PHAR 370 Midterm

Pharmacodynamics

effect of the drug on the body

Pharmacokinetics

how the body handles the drug (ADME)

Two goals of drug response

achieve a beneficial effect or exert a selectively toxic effect

Drug action on receptors

drugs modify the interactions between endogenous ligands and receptors

four types of receptors

regulatory proteins, transporters, enzymes, structural proteins

regulatory proteins

proteins that mediate the actions of endogenous chemical signals (like neurotransmitters)

regulatory protein action

an endogenous ligand or drug binds to and activates the receptor triggering a series of biochemical events (signal transduction)

drug-receptor-induced signalling

allow understanding of variation in drug response times and drug response selectivity

ligand-gated ion channels

regulatory proteins used to transport sodium, chloride, and other ions, channels span the cell membrane

ligand-gated ion channel activity

an endogenous ligand or drug binds to the receptor outside the cell membrane, a conformational change occurs, channel opens and the ions flow into the cell

ligand-gated ion channel example: nicotinic receptor

when acetylcholine in muscles bind, it opens to allow sodium ions to enter the cell, this causes muscle cell membrane depolarization and muscle contraction

G-protein coupled receptors

spans cell membrane, when a ligand binds it changes conformation and activates the G-protein which activates a secondary messenger system, slower than ligand-gated ion channels

common second messenger systems

cAMP, calcium ions, phosphoinositides

regulated transmembrane enzymes

receptors on the outside of the cell are linked to a protein kinase inside, ligand binding allows for enzyme activation which produces a biological effect

intracellular/nuclear receptors

lipid-soluble drugs bind to receptors inside cell to (if agonist) activate receptor, receptor moves to nucleus and binds genetic response elements to increase gene expression and protein synthesis

transporters

proteins that transport endogenous substances across cell membranes, drugs often inhibit

structural proteins

proteins contributing to cell structure, drugs disrupt the normal function

not receptor-mediated drug actions

some drugs interact non-specifically with the biological system

agonist

bind to the receptor and activate it causes the desired response

partial agonist

bind to receptor and activate it producing a weaker response than an agonist

allosteric activator

binds to a different area of the the receptor and makes it easier for the receptor to be activated

competitive antagonist

binds to the same spot on the receptor as the agonist, but does not produce a response, can overcome inhibitory effects by increasing the agonist concentration

non-competitive antagonist

binds irreversibly to a receptor, does not bind to the same site as the agonist or allosteric agonist, causes a conformational change to inhibit binding

dose response curve

x axis: dose of drug

y axis: percent response

threshold of effect: certain amount of drug bound to a certain number of activators to cause a response

ED50: dose that gives 50% response

activator dose response curve

A: agonist

B: partial agonist

C: agonist with allosteric activator

antagonist dose response curve

A: agonist

B: agonist + competitive antagonist (low dose)

C: agonist + non-competitive antagonist

efficacy

max. pharmacological response that can be produced by a specific drug in that biological system, more clinically important

potency

dose or concentration of a drug required to produce a certain magnitude

therapeutic range

above the minimum effective concentration and below the maximum safe concentration of a drug

absorption

movement of a drug from the site of administration into the blood

distribution

movement of a drug from the blood to the site of action and other tissues

metabolism

conversion of a drug into a different compound

excretion

removal of a drug and its products from the body

bioavalability

percentage of an administered dose that reaches the blood in an active form, specific to the drug

intravenous dose bioavalability

100% as it is placed directly into the blood

components of absorption

breakdown of excipients (medium for drug to enter the body)

dissolution into GI fluids

crossing biological membranes

diffusion through aqueous pores

drugs with small molecular weights that are water soluble dissolve into aqueous fluid surrounding cells and passes through openings between cells down the concentration gradient

diffusion through lipids

drugs with a molecular weight > 150 D pass through the membrane by dissolving in the lipid portion and moving down the concentration gradient

active or carrier-mediated transport

drugs bind to carrier proteins or transporters to carry the molecules across a membrane, can go down or against the concentration gradient

drug ionization

most drugs are weak acids or bases so they can exist in an ionized (charged) or unionized (uncharged) state, unionized form can readily cross the lipid membrane and ionized form is water-soluble and cannot

acidic environment

excess of proton, unionized form of a weak acid and ionized form of a weak base predominate

basic environment

few protons available, ionized form of a weak acid and unionized form of a weak base predominate

drug pKa

the lower the pH of the environment relative to the pKa of the drug, the greater the fraction of the drug that will be protonated

conditions for absorption

acids absorbed in acidic conditions

bases absorbed in basic conditions

absorption in stomach

drug disintegrates and dissolves, small proportion of drug absorbed depending on pKa

absorption in small intestine

primary site of drug absorption due to permeability, large surface area, and high blood flow, limited by short transport period

absorption in large intestine

poor for drug absorption due to low permeability and relatively small surface area, some absorption due to long period of transit

drug concentration equilibrium

concentration of the drug at the site of action is in equilibrium with the concentration of drug in the blood

organ specific distribution

not all drugs penetrate all organs equally, blood-brain barrier limits the access of many drugs to the brain and spinal cord, high penetration at placenta

detoxification

conversion of a toxic compound to a nontoxic compound during biotransformation

bioactivation

conversion of an inactive compound to an active compound during biotransformation

biotransformation in the liver

conversions of drugs into water-soluble compounds to be eliminated by the kidneys for excretion, two phases

biotransformation phase 1

purpose is to add or unmask a functional group so that the phase 2 reaction can occur, usually performed by cytochromes P450 (CYPs)

cytochromes P450 (CYPs)

family of enzymes in liver that perform biotransformations, variability in CYP genes causing variable metabolism in the population (genetic polymorphism)

oxidation of amines

amines are oxidized by monoamine oxidase

dehydrogenation of alcohols

dehydration of alcohol to aldehyde and acid through alcohol dehydrogenase and aldehyde dehydrogenase

biotransformation of esters and amides

converted to the acid and corresponding alcohol or amine by carboxyl esterases

biotransformation phase 2

adds a large, water-soluble group to the phase 1 product making the metabolite water-soluble

phase 2 conjugation enzymes

UGT: forms a glucuronide

SULT: forms a sulphate

GST: forms a glutathione conjugate

NAT: forms an N-acetylated metabolite

first pass effect

drug metabolized at a specific location that results in a reduced concentration active drug at the site of action or systemic circulation

drug excretion by kidneys

filters drugs that are not bound to proteins through glomerulus and into the tubular fluid

glomerulus

bundle of capillaries enclosed in Bowman’s capsule, filter blood to renal tubule

proximal tubule

first section of renal tubule, actively reabsorbs nutrients, ions, vitamins, proteins, drugs, and drug metabolites from filtrate

loop of Henle

reabsorbs water and solutes from filtrate

descending tubule

final section of renal tubule, secretes ions back into filtrate from blood

collecting duct

distal tubule empties, water is reabsorbed

glomerular filtration rate

amount of blood that passes through the glomeruli per minute, sign of kidney function

drug reabsorption

some lipid-soluble drugs can be reabsorbed back into the blood as they move down the concentration gradient

basic urine

basic urine increases excretion of acidic drugs

acidic urine

acidic urine increases excretion of basic drugs

GI tract excretion

drugs metabolized and conjugated in the liver are excreted into the GI tract via bile

bodily fluid excretion

milk, saliva, and sweat have minor roles in drug excretion

lung excretion

volatile drugs can be exhaled via the lungs

apparent volume of distribution

volume in which a drug appears to be distributed

total amount of drug/concentration of drug in the plasma

Vd < 14 L

drug likely bound to a plasma protein and is unable to exert a pharmacological effect

Vd > 42 L

drug is being distributed to extravascular storage deposits (fat)

drug clearance

eliminated unchanged or biotransformed

rate of elimination/concentration in the blood

first-order elimination

rate of elimination of a drug is directly proportional to the concentration of the drug, a constant fraction of the drug is eliminated over a period of time

zero order kinetics

a constant amount of drug is eliminated in a set period of time as elimination enzymes become saturated

elimination half-life

time needed for the liver and kidney to remove 1/2 of the drug from the blood

half-life=0.7\*(Vd/clearance)

plateau principle

when a drug is administered repeatedly, the plasma concentration of the drug will increase until the rate of administration is equal to the rate of elimination

plateau principle example

drug has half-life of 4 hours, Vd of 14 hours, and a 140 mg dose every 4 hours


1. after distribution of dose 1, plasma drug concentration is 10 mcg/mL
2. during first half-life, concentration drops to 5 mcg/mL
3. dose 2 increases concentration to 15 mcg/ml
4. after 4 hours 7.5 mcg/mL is eliminated
5. dose 3 increases concentration to 17.5 mcg/mL
6. after 4 hours, 8.75 mcg/mL is eliminated

dosage intervals

administer a new dose to replace the drug that is lost from the body since the last dose, produces plasma drug concentrations in the therapeutic range

dosages for children

child’s body responds differently to drugs as organs are not as well developed (different ADME) and drug response may be different, dose calculated by age, weight, body surface

child dose = (body surface area/1.73)\*adult dose

reasons for non-compliance

dissatisfaction with diagnosis, cost of drugs, inconvenience with having to the the drug often, having several drugs, onset of minor adverse effects, forgetting

assessing drug toxicity

assessed using therapeutic index (toxic dose 50/ED50)

higher therapeutic index means a safer drug

allergic reactions

antigen-antibody combination provokes an adverse reaction in the patient

drug effects in non-target tissues

when receptors for the drug exists outside the target area, you can observe effects in the non-target tissues or organs

adverse biotransformation reactions

occur when a drug is converted into a chemically reactive metabolite that can bind to tissues and cause damage

tolerance and withdrawal vs addiction

tolerance and withdrawal = physiological

addiction = psychological

drug idiosyncrasy

genetic, causes an unusual response to a drug only observed in a small number of people

teratogenesis

drug-induced defects in the developing fetus, multifactorial and depends on the drug

problems predicting drug toxicity

may be rare

may only appear after prolonged use

may not be detectable in animals

may be unique to a specific circumstance

at-risk risk groups for adverse reactions

age: newborns and the elderly (immature or damaged organs are more sensitive)

genetics: enzymes that biotransform exist in different forms

multiple diseases

drug-drug interactions

modification of the pharmacological effect of one drug by the presence of another drug, can be beneficial or detrimental

additive interactions

combined pharmacological effect of the two drugs is the sum of individual effects (same receptor)

synergistic interactions

combined pharmacological effect of the two drugs is greater than the sum of the individual effects (different receptors but same effect)

potentiation interactions

pharmacological effect of one drug is increased by the second, but the second is devoid of intended effect

altered physiology interactions

one drug may alter the normal physiology of the body so the response of another drug is altered

drug-drug interaction during absorption

one drug can combine with another drug in the GI tract, form a complex that cannot be absorbed, can increase intestinal motility, or can hinder the intestinal mixing