Pharmaco - Dynamic, Kinetics, & Genomics Flashcards
What drugs do to the body
Pharmacodynamics
What the body does to drugs:
Absorption
Distribution
Metabolism
Excretion
Pharmacokinetics
Specialized target that binds a drug or endogenous ligand and mediates the pharmacologic action
Drug Receptor
Nomenclature used when a drug is bound to a receptor.
Initial Phase: drug receptor interaction
Complex phase: biological response
Drug Receptor Complex
Occurs when all drug receptors are bound. No further complex & no further increase in response
Saturation
Compound that binds to the receptor and stimulates the biological response.
* Usually mimics the response of an endogenous ligand.
* Magnitude of the response depends on how many drug receptor complexes are formed.
Agonist
Blocks or reverses the effects of agonists.
- No effect on their own. Can be competitive or non-competitive.
Antagonist
Produces a biologic response but not 100% (even at high doses).
- Occupies all receptors but doesn’t activate ligand binding site.
- Opens ion channels differently or incompletely
- Can act as an antagonist if given with full antagonist.
Partial Agonist
Competes with agonists for the receptor site
- increase concentration = increased odds of winning the receptor site
Competitive Antagonists
Permanently bind with receptor sites and prevent activation by agonists.
- reduces maximal response an agonist can produce.
- cannot be overcome by increase the concentration of the agonist. (the agonist can bind there all it wants; it will still do no good)
Noncompetitive Antagonists
Substance that binds to a receptor and causes it to do the opposite of what the naturally occurring transmitter does.
- makes receptors tilt towards the inactive state
or
- decreases the amount of time receptors are open
Inverse Agonist
Maximal amount of response a drug can produce
Efficacy
Measure of the dose required to produce a response
Potency
Measure of drug safety
Therapeutic Index
How do you calculate the Therapeutic Index?
Lethal Dose₅₀/Effective Dose₅₀
Is a drug safer if the Therapeutic Index is larger or smaller?
Larger = Safer
Dose that kills half the population
Lethal Dose₅₀
Dose at which half the population responds
Effective Dose₅₀
At what number is the Therapeutic Index considered to be narrow?
< 2
When two drugs with the opposite effects are given together
Functional Antagonism
When an antagonist is administered with an agonist
- Narcan blocking the effects of Heroin.
Competitive Antagonism
Diminished response to a drug over time
- receptor desensitization
- receptor down regulation
Tolerance
Enhanced response to a drug (super-sensitivity)
- receptor up-regulation = increasing the number of receptors on a cell’s surface
Hyperactivity
When the body quickly develops a reduced response to the drug, requires higher doses for the same effect
Tachyphylaxis
Enhancement of one drug by another which has no effect on its own
- clavulanic acids potentiates amoxicillin (Augmentin)
Potentiation
Occurs when the effects of two drugs together is greater than the effect of either drug by itself
- Trimethoprim + Sulfamethoxazole (Bactrim)
Synergism
Dose related adverse effects of a drug
Toxicity
Movement of the drug from the site it was administered into the body
Absorption
Amount of drug that is absorbed after oral administration vs. the amount of drug that is absorbed after IV administration
Bioavailability (f)
Bioavailability Equation
AUCₒᵣₐₗ / AUCᵢᵥ = f
Bioavailability of drugs given IV
f = 1 (100%) because they do not undergo first pass.
Driven by a concentration gradient
- no carrier and non-saturable
- used by most lipid soluble and uncharged drugs
Simple Diffusion
Are most drugs polar or non-polar?
Non-polar
Carrier mediated and driven by concentration gradient.
- Competition by similar molecules and therefore saturable.
- NO ATP NEEDED
Facilitated Diffusion
Do drugs absorb faster if dissolved in aqueous or oily solutions?
Aqueous
Do drugs absorb faster if they have a smaller or larger molecular size?
Smaller Molecular Size
Do drugs absorb faster if they have a smaller or larger particle size?
Smaller Particle Size
- Most drugs are weak acids or bases
- only the nonionized (non-polar form) of the drug can cross the membrane.
- Ratio of ionized vs. nonionized is determined at the site of absorption and by the drug’s pKa.
Degree of Ionization
Likes Dissolve Likes
Acidic drugs = nonionized in acidic medium
Basic drugs = nonionized in basic medium
Tablet, liquid, capsule, injection, etc. can affect the rate and extent of absorption
- liquids given orally are absorbed more rapidly than tabs or caps
Route & Dosage Form
Some drugs cannot be absorbed in the GI tract so they must be given IV due to their chemical nature. What drug is an example of this?
Heparin
Non-active components of drugs can change absorption
- Metoprolol tartrate (IR) vs Metoprolol succinate (ER)
Formulation
How does concentration affect absorption?
Higher concentration is absorbed faster
How does Area of Absorptive Surface affect absorption?
Larger surface area = faster absorption
(intestine > stomach)
How does vascularity affect absorption?
Faster absorption in areas with more blood flow
(muscle > subcutaneous tissue > stomach)
How does pH affect drug absorption?
acidic pH favors acidic drug absorption
basic pH favors basic drug absorption
How might the presence of other substances affect absorption?
Foods or drugs may interact to alter the rate of absorption
How does GI motility affect absorption?
More contact time = more absorption
(diarrhea = poor absorption)
How does the integrity of the absorptive surface affect absorption?
Edema = decreased absorption
Skin thickness can affect topical absorption
Initial metabolism in the liver of a drug absorbed from the GI tract before the drugs reaches systemic circulation through the bloodstream
(this decreases bioavailability of drugs)
First Pass Effect
Initially inactive drugs that exert no pharmacology effects until they are metabolized
Prodrugs
Process by which an absorbed drug moves from the site of absorption to other area in the body
Drug Distribution
Binding to Plasma Proteins
- mostly albumin
- reversible, saturable, subject to competition
- SEQUESTERS DRUGS IN THE BLOOD, slows their transfer into tissues, and prolongs their duration of action
(Warfarin and Diazepam)
Binding to Tissue Proteins
- some drugs accumulate in certain tissues
(Benzodiazepines accumulate in fat)
Highly perfused organs reach higher concentrations of drug than poorly perfused
Vascularity
Other Distribution Factors
Age
Gender
Body Fat
The process of converting a drug into another chemical called a metabolite (biotransformation)
Drug Metabolism
What is the major metabolizing organ of the body?
Liver
What are the minor metabolizing organs of the body?
GI Tract
Lungs
Kidneys
Skin
How does metabolism affect most drugs?
Usually metabolism makes a molecule more water soluble (hydrophilic) to enhance its removal from the body (excretion) as most molecules are lipid soluble and thus normally are hard for the body to excrete
These reactions frequently involve the Cytochrome P-450 Enzymes.
- Introduces or unmasks a polar functional group to increase renal elimination
Liver Metabolism: Phase I
MAKES IT MORE POLAR TO INCREASE RENAL ELIMINATION
- reactions are conjugations (united).
- combine glucuronic acid, sulfuric acid, acetic acid, or an amino acid with the drug
Liver Metabolism: Phase II
Removal of drugs from the body, either unchanged or as metabolites
Drug Elimination
What organ eliminates most drugs from the body?
Kidneys
Drugs secreted into the bile, then reabsorbed in the small intestine. A fraction is then excreted into the bile, some enters systemic circulation once again.
- Prolongs the amount of time the drug is in the body
Enterohepatic Recycling
Inherited variation in the DNA sequence (mutation)
Polymorphism
Variation in a single base pair within the DNA
Single Nucleotide Polymorphism (SNP)
