IV Agent Uptake And Distribution Flashcards
Pharmacokinetics constitutes of: 4
Absorption, distribution, metabolism, excretion
What body does to a drug
Pharmacodynamics: 3
Mechanism of effect, sensitivity, responsiveness
What a drug does to the body
Pharmacokinetics measured in: 4
Elimination half time, bioavailability, clearance, volume of distribution (vd)
Compartmental models do what
Divides body into compartments that represent theoretical spaces with calculated volumes
Central compartment traits and components
Best perfused, 75% CO, 10% of body, rapid uptake, drug introduced here, then 2nd compartment, then back to central for clearance. Kidney, liver, lungs, heart, brain.
Peripheral compartment
Large calculated volume (90%), 25% of cardiac output, extensive uptake of drug
Rate of transfer between compartments changes with what
Decreases with aging which leads to greater plasma conc in certain drugs (thiopental)
Distribution: what happens
Following systemic absorption of a drug the highly perfused tissues (heart, brain, kidneys, liver) receive a large amt of the drug
Distribution: what happens after central compartment
As plasma conc decreases, drug to less perfused sites (muscle and fat). W continued elim of drug the plasma level goes below that in tissues, drug leaves tissues to re-enter circulation
Tissues that accumulate drugs do what
Preferentially act as reservoir to maintain plasma concentration and prolong effect
What large or repeated doses do to distribution
They saturate inactive tissue negating distribution, prolong duration of action, reduction of effect depends on metabolism rather than redistribution
% of blood flow and % cardiac output in:
Vessel rich
Vessel poor
10%, 75%
20%, <1%
% blood flow and % cardiac output in muscle group and fat group
50%, 19%
20%, 6%
Lung uptake does what
Uptakes basic lipophilic drugs (lidocaine, fentanyl, demerol) and acts as reservoir for release of drug back into systemic circulation
Blood brain barrier prevents what
Ionized, water soluble drugs from crossing barrier into brain circulation
Blood brain barriers can be overcome w what
Large doses of drug or in head injury and hypoxemia
Effect site
Where drugs exert their biological effect, at its “biophase” (otherwise known as effect site)
Effect site includes what
What is ke0
Membranes, receptors, and enzymes where drug acts on body
Rate constant of drug elim from the effect site
What is vd
Volume of distribution, sum of all the volumes of compartments
Dose of IV drug/ plasma conc before elim
Vd is effected by what
Physiochemical characteristics of drug: lipid solubility (directly correlated), binding to plasma protein (inversely), molecular size (inversely)
Elimination half time
Time for plasma conc of drug to decline 50% during elim phase
E 1/2 t of a drug is related to what two things
It is independent of what
Directly to Vd, inversely to clearance
Dose of drug administered
Half life refers to 3, half time refers to 1
Plasma, fat, and muscle
Plasma
Elimination half life
Time necessary to elim 50% of drug from the body. Drug accum occurs if dosing intervals are less than this
Elim half time and half life aren’t equal when what
When the decrease in plasma concentration doesnt parallel its elimination from the body
Half time: 0
Fraction of initial amt left
% amt eliminated
1
0
Half time: 1
Fraction of initial amt left
% amt eliminated
1/2
50%
Half time: 2
Fraction of initial amt left
% amt eliminated
1/4
75%
Half time: 3
Fraction of initial amt left
% amt eliminated
1/8
87.5%
Half time: 4
Fraction of initial amt left
% amt eliminated
1/16
93.8%
Half time: 5
Fraction of initial amt left
% amt eliminated
1/32
96.9%
Half time: 6
Fraction of initial amt left
% amt eliminated
1/64
98.4%
Distribution phase
First half of curve, from central compartment to peripheral
Elimination phase
Second half of curve, from central compartment to liver and kidneys for elimination
Context sensitive half time
Time req for blood or plasma concentrations of a drug to decrease by 50% after discontinuation of drug admin. Usually refers to d/c an infusion
Absorption
Depends on what
Drugs solubility, regardless of route of administration
Oral admin
Pros and cons
Pro: Convenient and economic
Con: Emesis, destruction by enzymes or acidic gastric fluid, irregular absorption w food or other drugs
First pass effect
Drugs absorbed from GI sys enter portal venous blood and pass thru liver before entering the systemic circ for delivery to tissue receptors. Here they are extensively extracted and metabolized
Sublingual and transmucosal routes
Rapid onset, bypasses liver and prevents first pass effect
Transdermal route
What it provides, where absorbed
Sustained plasma conc of drug. Absorp in sweat ducts and hair follicles that serve as diffusion shunts
Transdermal route
Rate limiting step
Factors for permeability of drug
What can occur
- diffusion across stratum corners of epidermis
- thickness and blood flow of skin
- contact dermatitis
Rectal mode.
Proximal
Distal
Overall
P- trans to portal sys via superior hemorrhoidal veins, 1st pass effect
D- bypasses portal sys
Unpredictable responses that follow rectal admin of meds
IV route
Achieves therapeutic plasma levels precisely and rapidly
Ionization
Most drugs are what
Non ionized drugs are what
- Weak acids or bases in ionized and non-ionized forms
- usually lipid soluble and can diffuse across lipid cell membranes ex BBB, renal, tubules, GI epithelium, hepatocytes
Ionization
-the fraction of drug is pharmacologically ___ and undergoes what
Active- undergoes reabsorption across renal tubules, is abs from gi tract, and is metabolized by liver
Ionized fraction of drug is what
Poorly lipid soluble, cant penetrate lipid cell membranes, and is repelled from portions of the cell w similar changes. They are excreted by kidneys unchanged
Degree of ionization depends on what
Dissociation constant (pk) and ph of the surrounding fluid
Changes in ph can result in what
Large degree of ionization. Acidic drugs are highly ionized at alkaline ph and vice a versa
Alkalotic pt giving a weak acid=
Will have less drug effect because more ionization
Acidotic pt giving weak acid drug
More nonionized drug, more effect
Ion trapping
Ex
Concentration difference of total drug can develop on 2 sides of a membrane that separates fluids w diff pHs. Ex placenta
Protein binding: ex., effect
Albumin acids, a1 acid glycoprotein bases, lipoproteins
Only free or unbound fraction of drug is readily able to cross cell membranes
Vd inversely proportional to
Unbound drug in plasma is metabolized and excreted ___ ___
Protein binding
More readily
Drugs that are highly protein bound (4 ex) are effected by what
Warfarin, propranolol, phenytoin, diazepam
Alterations in protein binding
Clearance
Volume of plasma cleared of drug by metabolism and excretion
First order kinetics
Almost all drugs administered in therapeutic dose range are cleared at a rate proportional to the amount of drug present in plasma
Zero order kinetics, ex 3
Drugs that exceed metabolic or excretory capacity of the body to clear drugs by first order kinetics even at therapeutic doses
Constant amt of drug metabolized per unit of time
Ex) asa, dilantin, etoh
Hepatic clearance, other term for it
Hepatic blood flow and hepatic extraction ratio. If extraction high (>0.7) the clearance of the drug depends on hepatic blood flow
Perfusion dependent elimination
Extraction ratio dep on blood flow
Total range
0.7-1
0-1
What = low extraction ratio
If extraction ratio low what will increase clearance
0.3 or less
A decrease in protein binding or increase in enzyme activity
What will have minimal change in clearance if extraction ratio is low
Changes in hepatic blood flow
What is capacity dependent elim
If extraction ratio low: protein binding or inc enzyme activity increases clearance. Changes in hepatic blood flow has min effect
Renal clearance
- most imp organ for what
- what is excreted better
- what isn’t excreted
- elim of unchanged drugs or their metabolites
- water soluble compounds > lipid soluble drugs
- highly lipid soluble drugs, little or no unchanged drug excreted in urine
Metabolism
Bio transformation to convert pharmacologically active, lipid soluble drugs into water soluble and often inactive drugs
Increased water solubility reduces what and enhances what
Reduces Vd
Enhances renal excretion
Metabolism not always synonymous with what
Inactivation or detoxification. Some metabolites of certain drugs are active
Which order kinetics most common
What it is basically
First order
Constant fraction of available drug is metabolized in a given time period
Zero order kinetics basically and ex
Plasma conc of drug exceeds capacity of metabolizing enzymes. Metab of a constant amt of drug per unit time
Etoh, dilantin, asa
4 pathways of metabolism
Oxidation
Reduction
Hydrolysis
Conjugation
Phase I
Oxidation, reduction, hydrolysis
Phase II
Parent or metabolite drug reacts w an endogenous substrate to form water soluble conjugates
Sites of uptake
Plasma, kidneys, lungs, gi tract, liver (hepatic microsomes enzymes are responsible for metabolism of most drugs)
Hepatic microsomes enzymes:
- located where
- cytochrome p450
- hepatic smooth ER
- large number of diff protein enzymes involved in oxidation and reduction and conjugation of large # of drugs
Enzyme induction
Drugs and chemicals stimulate activity of these enzymes
Nonmicrosomal enzymes
- metabolize by what
- present where
Mainly by conjugation and hydrolysis. Some by oxidation-reduction
Liver mostly, plasma, gi tract
Nonmicrosomal enzymes
- responsible for hydrolysis of what
- dont undergo what
- determined by
- drugs that contain ester bonds (succhs, esmolol)
- enzyme induction
- genetically
Pharmacodynamics
How drugs exert fx. Most common mechanism= interaction w specific macromolecules in lipid bi-layer of cell membranes called receptors
State of receptor activation theory
Non activated receptors are converted to active by the drug
Receptor occupancy theory
The more receptors occupied by drug the more effect
Nonreceptor drug action
Def and Ex
Mechanisms other than receptor drug interactions. Chelating drugs form bonds w metallic ions that are found in body. Ex antacids
Agonist drugs
Mimic cell signaling molecules by activating the same receptor sites and causing similar effects
Antagonist drugs
Bind to receptors and change configuration of agonist site or bind to it, preventing effect from cell signaling molecules
Structure activity
Affinity of a drug for a specific macro molecular component of the cell and its intrinsic activity are r/t chemical structure
Enantomerism produced by
Sp3 hybridized carbon atoms. Free rotation about chiral carbon not possible, 2 stable forms of molecule exist
Isomer differences w drugs
Interaction w biological receptors can differ, even to pt of no binding. Some may cause entirely diff side effects. Some may have little to no effect
Ephedrine isomers
2 chiral centers and 4 isomers
Potencies of ephedrine
D ephedrine 36
L epedrine 11
D pseudophedrine 1
L pseudophedrine 7
Efficacy
The ability of a drug to produce desired therapeutic effect
Potency
The relationship b/w therapeutic effect of a drug and dose necessary to achieve that effect
ED 50
Median effective dose. The wider the range, the more effective the drug
LD 50
Median lethal dose. Halfway pt where rats stop breathing
Ratio of LD50 to ED50
Indicates therapeutic index of a drug for that effect. Suggests how selective drug is in producing its desired effects. Estimates clinical therapeutic index
Hyperreactive
Ppl in whom lose dose of drug produces expected pharmacological effect
Hypersensitivity
Refers to allergies
Additive effect
Second drug acting w first produces sum of both
Synergistic effect
2 drugs interact to form greater effect than sum. Like fentanyl and versed
