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56 Cards in this Set

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1. Discuss the concept of drug selectivity, describe its importance, and list the determinants of drug selectivity.
a. Selectivity
i. Ability to affect one tissue, cell type, or organ, and spare others
ii. Dependent on
1. Dose: how much given
2. Distriubtion: where drug goes
3. Receptor distribution: where they are
4. Receptor selectivity: how good the drug fits (specificity)
2. Discuss the potential influence of chemical chirality on pharmaceutical action, toxicity and metabolism of drugs.
a. Often time only one isomer shows pharmacological activity
b. Other times both exhibit therapeutic properties
c. Sometimes one isomer has pharmacological activity while the other shows toxicity
d. Rare but sometimes the 2 isomers can have completely different activity
e. Finally, one enantiomer is often more susceptible than the other to drug-metabolizing enzymes
3. Describe the general receptor mechanisms for transmembrane signaling. (4)
a. Ligand regulated ion channel (Nicotinic receptor for ACh coupled to Na/K ion)
b. G-Protein
c. Tyrosine kinases (insulin/growth factors)
d. Intracellular (steroid)
a. Affinity
determines drug concentration required to form a significant number of drug-receptor complexes
a. Agonist
i. Activates the signaling cascade upon binding
b. Antagonist
i. Does not activate signaling upon biding
c. Non-competitive inhibition
i. Antagonist binds to sight different from agonist
ii. Thus the agonist cannot make more to compete it off
d. Competitive inhibition
i. Antagonist binds to same site as agonist
ii. Increase in agonist can work against the antagonist
Specificity
Receptor interacts with one type of ligand
Competition between related ligands
Ex: glucose transporter binds D-glucose specifically
c. High intrinsic activity? Low?
i. Ligand produces a large effect
ii. Low intrinsic: Ligand produces small effect
b. Receptor efficacy/Intrinsic activity
i. Extent to which a bound ligand activates a receptor
ii. Distinguishes agonist from antagonist
iii. Basically how much downstream effect something has
c. Saturability
Receptors exist in finite numbers
Binding sites can become fully occupied with ligand molecules
remember Vmax ….?
Additional ligand leads to non-specific binding
10. Discuss the advantages and disadvantages of irreversible inhibitors.
a. Irreversible totally inhibit the receptor. Forever. You need to make a new one if you want to activate that type of receptor
What is efficacy?
biological response
so high efficacy, means higher biological response
10. What is EC50?
a. Concentration that produces 50% of the maximal effect
c. How do responses correspond to the amount of dosage given?
i. Responses to low drug doses will usually increase in direct proportion to dose
1. Aka small does will have big effects
ii. At high doses, effect changes slowly
1. You will saturate the receptor
11. For a receptor, what is potency related to?
affinity
12. Low Kd means what for binding affinity?
a. High binding affinity
14. What is a full agonist? Partial agonist?
a. Full
i. Drugs that produce full effects in a system
ii. Produce an effect of 1 (arbitrary number assigned to drugs that stimulate maximally
b. Partial
i. Drug that interacts with a receptor but cannot produce maximal effects
ii. Effect less than 1
1. How do you tell if one drug is more potent?
a. You look at the EC50
b. The one with the lower dose is more potent
c. Lower EC50, further left on the graph, kd smaller, all more potent
2. What determines potency (2)
a. Affinity of receptor for the drug
b. Efficiency that drug-receptor interaction is coupled to response
4. What is threshold dose?
a. How much drug do you need to begin to have an effect
b. The least amount needed to produce the desired effect
7. What is a chemical antagonist?
a. Does not require a receptor
b. Chemical interaction of two substances
i. Effect of the active substance is lost
c. Ex: lead treatment; metal chelators + toxic metals
8. What is a pharmacological antagonist
a. Binds receptors but does NOT activate signal transduction
b. Biological effects derive from preventing agonist binding and receptor activation
9. What is a competitive antagonist
a. Binds to same receptor site as agonist
b. Primarily affects potency
c. Can be reversible (inhibition can be overcome by increasing drug concentration) or irreversible (inhibition can’t be overcome by increasing drug conc.)
10. What does an irreversible competitive antagonist do to ED50 and Emax?
a. Emax- lowered
i. Basically have less receptors
ii. Effect efficacy
b. Potency will remain the same
12. How does a non-competitive antagonist work?
a. Binds to a different site than agonist
b. Does not compete with agonist for binding
c. No amount of agonist can completely overcome the inhibition once it has been established
13. What does a non-competitive antagonist primarily affect?
a. Efficacy
b. In some cases a rightward shift (decrease potency)
16. How do physiological antagonists work?
a. Opposing effects by 2 agonists
b. Two agonists working on 2 different receptors and cancel each other out
c. You can target these to increase or lower an effect by affecting one of the 2 receptors
17. What are spare receptors
a. An excess of receptors exists at some sites
b. Maximum biological response is achieved with only a fraction of receptors occupied
c. Sensitivity of a cell to an agonist depends on receptor affinity and total receptor concentration
i. With more receptors, the chance of binding is greater
ii. The greater the proportion of spare receptors, the more sensitive the target cell to the agonist
d. The number of spare receptors can vary at different tissue sites
i. Thus, tissue sensitivity can be changed by changing spare receptor concentration
18. So what is the role of spare receptors
a. Increases the sensitivity of target cells to activation by low levels of ligand
20. What is effective dose (ED)
a. ED50= drug dose effective in 50% of population
21. What is lethal dose (LD)
a. LD50=leathal dose for 50% of the population
22. What is the therapeutic index?
a. LD50/ED50
i. Serves as margin of drugs safety
ii. Higher ratio= more safe and less toxic
iii. 20 or more = relatively save
iv. 100 preferred
23. When is an example of when you have a very low therapeutic index that you can still give to patients
a. Cancer medicine, give them as much as they can handle without dying
b. Same with digitalis
24. What is the ED99?
a. Dose in which the drug is effective for 99% of population
25. What is LD1?
a. Lethal dose for 1% of population
26. What is the certain safety factor (CSF)?
a. CSF=LD1/ED99
27. What are non-specific binding sites (2 examples); Is an action initiated as a result of binding?
a. The idea that drugs don’t just bind to receptors
b. They bind to other body molecules
c. a1-acid glycoprotein
d. serum albumin
e. No action is initiated as a result of binding to non-specific binding sites
28. What are anti-metabolites
a. Enter biochemical reactions in place of normal substrate “competitors”
b. Result in biologically inactive product
What determines if something is toxic?
DOSE, not nature
What does receptor affinity determine?
the drug concentration required to form a significant number of drug-receptor complexes
What is affinity a measure of?
tightness that a drug binds to a receptor
Km=?
concentration of substrate needed to reach one half Vmax
What is potency related to?
the drug binding affinity
what is efficacy related to?
rate and extent of receptor activation AFTER drug binding
how do responses correspond to amount of dosage given
low dose: large effect
high dose: small effect (do to saturation of receptor)
EC50 is directly equal to what other term?
Kd
Km=?
Vmax/2
What is Emax?
max response achieved by agonist
also referred to as efficacy
What is potency?
amount of drug needed to produce a given intensity effect
(eg. 10 mg of morphine is more potent than 100 mg of Demerol)
What is maximum effect?
greatest response produced regardless of dose used
what is efficacy?
large response of max effect (Emax) a drug can produce
Is a cell with more spare receptors more or less sensitive?
More!
with more spare receptors what happens to the relationship between ED50 and Kd?
get a greater difference (whereas they would be equal if there were no spare receptors)
What are 2 examples of non-specific binding sites?
serum albumin, alpha1-acid glycoprotein