Mechanisms of Drug-Receptor Interactions (Pharmacodynamics)

Question 1

Receptors location:

Answer 1

membrane, cytoplasm or nucleus

Question 2

Receptors structure:

Answer 2

protein

Question 3

Receptor function:

Answer 3

activates or inhibits

Question 4

What is signal transduction?

Answer 4

is the process by which molecular signals are transmitted from OUTSIDE a cell to INSIDE a cell, ultimately resulting in a cellular response

Question 5

What are the 4 receptor families?

Answer 5

1. G-protein-coupled receptors
2. Ligand-gated ion channels
3. Enzyme-linked receptors
4. Intracellular receptors

Question 6

G-protein coupled receptors (GPCRs):

Answer 6

most common site of drug action - most targeted by drugs

Question 7

G-protein coupled receptors (GPCRs) mechanism:

Answer 7

1. Receptor
2. G-protein
3. Second messengers (cAMP, IP3, DAG & Ca2+)
4. Protein kinases
5. Biological responses

Question 8

GPCR activation can either…

Answer 8

INCREASE or DECREASE production of second messengers

Question 9

What are examples of GPCRs?

Answer 9

ex: muscarinic receptors, adrenergic receptors, dopamine receptors

Question 10

What are the 3 G-protein isoforms?

Answer 10

Gαs → stimulates adenylate cyclase (AC↑) → cAMP↑

Gαi → inhibits adenylate cyclase (AC↓) → cAMP↓

Gαq → stimulates phospholipase C (PLC ↑) →IP3, DAG, Ca2+

Question 11

What is the Ligand-gated ion channels concept?

Answer 11

• Ion channels are pore-forming membrane proteins that control ions across membrane.
• Abundant on excitable cells, e.g. neurons, muscle cells

Question 12

Ligand-gated ion channels classification:

Answer 12

LGICs and Voltage gated ion channels (VGICs)

Question 13

LGICs vs. Voltage gated ion channels (VGICs)

Answer 13

LGICs: ligand binding

VGICs: Changes in electrical membrane potential

Question 14

Describe the LGICs mechanism:

Answer 14

• binds to ligands (conformational change in receptor) & opens channel
• SELECTIVE permeability
• DIRECTION of movement is determined by electrochemical gradient (influx or efflux)

Question 15

What are examples of Ligand-gated ion channels (LGICs)?

Answer 15

ex: nicotinic receptor (Na+), GABA receptor (Cl-), glutamate NMDA (Ca2+)

Question 16

What is the Enzyme-linked receptors mechanism?

Answer 16

induce tyrosine phosphorylation

Question 17

What are examples of Enzyme-linked receptors?

Answer 17

ex: growth factor receptors, insulin receptor, cytokine receptor

Question 18

Where are Intracellular (nuclear) receptors located?

Answer 18

in intracellular (cytosol or nucleus), NOT IN MEMBRANE

Question 19

What are the receptor ligands in Intracellular (nuclear) receptors?

Answer 19

are lipid soluble

Question 20

What is the mechanism of Intracellular (nuclear) receptors?

Answer 20

ligand binds to receptor –> bound receptor translocates to nucleus –> binds to DNA –> REGULATE GENE EXPRESSION

Question 21

What are examples of Intracellular (nuclear) receptors?

Answer 21

ex: steroid receptors (estrogen receptor), glucocorticoid receptor

Question 22

What is the duration of effect of activated receptors?

Answer 22

Intracellular (nuclear) receptors (LONGEST - hours to days) > Enzyme-linked receptors > GPCR > LGIC (SHORTEST - ms’s)

Question 23

What are the relationships b/t drug dose & the pharmacologic response?

Answer 23

1. Relationship of drug concentration to receptor binding
2. Relationship of drug concentration to pharmacologic
   effect

Question 24

Describe the relationship of drug concentration to receptor binding

Answer 24

Bmax: the maximal specific binding of a ligand (drug) to receptor

Kd: represents the concentration of drug at which half-maximal binding is observed

Affinity: strength of binding b/t a ligand & its receptor
- Kd –> affinity; Kd lower indicates affinity higher

Selectivity - preference for one receptor over another
- Kd R1 < R2 –> affinity R1 > affinity R2 –> selectivity R1 > selectivity R2

Question 25

Describe the relationship of drug binding to pharmacologic effect

Answer 25

Emax : the maximal effect induced by a drug (agonist)

EC50 : the concentration of drug producing an effect that is
50 percent of the maximum

Potency: detect drug amount required to produce a given percentage of its maximal effect
- EC50 –> potency; Lower EC50 indicates higher potency

Efficacy: the ability of a drug (agonist) to elicit a biological response
- Emax –> efficacy; Higher Emax indicates higher efficacy
- In selecting a drug, efficacy is usually more important than potency

Question 26

What are agonists?

Answer 26

bind to a receptor & elicit a biological response: have affinity & efficacy

can be blocked by antagonist

Question 27

Full agonists:

Answer 27

good efficacy

Question 28

Partial agonists:

Answer 28

low efficacy

Question 29

What happens when partial agonists are used alone?

Answer 29

When administered alone, partial agonist
activates the receptor

Question 30

What happens when partial agonists are used with full agonist?

Answer 30

When administered in the presence of a full
agonist, the partial agonist reduces the
effects of the full agonist

Question 31

What are antagonists?

Answer 31

bind to a receptor, no biological response: have affinity, but no efficacy (if an agonist is not present)
- can decrease the actions of another agonist drug or endogenous ligand

Question 32

Antagonist vs Partial agonist

Use alone: biological response?

Answer 32

Antagonists: produce no biological response

Partial agonists: produce biological response

Question 33

Antagonist vs Partial agonist

Use with full agonist: biological response?

Answer 33

Antagonists: reduce a full agonist-produced biological
response

Partial agonists: reduce a full agonist-produced
biological response

Question 34

Antagonist vs Partial agonist

Use antagonist with partial agonist together:
biological response?

Answer 34

Antagonists reduce a partial agonist-produced
biological response

Question 35

What is the Competitive antagonists mechanism? What is the effect on agonist?

Answer 35

bind to the same site with agonists; increasing agonist - overcome the inhibition;

• effect on agonist: shift dose-receptor curve to right; EC50 higher, potency lower; less effect on Emax & efficacy

Question 36

What are irreversible antagonists? What is the effect on agonist?

Answer 36

bind to same site (very high affinity) or allosteric site; increasing agonist - cannot overcome the inhibition

effect on agonist: no shift of dose-receptor curve; less effect on EC50 & potency; Emax and efficacy lower

Question 37

Describe the Variation in drug responsiveness: Hyporeactive, Hyperreactive, & Idiosyncratic

Answer 37

Hyporeactive: a lower response to a drug than
is usual among the population.

Hyperreactive: a higher response to a drug than
is usual among the population.

Idiosyncratic: individuals exhibit an unusual
drug response
- genetic differences, immunologic reaction

Question 38

Describe the Variation in drug responsiveness: Tachyphylaxis, Tolerance

Answer 38

Tachyphylaxis: an acute rapid loss of response to a drug

Tolerance: a chronic gradually loss of response to a drug

receptor desensitization –> tachyphylaxis & tolerance
- reduced receptor response to an agonist

Question 39

What are adverse effects of drugs?

Answer 39

an undesired harmful effect from a medication

Question 40

Therapeutic index (TI)

What is TI?

Answer 40

comparison of the drug amount that causes the therapeutic effect to the amount that causes toxicity.

TI = TD50/ED50

Used for safety measurement

Question 41

What is therapeutic window?

Answer 41

the range between the minimum toxic dose and the minimum therapeutic dose

TI is high - therapeutic window is wide - safety is high

High affinity - high selectivity - high TI - high safety