Pharmokinetics
describes how a drug gets to the site of action. The amount of drug in the body at any time is determined by 4 processes (ADME)
Ways drug molecules move around the body
1- in the bloodstream (over long distances)
2- molecule by molecule (short distances)
rate of diffusion depends on
molecular size (large - more slowly)
site of drug action
final destination of a drug
Absorption location
generally a drug will be better absorbed int the small intestine than in the stomach due to its larger surface area
Lipophilic drugs
penetrate the cell membrane much easier than water soluble, hydrophilic drugs which do not diffuse easily in the lipid layer and either pass through the aqueous pores or are prevented from entering the cell and thus are contained outside
Optimal drugs for absorption
should have a degree of both water solubility (to go through fluids to get to the cell) and lipid solubility (to get through the cell membrane)
intestinal/mucosal blood barrier
where the orally administered drug must cross the GI mucosa into the blood before being distributed to the target tissue/organ (site of action)
placenta barrier
filters out some substances that can harm the fetus, but allows other substances, including alcohol, to cross
oral mucosa/blood barrier
sublingually or buccally administered drugs must go through the epithelium of the oral mucosa before entering the blood and being distributed to the site of action
blood/tissue barrier
the membrane btwn the blood and the tissue
this occurs once the drug enters the blood, is transported to the various tissues in the body where it will exert its pharmacological effects
Absorption type
most drugs are absorbed by passive diffusion across a barrier and into the circulation
rate of diffusion is proportional to the concentration gradient
Facilitated diffusion
occurs when a carrier such as a protein is necessary to get a drug that is too large and/or too polar to diffuse across a lipid membrane
Active transport
the use of carrier proteins to move drugs against the concentration gradient with expenditure of energy. not a common process of absorption
Pinocytosis
engulfment of fluids or particles by a cell. involves energy expenditure and plays a minor role in drug movement
ionization
formation of ions from neutral molecules and involves the removal or addition or one or more electrons
The ionized form, has a low lipid solubility and has an electric charge, and cannot easily cross a lipid membrane
The nonionized from is usually lipid s
effect of pH on absorption of weak acids and bases
how much of the drug changes to the ionized from will depend on the pKa of the drug and hte pH of the solution
pH refers to concentration of H+ ions
Weak acids
will mostly be nonionized at the acidic pH (1.4) of the stomach, allowing easy absorption
weak acids are usually more readily absorbed from the stomach than weak bases
Weak bases
will be more ionized at the pH of the basic small intestine (6-7) and ionized in the stomach. the nonionized portion of the drug shows great lipid solubility and therefore greater absorption in the small intestine
small intestine absorption
regardless of the pH and ionization, most drug absorption (even weak acids) usually occurs in the small intestine, which has the greatest surface area
example of pKa
lidocaine (pKa 7.9) has a faster onset of action than bupivicaine (pKa 8.1)
the closer the drug is too neutral, the faster action
bioavailability
rate and extent of drug absorption into the blood
factors altering absorption
route of administration, blood flow to the organ, surface area of the small intestine, lipid/water solubility of the drug, salt from of the drug, and drug interactions with other drugs, herbal supplements, or food
orally administered drugs
low bioavailability, little absorption until the drug enters the small intestine
must be absorbed through two barriers--epithelial cells and blood vessels--in order to enter the blood
another disadvantage: must pass through the liver via hepatic portal ve
gut pH
plays important role, it affects how much of the drug is in the unionized form and how much of the drug is fat soluble and will be absorbed
Sublingual administration
adv is that a higher initial concentration of the drug is reached in the bloodsteam and at the site of action bc these drugs do not pass the hepatic circulation
Rectal administration
often unreliable are erratic but rapid. undergo little first-pass metabolism in the liver
Parenteral
bypass GI tract
IV
made directly into circulation through a vein, bypassing absorption barriers
distribution
once a drug is present in the bloodstream, it is distributed throughout the body fluids to tissues and organs that is is physically able to penetrate
Distribution phase
after the drug leaves the blood it is distribute to the extracellular fluid or enters the cells
volume distribution
volume of fluid in which a drug is able to distribute
Factors affecting drug distribution
1- membrane affinity refers to the drug's attraction to cell membranes in the body (hydrophillic drugs- cant penetrate lipid-cell membranes, lipophillic - cross lipid cell membranes and more evenly distributed in all fluids)
2- drugs exist in free form or
2 major forms of drug elimination
biotransformation
excretion
biotransformation
- liver is the primary site of this
- a drug must be in a water-soluble form to be eliminated from the body
- lipophilic drugs must be biotransformed before elimination so as not the be reabsorbed from the kidneys back into the blood, prolonging duration
Prodrugs
orally administered they are inactive, but become active after biotransformation in the liver
phases of biotransformation
phase 1- change a lipid-soluble drug to a more polar metabolite (redox rxns)
phase 2-if after phase 1 it is still fat soluble, it will go through phase 2. the drug or metabolite from phase 1 are linked with a water soluble compound such as glucuronic acid
Oxidative rxns
most common type of phase 1 met.
- liver uses enzymes to make lipid-soluble drugs more water soluble or hydrophilic
- cytochrome 450 enzymes in liver (several types like CYP3A4)
- grapefruit juice inhibits the CYP3A4 metabolism
Drug clearance
volume of plasma from which the drug is completely removed from the body per unit of time. amount eliminated is proportional to the concentration of the drug in the blood
bile excretion
some drugs are excreted in the bile by a process called biliary excretion.
Bioavailability
the rate and the extent to which a drug is absorbed into the systemic circulation
- a drug delivered iv has 100% bioavailability b/c the entire amount of drug enters the bloodstream
Drug dose
quantity of drug administered
Pharmacodynamics
actions a drug has on the body and involves drug-receptor interactions, mechanism or drug action, drug response, and the dose-response relationship
drug-receptor interaction
in order to initiate a physiological response, most drugs must first bind to a receptor
- drugs bind to their receptor by forming van der waal's forces or ionic bonds with receptor sites
- drug must have the affinity to the receptor which is a measure of
receptor
usually a protein, is any structural component of a cell to which a drug binds in a dose-related manner and produces a response
Signal transduction
the drug binding to the receptor causes a chain of biochemical events that leads to a pharmacologic or physiologic effect such as lowering BP
agonist
drug that rapidly combines with a receptor to initiate a response and rapidly dissociates or releases from the receptor, it has high efficacy
antagonist
drug that binds to the receptor but does not dissociate and has no positive response or efficacy. it blocks the rxn of an agonist and is referred to as a blocking drug
partial agonist
binds to the receptor and produces a mild or submaximal therapeutic response and may inhibit the action of an agonist when given concurrently, acting like an antagonist
competitive antagonist
drug which occupies a significant proportion of the receptors and thereby prevents them from reacting maximally with an agonist
Noncompetitive antagonist
may react with the receptor in such a way as not to prevent agonist-receptor combination but to prevent the combination from initiating a response, or may act to inhibit some subsequent even that leads to the final overt response
potency
dose required to produce a therapeutic effect
therapeutic index
the ration of a drug's toxic dose to its therapeutic index
efficacy
ability to produce a therapeutic effect regardless of dose. potency and efficacy describe the success of drug therapy
median effective dose
drug dose that produces 50% if the maximum possible response in test animals
lethal dose
dose at which 50% of test animals die
safe drug
will have a high TI
biological variation
the different responses seen among individuals within the same population, given the same dose of a drug