Lecture 29 Flashcards
With what bond does drug mostly bind to drug receptor? (3)
hydrogen, ionic, or hydrophobic bonds with receptor
*Rarely, drugs form covalent bonds with their receptor
Which characteristics of drug determine whether it will bind to a particular receptor or not? (3)
size, shape, and charge of a drug
3 examples of drug that target ion channel
local anesthetics (block voltage-gated sodium channel)
Sedative-hypnotics
Anti-epileptics
How does drug targeting ion channel work?
drugs act by altering the conductance of ion channels
How does local anasthetic work?
the drug permeate through cell membrane and bind to cytosolic side of voltage-gated sodium channel blocking the channel.
2 examples of drugs that target g-protein linked receptor
- albuterol (beta2-agonist)
2. Propranolol (beta-antagonist)
2 examples of enzyme-linked receptor
- insulin receptor
2. epidermal growth factor receptor
What happens if gain-of-function mutation occur in tyrosine kinase receptor?
Tyrosine kinase receptors play a role in cellular growth and differentiation, so it is proto-oncogene. If the mutation occur, it can lead to cancer. So inhibitor of receptor is anticancer agents.
What is the drug imatinib?
tyrosine kinase inhibitor effective for leukemia
3 examples of nuclear receptor
- steroid hormone
- thyroid hormone
- vitaminD
Mechanism of nuclear receptor
hormone permeates through cell membrane and binds to intracellular receptor in cytosol. Then, hormone-receptor complex enters nucleus to bind to DNA, which leads to transcription.
3 examples of drugs that target enzyme
aspirin, ibuprofen, omeprazole
Most of these drugs work by inhibiting enzyme
examples of drugs that target transporter
prozac block serotonin re uptake by bind to transporter at synamptic cleft (used for treating psychiatric disorder)
examples of drugs that target structural proteins
some anticancer drugs bind to tubulin and prevent polymerization of spindle fiber, arresting cell division at metaphase.
1 examples of drugs that does not bind to receptor
antacids does not interact with receptor, but neutralize gastric acid chemically.
2 types of dose-response curves
graded & quantal
Equation and shape of graded dose-response curve
E= (Emax *C) / (C+EC50)
Hyperbolic curve
B= (Bmax*C) / (C + KD)
What does equation mean?
it is a relation between drug bound (B) to receptors and the concentration (C) of free drug
B= (Bmax*C) / (C + KD)
In this equation, what does KD mean?
KD characterize the receptor’s affinity for the drug. Lower the KD, binding affinity is high.
Compare binding curve and dose-response curve
shape looks the same (hyperbolic)
but binding curve is the relationship between drug bound to receptors and concentration of free drug while drug-response curve is relationship between concentration of drug and maximal effect of drug.
How does logarithm of concentration change the shape of graded-dose-response curve and binding curve?
change from hyperbolic to sigmoidal curve
What does it mean if EC50 is lower than KD?
It means an agonist does not have to occupy all receptor to evoke a full response. because certain number of receptors are spare and signal amplification occur. Due to signal amplification, not all receptor has to be bound to induce full effect of drug.
Efficacy
magnitude of the response a drug produces.
maximal efficacy = E max
Potency
a measure of concentration or amount of drug necessary to produce an effect of a given magnitude, determined by EC50
Difference between agonist and antagonist and their effect on efficacy and affinity.
Agonist binds to receptor and brings about an effect, thus have receptor affinity and efficacy.
Antagonist inhibits the action of an agonist but has no effect in the absence of agonist. Thus it has receptor affinity but no efficacy.
Competitive antagonism can be reversible and irreversible. Compare and contrast in terms of Emax and EC50.
For reversible, Emax is the same, EC50 moves to left.
The antagonist is surmountable by adding more agonist
For irreversible, Emax is reduced, EC50 same.
The antagonist is insurmountable, since receptor can respond to agonist.
What is noncompetitive antagonism? (in terms of Emax, EC50)
it is allosteric antagonism, where antagonist binding at different site of agonist reduces action of agonist.
* Insurmountable, thus Emax decreased, EC50 decreased
The curve shape of irreversible competitive antagonism and noncompetitive antagonism, are the same?
YES
Two types of nonreceptor antagonism
physiological and chemical antagonism
What is physiological antagonism? & example
One drug opposes another drug but through different receptors
ex) epinephrine (increase BP and bronchodilation) & histamine (decrease BP and bronchoconstriction)
What is chemical antagonism? & example
a chemical antagonist reacts chemically with an agonist to form an inactive product.
ex) protamine, a protein which is positively charged, counteracts the effect of heparin (negatively charged)
Difference between full and partial agonist. Their effect on Emax and efficacy
Partial agonist produce submaximal response at full receptor occupancy than agonist»_space; lower E max»_space; less efficacy
* Partial agonist can act as competitive antagonist in the presence of full agonist, by competing with full agonist for receptor occupancy.
What is constitutive activity of receptor?
many receptor system shows some activity in the absence of agonist, that fraction of the receptors is always in the active state
What is inverse agonist
it reverse the constitutive activity of the receptor
What is quantal dose-effect curves?
it plots the fraction of population that responds to a given dose of drug as a function of drug dose, unlike graded, it defines response as either present or not present.
Difference between ED50, TD50, LD50
ED50 : Dose at which 50% individuals exhibit specified quantal effect
TD50: Dose at which a particular toxic effect in 50% of animals produced
LD50 : Dose required to cause death in 50% of animals
Therapeutic index (2)
TD50/ED50 or LD50/ED50
Describe safe drug in terms of TD50 and ED50
Safe drug will have large toxic dose and a small effective dose
What is therapeutic window?
the dosage range between the minimum effective therapeutic concentration and the minimum toxic concentration
