Pharmacokinetics and Pharmcodynamics Flashcards
The drug’s effect on the body is called?
pharmacodynamics
pharmacodynamics includes:
therapeutic and toxic effects of drugs -sensitivity and responsiveness of receptors (varies patient to patient) -mechanism of action effective dose
a substance that binds to a specific receptor and triggers a response in the cell; mimics the action of an endogenous ligand that binds to the same receptor
agonist
(drug will probably have an increased effect of the same actions on receptors, ex: Sch has same effect as Ach but not metabolized as quickly so lasts longer)
effect not to the full degree
partial agonist
causes maximal activation of all receptors
full agonist
a drug that has affinity for the receptor, but no efficacy
antagonist
Describe the action of an antagonist
-does not activate the receptor to produce a physiologic action
-combination with receptor may block a response, so it does have a physiologic consequence
-typically has higher affinity for receptor than the agonist
(Narcan sometime higher affinity for opioid receptors and may even knock opioid off of receptor)
what is the difference between competitive and noncompetitive antagonists?
- competitive antagonists may be overwhelmed if enough agonist is built up and forces the antagonist off the receptor
- noncompetitive antagonists bind to the receptor and does not come off; a new receptor must be generated allowing a longer effect since it takes time to synthesize a new receptor
what are the two types of antagonism?
- physiologic antagonism: two agonist drugs bind to different receptors, causing opposing responses
- ex: alpha1 agonist causes vasoconstriction, beta2 agonist causes vasodilation
- chemical antagonism: no receptor activity involved; one drug binds with 2nd drug to inactivate it
- ex: protamine binds with heparin eliminating anticoagulation effect but with no heparin, protamine is an anticoagulant
possibly have both agonist and antagonist effects; activates a receptor, but cannot produce a maximum response (lower efficacy); may partially block effect of full agonists
partial agonist or agonist-antagonist
when are agonist-antagonist drugs commonly used
- in labor and delivery since you don’t want the maximum opioid effect crossing the placenta
ex: Nubain and Stadol act as agonists for some opioid receptors and antagonize others; antagonize MU-II opioid receptors to block respiratory depression but may have some effect on some MU-I receptors affecting analgesic effect of opioids
component of a cell that interacts with a drug and initiates the chain of events leading to the drug’s effect
receptor
describe receptors
- can be extracellular and can go through from outside to inside
- responsible for selectivity of drug action
- mediate actions of both agonist and antagonists
- affinity of receptor for a drug and the number of receptors may limit the maximal effect of a drug
the degree of drug receptor interaction for a given drug; the attraction between drug and receptor
affinity
differentiates between different agonists that activate the same receptor, can all produce the same maximal response, but a differing concentrations
potency
a drug’s ability to produce the desired response expected by stimulation of a given receptor; the maximum effect that can be achieved with the drug
“intrinsic activity”
efficacy
explain the spare receptor concept.
maximal or nearly maximal response can often be produced by activation of only a fraction of the receptors present; relationship between the number of receptors stimulated and the response is usually nonlinear (an increased number of receptors stimulated does not mean an increase in response)
how does the spare receptor concept effect muscle receptors and antagonists?
It takes 70% of receptors blocked before reduction in muscle response is seen; showing that only 30% of the receptors must be activated by Ach to produce a maximal muscle response
- it takes 90% of muscle receptors blocked by muscle relaxants for surgical relaxation
- once decreased to only 70% blocked, considered fully recovered
desensitization with agonists; repeated use causes body to decrease the number of receptors and effect is diminished
down-regulation
- tolerance
ex: beta agonist bronchodilators (albuterol)- tolerance develops from repeated use and an increased dose is required for the same effect
chronic exposure to antagonists cause receptor number and sensitivity to increase
up-regulation
ex: beta blockers cause up regulation of receptors
* reason you don’t stop beta blockers before surgery; increase in receptors will lead to a major reaction
What factors affect pharmacologic response?
age, sex, weight, body surface area, basal metabolic rate, pathologic state, genetic profile
the actions of the body on the drug
pharmacokinetics
what are the stages of pharmacokinetics
- absorption
- distribution
- metabolism
- elimination of drugs and metabolites
what is the first pass effect of absorption?
the liver extracts and or metabolizes the drug first before it goes to the site of action causing a lesser amount of drug getting to the site
- reason for difference in effect of po and IV doses
- po and rectal routes go through first pass effect
- sublingual is absorbed directly into the superior vena cava
what effects does ionized vs. nonionized have on distribution?
-ionized charged, water soluble not lipid soluble; do not cross the BBB *smaller distribution -nonionized no charge; lipid soluble *larger volume of distribution *cross lipid bilayers like BBB, GI, hepatocytes, renal tubular and placenta ex: muscle relaxants are water soluble, do not cross the BBB, so must give a sedative that can cross the BBB
describe the Two Compartment Model.
A) 1st compartment: central compartment; plasma and vessel rich group (VRG); drug quickly hits high level in plasma and diffuses to VRG then other areas (redistribution phase)
2nd compartment: peripheral group (muscle group, lipid group, vessel poor group)
B) metabolism/clearance: begins to diffuse to other areas and must be metabolized and excreted (elimination phase)
what is an example of the significance of the two compartment model?
- propofol is administered IV and goes straight into plasma into systemic circulation
- distributes to site of effect in CNS
- when significant concentration builds up in CNS, plasma concentration has dropped
- diffusion causes redistribution back into plasma
- need to give anesthetic gas to keep sleep since propofol will start being metabolized and excreted. As excreted, drug stored in muscle lipid compartments begin to come back into plasma for excretion
phase of two compartment model when the plasma concentration of the drug has declined to the point that the drug moves out of the vessel rich central group and is then taken into the peripheral group
redistribution (alpha) phase
phase of two compartment model involves metabolism and excretion
elimination (beta) phase
describe the vessel rich groups.
brain, heart, liver, kidney, endocrine
*receive 75% of CO but make up only 10% of body mass
describe the lean muscle groups.
muscle and skin
*receives 19% of CO but make up 50% of body mass
describe the fat group.
receives 6% of CO, make up 20% of body mass
describe the vessel poor group.
bone, ligament, cartilage
*receives 0% of CO, make up 20% of body mass
what’s the function of metabolism?
take lipid soluble materials and turn into water soluble to allow the kidneys to metabolize and excrete
what are the four basic pathways of metabolism?
- oxidation
- reduction
- hydrolysis
- conjugation
what are the two phases of metabolism?
- Phase I: oxidation, reduction, and hydrolysis
- increases the drug’s polarity, preparing it for phase II
- Phase II: conjugation
- drug (or metabolites if already gone through phase I) are linked to a highly ionized molecule making it more water soluble so it can be excreted
what are sites of metabolism?
- liver
- plasma
- lungs
- kidneys
- GI tract
describe liver metabolism.
- hepatic microsomal enzymes
- most metabolism occurs here
describe plasma metabolism.
- plasmaesterases are enzymes found in the plasma
- Hoffmann elimination- organ independent metabolism affected by pH and temperature
- pt in renal or liver failure can use the drugs metabolized here since it doesn’t affect any organs
describe metabolism in the lungs.
some drugs are taken out of the body partly by the lungs including opioids, Inderal, and propanolol
describe kidney metabolism.
eliminates unchanged drug
describe GI tract metabolism.
NO2 metabolized by normal flora
what are cytochrome P-450 enzymes?
- phase I metabolism enzyme
- one of the main metabolizing enzymes in the liver (hepatic microsomal enzymes)
- uses oxidation
what effects can drugs have on cytochrome P-450 enzymes?
- some drugs induce enzymes, stimulating activity of cytochrome P-450 enzyme; significantly shorten duration of drugs due to increased metabolism
ex: benzos, opioids, seizure meds (*Dilantin) - some drugs inhibit enzymes, slowing metabolism and causing drugs to have a prolonged effect
ex: Tagamet
what are non cytochrome P-450 enzymes of phase I metabolism?
- plasma esterases and plasma cholinesterases
- nonmicrosomal enzymes
- metabolism by conjugation, hydrolysis, and some oxidation and reduction
- present largely in the liver but also in GI tract and plasma (in plasma metabolism started before reaches site of action)
- not inducible (cant rev up or inhibit)
- activity is determined genetically
- if deficiencies occur, can cause longer effects of these drugs allowing more of drug to get to the site of effect
What are phase II enzymes?
-Glucoronosyltransferases
*propofol, morphine, versed
*infants unable to produce so usually avoid these drugs
-Glutathione-S-transferases
-N-acetyl-transferases
*some patients are either “fast” or “slow acetylators”
*protonix related drugs have complications with “fast
acetylators”
“slow acetylators” also have side effects
-sulfotransferases
describe elimination or clearance
- major sites: liver and kidneys
- renal clearance: excretion of unchanged drug or its metabolites
- in the liver, drug is metabolized or excreted unchanged in the bile, or both
- important in determining the appropriate drug to administer to patients
the time for the drug in the body to decrease by 50%; affected by volume of distribution and changes in clearance
Elimination 1/2 life
the time for the plasma concentration of the drug to decrease to 50% during the elimination phase
Elimination 1/2 time
time for the plasma drug concentration to decrease by 50% after discontinuing a continuous infusion of a specific duration
context-sensitive half-time
- considers distribution, metabolism, and duration of infusion
- typically, the longer the duration of the infusion, the longer the context-sensitive half-time
- propofol and remifentanil special cases; both still metabolized quickly
the half time of equilibrium between drug concentration in the blood and the drug effect; accounts for delay between IV injection into the plasma and the delivery of the drug to its site of action
effect-site equilibrium time
*important when considering redosing intervals
how do you calculate the volume of distribution?
dose of drug given divided by the resulting plasma concentration prior to elimination
what affects volume of distribution?
- lipid solubility
- binding to plasma proteins
- molecular size
how does protein binding affect volume of distribution?
- plasma proteins
- albumin-acidic drugs bind
- alpha1 acid glycoprotein-basic drugs bind
- only unbound drug can cross the cell membranes
- increased binding leaves less effect
- vd is inversely proportional to protein binding
- elderly or alcoholics have less albumin, meaning less protein binding and greater drug effect
combined effect of two drugs equal the expected sum of their individual actions
1+1=2
additive
combined effect of two drugs is greater than the expected sum of their individual effects
1+1=3
synergistic
action of one drug opposes the action of another
1+1=0
antagonistic
the enhancement of the action of one drug by a second drug that has no detectable action of its own
1+0=3
potentiation
very rapid development of tolerance, frequently with acute drug administration
tachyphylaxis
abnormal or excessively sensitive, either psychologically or in physical response
hypersensitive
showing a greater than normal response to stimuli
hyperreactive
showing less than normal response to stimuli
hyporeactive
an increasing concentration of drug is required to produce a given response
tolerance
