration changes are proportional to drug dosing changes; constant PROPORTION of drug (% per hour) is eliminated

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6
Q

Nonlinear or zero order PK

A

constant amount of drug (mg per hour) is eliminated; more dose dependent

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7
Q

Michaelis-Menten kinetics

A
  • below a given serum concentration, elimination follows 1st order kinetics
  • above the given serum concentration, elimination follows zero order kinetics
  • ex) phenytoin
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8
Q

Protein-binding non-linear PK

A

-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

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9
Q

Therapeutic Window/Index

A
  • 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
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10
Q

Therapeutic Drug Monitoring is important for:

A
  • optimizing clinical response
  • avoiding toxicities
  • assessing patient adherence
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11
Q

Peak of AUC curve

A

Cmax=maximum drug concentration

measured 30-60 minutes after a dose for most drugs-allows time for tissue distribution

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12
Q

Trough of AUC curve

A
  • Cmin=minimum drug concentration
  • measured immediately (within 30 mins) prior to next dose
  • to determine of drug is high enough at lowest point
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13
Q

Phenytoin/Fosphenytoin Basics

A
  • anticonvulsant in CNS
  • treatment and prevention of seizures
  • follows Michaelis-menten kinetics
  • requires therapeutic drug monitoring
  • has many drug interactions
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14
Q

Phenytoin Mechanism of Action

A

blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and slowing its rate of recovery

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15
Q

Phenytoin Dosage Forms

A
  • IV injection: max of 50 mg/min

- oral: immediate release or extended release, chewable tablet, suspension

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16
Q

Fosphenytoin Dosage Forms

A
  • 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

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17
Q

Phenytoin Absorption/Bioavilability

A

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)

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18
Q

Phenytoin Distribution

A
  1. 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
  2. Highly protein bound: 90-95% in adults; assays measure total phenytoin(bound/unbound)
    - adjustments necessary in hypoalbuminemia (<3.5 g/dL)
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19
Q

Phenytoin Metabolism/Excretion

A
  1. Renal excretion=negligible, mostly metabolites
  2. Cleared primarily by capacity-limited (saturable) hepatic metabolism
  3. Demonstrates Michaelis-menten (nonlinear kinetics)-small increases in the daily dose, can produce large increases in plasma concentration resulting in drug induced toxicity
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20
Q

Phenytoin Dosing

A
  • weight based (initial dosing)

- loading doses given to reach target serum concentrations faster to stop the seizure

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21
Q

Fosphenytoin Dosing

A
  • based on phenytoin equivalents (PE)
  • 1 mg PE=1 mg phenytoin sodium
  • adjust maintenance dose based on serum concentration
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22
Q

Phenytoin Drug Monitoring

A
  • 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
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23
Q

Phenytoin/Fosphenytoin Toxicites and therapeutic levels

A

arrhythmia and hypotension can occur with rapid infusion
TL= 10-20 mg/L
Toxic above 30 mg/L
Lethal above 100 mg/L

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24
Q

Side effects of concentration -related Phenytoin

A

Nystagmus, ataxia and impaired motor function, CNS depression

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25
Q

Phenytoin effects on enzymes

A

strong inducer of CYP enzymes-2B6, 2C9, 2C19, 3A4

decreases levels of drugs that are metabolized by these enzymes

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26
Q

Phenytoin drug interactions

A

drug disease interactions: hepatic disease or renal failure

highly protein bound drug so in liver disease, less albumin made my liver

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27
Q

Gentamicin/Tobramycin Basics/Category

A
  • aminoglycoside antibiotics
  • variety of dosing formulations
  • therapeutic drug monitoring
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28
Q

Gentamicin/Tobramycin Mechanism of Action

A

binds irreversibly to the 30S ribosomal subunit, inhibiting bacterial protein synthesis

29
Q

Gentamicin Dosage Forms

A
  1. injection, IM or IV
  2. topical cream and ointment
  3. ophthalmic solution and ointment
30
Q

Tobramycin Dosage Forms

A
  1. Injections
  2. nebulizer solution for cystic fibrosis
  3. ophthalmic solution and ointment
31
Q

Gentamicin/Tobramycin Absorption

A

Oral: poorly absorbed, not used

IM/IV: 100% bioavailability

32
Q

Gentamicin/Tobramycin Distribution

A
  1. Highly hydrophilic, primarily extracellular fluid
  2. high concentration on renal cortex
  3. poor CNS penetration
  4. smaller Vd but larger Vd in neonates due to greater water concentration
  5. protein binding < 30%
33
Q

Gentamicin/Tobramycin Metabolism/excretion

A 
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
34
Q

Gentamicin/Tobramycin Toxicities

A

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

35
Q

Gentamicin/tobramycin dosing based on:

A

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

36
Q

What populations are not recommended to take gentamicin/tobramycin?

A

pregnancy, cystic fibrosis, gram positive bacteria-synergistic with other antibiotics, pediatric patients

37
Q

Bayesian calculations of gentamicin/tobramycin

A

computer model of normal population parameters

dosing based on clinical circumstances

38
Q

Nomogram dosing of gentamicin/tobramicin

A

dosing based on weight
adjustments based on chart
individualized calculations preferred because not all patients fit the parameters

39
Q

Gentamicin/tobramycin drug monitoring: peaks and troughs

A

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

40
Q

Vancomycin Basics/category

A

glycopeptide antibiotic
reserved for resistant infections, most commonly MRSA:gram positive only
Need antimicrobial stewardship and therapeutic drug monitoring

41
Q

Vancomycin MOA

A

inhibition of cell wall biosynthesis by inhibition of phospholipids and peptidoglycans

42
Q

Vanco dosage forms/absorption

A

injection for MRSA infections

oral capsules/solution: only for Cdiff because of poor tissue penetration and concentrates in lower GI tract

43
Q

Vanco Distribution

A

Vd: .4-1 L/kg
wide distribution via IV but not to the CNS
protein binding=50%

44
Q

Vanco metabolism/excretion

A

no metabolism!

excreted by urine with IV dose (80-90% as unchanged drug)
excreted by feces with oral dose

45
Q

Vanco dosing

A

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

46
Q

Vanco Nephrotoxicity

A

acute kidney injury
Risk factors: prolonged duration of therapy, high doses, advance age, sepsis/decreased renal perfusion, other nephrotoxic drugs like ahminoglycosides

47
Q

Vanco Ototoxicity

A

Rare, unless given with other ototoxic drugs or at excessive doses
-tinnitus, hearing loss, dizziness, vertigo

48
Q

Vanco Infusion Reactions

A

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

49
Q

Vanco Dosing-AUC dependent activity

A

Area under concentration time curve correlates with efficacy

  • overall serum concentration over a period of time
  • peak and trough drawn once hit steady state
50
Q

Vanco drug monitoring via AUC

A
  1. new standard of care
  2. 2 random levels ( peak and 1 half life later)
  3. Requires inputting patient-specific info into Vanco dosing calculator
  4. decreased risk of nephrotoxicity compared to trough monitoring
51
Q

Vanco monitoring via trough levels

A
  1. traditional standard of care (maybe in unstable renal function)
  2. immediately prior to next dose once at steady state
  3. steady state typically achieved by the 4th or 5th dose
  4. may take longer to reach steady state in obese patients due to longer distribution times
52
Q

Vanco drug -drug interactions

A

increased risk of kidney injury when combined with zosyn or aminoglycosides like gentamicin/tobramycin

53
Q

Warfarin Basics/Category

A

Anticoagulant and Vitamin K ANTAGONIST

Drug, disease, and diet interactions

54
Q

Warfarin MOA

A

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

55
Q

Two enantiomers of warfarin

A

S-enantiomer is 2.7-3.8x greater potency than R-enantiomer

56
Q

Warfarin dosage forms/absorption

A

Oral tablet and rapid, complete absorption

57
Q

Warfarin Distribution

A

Vd=.14 L/kg so small

protein binding=99%

58
Q

Warfarin Metabolism and half life

A

Hepatic via CYP2C9
lesser extent by CYP2C8, 2C18, 2C19, 1A2, 3A4
Half life: 40 hours (ranges from 20-60 hrs)

59
Q

Warfarin Clotting Factors that are inactivated/Half lives

A 
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
60
Q

Warfarin Dosing

A

Adults Initial dose: 2-5mg daily

doses adjusted based on INR

61
Q

INR

A

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

62
Q

Warfarin target range/monitoring

A

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

63
Q

Warfarin CYP-mediated interactions

A

Inducers= decrease INR=increased risk of clotting

Inhibitors=increase INR=increased risk of bleeding

64
Q

Warfarin/other anticoagulants interaction

A

therapeutic duplication causing increased risk of bleeding

65
Q

Mechanistic interaction with warfarin

A

Antibiotics disrupt intestinal flora
fewer number of bacteria to produce vitamin K
warfarin concentration is increased
INR levels increase causing risk of bleeding

66
Q

Food/disease interactions with warfarin

A

Vitamin K containing foods can decrease INR levels which increases risk of clots
Acutely ill patients tend to have unstable INRs

67
Q

What are the two main concerns with warfarin?

A

bleeding and clotting

68
Q

Warfarin Toxicities: less common side effects

A

purple toe-can be reversed by stopping warfarin
osteoporosis, rash, taste change, hepatitis, paresthesia

contraindicated in pregnancy!

Intro to Clinical Medicine (3 decks)

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