Pharm Exam 1 Review

Mechanism of Action (MOA)

Mechanism of Action (MOA)

A term describing the effects of drugs that interact with other chemicals in the body.

pharmacodynamics

what the drug does to the body

pharmacokinetics

what the body does to the drug; absorb, distribute, metabolize, excrete

pharmacogenetics

the study of how genetic variation affects an individual's response to drugs

receptor

protein on the cell that interacts with drug

ligand

molecule that binds to a receptor

hormone

natural substance that is produced in the body and influences the way the body grows/develops

xenobiotic

substance that is foreign to the body

toxin

poison of biologic origin

toxicant

poisons of non-biologic orogin

agonist

binds to a receptor and activates it

affinity

how tightly a drug binds to a receptor

potency

amount of drug necessary to elicit a response

efficacy

drug's ability to produce the maximal desired response

full agonist

produces a full response at full receptor occupancy

partial agonist

binds to a receptor but partially activates the receptor; if you bind 100% of the receptors, you get 50% effect

antagonist

blocks the action of agonist

competitive antagonist

binds to receptors and prevents binding by other molecules; direct competition (beta-blocker)

non-competitive antagonist

Binds to the receptor with such strong affinity that the receptor is no longer available to bind with an agonist regardless of the concentration

allosteric antagonism

binds to allosteric site and prevents agonist action

chemical antagonism

binds directly to agonist

functional antagonism

indirectly inhibits physiologic actions of the agonist

reversible antagonist

disassociate from their receptor

irreversible antagonists

permanent, irreversible chemical bond with their receptors

high specificity

one type of receptor; very specific tissue/cell sites (abx)

low specificity

multiple receptors, more adverse effects (chemo)

stereochemistry

drugs can have left-handed and right-handed version

down regulation

protective response that the body produces in response to a drug so the body reduces the number of receptors; responsiveness is diminished

what would you have to do to overcome down regulation?

increase dose to retain effectiveness

up-regulation

body increases number of receptors; seen with antagonists

bioavailability

amount of a drug that reaches it site of action through a given route

which route of drug has the highest bioavailability?

IV; 100%

first pass effect

The initial metabolism in the liver of a drug absorbed from the gastrointestinal tract before the drug reaches systemic circulation through the bloodstream.

prodrug

An inactive drug dosage form that is converted to an active metabolite by various biochemical reactions once it is metabolized by the liver

Volume of distribution (Vd)

how extensively a drug distributes into the tissue as opposed to blood

IV administration

advantages: fast onset, 100% bioavailability,
disadvantages: can't take back what you give, precipitation can cause crystals, extravasation

extravasation

drug leakage from a vessel into the tissue

intraosseous administration

into the bone; used in children in emergent situations as an IV alternative

subcutaneous administration (SQ)

advantages: good for slow-release implants and self-administration, high bioavailability, slower onset
disadvantages: painful, could cause necrosis

intramuscular administration (IM)

advantages: less invasive, high bioavailability, fast onset
disadvantages: painful, limit volume (3ml), requires blood flow, obese and emaciated pts may have altered absorption, exercise/heat could affect absorption

intrathecal (IT)

BBB limit/slow absorption of drugs; injections into subarachnoid space

sublingual (SL)

advantages: bypasses liver, good for pts who cannot swallow
disadvantages: few drugs can be used SL

oral (PO) administration

advantages: most common, safest, economical
disadvantages: patient compliance, swallowing, first pass effect, food/drug interactions (ex milk)

rectal (PR) administration

advantages: alternative to PO, 50% bypass liver
disadvantages: irregular and incomplete absorption, patient compliance

inhalation (INH) administration

advantages: drug directly to the area is needed, fast
disadvantages: incorrect use

transdermal (TD) administration

advantages: controlled-release patches increase patient compliance
disadvantages: not all drugs penetrate on skin, can't be used on open wounds, used patches still contain large amount of drug (hazardous)

after how many years does a generic drug become available?

20 years

clinical phases of human testing

phase 1: 10-100 healthy volunteers to determine dose
phase 2: 50-500 patients with the disease to determine efficacy
phase 3: 1000s to further establish safety and efficacy
phase 4: post-marketing surveillance, monitors safety

effector

mechanism that is activated by receptor

second messenger

Small intracellular signaling molecule generated or released in response to an extracellular signal.

contact-dependent signaling

Cells must be in direct contact. Important during development and for some types of immune function.

paracrine signaling

effects on cells in the local vicinity of the signaling cell

synaptic signaling

very specific and very rapid delivery of highly concentrated signaling molecules, neurotransmitter released

endocrine signaling

slow, nonspecific delivery, hormones released

receptor types

enzymes, transport proteins, structural proteins

enzyme receptors

may be inhibited or activated by binding to a drug

transport protein receptors

involved in movement of chemicals across a biological membrane

structural proteins receptors

primary purpose of producing essential structural components of cells

ion channel receptors

gated by neurotransmitters; coded for a specific ion channel, channels are constructed from 5 distinct subunits

G protein-coupled receptors

most diverse and numerous cell surface receptors; one ligand can often activate more than one type of G-protein coupled receptor

Half of all known drugs work through ____.

G-protein coupled receptors

Enzyme-linked receptors

transmembrane proteins with extracellular binding domain

intracellular receptors

located intracellularly for drugs that can penetrate the membrane

second messengers

relay signals from receptor to target molecule

what are second messengers activated by?

enzymes or opening of ion channels

most common second messengers

cAMP, cGMP, Ca2+ and phosphoinositide

cAMP

generated from ATP by adenyl cyclase, targets protein kinases

cGMP

GC signals cGMP which regulates the activity of protein kinases

common use of cGMP

regulate ion channel conductance in intestinal mucosa, relaxes vascular smooth muscle, affects vasodilation in vessels

common use of cAMP

metabolization of stored energy in liver (glucagon), conservation of water by kidneys via vasopressin, calcium homeostasis of PTH, increased HR and force of contraction

Ca2+ and inositol triphosphate (IP3)

main function is to mobilize Ca2+ from storage; inc Ca2+ results in muscle cell contraction, secretion of insulin, cell division

dose-response relationship

the relationship between the drug concentrations and the responses they generate

ED50

Effective dose in 50% of the population

graded response

effect of various doses on an individual

quantal response

all or none response; effect of various doses on population

as concentration of a drug increases, magnitude of its effect........

increases

Graded dose-response curve

illustrates relationship between the drug dose, receptor occupancy, and magnitude of resulting physiologic effect

maximum response

when all receptors are fully occupied

half-max response

when 50% of functional receptors are occupied

What does a low ED50 indicate?

more potent drug

Potency versus Efficacy

potency measures strength while efficacy is the effectiveness (fentanyl is more potent than morphine, but they are equally efficacious at equipotent doses; morphine is more effective than tylenol)

what does a drug with high efficacy indicate?

more therapeutically beneficial than one that is more potent

TD50

toxic dose in 50% of the population

LD50

lethal dose for 50% of the population

is a high or low therapeutic index preferred?

high; you would want to take a MUCH higher dose to reach TD50 compared to ED50

therapeutic index

the ratio between the toxic and therapeutic concentrations of a drug

TI formula

TI = TD50(or LD50)/ED50!!!!!!!!

narrow TI drugs

small dose range between what is effective and lethal

idiosyncratic drug response

drug response that is unanticipated/uncommon for the type of drug and its typical use and outcome; cannot be explained pharmacologically

Hypo-reactive or Hyper-reactive Response

intensity of effect of a given dose of drug is diminished OR increased compared to what is typically seen (ex: benedryl excitation or drowsiness)

tolerance

diminished response to a dose of a drug with continued use (opioids, stimulants, alcohol)

Tachyphylaxis

rapid decrease in response to a drug; increasing dose doesn't increase response; sometimes caused by depletion/reduction of neurotransmitter responsible for creating the drug's effect (common in amphetamines)

4 mechanisms of response that may contribute to variation in drug responsiveness

1. alteration in drug concentration that reaches receptor
2. variation in endogenous ligan concentration
3. alteration in number and function of receptors
4. changes in components of response downstream of the receptor

what causes alteration in drug concentration that reaches receptor?

pharmacokinetic factors: absorption, distribution, metabolism, excretion
other factors: age, gender, weight, disease state, genetics, change in active transport

Desensititzation

repeated or continuous admin of agonist/antagonist may lead to changes in responsiveness of receptor; receptors are still present but become desensitized to drug action (refractory period)

rebound phenomenon

body increases number of receptors in critical cells and tissues maintain homeostasis in response to a drug; if the drug is withdrawn, pt will have increased available receptors causing an exaggerated response

Beneficial and Toxic Effects Mediated by the Same Receptor-Effector Mechanism

when the intended effect of the drug also causes toxicity because of its direct intended effect (warfarin can cause too much blood thinning leading to stroke)

Beneficial and toxic effects mediated by identical receptors but in different tissues or by different effector pathways

certain drugs which are used to treat an issue in one area of the body (prednisone for COPD) can cause toxicities in other areas bc they bind to receptors elsewhere (increase glucose--> DM, fluid retention)

Beneficial and toxic effects mediated by different types of receptors

by making drugs more selective to ONE receptor, you can eliminate unintended effects and keep intended ones

Clinical sensitivity

relative to how many different receptor types a drug can interact with