kenetics Flashcards by Caleb Houghton

alterations in ADME main causes

Age
Genetic factors
End-organ damage
Drug interactions

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types of variability

Pharmacokinetic
Pharmacodynamic
Idiosyncratic

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idiosyncratic variabilty

Occur in a small minority of patients
Sometimes with low or normal doses
Poorly understood

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Pharmacodynamic interaction

Interaction between 2 or more drugs that leads to

Accentuation/synergism
Attenuation/antagonism

Don’t directly involve absorption, distribution, metabolism, or excretion

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Pharmacokinetic interaction

Interaction that changes the basic kinetic properties:
Absorption
Distribution
Metabolism
Elimination

Example: warfarin +sulfamethoxazole

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RED FLAG DRUGS for possible interactions

∙Warfarin
∙Digoxin
∙TCAs (amitriptyline, doxepin, nortriptyline, desipramine)
∙Phenytoin
∙Carbamazepine
∙Lithium
∙Methotrexate / cyclosporine / tacrolimus
∙HIV medications – protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir)
∙Rifampin

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tetracycline ABX (tetracycline, doxycycline, minocycline) + antacids

antacid impairs absorption of ABX → ↓ ABX efficacy

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erythromycin / clarithromycin / metronidazole / ciprofloxacin / trimethaprim-sulfamethoxazole + warfarin

ABX inhibit the metabolism of warfarin → ↑ serum concentration of warfarin → ↑ risk of bleeding

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NSAID + warfarin

Additive effect on ↓ platelet aggregation → additive risk for bleeding (especially GI bleeding)

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ASA + warfarin

Additive effect on ↓ platelet aggregation → additive risk for bleeding (especially GI bleeding)

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Tramadol + antidepressants (DDI highest risk for MAO-I)

↑ risk of serotonin syndrome (excess serotonin)

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Protease inhibitors (indinavir, nelfinavir, ritonavir, saquinavir) + BZD

protease inhibitors are CYP450 3A4 inhibitors → ↓ metabolism of benzodiazepine → ↑ benzodiazepine concentrations → ↑ risk of benzodiazepine side effects (↑ sedation depth and duration)

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pregnancy physio effects and result of these

Increased cardiac output
Increased renal blood flow: more filtrate/elimination
Decreased albumin: less drug protein bound

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drugs and the placenta

lipophilic drug may cross the placental bloood barrier and are eliminated more slowly, increased half life

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Diabetes and altered physio with effects

gastric stasis: decreased absorbtion
nephrotic syndrome : proteinuria=hypoalbuminenmia

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MG pts, caution with what drugs

Aminoglycosides
Fluoroquinolones
Tetracyclines
Macrolides
Magnesium
Beta blockers
Procainamide
Neuromuscular blockers*

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drug side effects

unrelated to clinical effect, predictable and dose related

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toxic rxn

related to clinical effect and predictable= exaggeration of clinical effect

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allergic rxn

less predictable, immunological base
not related to clinical effect

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dental drugs upside

Primarily single-dose or short term Tx
Large margin of safety
Extensive history of use

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Pharmacokinetics

What the body does to the drug

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Pharmacodynamics

What the drug does to the body

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How we use kinetics

Important in drug development and clinical testing, needed to determine optimal dose

Important in the clinical setting:
Toxicology
Therapeutic monitoring (clinical effect, labs)
Drug interactions
Dose adjustments
Effect of illness, organ dysfunction

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Time course of drug concentration depends on what events?

Study These Flashcards

Time course of drug concentration depends on ADME

Kinetics focuses on? Can be used to calculate?

focuses on concentrations of drug in plasma Can use kinetics to calculate precise doses to achieve a precise concentration

Plasma concentration = Cp Goal is to get Cp within a therapeutic window in order to elicit appropriate response without causing toxicity

MTC vs MEC

Minimum toxic concentration: minimal con for toxic effect Minimum effective concentration: minimal con for any effect (non-therapeutic)

therapeutic window

desired concentration between MTC and MEC

Important parameters of kenetics and what they determine

Clearance – determines the maintenance dose-rate Volume of distribution (Vd) – determines the loading dose Half-life – determines the time to steady state and dosing interval

Parameters for a drug are determined by using what administration and why?

Parameters for a drug are determined by using IV injection or infusion since IV = 100% bioavailability Cl, Vd, and t½ are then derived from a time/concentration curve

clearance Volume of? Index of? Determines the? way to correlate?

Volume of plasma cleared of drug per unit time Index of how well a drug is removed irreversibly from the circulation Determines the dose-rate (dose/unit time) required to maintain a Cp Creatinine clearance = way to correlate

Zero order Kinetics

* Rate of absorption /elimination doesn’t depend on the drug concentration * Rate limited process * Fixed number of enzymes, carrier, or active transport proteins; saturation occurs * Half life (t ½ ) decreases over time

substances with zero order kenetics

Phenytoin Warfarin Heparin Ethanol Aspirin (high dose) Theophylline

First order kinetics

* The decline in Cp is not constant with time, but varies with concentration * The half life (t ½ ) stays the same * * Concentration decreases by 50% per each t ½ * Majority of drugs follow first order elimination

expression for rate of absorbtion/elimination

clearence calculation index of? determines? to maintain Cpss

Index of how well a drug is removed irreversibly from the circulation Determines the dose-rate required to maintain a Cp To maintain steady state (Cpss), , administration rate must equal rate of elimination

Steady state / plateau effect with first order kinetics

When repeated doses of a drug are given in short enough intervals and elimination is 1st order, the Cp will eventually reach steady state During IV infusion, drug level increases exponentially in a way equivalent to the drug’s t1/2: 1 half life = 50% of final concentration 2 half lives = 75% of final concentration 3 half lives = 87.5% of final concentration, etc.

steady state diagram IV and injection

how many t1/2 pass for SS?

usually achieved after 5

what could increase the amount of dosages/time to reach Cpss?

any alterations to drug t1/2 such as renal dx

Volume of distribution (vd)

Volume into which a drug appears to be distributed with a concentration equal to that of plasma Tells you where the drug distributes To reach a target Cp, you have to “fill up the tank”, i.e., Vd

Vd equation

important notes of Vd IV F? body volume and Vd? small Vd?

Remember: bioavailability (F) for IV drugs equals 1 (100%) Note: Vd can far exceed the actual body volume, e.g., digoxin Vd = 500L Drugs with small Vd tend to be polar and water soluble

t1/2 provides index of:

Time course of drug elimination Time course of drug accumulation Choice of drug interval

how many t1/2 to reach Cpss or elimination

Takes approximately 5 half-lives for a drug to either reach steady state (Cpss) or be eliminated from the body

t1/2 calc