Uptake and Distribution of IV agents Flashcards
Pharmacokinetic
what the body does to a drug
-absorption -distribution -metabolism -excretion
Volume of Distrubution
the volume in which the drug has effect before elimination
the drug moving from the central compartment to the peripheral
VD= drug given/ serum [ ]
Central compartment
highly perfused tissue
kidney, liver, lungs, heart, brain
receives 75% CO
represents only 10% of body mass
Peripheral compartment, what happens with age?
large calculated volume
extensive uptake of drug
?less well-perfused ex muscle, fat?
rate of transfer btwn compartments decrease with age—leading to greater plasma concentration in certain drugs
Distribution, how it happens
- drug has systemic absorption then
- drug goes to central compartment and the plasma concentration decrease
- drug enters peripheral then
- with continued elimination the drug plasma concentration decreased below the tissue concentration and the drug re-enters the plasma from the tissue
large dose or repeated doses
saturate inactive tissue preventing redistribution
- prolonging duration of action
- reduction of effect now depends on metabolism rather than redistribution
lung uptake
basic lipophilic drugs
acts as a reservoir to release drug back into the systemic circulation
blood brain barrier
prevents ionized, water soluble drugs from crossing
-can be overcome by large dose, head injury, and hypoxemia
Vd is influenced by: 3 physiochemical characteristics
- Lipid solubility- increase lipiophylic increase vd
- Binding to plasma protein– more binding less vd
- Molecular size–bigger less vd
Elimination Half-Time and its relationships
time needed for plasma [ ] of drug to decreased by 50%
- directly proportional to vd
- inversely to clearance
- independent pf drug dose
Elimination Half-Life, fully eliminated when? Drug accumulation when?
time needed to eliminate 50% of drug from body
- regarded as fully eliminated when approximately 98%? has been eliminated or 6 half lifes
- drug accumulation occurs if dosing intervals are less than 4-5 half lifes
absorption oral
most convenient and economic
disadvantages:
- many conditions can change GI environment therefore lower bioavailability
- destruction by enzymes or acidic gastric fluid
- first pass effect
first pass effect
hepatic effect
- drugs absorbed in GI tract enter the portal venous blood and pass through the liver first
- liver metabolized drug before enter systemic circulation
sublingual absorption
rapid onset
bypass liver prevents first pass effect
transdermal
provided sustained therapeutic plasma [ ]
- water soluble: penetrate hair follicles and sweat ducts
- lipid soluble: once in system transfers skin
- rate-limiting step–diffusing across stratum corneum of epidermis
- should apply to thing epidermis with sufficient blood supply
rectal absorption
proximal rectum–transported to portal system via superior hemorrhoidal veins—first pass
-distal rectum-bypass portal system, more predictable circulatory level
IV absorption
achieve therapeutic plasma levels precisely and rapidly
Ionization
- most drugs are salts of either weak acids or weak bases
- present in both ionized (charged, water soluble) and Nonionized (uncharged, lipophilic)
Nonionized
Lipophilic, can diffused across cell membrane
ex: BBB, renal tubules, GI epithelium, hepatocytes, placenta
* pharm active
- absorbed from GI tract, metabolized by liver, reabsorbed across renal tubes
Ionized
poorly lipid soluble
- cannot penetrate lipid cell membrane
- is repelled by portions of the cell with similar charge
- excreted by kidneys unchanged
Degree of Ionization
the higher the degree of ionization the less access the drug has to diffuse across tissue
- depends of the pKa of the drug and in pH of the surrounding fluid
- when pH=pKa 50% of the drug is ionized
More Nonionized
weak base pH>pKa
weak acid pH<pKa
More ionized
weak base pHpKa
Ion trapping
[ ] difference of a drug/degree of ionization of drug can develop on either side of a membrane that separates fluids with different pHs
ex: placenta, fetus more Acidic, basic drug can cross membrane buy once on fetus side becomes ionized can cross back over, accumulates in fetus
Protein binding: what proteins, VD, drugs effected
most drugs bind to plasma proteins in various degrees
Proteins: albumin
-a, acid glycoprotein-bases lipoproteins
**only free or unbound fraction of drug is easily and readily available to cross cell membrane and is metabolized, excreted more readily too.
-protein bound-too lg to cross membranes–trapped in circulation
**VD is inversely proportional to protein binding
**high protein bound: Warfarin, Propranolol, Phenytoin, Diazepam
Clearance
Volume of plasma cleared of drug by metabolism and excretion per unit of time
First-order kinetics
drugs administer in the THERAPUTIC dose ranges are cleared at a rate PROPORTIONAL to the amount to drug in the plasma (1/2 life thing)
-constant FRACTION of drug eliminated per unit of time
Zero-order kinetics
drugs that exceed the metabolic or excretory capacity of the body to clear drugs
- dose doesn’t make a difference
- CONSTANT amount of drug is cleared per unit of time
- ex: ASA, ETOH, Dilantin
Hepatic clearance: ratio, 2 different types
ratio btwn hepatic blood Flow and hepatic Extraction
- if ratio is high >0.7 clearance depends on blood flow **perfusion dependent elimination
- if ratio is low <0.3 clearance depends on protein binding and enzyme activity and blood flow will have minimal effects (decreased pb or increase e to increased clearance) ** Capacity- dependent (enzyme-dependent)
Renal Clearance
most important organ for the elimination of unchanged drugs or their metabolites
- Water soluble compounds are excreted more efficiently
- highly lipid soluble drugs are reabsorbed such that little or no unchanged drug is excreted in urine
Metabolism: does what where, why
biotransformation to convert pharm Active LIPID soluble drugs to WATER soluble often Inactive drugs
- liver is the main site with enzymes to break down drugs
- some drugs have active metabolites
- *metabolism is not always synonymous with Inactivation -some metabolites of certain drugs are active.
Increased water solubility in a drug therefore….
Decreased VD and Increased Renal excretion
Pathways of metabolism 4
- Oxidation 2. Reduction 3. Hydrolysis 4. Conjugation
Phase 1 reactions
Oxidation: oxygen is introduced into molecule, lose electron
Reduction: gain of electron
(Oil Rig)
Hydrolysis: addition of water to an ester or amide to break the bond and form 2 smaller molecule, do not include CP450 and is often outside the liver
**phase 1 reactions: increased the drugs polarity and prepares it for phase 2
Phase 2 reactions
Conjugation: covalently links the drug or metabolite with a highly polar molecule rendering it Water soluble
- synthetic reaction
sites: plasma, kidneys, lungs, GI tract, liver - *hepatic microsomal enzymes are responsible for metabolism of most drugs
hepatic microsomal enzymes
located in hepatic smooth ER
- Cytochrome P-450
- large number of different protein enzymes involved in Oxidation and Reduction and Conjugation of lg # of drugs
Enzyme induction
drugs and chemicals stimulates activity of these enzymes
*burn through drugs quickly
Nonmicrosomal enzyme
metabolize drugs mostly by conjugation and hydrolysis
- to lesser degree-also redox
- mostly in plasma, GI also in: liver
- responsible for hydrolysis of drugs that contain ester bonds (succs, esmolol)
pharmacodynamics
what a drug does to the body
- mechanism of effect
- sensitivity
- responsiveness
- most common mechanism–interaction with Receptors
Concentration of Receptors
up-reguate or down-regulate
in response to specific stimuli
non receptor drug action
-not at common
-mechanisms of other that receptor-drug interaction
ex Chelating drugs form bonds with metallic cations that may be found in body
-antacids neutralize gastric acids by a direct action
Agonist drug
mimic cell signaling, activating, causing similar effects
Antagonist drug
bind to receptor, prevent agonist from binding, prevent effect
Structure-activity
affinity of a drug for a specific receptor and its intrinsic activity are intimately related to CHEMICAL STRUCTURE!
-subtle change such as stereochemistry can result in a major change in pharmacological properties
Stereochemistry
enantiomers: stereoisomers that are non-superimposable mirror images of each other
- chiral centers-carbon with 4 different asymmetric substituents–1 chiral carbon has 2 stereoisomer
* *interaction with biological recptors can differ greatly btwn 2 enantiomer to the point of no binder
* *some isomers may cause side effects or entirely different effects than its mirror image.
Efficacy
ability of a drug to produce desired therapeutic effects
potency
relationship btwn therapeutic effect of drug and dose necessary to achieve effect
ED50 vs LD50
therapeutic index
ed-mean effective dose
ld-mean lethal dose
-ratio btwn the 2 indicates the therapeutic index of the drug for that effect.
-suggest how selective the drug is in producing its desired effects
-estimates the clinical therapeutic index **shorter is WORSE
Hyper-reactive
low dose produces its expected pharm effect
hypersensitivity
allergic
Additive effect
2nd drug acting with 1st produce effect = to sum of both 1+1=2
Synergetic effect
2nd drug acting with 1st produce effect Greater than their sum 1+1=3
