Pharmacodynamics (EXAM 2) Flashcards
what is pharmacology?
science of interactions of chemical compounds with biological systems
what is pharmacodynamics?
the study of biochemical and physiological effects of drugs and the mechanisms of their actions
what is pharmacokinetics?
the study of absorption, distribution, biotransformation, and elimination of xenobiotics
what are the many characteristics of drugs?
- Defined by actions
- Most act on receptors
- Endogenous drugs or xenobiotics
- Includes poison/toxin
solids/liquids/gasses - Covalent, electrostatic, and hydrophobic interactions
- Ions to larger proteins/antibodies/vaccines, majority are small molecules
- Drug shape and rational drug design for receptor specificity
what are the sites of drug action?
extracellular, intracellular, on the cell target
describe the extracellular site?
- Neutralization of excessive gastric acid by antacids
- Ex: cholestyramine resin in reducing cholesterol absorption
describe the intracellular site?
- Drugs used to treat infections
- Drugs used for cancer therapy
- Ex: hormones such as estrogen
describe the on cell target site?
- Comprises cell-membrane receptors
- Many drugs act by combining with receptors on the surface of the cell
- Examples
— Acetylcholine and muscarinic or nicotinic receptors
— Growth factors (EGF/FGF) and GF receptors
— Monoclonal antibodies (mABs)
how can we relay affinity to the law of mass action and receptor occupancy?
- Effect of a drug is directly proportional to the amount of drug-receptor complex formed
- Lower Kd (d*r/dr) → higher affinity
- Higher affinity → more drug receptor complex and receptor occupancy → more intense drug effect
- Based on koff and kon rates of drugs
what are the components in a receptor binding assay?
- orthosteric: agonist/antagonist, partial agonist, inverse agonist
- allosteric: PAMS, NAMS
- each receptor has one orthosteric site and can have many other allosteric sites
what are the principles of receptor bindng assays that measure affinity?
- affinity is the ability to interact with the receptor
- kD is a measure of affinity
– low= tight
– high= loose - affinites can differ from drug to drug
- affinity = potency
what is pharmacologic profiling?
heterologous competition testing several unlabeled compounds simultaneously
how can we use the graphical data for pharmacologic profiling?
- cheng-prusoff equation
– has IC50 value and from that we can determine the Ki - Ki is a measure of kD
- Ki for each can be computed and compared and affinity rank can be calculated
how can we apply affinity to receptor selectivity?
- the log 3 rule
– 10%, 50%, 90%
—> one log above and one log below
what is Bmax?
total number of receptors on a given cell or tissue
how can we use bmax with drug action?
it is the max affect of a drug
– it is the concentration of all receptors where they are all occupied and reach max conc.
how can we identify and compare dose response curves for each type of ligand in the spectrum?
- Super agonist is > 100% response
- Agonist is 100% response
- Partial agonist is 50% response
- Silent antagonist is 0% response or opposite
- Partial inverse agonist is -50% response or negative effect
- Full inverse agonist is -100% response
what is the difference between agonist and antagonist receptor binding?
- Agonist binding: binding of an agonist results in an induced fit that activates the receptor
- Antagonist binding: binding of an antagonist results in a different induced fit that does not activate the receptor
how can we use graphical data to compare potency and efficacy for active ligands?
efficacy: goes toward max response or up
potency: goes to the left for increasing potency
what is a partial agonist?
- Produces a reduced response even at full receptor occupancy
- Cannot produce the same max effect as a full
- Partial agonist may inhibit competitively the response to a full agonist
- Mechanisms complex but probably related to drug binding to inactive form of receptor
EXAMPLES: abilify, buspar, buprenorphine
how can we apply the concept of partial agonist theory to managing drug therapy?
We know an agonist can open an ion channel immediately, so when we have a partial agonist we can see that there is a complex in between the open and closed state. It can also take longer with both a complex and a flip state before closing or opening the channel
Also we can use this theory to determine the total response between full agonists and partial agonist and produce a dose response curve to compare the two
what are the features of inverse agonists?
- Requires constitutive activity
- Produces the opposite response of an agonist
- Can have full and partial inverse agonists
- Response can be altered by agonist, partial agonist, and antagonist
- Stabilize inactive form of receptor
—- Ex: rimonobant
what is reversible competitive inhibition?
- Antagonist combines with the same site on the receptor as the agonist
- Antagonism can be reversed by increasing the dose of the agonist
- competitive goes to the right and is same as regular in size
what is irreversible non-competitve inhibition?
- Usually bind to the same site as an agonist, but will not be readily displaced
- Irreversible inhibition is generally caused by covalent reaction between antagonist and receptor
- Inhibition persists even after an irreversible antagonist is removed. Duration of action dependent of receptor turnover
how can we use spare receptor to explain drug action?
- When max response can be elicited by an agonist at a conc. That does not result in 100% occupancy of available receptors
—> Ex: response of heart muscle to catecholamines can still be obtained when 90% of beta receptors are occupied by an irreversible antagonist - Important in the action of irreversible antagonists
what is chemical antagonism?
- occurs between an agonist and an antagonist to form an inactive product
- Agonist is inactivated in direct proportion to the extent of the chemical reaction with the antagonist
–> Ex: calcium antacids and tetra. Antibiotics, cyanide and sodium nitrite
what are the mechanisms of allosteric modulators?
PAMS
NAMS
Signaling texture
what are allosteric modulators potential benefit in drug therapy?
- Bind at sites unique from agonist or antagonist
- Increased specificity for receptors that have similar orthosteric binding site
- Increased safety due to ceiling effect
- Provide more physiological/ temporal signaling
—> EX: PAMS of dopamine receptors for parkinsons
what is efficacy?
biological response resulting from receptor interaction
what is potency?
does of drug required to produce a particular effect of given intensity
what is a non-competitive antagonist
- produces its effect at a site of the receptor other than the site used by the agonist
- Agonist and noncompetitive do not compete with one another for a single binding site
- Cannot be completely reversed by increasing the conc. Of agonist
- Increasing antagonist conc. Increase the KD and dec. Emax of agonist
spare receptors are:
system/tissue dependent
- some cells have no reserve
- coupling efficiency is a determinant
- may differ for responses with same receptor
what is functional antagonism?
- 2 drugs influence a physiological system but in opposite directions
- Each drug is unhindered in the ability to elicit its own characteristic
–> Ex: effect of histamine on BP can be offset by epinephrine - Can lead to contraction or relaxation based on path
what are the 5 classes of receptors
intracellular receptors
cytokine receptors
protein kinase receptors
ion channels
GPCRs
what are intracellular receptors
- Intracellular receptors (regulate gene expression) (steroids)
— Stimulate the transcription of genes in the nucleus by binding to specific DNA sequences near the gene whose expression is regulated
– Additional non receptor receptors
——– Effector enzymes that regulate cellular function include membrane potential, protein phosphorylation, translation, transcription, etc.
———–> Kinase, cyclase, phosphatases, ubquitinases
what are cytokine receptors
simplest
- JAK-STAT pathway
- mechanism: binds, activation leads to JAK, phosphorylation to STAT, dimerizes and travels to regulate transcription
–> Examples: GHs, erythropoietin, interferons