study of the biochemical and physiologic effect of drugs and their mechanism of action

the actions of the drug on the body

the actions of the body on the drug

involves absorption, dirstribution, metabolism, and elimination (ADME)

knockout

knockdown

knockin

component of a cell or organism that interacts with a drug

initiated the chain of biochemical events leading to the drug's observed effect

plays a regulatory role in the drug molecular interaction with specific molecules in the biological system

molecule that binds to a receptor

involved in chemcial signaling

neurtransmitter

hormone

drug

messenger molecule

poisons of biological origin

harmful effects

drugs bind to an activate the receptor

directly or indirectly brings about the effect

aqueous diffusion

lipid diffusion

transport by special carriers

endocytosis and exocytosis

occurs within the larger aqueous compartemtns of the body

across epithelial membrane junctions

through aqueous pores of the endothelial lining of blood vessels

governed by Fick's Law

most important limiting factor for drug permeation is the lipid barriers

the ability to move from aqueous to lipid (or lipid to aqueous) vares on the pH of the medium

governed by Fick's law

exist for certain substances that are important for cell function

may be too large to diffuse passively through the membrane

not governed by Fick's law and is capactiy-limited

Aqueous diffusion

lipid diffusion

amino acids carriers in teh BBB

weak acid carriers in renal tubules

MDR1

also known as P-glycoprotien

found in brain, testes, many neoplastic cells and other tissues

cancer drug resistance in GI tract epithelium

Multidrug resistance-associated protein transporters

(MRP1-MRP5)

important role in excreation of some drugs/metabolites into the urine and bile

uptake of neurotransmitters across nerve ending membranes

substance is too large, lipid-insoluble or impermeant to the cell

the process by which the substance is engulfed by the cell membrane and carried into the cell by pinching off of the newly formed vesicle inside the membrane

content of resulting vesicle are release into the cytoplasm of cell

B12 with intrinsic factor

Iron with transferrin

calcium into the blood stream

enzymes from pancreatic cells

hormones from endocrine glands

involves passive diffusion of molecualr down a concentration gradient

Flux = (C1 – C2)  x      area x permeability coefficient

 thickness

quantifies relationships

-drug absorption occurs faster from organs with large surface are vs organs with small absorbing areas

-drugs absorption is faster from organs with thin membrane barriers than those with thick membranes

(lungs vs. skin)

charged drug molecules

more charged= more water soluble

inversely proportional

more charged= less lipid solubility

uncharged= more lipid soluble

HA ↔ H+ + A-

protonated form is neutral

RNH3+  ↔ RNH2 + H+

unprotonated form is neutral

more WA will be lipid soluable at acidic pH

More WB will be lipd soluble at alkaline pH

renal elimination: polar species= water soluble

biliary elimination: non-polar= lipid soluble

Weak acids

most drugs are freely filtered in the glomerulus but lipid-soluble drugs can be rapidly reabsorbed

give bicarbonate to speed up excretion

size

shape

electrical cahrge

mediated the actions of endogenous chemical signals

mediates the effects of many of the most useful therpeutic agents

have unknown ligands

(receptors are being discovered based on perdicted structure or likeness to already known receptors

drugs that bind to them are developed accordingly)

may be inhibited or activated by binding to a drug

examples: dihydrofolate reductase is targeted by methotrexate (MTX)

portein involved in the movement of a chemical across a biological membrane

example: Na/K ATPase is the membrane recceptor for digoxin

those proteins with the primary purpose of producing the essential structural components

example: tubulin is the receptor for colchicine

          C + EC50

B   =   Bmax x C

           C + Kd

equilibrium constant

concentration of free drug at which half maximal binding is observed

produces a lower response at full receptor occupancy

response similar to that when a competitive antagonsit irreversibly blocks some of the receptos sites

binds to the receptor and prevents binding of the agonist (bind to the same site)

does NOT activate it

ionically binds to drugs to make it unavailable for interaction with receptors or other substances

examples: protamine (positively charged) binds to heparin (negatively charged) to reverse/stop anticoagulant effects of heparin

1. Lipid soluble

2. extracellular

3. extracellular domain

4. Direct binidng

5. binidng via G proteins

chemical signal crossed the plasma membrane

acts on an intracellular receptor

signal binds to extracellular domain of the transmembrane protein

activated an enzymatic activity of its cytoplasmic domain

substrate A results in Product B

signal binds to an extracellular domain of a transmembrane receptor

the transmembrane receptor is bound to a protein tyrpsine kinase

the protein tyrosine kinase is activated

signal binds directly to the ion channel

ion channel is opend and regulated directly by the signal

signal binds to cell-surface receptor

cell-surface receptor is linked to a G protein

G protein is linked to an effector enzyme

 (enzyme or ion channel)

the effector enzyme converts substrate into product

process by normal cell receptor degradation exceeds the synthesis of new receptors

end result is less receptors to activate