Exam 1 - Lecture 1 & 2, Drug Action Flashcards
How to study receptors
- Isolate and purify macromolecular component and study drug “structure-activity” relationships
info inferred from kinetics of drug-receptor interaction = binding sites
- Determine amino acid sequence; clone and express receptor in cultured cells
enables study of receptor function in living cells, but isolated from components of native cells in intact tissue
Types of binding of drugs to receptors
- van der Waals attraction (weakest)
- Hydrogen bond
- Hydrophobic interaction
- Ionic bond
- Covalent bond (strongest)
Receptor locations
typically cell surface, embedded in cell membrane
Drugs that don’t act through receptors
Antacids
Osmotic diuretics and cathartics
Chelating agents which bind heavy metals
Nature of drugs
Physical nature (solid, liquid, pH [affect absorption], hydrophilicity and hydrophobicity [changes receptor interaction])
Drug size ( small, large, typically MW 100-1000…as size increases absorption isn’t as effective)
Drug shape (stereoisomerism, ie carvedilol…R+ binds to Beta receptors much worse than S- (Kd = 54 vs 0.5)
Agonist
Drug that causes specific physiological effect due to direct interaction with a receptor
Antagonist
Compound that is devoid of intrinsic pharmacological activity but blocks the action of a specific agonist or an endogenous substance which produces the effect
Allosteric modulator
A drug which binds to a different site on the receptor than that bound by endogenous ligands; can modulate positively or negatively
Addition
When two agonist which produce the same effect are administered together, they produce an effect equal in magnitude to the sum of the effects of the individual drugs
A + B = A (solo) + B (solo)
Synergism
When two agonist which produce the same effects are administered together, they produce an effect greater in magnitude than the sum of effects of the individual
A + B > A (solo) + B (solo)
Potentiation
When drug is itself without effect, but if administered with a second drug, increases the effect of the second drug
Drugs A and B can target….
One receptor or two separate receptors producing interacting effects
Quantal ( all or none) dose response curves
Relates drug dose to frequency of drug-induced “all-or-none” pharmacological effect
Plot of response frequency vs dose yields normal distribution
Replotting curve in terms of percentage of subjects responding vs log of dose yields a sigmoid (S-shaped) curve
Examples include (dose of barbiturate to induce sleep)
Wide distribution yields shallow cumulative curve (S-shaped)
Graded (quantitative) dose response curves
relates dose of drug to size of response of a single biological unit
Plot of magnitude of response vs log doe yields sigmoid curve
Examples include drug induced, graded changes in HR
ED50
smallest dose of drug which is effective in 50% of individuals receiving the drug
Linear vs Log plot
Linear - intuitive scaling
Semi-log plot - compact scaling
Tolerance
When repeated admin of given dose of drug produces a decreased effect, or conversely larger doses must be administered to obtain the same effect observed with the original dose.
Time scale: days to months
Tachyphylaxis
Very rapidly developing tolerance; decreasing effect of a drug following consecutive doses given at short intervals
Time scale: minutes to hours
Supersensitivity
A heightened state of pharmacological responsiveness of a tissue or organ, leading to an exaggerated effect of an agonist
may be due to a compensatory increase in number of receptors, “up regulation”
Changes can be drug induced (prolonged exposure to antagonist) or due to denervation (destruction of neuronal input to the tissue)
Desensitization
A reduced state of a pharmacological responsiveness of a receptor due to continuous presence of the agonist at that receptor
Maybe due to decrease in receptor number ie. down regulation or to a change in receptors conformational state to an inactive “desensitized” state
LD50
smallest dose of a drug which is lethal in 50% of individuals receiving the drug
Therapeutic index (TI)
LD50 / ED50
Margin of safety
LD0.1 /ED99.9
More useful expression of drug safety
Small Kd
its affinity for receptor is high
Large Kd
its affinity for the receptor is low
Kd = [D] when…
50% of receptors occupied
Kd
K2/K1
equilibrium dissociation constant and is related to the affinity of the receptor for the drug
K2 = {D][R]
K1 = [DR]
PAM effect on log chart
Can be left-ward shift, typically accompanied by an upward shift
Agonist + Competitive Antagonist on Semi-log plot
Moves to right
Agonist + Irreversible or Non-competitive antagonist on semi-log plot
lowers efficacy from agonist alone
Intrinsic activity or efficacy
independent of the slope or position of dose-response curve
degree of effect obtainable for a given level of receptor occupancy, drugs with same efficacy elicit same maximal response
Potency
used in comparing 2 or more drugs when specifically referring to the doses of each required to produce same effect
Location on access, slope show potency
Efficacy is more important than potency in selecting drugs for use in clinical situation
Coupling
overall transduction process that links drug occupancy of receptors and pharmacologic response
Spare receptors
Example:
If 4 coupling events yield max effect and only 4 G proteins are present to transduce signaling, having more receptors does not cause more effect….extra receptors are “spare”
Pharmacological antagonism
Antagonist prevents an agonist from acting upon it receptor to produce a response
Physiological antagonism
Occurs when 2 agonist act upon a tissue to produce opposing response, each agonist interacts independently with specific but different receptors
ex. Epinephrine and histamine
Antagonism by neutralization
2 drugs combine with one another to form an inactive compound
ex. Heparin (-) and Protamine (+) form inactive ionic complex
