kenetics Flashcards
alterations in ADME main causes
Age
Genetic factors
End-organ damage
Drug interactions
types of variability
Pharmacokinetic
Pharmacodynamic
Idiosyncratic
idiosyncratic variabilty
Occur in a small minority of patients
Sometimes with low or normal doses
Poorly understood
Pharmacodynamic interaction
Interaction between 2 or more drugs that leads to
Accentuation/synergism
Attenuation/antagonism
Don’t directly involve absorption, distribution, metabolism, or excretion
Pharmacokinetic interaction
Interaction that changes the basic kinetic properties:
Absorption
Distribution
Metabolism
Elimination
Example: warfarin +sulfamethoxazole
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
tetracycline ABX (tetracycline, doxycycline, minocycline) + antacids
antacid impairs absorption of ABX → ↓ ABX efficacy
erythromycin / clarithromycin / metronidazole / ciprofloxacin / trimethaprim-sulfamethoxazole + warfarin
ABX inhibit the metabolism of warfarin → ↑ serum concentration of warfarin → ↑ risk of bleeding
NSAID + warfarin
Additive effect on ↓ platelet aggregation → additive risk for bleeding (especially GI bleeding)
ASA + warfarin
Additive effect on ↓ platelet aggregation → additive risk for bleeding (especially GI bleeding)
Tramadol + antidepressants (DDI highest risk for MAO-I)
↑ risk of serotonin syndrome (excess serotonin)
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)
pregnancy physio effects and result of these
Increased cardiac output
Increased renal blood flow: more filtrate/elimination
Decreased albumin: less drug protein bound
drugs and the placenta
lipophilic drug may cross the placental bloood barrier and are eliminated more slowly, increased half life
Diabetes and altered physio with effects
gastric stasis: decreased absorbtion
nephrotic syndrome : proteinuria=hypoalbuminenmia
MG pts, caution with what drugs
Aminoglycosides
Fluoroquinolones
Tetracyclines
Macrolides
Magnesium
Beta blockers
Procainamide
Neuromuscular blockers*
drug side effects
unrelated to clinical effect, predictable and dose related
toxic rxn
related to clinical effect and predictable= exaggeration of clinical effect
allergic rxn
less predictable, immunological base
not related to clinical effect
dental drugs upside
Primarily single-dose or short term Tx
Large margin of safety
Extensive history of use
Pharmacokinetics
What the body does to the drug
Pharmacodynamics
What the drug does to the body
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
Time course of drug concentration depends on what events?
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
Cp
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
SS kenetics: what is SS and calc?
Point at which the amount absorbed equals amount eliminated per unit time
how could Ka be calculated using Css
Css calc rearranged
For continuous infusion, ka units are?
dose/unit time
Calculating oral doses for Css
w
Calculate a loading dose: initial and repeating
Cl calc
Css calc (IV)
Css calc (PO)
loading dose calc
Vd calc
Ke and t1/2 calc
C
Cp0
Css
ke
ka
t
cl
Vd
D
F
