PCL201 lec 1-4

affinity

strength of D-R interaction

classical theory

response is relative to drug concentration and the number of receptors activated

log dose response curve

expands concentration scale at low conc, where binding changes rapidly, and expands it at high conc, where binding doesn’t change much

Emax

maximal response. indicates efficacy of the drug

EC50

drug concentration at 50% of emax. indicates potency. (how much drug is needed to achieve a response)

T

Therapeutic index

toxic TD50 / Beneficial EC50

larger TI = safer drug

salbutamol

B2 adrenergic receptor agonist. full agonist. bronchospasm

full agonist

produces a full response when all receptors are bound. intrinsic activity (a) = 1

partial agonist

won’t produce a full response, even if al the receptors are bound. so less effective, intrinsic activity < 1

pindolol

B adrenergic receptor partial agonist. treats hypertension, reduces cardiac activity

positive allosteric modulator

binds at site distinct from Ag binding site. will shift an agonist dose-response curve LEFT (increase efficiency). PAM binds, and increases affinity for agonist.

diazepam

positive allosteric modulator of GABA receptor - treats anxiety, insomnia, seizures

increases frequency of ion channel opening and more chloride ions entering the nueron.

antagonist

binds receptor at agonist site - does not initiate biological activity. prevents natural or endogenous agonist from binding, and prevents receptor activation.

antagonist alone has zero efficacy

propranolol

competitive, non-selective (can bind to different receptors, but no response) beta antagonist at the beta adrenergic receptor

treats hypertension. beta blocker.

competitive agonist

binds to the same site as the agonist, so inhibition can be overcome by increasing agonist concentration.

affects agonist potency - shifts D-R curve right.

non-competitive antagonist

irreversible - covalent bonding

negative allosteric modulator - binds to different receptor site from agonist

reduced potency and efficacy - shifts D-R curve right and down

B-carboline

alkaloid - negative allosteric modulator of the GABA receptor, induce convulsions and increase anxiety

ibuprofen

inhibits enzyme cyclooxygenase

fluoxetine

SSRI

other mechanisms of drug action

create osmotic load (laxatives)

change pH (acidifies urine and traps toxins)

chelation (EDTA - binds divalent metal cations)

disruption of membranes (antibiotics, disrupt bacteria cell memrbanes)

damage DNA (chemotherapeutic agents)

total body water (TBW)

roughly 60% in adults

physiochemical properties that affect drug movement

molecular size

solubility in water & lipid phases (P_ow and topological polar surface area TPSA)

extent of ionization

partition coefficient P_ow

measure of hydrophilicity. affects the ability to cross membrane or distribute in water

drug dissolved in octanol (lipid) / drug dissolved in water

logP = 1.04 is P_ow of 11, 55:5 octanol to water ratio

LogP of drugs is usually 0.5 - 5

common molecular size of drugs

200-500 Da

proteins are much larger, can be 6000Da to 65000Da

topological polar surface area

measure of polarity. 60-140Å is ideal for permeating cell membranes

to access the brain, TPSA has to be < 90Å

high K_ow

high lipid solubility - good permeation across membranes, but too high might mean it is so lipophilic it cannot exist in the aqueous environment

Lipinski’s Rule of 5

logP < 5

molecular weight < 500 g/mol

no. H bond acceptors < 10

no. H bond donors < 5

% ionization

pH - pKa

-3 means if the drug is an acid, 99.9% of it isn’t charged

if the drug is a base, 99.9% of it IS charged.

so closer to -3, good for acids, bad for bases

barriers to drug movement in the body

physical and anatomical - tight junctions and biological membranes. drugs must pass through cells

functional - transporters, efflux transporters

glycocalyx

layer of water and glycocalyx on the surface of membranes. is hydrophilic - which is why the cut off phenomenon happens

BBB

endothelial cells are joined by tight junctions / occluding zonulae

there are some exceptions, pituitary gland, pineal gland, choroid plexus

placental crossing

assume all drugs cross the placenta

physiochemical properties determine relative ability to cross placenta

limited maternal blood flow, so equilibration between mother and fetus takes at least 10-15 minutes

sites of drug transporters

commonly found in enterocytes (intestine), hepatocytes, renal tubular cells, BBB epithelial cells.

solute carrier (SLC) transporters

move drugs across cellular membranes by facilitated and secondary active transport

localized to cellular membranes and organelle membranes

most are transport-specific molecules, some are broad-range

ATP binding cassette (ABC) transporters

use energy from ATP hydrolysis to move diverse substances like nutrients, lipids, ions, and drugs across cellular membranes, acting as importers or exporters

primary active transport

limit cell exposure to drugs and toxins. can limit therapeutic efficacy of cytotoxic drugs such as chemotherapeutics and antibiotics

plasma glycoprotein structure and binding

moving substrate from inside to outside

substrate becomes locked in a p-gp drug-binding pocket

2 ATP molecules bind to the intracellular ATP-binding sites

hydrolysis of ATP, conformational change in p-gp

substrate is released to the extracellular environment

P-gp localization

favours preferential transport of substrates out of tissues, into blood, feces, mucus, or urine

multidrug resistance transporters

p-gp,

MRPs, BCRP (ABC transporters)

Enteral

through or within the GI system, oral, rectal or sublingual

parenteral

bypass the GI system, through IV, IM, or SC

systemic effect

drug is absorbed into the systemic circulation and distributed throughout the body to reach the site of action

local

drug enters the site of administration to reach the site of action without entering circulation

bioavailability (F)

the proportion of administered dose that is absorbed from the site of administration and reaches systemic circulation unchanged.

affected by incomplete absorption, and first pass metabolism

first pass metabolism

metabolism of drugs before reaching the general circulation. at the liver, gut wall and portal blood. occurs mostly for orally administered drugs

oral administration absorption

depends on pH of GI, physiochemcial properties, stability and solubility of drugs in GI fluids, gastric emptying rate, drug concentration, intestinal motility

enteric coating

resists degradation in the stomach, but it may reduce absorption in intestine

extended or controlled release (ER, CR)

slow, uniform dissolution and absorption of drugs. decreases frequency of dosing and increases compliance

advantages of oral administration

convenient, easy to administer, pain free

economical (don’t need a nurse)

disadvantages of oral administration

affected by first pass metabolism

may be subject to degradation in gastric acid and digestive juices

may irritate gastric mucosa

slow onset of action

not suitable for some patients- vomiting, unconscious

suppository administration advantages

no first pass

no degradation in stomach or small intestine

large doses may be given

disadvantages of suppository administration

absorption is irregular (blood flow often incomplete)

drug may be irritating to mucosa

less accepted than oral routes (poorer compliance)

sublingual

drug is placed under the tongue or held in the mouth. absorbed through oral mucosa into general circulation, rapid absorption and rapid onset

buccal administration

in the space between the gum and cheek where it diffuses through oral mucosa

advantages of sublingual administration

no first pass or degradation

absorbed rapidly

rapid onset

disadvantages of sublingual adminstration

limited to drugs that can penetrate oral mucosa well, not irritating

may not be convenient for large doses

injection advantages

predictable drug concentrations in blood

accurate dosing

fastest and most certain

depend on site of injection and blood flow

disadvantages of injection

higher risk of toxicity

strict asepsis, pain, self administration is difficult

more expensive

subcutaneous injection

injection of blood into subcutaneous tissue

absorption is even and slow, affected by blood flow

intramuscular injection

into skeletal muscle tissue

rapid absorption of aqueous solutions

slow/even absorption

depot injections

lipid vehicle for slow, even absorption

mostly in large skeletal muscles, but can be delivered subcutaneously

advantages of intramuscular injection

rapid absorption and rapid onset

no first pass or degradation

disadvantages of intramuscular injection

limited to small volumes of non-irritating drugs

strongly acidic or alkaline can cause abscesses and pain

intravenous injection

100% bioavailability

potential adverse effects like embolism, injection, bleeding, vascular injury

pulmonary administration

absorption is rapid due to thin membranes, large surface area, and high blood flow to the lungs

may be used for local action only

disadvantages of pulmonary administration

hard to regulate exact dosage

suitable only for volatile agents and aerosols

irritation/tissue damage in lungs is possible

percutaneous or transdermal

drug absorption into systemic circulation through the skin

only system and not local effect (specifically designed to bypass local metabolic destruction and pass through the skin barrier to enter the bloodstream)

best with lipid soluble and low molecular weight drugs

advantages of percutaneous/transdermal administration

no first pass/degradation

controlled long term release - stable blood levels

easy administration

good patient compliance

Lipophilic, low dose, low molecular weight

disadvantages of percutaneous/transdermal administration

highly dependent on drug properties - favourable physiochemical properties, small and lipid soluble

surface area is important - drug must be concentrated/potent enough

skin irritation may occur

topical administration

direct local application to body surface / intended site of action

drug is intended to work locally

disadvantages of topical administration

limited to small volume/doses

not suitable for systemic diseases/targets

some are impractical to administer