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PK/PD

Terms in this set (50)

pharmacokinetics
what the body does to the drug
absorption
distribution
metabolism
excretion
absorption
how the drug gets into the body, and then into cells:
enteral (GI): oral, sublingual, rectal
parentral (non-GI): inhalation, IV, SQ, IM, topical, transdermal

depends on gastric motility, surface area available, solubility of the drug, drug-drug interactions, pH, hepatic blood blow, drug particle size, drug formulation
absorption from GI tract into cells
depends on lipid solubility: to be absorbed to the blood stream from GI tract, must be lipid soluble

depends on gastric pH.

Then enters cell by direct diffusion across cell membrane, through aqueous pores, or transmembrane carrier proteins
distribution
how the drug travels to the site of action, the pattern by which drugs are distributed throughout various tissues after entering the circulatory system

Via transport proteins
via storage in adipose/other tissues
limitations of distribution due to blood brain barrier

only unbound drug will diffuse through capillary walls, produce pharmacological effect, and then be metabolized and excreted
elimination
how the drug is metabolized and or excreted
metabolism
how the drug is processed by the body, by the GI tract, liver, kidney.

The general goal is to make the drug more water soluble so that it can be excreted by the kidneys
prodrug
drug administered in inactive form that becomes activated after metabolism
active metabolites
metabolic proces cause metabolite to retain activity...processed into still active form
excretion
how the drug exits the body after metabolism generally either by the liver in bile or by the kidneys in urine

drugs can be excreted unchanged, without metabolism
linear pharmacokinetics
the general curve exhibited by absorption, distribution, metabolism, excretion by most drugs.

Sharp incline, peak, steady decline, long tail
area under the curve (AUC)
a measurement of total drug exposure, or concentration of drug in the blood, against time

a way to quantify how long the drug is active in the system
bioavailablity (F)
refers to the ability of a drug to reach the system circulation after an oral dosage; a measure of the potency of PO vs IV medication

AUC of a PO medication divided by AUC of IV medication. Fraction or decimal created. Close to 1=highly bioavailable, .2 less bioavailable

takes into account the first-pass effect
bioequivalence
how similar a generic drug is to its brand counterpart
clearance
how the drug is removed from the body

determined by:
blood flow to the eliminating organ (consider shock, renal occlusion, ect) &
ability of the organ to excrete the substance, extraction ratio (consider kidney injury or cirrhosis)

measured in volume per time. example: milliliters per minute

volume cleared is DIFFERENT from about cleared!
steady state
the amount of drug entering body = amount of drug leaving body

concentrations fluctuate between a fixed maximum (Cmax) and fixed minimum (Cmin)
clearance example
clearance rate x drug concentration = amount of drug excreted

example: 10ml/min x 10mg/min =100mg drug removed
CrCl
To estimate renal clearance, we calculate Creatinine clearance by the Cockcroft-Gault equation.

Limitations: Pediatric patients, Obese patients, lots of drug companies used this in dosing formula, must use same false "yardstick"
Volume of distribution (Vd)
A theoretical concept to understand where the drug goes once its absorbed, the drug is said to distribute in an imaginary volume. example: in fat tissues, plasma, other interstitial areas, difficult to actually calculate, therefore use an "average"

Different for each drug, considers solubility, lipophillic vs. hydrophilic

Different for each person, size, adipose tissue, body water content
half life (t 1/2)
time it takes for the drug to be fully "practically" eliminated

assumes constant rate of elimination (Ke)

about 3-6 half lives to be "fully" eliminated and to reach steady state!

no such thing as ideal half life, varies based on purpose of drug. Example: short-acting esmolol for unstable patient vs. sleeping pill to stay asleep
loading dose
used for medications with a long half life that take a long time to reach steady state
pediatric dosage alterations
absorption: different gastric pH.
distribution: different body water content.
metabolism/elimination: immature kidney and liver function.

Different administration, No pills due to inability to swallow
Dosing often weight-based. Do not exceed adult dose!
geriatric dosage alterations
absorption: different gastric pH and delayed gastric emptying
distribution: different body water and fat content
metabolism/elimination: aging/pathologic changes in kidney and liver function.

Have different responses to drug at same concentration.
Beers list: inappropriate drugs for elderly
concurrent disease state dosage alterations
renal dysfunction: calculate Creatinine clearance and adjust dose accordingly, also consider dialysis

heart failure: decreased blood flow to target organs

hepatic dysfunction: defects in drug metabolism

obesity: increase in adipose tissue, affects volume of distribution especially if drug is hydrophilic or lipid soluble
Single Nucleotide polymorphism (SNPs)
mutations in single nucleotides that cause altered gene expression, and therefore altered drug metabolism, particularly of CYP enzymes

can cause increase or decreased expression or induce or inhibit CYP metabolism, therefore increased or decreased drug metabolism. cause drug interactions

must consider prodrug, active metabolite...
Therapeutic
consider drug to be ____ if has intended effects with as few of side effects as possible

consider time it takes to reach steady state, 3-5 half-lives
consider adherence: are they taking it as directed?, right dose?, same time every day?
drug concentration considerations
peak: 30 to 60 minutes after administration
trough: up to 30 minutes before next administration

free/unbound level: greater affect on tissues, more expensive to measure, not always practical

total = bound + unbound, can be very different if drug is highly bound
Big picture/clinical consequence
when looking at drug effect, must monitor blood drug levels AND clinical consequences. Don't just treat a number, treat a patient!

are they taking it appropriately? factors influencing adherence: money, time, education, dietary factors

Consider long-term markers: A1C, total cholesterol
subjective measures: wound healing, how does the patient feel? appear?
objective measures: presence of fever, bacterial colony counts
Pharmaodynamics
what the drug does to the body: Biochemically, physiologically, and how does it do it...mechanism of action
drug receptors
any portion of a tissue or cell to which a drug can bind and initiate its effects. Medications alter the body's normal control systems...chemotransmitters, neurotransmitters, hormones, enzymes, receptors...and affect the physiological system to which it is attached
affinity
the strength of the binding between a drug an its receptors
efficacy
the ability of a drug to initiate a biological effect or stimulate its receptor in a way that produced a pharmacological response

the response possible from each specific agent

example: pain control with morphine vs. tylenol
potency
a measure of the ability of a set dose to produce its maximal pharmacological effect

the size of the dose needed

example: 180mg Allergra vs. 10mg Claritin
Claritin more potent
strength
related to the dose, the number of milligrams

example: tylenol regular vs. tylenol extra strength
agonist
have binding affinity for receptor that mimics or induces the same response produced by an endogenous substance: hormone, transmitter, enzyme

usually resist degradation and act longer than the natural substances they are designed to mimic. Example: albuterol longer activity than naturally occurring epinephrine for bronchodilation
antagonist
have binding affinity for receptor, therefore occupy receptor site, but do not turn on the receptor's natural effects.

block endogenous stimulation of receptor
competitive antagonist, reversible antagonist
a drug that competes with an agonist for binding to a receptor, the agonist response is abolished or diminished as long as ___ successfully competes for binding sites

example: naloxone vs. opioids
noncompetitive antagonist, irreversible antagonist
a drug that binds to receptors and stays bound

example: aspirin effect on platelets...for life of platelet
selectivity
how specific a drug's preference is for binding at a particular site

selective: only act on certain sites. Example: selective B1 blocker
nonselective: act on many sites. Example: nonselective aderenergic, affect A1, A2, B1, B2
General pharm rules of thumb:
General pharm rules of thumb:
intensity of response is generally proportional to the number of receptors occupied, up to a limit

a drug can produce numerous effects, side effects, if it binds to many receptors

receptors can exist on the cell membrane or inside of the cell on any of its structures
How drugs affect cells:
How drugs affect cells:
G-protein coupled receptor binding
activation of second messenger systems
blocking/activating ion channels
blocking/activating enzymes
blocking/activating transporters
blocking metabolic pathways (antimetabolites)
chirality, chiral forms
drugs that exist in mirror-image arrangements...enantiomers/isomers...one may exert desired effect, one may exert side effect
offsetting effects
antagonist with an agonist

example: warfarin and vitamin k.
Must find balance
additive effects
two drugs with the same purpose

example: blood pressure meds, diabetic meds
synergistic effects
two drugs with the same purpose that work better together than the sum of their individual effects

example: cancer treatment, one kills both good and bad cells, one saves good cells
placebo effect
effect is not attributable to the drug
EC50
concentration of a drug yielding half of the maximum effect
Effective Dose 50 (ED50)
median effective dose for 50% of population
Lethal Dose 50 (LD50)
median lethal dose (for 50% of population)
Toxic Dose 50 (TD50)
median toxic dose (for 50% of population)
therapeutic window/index
ratio of the LD50: ED50

median lethal dose to median effective dose

example:
narrow 2 to 1
wider 10 to 1
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