Pharmacology Flashcards
define pharmacology
the branch of medicine concerned with the uses, effects, and modes of action of drugs
define pharmacokinetics
the actions of the body on drugs
define pharmacodynamics
the actions of drugs on the body
what is ADME?
- absorption
- distribution
- metabolism
- elimination
what is an agonist?
- a drug or a natural ligand that binds to and activates receptors
- sometimes selective and sometimes not
understand what is going on in this figure
what is an antagonist?
- bind to receptors but do not activate the receptor
- instead, it interferes with the agonist, typically causing a shift to the right
- *in order for the receptor to activate in the presence of antagonists, there must be more agonists than antagonists
what is an allosteric activator?
- aka positive allosteric modulator
- binds a receptor site separate from the agonist site
- potentiates effects
what is an allosteric inhibitor?
- aka negative allosteric modulator
- binds receptor site separate from agonist site
- noncompetitive
- actions are often reversible
describe what is going on in this figure
- Ra = active receptor, even in absence of drug (i.e., produce small observable effect referred to as constitutive activity)
- Ri = inactive receptor, even if paired with most drugs; the inactive form is usually favored
- D = drug
- in the absence of drugs, the two isoforms are in equilibrium, and Ri is favored
describe what is happening in this figure
- the full agonist has a much higher affinity for the Ra conformation, and mass action thus favors the formation of the Ra - D complex with a much larger observed effect
- the partial agonist produces lower response at full receptor occupancy than full agonists
- intermediate affinity for both Ri and Ra
- do not stabilize Ra - D as well as full agonists
- the inverse agonist has greater affinity for Ri, reduces constitutive activity, and may produce a contrasting physiologic result
- the conventional antagonist has equal affinity for Ra and Ri, and thus no change in constitutive activity
what is EC50?
the drug concentration where the effect is half maximal
what is Kd?
the drug concentration where the receptor occupancy is half maximal
what is Emax?
maximum binding of a drug, resulting in the maximum effect of the drug
what is IC50?
- the concentration of drug where 50% of effect is blocked
- think about when there is no antagonist present, the effect will be very high, but once you start adding antagonists, the effect will be reduced
what happens to the EC50 when a competitive antagonist is added to an agonist?
- the EC50 will shift right
what happens to the EC50 when a noncompetitive antagonist (or irreversible antagonist) is added to an agonist?
- the EC50 does not shift
what are the plateau and threshold doses?
- plateau - dose required for maximum effect
- threshold - smallest does that causes an effect
what are spare receptors?
- receptors are spare for a given pharmacologic response if it is possible to elicit a maximal biologic response at a concentration of agonist that does not result in occupancy of the full complement of available receptors
- At D and E, the spare receptors have been used up
understand this figure
- note that the full agonist is present at a single concentration
describe the general drug-receptor interactions of additive, synergistic, and antagonistic drugs
- additive: drug effect = sum of individual effects
- synergistic: drug effect is greater than the sum of individual effects
- antagonistic: drug effect is less than the sum of individual effects
describe a chemical antagonist
- does not involve a receptor
- example: protein that is positively charged at physiologic pH counteracting the effects of a drug that is negatively charged by ionic binding that makes the other drug unavailable to interact
describe a physiological antagonist
- involves endogenous regulatory pathways mediated by different receptors
what is efficacy?
- the number of receptors that must be activated to yield a maximum response
- a drug with high efficacy needs to stimulate only a small percentage of receptors, whereas a drug with lesser efficacy has to activate a larger proportion of receptors
what is potency?
- the relative concentrations of two or more drugs that produce the same drug effect
- this effect usually chosen is 50% of the maximal effect and the dose causing this effect is called the EC50
what two factors govern drug action?
affinity and intrinsic activity
what is the therapeutic index?
dose of the drug that causes toxicity divided by the dose of the drug that causes therapy
TI = TD50/ED50
what is the therapeutic range?
range in dose between toxicity and therapy
what is meant by a drug with a wide margin of safety
large difference between toxic dose and therapeutic dose
the amount of drug that gets to its target is inversely proprotional to what two things?
- distance from site
- amount of tissue the drug must pass through
what is parenteral administration?
administration by means other than intestine or GI tract
what is intravenous administration?
- administration directly into blood circulation
- type of parenteral administration
- very rapid, easier to titrate, avoids irritation, overdoses may have effects too immediate to reverse
what is intramuscular administration?
- administration into musculature
- type of parenteral administration
- prompt absorption, uniform absorption of solutions, large volumes possible, sometimes painful
what is subcutaneous administration?
- type of parenteral administration
- adsoprtion may be less rapid, smaller volumes, sometimes painful
what is enteral administration?
- by way of the intestine or GI tract
- buccal or sublingual
- oral - most common and convenient; onset of effects in 30 minutes
- rectal - solution (enema) or suppository; less first pass effect than oral
describe oral administration
- enteral administraiton
- most unpredictable
- absorption via duodenum
- first pass metabolism
the initial distribution of drug into tissues is determined by ___
rate of blood flow
the ___ of a drug at a particular site is related to affinity
concentration
___ and ___ can play roles in drug absorption
plasma binding proteins and gastric emptying time
what are 3 possible non-IV, non-enteric administrations of drugs?
- inhalation - very fast (within 5 min)
- topical - applied to a surface
- transdermal - onset of effect in 15 min
define drug
any substance that brings about a change in biologic function through its chemical actions
define medicine
a subset of drugs used for selective, therapeutic effects
define xenobiotic
chemicals not synthesized in the body
define side effect
any unintended effects
absorption is affected by what 4 factors?
- route of administration
- blood flow
- drug characteristics
- cell membrane characteristics (diffusion or active transport)
what are 5 drug characteristics that should be taken into consideration?
- solubility
- lipid soluble or water soluble
- size of molecule
- large or small
- formulation
- concentration
- acidity
- acidic drugs become non-ionized in the acidity of the stomach and diffuse across membranes
- basic drugs are not well absorbed in the stomach
only ___ drugs are soluble in lipid
non-ionized
define bioavailability
the fraction of unchanged drug reaching the systemic circulation following administration by any route
what are two things bioavailability is affected by?
- dissolving of drug in the GI tract
- destruction of drug by the liver
*if drug is administered intravenously, it has 100% bioavailability because all of the drug is reaching systemic circulation
understand this figure in relation to distribution and clearance
- important determinants for determining dose to be administered to patient
- volume of the beakers into which drug diffuses represents volume of distribution, and the size of the outflow drain represents clearance
describe volume of distribution
- the measure of the apparent space in the body available to contain a drug
- V = (amount of drug in body)/C
- can exceed any physical volume in the body because it is the volume apparently necessary to contain the amount of drug homogeneously at the concentration found in the blood, plasma, or water
what are 4 major variables that affect volume of distribution?
- binding to plasma proteins
- binding to tissue proteins
- absorption into adipose tissue
- drug lipophilicity/hydrophilicity and molecular weight
volume of distribution levels of 3L, 14L, and 42L tell us what about the physiological compartments where the drug is located?
- 3L = plasma
- 14L = extracellular space
- 42L = total body water
- As the numbers get bigger, it tells you that the drug is constricted to a smaller area in the body
drugs with very high volumes of distribution have much higher concentrations in ___ tissue than in the ___ compartment
- extra-vascular
- vascular
drugs that are completely retained wtihin the vascular compartment would have a minimum possible volume of distribution equal to the ____ in which they are distributed
blood component
drugs with a ___ volume of distribution are limited to certain areas within the body, whereas those with a ___ volume of distribution penetrate extensively into tissues throughout the body
- smaller
- higher
generally, dosing is ___ to the volume of distribution
proportional
how is clearance calculated?
- (rate of elimination)/(concentration of the drug)
- defined as the volume of fluid cleared of drug from the body per unit of time
___ describes the process of drug elimination from the body or from a single organ without identifying the individual processes involved
clearance
describe the excretion of drugs
- generally eliminated in urine
- some excretion via feces
- lungs excrete volatile compounds - nitrous oxide and volatile anesthetics
- salivary glands, sweat, and hair
describe glomerular filtration involved in renal elimination of drugs
all drugs are filtered through the glomerulus to enter the renal tubules. the amount of drug varies acording to the degree of plasma protein binding, and bound drugs are not subjected to filtration
describe tubular reabsorption involved in renal elimination of drugs
once drugs enter the renal tubules, drugs may be reabsorbed back into the blood stream through the renal tubule cells. Reabsorption favors the highly soluble agents; the converse is that highly polar compounds are not effectively reabsorbed and are effectively excreted from the renal tubules
active transport through renal tubular cells:
the rate of renal elimination depends on whether what occurs?
active transport into or out of the tubular fluid
name 2 drug transporters
- solute carrier transporters (SLC - ex. OCTs and OATs)
- ATP binding cassette (ABC) transporters (ex. p-glycoproteins)
what transports drug molecule from cells back into the intestinal lumen for excretion?
p-glycoprotein
describe half-life
- the time it takes to eliminate 50% of a drug
- t1/2 = 0.693 Vd/Cl
- 95% eliminated after 4.5 half lives, assuming 1st order kinetics
describe zero order kinetics
- a constant amount of drug is eliminated per unit time
- the process that takes place at a constant rate independent of drug concentration involved in process
describe first order kinetics
- the process that is directly proportional to the drug concentration involved in process
describe metabolism
- often inactivates drug, but sometimes activate (pro-drug)
- generally makes drugs more hydrophilic and thus more easily excreted
- usually makes substances less toxic, but sometimes more toxic
- phase II can precede phase I
what are microsomes?
- purified liver endoplasmic reticulum
- rough microsomes contain ribosomes
- smooth microsomes contain mixed function oxidases (monooxygenases)
- NADPH-cyp450-oxidoreductase
- Cyp450
describe phase 1 hepatic metabolism
- includes oxidation, reduction, and hydrolysis
- phase 1 metabolites that are hydrophilic are excreted, and all other metabolites go on to phase II metabolism
describe cytochrome p450
- heme-containing enzymes primarily found in liver hepatocytes and small intestine enterocytes
- key for drug metabolism (oxidation), biotransformation, and detoxification
- each enzyme is referred to as an isoform
- some individuals are deficient in CYP enzymes
what are 2 of the most common cytochrome p450 enzymes?
- CYP3A4 and CYP2D6
- CYP3A4 is most abundant in the human liver and intestine
define a substrate
a drug that is the target of a particular enzyme
define inducer
increases the activity of a particular p450 enzyme and thus increases metabolism and clearance of a drug
define inhibitor
inhibits the activity of a particular p450 enzyme and thus decreases metabolism and clearance of a drug
describe phase II hepatic metabolism
- includes glucuronidation and glutathione conjugation, thus making drug more hydrophilic
- glucuronic acid, etc. combines with newly incorporated functional group to increase polarity
what are 3 types of phase II conjugation reactions?
- glucuronidation
- acetylation
- glutathione conjugation
what are 4 factors affecting hepatic drug metabolism?
- microsomal enzyme inhibition (many drugs inhibit CYP450)
- microsomal enzyme induction
- plasma binding protein (drugs highly bound will not enter liver and thus have a longer half life)
- liver disease
describe affinity
a measure of the tightness that a drug binds to the receptor
describe intrinsic activity
a measure of the ability of a drug, once bound to the receptor, to generate an effect activating stimulus and producing a change in cellular activity
define pharmacogenomics
the study of genetic factors that underlie variation in drug response
define toxicology
the branch of science concerned with the nature, effects, and detection of poisons.
what is a pro-drug?
a drug that is activated by metabolism
