test 1 Flashcards
agonist
a drug that activates a receptor by binding to that receptor
agonist bind
ionic, hydrogen, and van der waals interactions (making them reversible)…rarely covalently (irreversible)
When is the effect of the drug produced
when the receptor is bound to the agonist ligand
receptors are either
bound or unbound (binary)
The most drug effect occurs when
every receptor is bound
Antagonist
a drug that binds to the receptor without activating the receptor
antagonist bind
either ionic, hydrogen, and van der waals interactions, reversible
antagonist block
the action of the agonist by getting in the way, preventing the agonist from binding to the receptor and producing the drug effect
competitive antagonism
is present when increasing concentrations of the antagonist progressively inhibit the response to the agonist, shifts the agonist dose response curve to the right. (the more antagonist you give the more it’ll knock out the agonist, but it is irreversible)
noncompetitive antagonism
present when, after administration of an antagonist, even high concentrations of agonist can not completely overcome the antagonism. causes both a rightward shift of the dose-response relationship as well as a decreased maximum efficacy of the concentration versus response relationship
partial agonist
A drug that binds to a receptor (usually at the agonist site)_ where it activates the receptor but not as a full agonist, even at supramaximal doses
agonist-antagonist
partial agonist may have antagonist activity. Ex: when butorphanol is a modestly efficacious analgesic. given with fenanyl, it will partly reverse the fentanyl analgesia
inverse agonist
bind at the same as the agonist (and compete with it) but they produce the opposite effect of the agonist
receptors have many different conformations (shape or structure)
inactive (80%) and active (20%)
receptor state for an full agonist
100% active. conformation of the active state to be strongly favored
receptor state for a partial agonst
50% active, 50% inactive. not as effective in stabilizing the receptor in the active state
receptor state for antagonist
does not favor either state, it just gets in the way of the agonist binding
receptor state for inverse agonist
100% inactive, favors the inactive state, reversing the baseline receptor activity
receptor upregulating
(putting receptors on the cell surface) increasing the number of receptors, leading to an exaggerated response. Ex: lower motor neuron injury cause increase in the number of nicotinic acetycholine receptors in the neuromuscular junction, leading to an exaggerated response to succinylcholine.
receptor downregulating
(endocytosis of receptors, receptors going into cell). Ex: a patient with pheochromocytoma has an excess of circulating catecholamines, and there is a decrease in the number of B-adrenergic receptors on the cell membrane in an attempt to maintain homeostasis.
tachyphylaxis
in asthma pts, decrease response to same dose of B-agonist, looks like tolerance, because of the decreased in B-adrenergic receptors
location of most receptors for anesthetic drugs
in the cell membrane lipid bilayer
What interacts with membrane bound receptors
opiods, benzos, beta blockers, IV sedative hypnotics, muscle relaxants, catacholamines (most are antagonist)
drugs that interact with intracellular proteins
caffeine, insulin, steroids, theophylline, milrinone
circulating proteins
another target for drugs, Ex: coagulation cascade
some drugs dont bind to receptors
stomach acid like sodium citrate work by changing the gastric pH
cation
ion with a positive charge
anion
ion with a negative charge
chelating drugs
work by binding to divalent cation
iodine kills bacteria by
osmotic pressure (intracellular desiccation, best to let iodine dry)
IV sodium bicarb
changes plasma pH
define catalyze
start or accelerate
the proteins response to binding
of the drug is responsible for the drug effect
pharmacokinetics
study of absorption, distribution, metabolism, and excretion/elimination of injected and inhaled drugs and their metabolites, what the body does to the drug
pharmacodynamics
study of the bodys response to the drug, what the drug does to the body
PK determines
the concentration of a drug in the plasma or at the site of drug effect
PK variability
results from genetic modification in metabolism, interactions with other drugs, or diseases of the liver, kidneys, or other organs of metabolism
IV administered drugs
mix with body tissues and are immediately diluted from the concentrated injectate in the syringe to the more dilute concentration measured in the plasma or tissue
concentration =
amount (mass)/ volume
central volume
is the volume that IV injected drug initially mixes into
central compartment
the initial distribution (within 1 min) after bolus injection is considered mixing with the central compartment= composed of those elements of the body that dilute the drug within the first min
elements of the body that dilute within the first min
venous blood volume of the arm, the volume of the great vessels, the heart, the lungs, and the upper aorta, first passage through the lungs
drugs that may be taken up in the first passage through the lungs
drugs that are highly fat soluble
many of the volumes are fixed
except the lungs, likes fat soluble. when the lungs take up more drug it makes the apartment volume of the central compartment increase (bc lower concentration)
minutes later the drug will mix with
the entire blood volume, may take a long time for fully mix with all tissues bc some tissues have low perfusion
polar drugs are drawn to
water, where the polar water molecule find a low energy state by associating with the charged aspects of the molecule
nonpolar drugs are drawn (higher affinity) to
fat, where van der waals provide numerous weak binding sites
VD for highly fat soluble drugs
the molecule will have a large volume distribution bc it will be taken up by fat, diluting the concentration in the plasma
many anesthetic drugs are
highly fat soluble and poorly water soluble
imaginable VD
imaginable L in the plasma that is required to dilute the initial dose med to achieve the measured concentration
vessel rich group
brain, heart, kidneys, liver: bolus injection the drug initially goes to the tissues that receive the bulk arterial blood flow
for highly lipid soluble drugs
the capacity of the fat to hold the drug greatly exceeds the capacity of the highly perfused tissues, this offsets the drugs effect following a bolus
the fat is invisible at first
bc the blood supply is so low, the fat gradually absorbs more drug, removing it away from the highly perfused tissues
muscles in distribution
they have a blood flow that is intermediate between highly perfused tissues and fat, intermediate solubility for lipophilic drugs
most drugs are bound to
plasma proteins (mostly albumin), alpha1-acid glycoprotein, and lipoproteins
most acidic drugs bind to
albumin
most basic drugs bind to
alpha1-glycoproteins
protein binding effects the
distribution of drugs (b/c free/unbound drugs can cross cell membranes), and the apparent potency of drugs (b/c free drugs determine the concentration)
drugs that are hydrophobic
more likely to bind to proteins in the plasma and to lipids in the fat
binding of drugs to albumin
is nonselective and substances alike may compete for the same binding site Ex: sulfonamides can displace unconjugates bilirubin from binding sites on albumin causing bilirubin encephalopathy
what can decrease plasma protein concentration
age, hepatic disease, renal failure, and pregnancy
alterations in protein bindings sites are important for
highly protein bound drugs (<90%)
free fraction changes
as an inverse proportion with a change in protein concentration (increase protein less drug, decrease protein more drug)
an increase in free fraction of a drug
may increase the pharmacologic effects of the drug
the free drug concentration may change little d/t protein bc
the free drug concentration in the plasma and tissues represents the shared binding with all binding sites, not just plasma
metabolism
converts active, lipid-soluble drugs into water-soluble and usually inactive metabolites
prodrug
inactive parent compound that is metabolized to an active drug. Ex: codeine into morphine, morphine-6-glucuronide (metabolite of morphine)
4 basic pathways of metabolism
oxidation, reduction, hydrolysis, conjugation
phase 1 metabolism includes
oxidation, reduction, and hydrolysis, which increases the drugs polarity prior to phase two
phase 2 reactions
are conjugation reactions that covalently link the drug or metabolite with a highly polar molecule (carbohydrate or amino acid) that renders the conjugate more water soluble for subsequent excretion
what are mostly responsible for the metabolism of most drugs
hepatic microsomal enzymes
other areas of metabolism
plasma (Hofmann elimination, ester hydrolysis), lungs, kidneys, GI tract, placenta (tissue esterase)
where are hepatic microsomal enzymes located
hepatic smooth endoplasmic reticulum. also present in the kidneys, GI, and adrenal cortex
microsomes
vesicle-like artifacts reformed from pieces of the ER bilayer sliced apart as cells are cut up
microsomal enzymes
enzymes that are concentrated in these vesicle like artifacts
enzymes responsible for phase 1 metabolism
CYP 450 enzymes, non-CYP 450 enzymes, and flavin-containing monooxygenase enzymes
CYP 450 enzymes
large family of membrane-bound proteins containing a heme cofactor that catalyzes the metabolism of compounds, mostly hepatic microsomal enzymes, some mitochondrial P450
CYP absorption peak
450nm when heme is combined with carbon monoxide
CYP involves
oxidation and reduction steps. The most common reaction catalyzed by CPY is the monooxygenase reaction
monooxygenase reaction
insertion of one atom of oxygen into an organic substrate while the other oxygen atom is reduced to water
CYP family
share more than 40% sequence homology and designated by a number “CYP2”
CYP subfamily
share more than 55% homology and designated by a letter “CYP2A”
individual CPY enzymes
identified by a third number “CYP2A6”
most abundantly expressed CYP
CYP3A4, most for anesthetic drugs
CYP3A4 metabolizes
opioids (alfentanil, sufentanil, fentanyl), benzo, local anesthetics (lidocaine, ropivacaine), immunosuppressants (cyclosporine), and antihistamines (terfenadine)
induction
increased expression of the enzymes. Ex: phenobarbital induces microsomal enzymes and thus can render drug less effective through increased metabolism
inhibition
drugs directly inhibit enzymes, increasing the exposure to their substrates. Ex: grapefruit juice inhibits CYP3A4, increasing the concentration of anesthetic drugs
oxidation reaction
require an electron donor in the form of reduced nicotinaminde adenine dinucleotide and molecular oxygen for their activity
steps in oxidation
the oxygen molecule is split, with one atom of oxygen oxidizing each molecule of drug and the other oxygen atom being incorporated into a molecule of water
examples of oxidative metabolism of drugs
hydroxylation, deamination, desulfuration, dealkylation, and dehalogenation
hydroxylation
a chemical process that introduces a hydroxyl group (−OH) into an organic compound
deamination
Deamination is the removal of an amino group from a molecule
desulfuration
removal of sulfur from a molecule
dealkylation
Alkylation is a chemical reaction that entails transfer of an alkyl group. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene
dehalogenation
chemical reactions that involve the cleavage of carbon-halogen bonds, oxidation of a carbon-hydrogen bond to form an intermediate metabolite that is unstable and spontaneously loses halogen atom
demethylation
chemical process resulting in the removal of a methyl group from a molecule. Ex: morphine to normorphine (example of dealkylation)
dehalogenation of volatile anesthetics
leads to a release of bromine, chloride, and fluoride
aliphatic oxidation
oxidation of a side chain. Ex: oxidation of the side chain of thiopental converts the highly lipid-soluble drug to the more water-soluble carboxylic acid derivative
thiopental desuluration
transforms into pentobarbital
epoxide intermediates
capable of forming a covalent bond with macromolecules and can be responsible for drug-inducted organ toxicity, in oxidation
CYP reduction
transfer electrons directly to a substrate such as halothane rather than to oxygen, electron gain happens only when insufficient amounts of oxygen are present to compete for electrons
conjugation with glucuronic acid
glucuronic acid is synthesized from glucose and added to lipid-soluble drug to render them more water-soluble=glucuronide conjugates that are excreted into bile and urine
reduced microsomal enzymes in neonates
interferes with conjugation leading to neonatal hyperbilirubinemia and the risk of bilirubin encephalopathy. decreased enzyme activity leads to increase drug effect and toxicity
hydrolysis
do not involve the CYP enzymes, happens at the ester bond, occurs outside of the liver, adding water to a molecule to break it down and form smaller molecules
phase 2 enzymes
glucuronosyltransferases, glutathione-S-transferases, N-acetyl-transferase, sulfotransferases
uridine diphoshate glucuronosyltransferase
cataylzes the covalent addition of glucuronic acid to a variety of endo/exogenous compounds making them more water-soluble
glucuronidation
propofol, morphine (morphine 3 glucuronide, morphine 6 glucuronide), midazaolam (alpha 1 hydroxymidazolam)
Glutathione s transferase enzyme
defensive system for dextoificatin and protection against oxidative stress
N acetyltranferase
common phase 2 reaction for metabolism for hertercyclic aromatic amines (serotonin), and arylamines (isoniazid)
the rate of metabolism
is proportional to drug concentration, clearance of the drug is constant
metabolic capacity
metabolism is no longer proportional to drug concentration b/c the metabolic capacity of the organ has been exceeded…450s are al busy
Q
liver blood flow
rate of drug metabolism (R)
Q(Cin)-Q(Cout)
R
difference between drug concentration flowing into the liver and the drug concentration flowing out of the liver X the rate of liver blood flow
metabolism can be saturated
liver does not have an infinite amount of metabolic capacity
equation used for metabolic saturation
Response= C/C50+C
C=drug concentration
R=fraction of maximal metabolic rate (0-1)
Response 0
no metabolism
Response 1
maximal metabolism rate
When C=0
the response is 0
if C is between 0-50
response=C/C50
C50
it is the concentration associated with 50% response
C=C50
response = 0.5
C= greater than 50
response = 1
high concentrations the response saturates at
1
most common view of rate of metabolism
function of the concentration flowing out of the liver Coutlow
ER equation
Cinflow-Coutflow/Cinflow
Hepatic clearance
QXER
Drugs with an ER nearly 1
propofol, a change in liver blood flow produces a nearly proportional change in clearance
Drugs with lower ER
alfentanil, clearance is nearly independent of the rate of liver blood flow
capacity-limited clearance
ER less than 1, clearance is limited by the capacity of the liver to take up and metabolize the drug, changes in the liver blood flow will have little influence on clearance
flow-limited capacity
nearly 100% of the drug is extracted by the liver, the liver has tremendous metabolic capacity for the drug. flow of drug to the liver is what limits the metabolic rate.
renal excretion
involves GFR, active tubular secretion, passive tubular reabsorption
the amount of drug that enters the renal tubular lumen depends on
the fraction of drug bound to protein and the GFR
renal reabsorption is most prominent for
lipid-soluble drugs that can easily cross cell membranes of renal tubular epithelial cells to enter pericapillary fluid. Ex: thiopental
products less lipid-soluble
limit renal tubule reabsorption and facilitate excretion in the urine
rate of reabsorption from renal tubules is influenced by
pH and urine flow in the renal tubules
passive reabsorption of weak bases and acids is altered by
urine pH
weak acids
excreted more rapidly in alkaline urine, alkalinization of the urine results in more ionized drug that cannot easily cross renal tubular epithelilal cells, less passive reabsorption
renal blood flow and creatinine clearance is inversely correlated with
age
creatinine clearance is closely related to
GFR b/c creatinine is water-soluble and not resorbed in the tubules
cockcroft and gault creatinine clearance (ml/min) equation
Men: (140-age)Xwightkg/72Xserum creatinine
zero order kinetics
rate of change is constant, decreased by a fixed amount with each half-life
first-order kinetics
which means that each half-life decreases the concentration by 50%
undergo ester hydrolysis in the plasma and tissues.
Succinylcholine, remifentanil, esmolol, and the ester local anesthetics
most drugs are
weak acids or weak bases, that are present in ionized and nonionized forms
nonionized molecules
usually lipid-soluble and can diffuse across cell membranes including the BBB, renal tubular epithelium, GI epithelium, placenta, and hepatocytes.
nonionized form of the drug
that is pharmacologically active, undergoes reabsorption across the renal tubules, is absorbed in the GI tract, and susceptable to hepatic metabolism
ionized molecules
poorly lipid-soluble and cannot penetrate lipid cell membranes easily
ionized drugs
ionization impairs absorption of drugs from the GI tract, limits access to drug-metabolizing enzymes in the hepatocytes, and facilitates excretion of unchanged drugs, reabsorption is unlikely.
pKa
the drugs disassociation constant, where is 50/50
degree of ionization is a
function of its pKa and its pH of the surrounding fluid
when pK and pH are identical
50% ionized, 50% unionized
acidic drugs like barbiturates
tend to be highly ionized at an alkaline pH, usually supplied in a basic solution to make them more soluble in water
basic drugs like opioids and local anesthetics
tend to be highly ionized in acidic pH, usually supplied in a acidic solution to make them more soluble in water
ionized
charged, impermeable to the cell membrane
bases are more ionized below
acids are more ionized above
systemic administration of a weak. base (opioid) can result in
accumulation of ionized drug (ion trapping) in the acid environment of the stomach, also basic drugs cross the placenta from mother to fetus bc the fetal pH is lower than the mother pH
ion trapping from mother to fetus
the lipid-soluble nonionized crosses the placenta and is converted to a poorly lipid-soluble ionized fraction in the more acidic environment of the fetus. the ionized fraction in the fetus can not easily cross the placenta to the maternal circulation
pregnancy is a/w
increased creatinine clearance and a higher dose requirment
systemic absorption of the drug depends on the drugs
solubility
disadvantages or oral route
emesis caused by irritation of the GI mucosa by the drug, destruction of the drug by digestive enzymes or acidic gastric fluid, irregularities in absorption in the presence of food or other drugs
oral drug onset of drug effect
determined by the rate and extent of absorption from the GI tract
oral mostly absorbed in
small intestine d/t large surface area, small intestine is alkaline, enhances the absorption of weak bases (opioids) but even weak acids are mostly absorbed here bc of the large surface area
pH in the GI tract that favor the drug in the nonionized form
lipid soluble, favor systemic absorption
first pass hepatic metabolism
drugs absorbed from the GI tract enter the portal venous blood and thus pass through the liver before entering the systemic circulation for delivery to tissue receptors, this is the reason for large differences in the pharmacologic effect of oral and OV doses (lidocaine/propranolol)
which route bypasses the liver, preventing first pass metabolist
sublingual or buccal , these drugs flow into the superior vena cava, nasal also bypasses
transdermal route
provides sustained therapeutic plasma concentrations of the drug and decreases the likelihood of loss of therapeutic efficacy d/t peaks and valleys a/w intermittent drug injections
transdermal high pt compliance
not as complex as continuous infusion techniques and low incidence of s/e
drugs that favor transdermal absorption
combined lipid and water solubility, molecular weight of <1,000, pH 5-9 in a saturated aqueous solution, absence of histamine releasing effects, daily dosing requirements <10mg
scopolamine and nitroglycerin
sustained plasma concentrations by the transdermal absorption results in tolerance and loss of therapeutic effect
skin layer that deals with rate-limiting
diffusion across the stratum corneum, hair follicles and sweat ducts is where initial absorption occurs
what effects skin absorption
skin permeability, thickness, scopolamine only works behind the ear (postauricular zone) its the thin and high temp
day limit to transdermal patches
7 days b/c the stratum corneum sloughs and regenerates about 7days, also bc of contact dermatitis
drugs administered in the promixmal rectum
are absorbed into the superior hemorrhodial veins and transported via the portal venous system to the liver, undergoing the first pass metabilizism
drugs administered more distally
absorbed directly into the systemic circulation bypassing the liver
systemic clearnace
the clearance for drugs permantely removed from the central compartment, clears drug from the entire system
intercompartmental clearnace
clearances between the central compartment and the peripheral compartment
concentration equation
Co=Xo/V
Xo is the amount of drug at time zero
V is the volume of that compartmenth
how to rearrange the concentration equation for target concentration
Dose=CtXV
