Pharmacodynamics I and II Flashcards Preview

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Flashcards in Pharmacodynamics I and II Deck (71):
0

What are receptors?

specific molecules in a biological system with which drugs interact to produce changes in the function of the system. (Most are proteins)
*High affinity - low capacity

1

What are effectors?

Molecules that translate the drug-receptor interaction into a change in cellular activity

2

What are some examples of receptors that are not proteins?

receptors that are not proteins: nucleic acids (DNA, RNA), sugars, lipids

3

What are four factors of affinity?

- shape
- size
- charge
- atomic composition

4

Are drugs irreversibly or reversibly bound to receptors?

some drugs bind irreversibly (via covalent bonds - whole things gets endocytosed), some bind reversibly

5

Which drug has a higher affinity?
a - Drug A with Kd of 1mM
b - Drug B with a Kd of 1 nM
c - Drug C with a Kd of 1uM
d - Drug D with a Kd of 0.1uM

want drug with the smallest Kd
smallest Kd has highest affinity

answer: b - drug B with a Kd of 1nM
*Kd = dissociation constant

6

How well a drug binds to a receptor is dictated by the ____ of the drug for the receptor

affinity

D+ R DR
Kd = k^-1 / k^+1

7

Lower Kd has high or low affinity?

high affinity
(doesn't mean it will have highest effect)

8

Why do companies want to make drugs with higher affinities?

less side effects

9

What is the evidence for receptors?
FIX QUESTION

- extreme potency/efficacy of drugs
- chemical selectivity (i.e., similar molecules produce similar effects)
- molecular cloning and reconsititution

10

What are the three interrelated components of drug receptors?

- recognition
- transduction
- amplification

11

agonist

fill in

12

antagonist

fill in

13

What are two mechanisms of ...??

- ligand-gated channels

-2nd messenger linked

14

Influx of what ion will cause depolarization?

Na+

15

What are three types of metabotropic receptors involved in 2nd messenger-linked SOMETHING?

- G-protein-coupled receptors
- kinase-linked receptors
- nuclear receptors (steroids will bind these)

16

g-protein

fill in

18

What is efficacy?

- ability of a drug to induce a response by itself (i.e., antagonist has no efficacy)

18

Drugs may produce their biological effects by means of different actions on what locations?

- enzyme active sites
- on nucleic acids
- on membrane protein structures
- on transport mechanisms
- on gene transcription
- on ion channels

19

What is potency?

- potency is dosage (concentration) of a drug that is needed to induce, or block a response
--> e.g., EC50 is concentration or dose of drug that causes 50% of maximum effect

20

A drug's binding to a receptor is usually weak and easily reversible. What type of bonding/forces do these weak binding forces include?

- ionic bonds (complementary charges)
- hydrogen bonds
- van der Waals forces

*stronger, irreversible binding is done via covalent bonds

21

The binding of which, an agonist or antagonist, to a receptor causes a change in the shape of the receptor?

agonist

*after binding of an agonist, changes in membrane function or receptor conformational folding may occur - (change in shape)
* an antagonist will bind a receptor without change in receptor shape, but block the binding pocket for agonists

22

After a drug molecule interacts with a receptor, what changes occur?

- changes in distribution of chemical charges
- changes in folding of the receptor protein
and/or
- changes in drug receptor conformation

*these occur to activate the transducer mechanism to which the receptor is coupled

23

What are the three interrelated components of drug receptors?

- RECOGNITION SITE that binds the drug molecule
- TRANSDUCER mechanism that translates binding into a biochemical change
- an AMPLIFICATION mechanism

*result in alteration of cellular function

24

What does an antagonist do?

interacts with receptor recognition site to induce change in cell function (increase or decrease)

25

What does an antagonist do?

interacts with receptor recognition site but does not itself induce change in cell function, only blocks access of agonist (exogenous or endogenous) to receptor site

26

What does a partial agonist do?

interacts with receptor recognition site but a partial agonist cannot induce a maximum response

27

What is affinity?

ability and attraction of drug-receptor interaction

28

What is intrinsic activity?

ability of a drug to induce intracellular activity

29

What do ligand-gated channels (inotropic receptors) result in?

hyperpolarization or depolarization

30

What are the four drug targets (receptors) that drugs act on?

1 - ligand gated ion channels (inotropic)
2-4 - Second Messenger receptors (metabotropic)
--2- G-Protein coupled receptors (GPCRs)
--3- Kinase receptors
--4- Nuclear receptors

(enzymes (NSAIDS cox1 and cox2) and transporters are two other categories of receptors)

31

How does a G-protein-coupled receptor work?

agonist binds to receptor which activates G (+/-) by associated with receptor and exchanging of GDP on G with GTP. G protein is now active, dissociates from receptor and other subunits (gamma, beta) and interacts with other proteins/enzymes (effectors) that amplify the effect. (open up an ion channel or activate effector and second messengers)

32

How does Kinase-linked receptor work?

Receptor and Effector are same substance. R/E gets bound by substance (drug, etc.) which leads to intracellular response: protein phosphorylation --> gene transcription --> protein synthesis --> cellular effects

33

How do nuclear receptors work?

drug, etc. enter cell, enter nucleus and bind receptor in nucleus which results in gene transcription --> protein synthesis --> cellular effects

34

What are six 'pieces' of evidence for the existence of drug receptors?

- extreme potency of some drugs
- similar molecules often produce similar effects
- stereoisomers usually differ in pharmacological activity or potency
- competitive antagonists
- radioligand binding
- cloning

35

What is the overall function of Gq proteins?

to increase phospholipase C activity leading to release of PIP2 into two components:
- IP3: results in release of intracellular calcium which activates CA2+ dependent kinases
- DAG: activates protein kinase C

36

Some G proteins can activate phospholipase A2 (PLA_2) which results in the release of what from the cellular membrane?

Arachidonic acid, which is acted upon by enzymes to produce many factors including prostaglandins, thromboxanes, and leukotrienes

37

What is the overall function of Gq proteins?

to increase phospholipase C activity leading to release of PIP2 into two components:
- IP3: results in release of intracellular calcium which activates CA2+ dependent kinases
- DAG: activates protein kinase C

*exchange of GDP for GTP; alpha portion will turn on PLC; PLC will convert a lipid into triglycerol, and increases intracellular Calcium, and activates protein kinase C
(PLC activates lipids to release Calcium)

38

What can block the arachidonic Acid pathway?

- NSAIDS
- aspirin

*these act on COX

39

What happens when a nuclear receptor (found in the cytoplasm) is bound by an agonist?

these receptors will enter the nucleus and alter gene transcription

40

The concentration of drug required to bind to a receptor is a measure of what?

affinity

41

Activation of G_alpha,s leads to...

increased cAMP and PKA activity

42

Activation of G_alpha,i leads to...

decreased cAMP and PKA activity

43

Activation of G_alpha,q leads to...

- increased IP3 and DAG
- increased PKC and CAM kinase activity

44

Activation of PLA2 leads to...

increased Arachidonic Acid Release

45

Activation of Tyrosine Kinase Receptors leads to...

phosphorylate proteins

46

Activation of Adenylate Cyclase leads to...

increased cAMP and PKA activity

47

Define mass-action relationships

the greater the number of agonist molecules, the greater the number of receptors occupied at any given moment

*therefore, responses to drug are graded or dose-dependent

48

What axis is expressed on a logarithmic scale?

dose

49

What is the threshold dose?

the lowest dose that just begins to cause a response

50

What is the shape of dose-response curves?

sigmoid

51

What is ED50?

the dose that produces a 1/2-maximal response

52

What can be indicative of the presence of 'spare receptors'?

when the maximum response occurs when less than 100% of the receptors are occupied

53

What are partial agonists?

agonists whose maximum effect is less than that of full agonists and less than the maximum response of the tissue
*even if partial agonists occupy 100% of receptors, a maximum tissue response is not produced

54

What is efficacy?

the ability of an agonist to induce a biological response after interaction with a receptor

*also referred to as intrinsic activity

55

How does tissue amplification differ?

ex: biological responses can differ in children vs middle aged adults vs the elderly

56

What is potency?

the amount of drug required to bring about a response

57

Full agonist: affinity, efficacy?

- has affinity
- has full efficacy

58

Partial agonist: affinity, efficacy?

- has affinity
- deficient in efficacy

59

Pure antagonist: affinity, efficacy?

- has affinity
- no efficacy

60

What are antagonists?

they bind to the recognition site and occupy it, but are not able to activate the transducer component of the receptor system

61

What is the action of a pure antagonist?

to diminish access of agonist molecules to the receptor

62

How can an antagonist help?

it can block the excess in case of overdose of a drug or when the body itself makes too much of an endogenous molecule

63

What is characteristic of a competitive antagonist?

it can be overcome by increasing the concentration of agonist

64

What is a noncompetitive antagonist?

an antagonist that interacts irreversibly with the receptor recognition site (usually by formation of stable covalent chemical bonds)
*also referred to as irreversible antagonist

65

What is the equation for therapeutic window?

therapeutic window = TD50/ED50

66

What is the therapeutic index? How do you calculate it?

a relative measure of safety, calculated as the ratio of LD50 (lethal dose) to the ED50 for the desired effect (but can also referencce to unwanted side effects, not desired effects)

therapeutic index = LD50/ED50

67

The safer the drug, the _____ the therapeutic index.

larger

68

What happens when a partial and full agonist are used together?

a partial agonist can act like a partial antagonist in the presence of a full agonist

69

If ED50 is less than Kd, what does this say about the number of receptors?

there are excess receptors

Kd is 50% mark on drug binding curve

70

How do you tell which drug is more potent?

ED50