1 Pharmacokinetics Flashcards
Pharmacokinetics
- what the body does to the medication
- body wants gone, ASAP, sees meds as poison
Absorption
- movement of a medication to the blood stream/site of action
- dependent upon route of admin
ionization
dissociation
lipophilicity
- “fat loving”
- less ionized (not changing charge), move across lipid bilayers more easily
hydrophilicity
- “water loving”
- more ionized, more likely to stay in solution/blood
bioavailability
- % of med that reaches systemic circulation
- IV meds = 100%
- useful when converting between forms
Salt form
- med + salt = ionized form of drug –> increased solubility
- hydrochloride, sodium, sulfate
Considerations for oral administration
pH contents surface area blood flow GI motility gut flora
Sublingual/Buccal dosing
- drains directly into vena cava (ideally 100% bioavailability)
- must be highly lipid soluble & potent
- lipophillic, less ionized
- no first pass
First Pass Metabolism
- drug concentration greatly reduced prior to reaching systemic circulation
- small intestine –> hepatic circulation –> detox
Topical Administration
-must be highly lipophillic for systemic effect
Eye administration
careful of nasolacrimal duct –> systemic
Inhalation admin
- large surface area, high blood interaction
- avoid first pass
IV, SQ, IM
-same bioavailability, different rates of onset
Simple Diffusion: Rate Limits
- amount of capillaries
- solubility
- molecular size
Distribution
- drug moving in blood and through compartments
- ASSUME there is a homogenous mixture throughout all compartments since we only collect blood sample (dumb, but true)
Loading Dose
-dose required to reach desired concentration based on calculated volume of distribution
-will not decrease time to steady state
Loading Dose = (Volume of distribution)(desired concentration)
Multi-compartment Model
med admin –> compartment 1 (blood) where it can then travel to compartment 2 (major organ systems) OR compartment 3 (fatty tissue)
-moves back to compartment 1 for elimination
Protein Binding
- required for some meds to travel across membraines
- results in 2 forms of circulating med - bound and unbound
- competitive - can result in interactions
How does low albumin relate to protein binding meds?
- low albumin –> increased free drug and potential for toxicity
- ex.) burns, malnutrition, liver/kidney disease
- change dose
Tissue Binding
Fat: reservoir for lipid soluble
Bone (tetracyclines)
Heart (digoxin)
Membrane Permeability
-med must permeate all levels of membrane to permeate target organ
Blood Brain Barrier
-very protective, difficult to cross
Placental Transfer
- essentially everything mom takes, baby gets
- fetal plasma is acidic –> ion trapping
- P-glycoproteins
Qualities of molecules that have a high likelihood to absorb into fetal circulation
- low molecular weight
- high lipid solubility
- unbound
P-glycoproteins
- protective, limit transport into cells
- found all over body (BBB)
- requires ATP
Passive Diffusion
- no energy required
- no carrier required
- slides across
- rapid for lipophilic, small, nonionic molecules
Facilitated Diffusion
- no energy required
- NEEDS carrier
- bond to carrier by noncovalent mech.
- chemically similar drugs will compete
Aqueous Channels
- no energy required
- no carrier required
- small, hydorphilic drugs diffuse along concentration gradient by channels/pores
Active Transport
- NEEDS energy
- NEEDS carrier
- just like facilitated diffusion except ATP powers drug transport against concentration gradient
Metabolism
- breakdown of medication
- reduces size, increases hydrophilicity (increases ionized)
- can make drug more or less active
Metabolites
- products of metabolism
- may be toxic, active or inactive
Metabolism: Phase 1
- exposes functional group (often more ionized)
- goal is to increase ionization
- then, hydrolyzed or ester linked for rapid elimination
Oxidation
- type of phase 1 metabolism
- loss of electrons via split of O2 molecules
Reduction
- type of phase 1 metabolism
- gain electrons via electron transfer
Hydrolysis
- type of phase 1 metabolism
- addition of water to break bonds
Metabolism: Phase 2
- addition of functional group
- conjugation reactions- attachment of small hydrophilic endogenous molecule to form water-soluble compound
- results in larger molecular weight and increased hydrophilicty
Enzymes
- catalyst for bio-reactions
- largely produced in liver
Cytochrome P450
largest family of enzymes responsible to breakdown
Subfamilies of CYP450
family –> CYP1, CYP2, CYP3, etc
subfamily –>CYP3A, CYP2D
isoforms–> CYP3A4, CYP2D6
CYP3A4 & CYP3A5
-not the highest amount in the body, but metabolize the greatest amount
Inhibition of enzymes
- prevents enzyme from working properly
- cannot give inhibitor & substrate = increased substrate
Induction of enzyme
- enhances enzymes ability to work
- cannot admin inducer & substrate = less substrate d/t increased metabolism
ex.) administration of carbamezepine (CYP3A4 inducer) with midazolam (substrate) will create...
difficult induction or early awakening
ex.) administration of ketoconazole (CYP34 inhibitor) with midazolam (substrate) will create…
prolonged sedation
Factors Affecting Metabolism
Genetics
Disease- kindey & liver
Age
Elimination
- body riding of material
- unchanged, metabolite or mix of the two
- easier to eliminate polar, hydrophilic, ionic compounds
Renal Elimination
- ) Glomerular Filtration
- ) Active Tubular Secretion
- ) Passive Tubular Reabsorption
Glomerular Filtration
- renal elimination
- determined by renal blood flow, GFR, plasma protein binding
- only free drug is filtered
Active Tubular Secretion
- transfer of materials from peritubular capillary to renal tubular lumen
- opposite of reabsorption
- active & passive transport
- important for highly protein bound drugs
Passive Tubular Reabsorption
- lipophilic drugs
- modulated by urine pH & drug pKa
- attempting to remove water, sometimes get extra
First Order Kinetics
-constant fraction of drug is removed per unit of time
Zero Order Kinetics
-predictable, set constant rate
Elimination Rate
fraction or % of total amount of drug in the body removed per unit of time (hrs)
Half Life
-amount of time it will take until concentration in the body is half original amount
Steady State
rate in = rate out
- drug will be effective at max effect
- not affected by loading dose
- requires 5 half lives
Interpreting drug levels….
- never take just one value, acknowledge trends
- pt status!
Serum Concentations
measure trough –> efficacy
measure peaks –> toxicity
*supply staff with painfully precise directions on timing
Context Sensitive Half Life
- time it takes after a continuous infusion, at desired concentration, takes to reach half life after stopping medication
- specific to anesthesia
CSHT < half life at time of d/c…
med did not have enough time to fully distribute
Creatinine Clearance
female: 88-128 mL/min
male: 97-137 mL/min
* measure of kidneys ability to breakdown creatine (normal biproduct) and indicative of GFR
- use lower weight when calculating
Ideal Body Weight
Female:
IBW = 45.5 + (2.3 x inches > 5 ft)
Male:
IBW = 50 + (2.3 x inches > 5 ft)
*measured in kg
eGFR
estimated glomerular filtration rate
normal = >90 mL/min
GFR
normal = >90
-adjusted based on sex, and if pt is black
Modification of Diet in Renal Dysfunction Calculation
- more accurate calculation for excessive body weight and renal dysfunction
- female, black
- better for chronic kidney dysfunction, not acute
ABW
actual body weight
kg
Adjusted body weight
- for pts who are over 30% of IBW
- 0.4 (ABW - IBW) + IBW
Estimated Creatinine Clearance d/t Dialysis?
30 ml/min
Dialysis
- removes same shit kidneys do
- unbound, small, ionic
Elderly PK changes
- reduced absorption
- reduced first pass metabolism
- increased fat %, reduced free water
- reduced albumin –> increased alpha-1 glycoprotein
- reduced phase 1 metabolism - CYP450
- reduced kidney function
- *increased parent compound in circulation
Pediatric PK changes
- higher gastric pH
- higher water, less fat
- immature enzymes
- reduced protein binding
- reduced renal clearance
