Pharmacodynamics Flashcards
What’s the difference between pharmacokinetics and pharmacodynamics?
Pharmacokinetics: Body’s effect on the drug: ADME = absorption, distribution, metabolism, excretion
PharmacoDynamics: Drug’s effect on the body: dose-response and drug-receptor relationships
__ is the cornerstone of pharmacology.
The receptor
The __ is the drug whose interaction with the receptor __ a biological response.
agonist; stimulates
Main effect
characteristic intended effect
Side effect
unwanted or bothersome effect USUALLY RELATED to the main effect
Toxic effect
harmful or adverse effect of the drug; generally NOT DIRECTLY RELATED to main effect
often related to excessively high drug concentrations
“How quickly will the drug act?” is a question of … (pharmaco-dynamics or -kinetics)
Pharmacokinetics
What are the the three general sites of drug action?
1) Intracellular
2) Extracellular
3) Cell surface
Neutralization of excessive gastric acid by antacids is an example of which site of action?
Extracellular (also, heparin in preventing blood coagulation)
Hormone treatment is an example of which site of action?
Intracellular (also, cancer chemotherapy and infection tx)
Agonist
Drug that binds to receptor and stimulates a biological response
Antagonist
Drug that binds to a receptor without altering receptor function (doesn’t stimulate a response)
EC(50)
The concentration of a drug at which the drug effect is either at 50% of its maximum or compared to another known drug with the same effects
Law of mass action
[D] + [R] –> [DR] –> Effect
Words: Effect of a drug is directly proportional to the amount of drug-receptor complexes formed
Rate of association =
= k(1) [D][R]
Rate of dissociation =
= k (-1) [DR]
Equilibrium Dissociation Constant
rate of assoc. = rate of dissoc. at equilibrium; therefore, [D][R}/[DR] = K(D)
The lower the K(D) the higher the affinity
How can you determine the number of occupied receptors from the drug concentration, max % of bound receptors (B) and K(D)?
C x B / C + K(D)
What are the three assumptions being made in the law of mass action?
1) binding is totally reversible
2) D and R only exist as free and bound
3) all receptor sites are considered to have equivalent affinity for D and to be independent (vs. cooperativity)
Potency
The dose of a drug required to produce a particular effect of given intensity (usually measured as ED50). A response measurement.
Affinity
The ability of the drug to interact with the receptor (measured as K(D)). Usually in vitro.
Efficacy
Biological response resulting from drug-receptor interaction. (Typically plotted along y-axis)
Maximal efficacy is often limited by ___.
Toxicity
Partial agonist
Work by shifting equilibrium of a receptor to be stimulated more frequently but not as much so as the full agonist.
Look at the “example of concepts” slide to differentiate potency, efficacy, agonists, and partial agonists.
Just do it…
Log dose-response curve when adding competitive antagonist
Magnitude of shift to the right is proportional to the concentration of antagonist added; the shape and maximal response are not altered
Spare receptors
when a maximal response can be elicited by an agonist at a concentration that does not result in 100% occupancy of available receptors
Important in the action of irreversible antagonists
What makes a competitive antagonist irreversible?
The covalent binding (usually to the same site as the agonist)
Noncompetitive antagonist
Different binding site; the antagonism cannot be completely reversed by increasing the concentration of agonist –> decrease Emax by occupying receptors
** Is reversible with drug withdrawal **
As dose of noncompetitive antagonist is increased the ___ is progressively decreased.
Maximal response
Functional (physiological) antagonism
two drugs influence the same physiological system but in opposite directions
Exp. Ach decreased blood pressure, but can be offset by epinephrine
Chemical antagonism
Direct i/a of agonist and antagonist where they react and form an inactive product
Exp. calcium-containing antacids and tetracycline antibiotics
Threshold of quantal log dose-response curves
The minimum effective dose of the drug which evokes an all-or-none response
How does one make a quantal dose-response curve?
Doses required to produce a specified (yes or no) effect are log-normally distributed.
Responses are then summated for each given dose and the resulting cumulative frequency distribution constitutes the curve
ED(50)
= Median effective dose
= Dose required to produce the stated effect in 50% of the population
LD(50) or TD(50)
Dose required to produce death or a particular toxic effect in 50% of the population
Therapeutic Index
The relative safety of a drug expressed as the ratio of LD(50):ED(50)
-Larger ratio–> greater relative safety
This type of drug produces its effects after a characteristic lag period (can not alter a pathologic state within minutes).
Intracellular/hormonal drugs
Effect can persist long after the agonist concentration is reduced to zero.
What is an important structural characteristic of protein tyrosine kinases?
The span the lipid bilayer ONE time. –> Usually act as dimers.
Exps. Insulin, EGF, and platelet derived growth factor receptors
How is protein tyrosine kinase activity turned off?
Receptor down regulation by stimulating endocytosis once the receptor is stimulated.
Ach, GABA, and many excitatory a.a. like glycine, aspartate, and glutamate are examples of _
Drugs that acts as ligands for gated ion channels
How does the lag of action in ligand-gated channels/drugs compare to intracellular drugs?
Time elapsed after ligand/agonist binding to cellular response is often milliseconds- much shorter than that of intracellular drugs that must induce genetic change to have an effect.
Adrenergic amines, serotonin, acetylcholine (for muscarinic effects) are examples of __.
Ligands for g-protein coupled receptors
Effector enzyme and target enzymes of cAMP
Effector enzyme- adenylyl cyclase
Stimulates cAMP-dependent protein kinases (also EPAC)
Effector enzyme and effects of phosphoinositides and diacylglycerol
Effector enzyme- phospholipase C (PLC)–> releases IP3 and DAG
IP3-release of calcium
DAG- can activate protein kinase C
Effector enzyme and effects of cGMP
Effector enzyme- guanyl cyclase
Activates cGMP-dependent protein kinases
Much more specific than other messenger systems
“Drug disposition tolerance”
a decrease in effective concentration of the agonist at the site of action–> decreased effect of drug
Exp. Phenobarbital increases rate of biotransformation of a number of drugs which are metabolized by liver enzymes
“Cellular or pharmacologic tolerance”
a decrease in the normal reactivity of the receptors i.e. down regulation or change in receptor affinity
Most often seen with CNS drugs (narcotics, depressants, stimulants)
Tachyphylaxis
ACUTE development of tolerance following rapid, repeated administration of a drug. Often happens when drugs have an indirect effect on target response.
Can NOT overcome this type of tolerance with increasing dose
What is an example of a drug that causes tachyphylaxis?
Ephedrine
Idiosyncratic reaction
a genetically-determined abnormal reactivity to a drug ; often due to differences in drug metabolizing enzymes
Type I Hypersensitivity (briefly)
- Immediate hypersensitivity or anaphylaxis
- IgE production
- IgE becomes fixed to mast cells
- Subsequent exposure causes drug to bind to IgE and histamine, PGs etc to be released
Type II Hypersensitivity (briefly)
- Antibody and complement mediated cytolytic reaction
- Drug binds to cell surface –> makes cell look foreign
- IgG and IgM activate classic complement system
- Blood cells are primary target tissues
- Subsides within months after removal of drug
Type III Hypersensitivity (briefly)
- Immune complexes
- Drug reacts in the blood with soluble IgG
- Immune complex is deposited in vascular endothelium
- Cell mediated immune response–> local inflammation and complement activation
- SERUM SICKNESS, hemolysis and allergic nephritis
- Subsides 1-2 weeks after drug is removed
Type IV Hypersensitivity (EXTENDED VERSION)… jk (briefly)
- Delayed hypersensitivty (lymphocyte mediated)
- Hours or days after exposure
- Mediated by antigen contact with sensitized T cells and macrophages
- Release of lymphokines/cytokines
- Influx of neutrophils and macrophages
- CONTACT DERMATITIS/TOPICAL DRUGS
