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Pharmacology > Pharmacodynamics: Drug-Receptor Interactions > Flashcards

Pharmacodynamics: Drug-Receptor Interactions Flashcards

1
Q

Pharmacokinetics v. Pharmacodynamics

A
  • Pharmacokinetics = the study of what body does to a drug to affect the movement of drug into, through, and out of the body (ADME)
  • Pharmacodynamics = the study of the mechanisms of drug action and the relationship between drug concentration and effect
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2
Q

Components of pharmacodynamics

A
  • Drug-receptor interaction
  • Mechanism of drug action
  • Efficacy/toxicity
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3
Q

Effective dose (ED)

A

= the amount of drug (mg, gram, grains) administered that results in drug plasma concentrations within the therapeutic range

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4
Q

ED50

A

= the dose needed to produce the desired therapeutic effect in 50% of the population of animals to which it is given
–Starting point for therapeutic index

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5
Q

Therapeutic index (TI)

A

= a measure of drug safety; the ratio of the dose that produces toxicity to the dose that produces a therapeutic response in 50% of the individuals
TI = TD50/ED50

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6
Q

Therapeutic window

A

High TI = big therapeutic window = safer drug

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7
Q

Type of drug effect

A
  • Stimulation
  • Inhibition
  • Replacement
  • Irritation
  • Cytotoxicity
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8
Q

Mechanism of drug action

A

Non-receptor mediated:

  • Osmotic diuretics/purgatives
  • Heavy metal chelating agents
  • Local antacids

Receptor mediated:
-Majority of targeted drug therapy

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9
Q

Drug is designed based on the ligand-receptor response

A

Ligand/drug binds to receptor –> send cell signal –> cellular event

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10
Q

Major site of action - Receptor

A

A macromolecular component (usually protein) of a cell with which a drug interacts to produce a response:

  • Membrane proteins
  • Enzymes
  • Nucleic acids
  • Others: lipids and polysaccharides
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11
Q

Macromolecular types of protein receptors

A
  • Transport proteins (ex: Na/K ATPase ion channel targeted by Digoxin (cardiac drug))
  • Catalytic enzymes (ex: Dihydrofolate reductase targeted by methotrexate (anti-cancer drug))
  • Structural proteins (ex: Tubulin targeted by colchicine (anti-gout drug))
  • Regulatory proteins (ex: Glucocorticoid receptor targeted by glucocorticoids (anti-inflammatory drug))
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12
Q

Receptor Functions

A
  • Interaction with specific ligand (ligand binding domain)

- Transduction of signal into response (effector domain)

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13
Q

Characteristics of ligand-receptor response

A
  • Receptors must have structural features that permit ligand affinity and specificity
  • Receptors must be biologically important molecules with selectivity of response
  • The biological response is proportional to ligand bound receptors with sensitivity (predictable amount of response when it binds to that receptor)
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14
Q

Receptor occupation theory

A

Effect (E) is proportional to the fraction of occupied receptors (DR) - determined by drug concentration (D) and receptor binding ability (K); receptor (R)
K1
D + R DR –> E
K2

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15
Q

Efficacy

A

Potential maximum drug response (E)

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16
Q

Affinity

A

Propensity of a drug to stay binding to the receptor (K)

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17
Q

Potency

A

Amount of drug needed to produce an effect (D)

more potent –> less drug needed

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18
Q

Functional types of ligands

A
  • Agonist

- Antagonist

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19
Q

Agonist

A

Has affinity for binding to the receptor and efficacy for eliciting the response (Induces active conformation of the receptor protein and elicits a response)

  • Agonist alone elicits full efficacy
  • Example: epinephrine
20
Q

Antagonist

A
  1. Has affinity but no intrinsic efficacy (does not trigger an intrinsic response, even though it fits in the binding site)
  2. Blocks the action of agonist
  3. Action only observed in presence of agonist
    (Occupies receptor without conformational change –> no response)
    -Example: Adrenergic receptor beta-blocker
21
Q

Competitive Antagonist

A

Agonist efficacy can be fully rescued by increasing agonist at the cost of potency

  • If competitive antagonist is > agonist –> limited response
  • If agonist is > competitive antagonist –> can overcome and produce a significant response
  • *Decreased potency –> more drug needed –> reach full efficacy
22
Q

Non-competitive Antagonist

A

Agonist efficacy cannot be rescued by increasing agonist

*Agonist cannot compete against a non-competitive antagonist (irreversible binding) –> decreased efficacy

23
Q

Potency v. Efficacy

A
  • Maximal effect % (y axis) v. log concentration (x axis): logarithm compresses and proportionate doses at equal intervals
  • EC50: the agonist concentration that can produce 50% of maximal effect
  • Lower EC50 indicates higher potency
24
Q

Agonists differ in efficacy

A

Highest % response has the greatest efficacy

25
Q

Agonists differ in potency

A

The more potent drug takes smaller drug concentration to achieve the max % response
*Compare EC50 - smaller EC50 has the greatest potency

26
Q

Competitive antagonists decrease agonist potency

A

Agonist + competitive antagonist take more drug concentration to achieve the max % response

27
Q

Non-competitive antagonists decrease agonist efficacy

A

Agonist + non-competitive antagonist decreases the drug response at the same drug concentration

28
Q

Partial agonist

A

Has affinity but lower efficacy and potency than a full agonist
*Can have both full agonist and partial agonist present at the same time

29
Q

Two state receptor theory

A
  • Full agonist binds to active receptor - sustained activation
  • Antagonist binds equally to both active and resting receptor - balanced
  • Inverse agonist binds to resting receptor - sustained inactivation
30
Q

Inverse agonist

A
  • An inverse agonist binds to the receptor to exert the opposite pharmacological effect of an agonist
  • -Ex: Histamine H2 blocker - Cimetidine reduces basal cAMP level
  • Different from an antagonist, which binds to the receptor but does NOT reduce basal activity of the receptor
31
Q

Agonist v. antagonist v. inverse agonist

A
  • Agonist –> positive efficacy
  • Antagonist –> zero efficacy
  • Inverse agonist –> negative efficacy
32
Q

Receptor occupancy and biological response

A
  • Biological stimulus
  • -Threshold effect (0% response)
  • -Max effect (100% response)
  • Receptor occupancy
  • -Threshold effect (20% occupancy)
  • -Max effect (70% occupancy; with receptor reserve - 100% occupancy)

-In some systems, maximal effect does not require occupation of all receptors by agonists (=spare receptor)

33
Q

Effect of spare receptor on partial agonist

A

In the presence of spare receptor, increasing partial agonist can reach maximal effect

  • Full agonist - full intrinsic efficacy
  • Partial agonist - lower intrinsic efficacy
34
Q

Tolerance

A

Reaction to a drug is reduced, requiring an increase in concentration to achieve the desired effect

  • Innate
  • Acquired
  • Acute
  • Cross
35
Q

Innate tolerance

A

Lack of sensitivity to a drug due to genetic variation

36
Q

Acquired tolerance

A
  1. Pharmacokinetic tolerance: repetitive administration causes a decrease in drug absorption or an increase in drug metabolism
  2. Pharmacodynamic tolerance: decrease in the number/sensitivity of receptors
37
Q

Acute tolerance (Tachyphylaxis)

A

Acute development of tolerance after a rapid and repeated administration of a drug in shorter intervals
-Ex: Sympathomimetic ephedrine depletes noradrenaline from the nerve terminal

38
Q

Cross tolerance

A

Among drugs that belong to the same or similar pharmacological category
-Ex: Anti-anxiety drug-hypnotics-anesthetics

39
Q

Desensitization and Down-regulation

A
  1. Prolonged/continuous use of an agonist: Decreased receptor sensitivity (activity on signaling transduction) or receptor number
    - Ex: Bronchodilator beta2-agonist - NOT for continuous use
  2. Inhibition of ligand degradation
40
Q

Sensitization and Up-regulation

A
  1. Prolonged/continuous use of a receptor blocker: Increased receptor sensitivity (activity on signaling transduction) or receptor number
    - Ex: Anti-arrhythmic Beta-blocker - DO NOT discontinue abruptly
    - -Body tries to compensate with sympathetic nervous system by releasing epinephrine –> increased number of receptors are open for epinephrine binding –> extreme tachycardia
  2. Inhibition of ligand synthesis or release
41
Q

After ligand/drug receptor interaction

A

–> Activation of the receptor to induce downstream signaling transduction

42
Q

Functional types of receptors

A
  • Ligand-gated ion channel
  • G protein-coupled receptor
  • Enzyme-linked receptor
  • Nuclear receptor
43
Q

Ligand-gated ion channel

A
  • Ligand-binding and pore-forming proteins in the cell membrane
  • Signal molecule binds as a ligand at a specific site on the receptor –> conformational changes open the channel allowing ions to flow into the cell –> the change in ion concentration within the cell triggers cellular responses
  • -Ex: Na/K ATPase ion channel
44
Q

G protein-coupled receptor

A
  1. Seven-transmembrane polypeptide helices
  2. Receptor interacts with G protein at the cytoplasmic side of the helices upon ligand binding
    - Ex: Adrenergic receptor
45
Q

Enzyme-linked receptor

A

Ligands bind to both receptors –> the two receptor polypeptides aggregate forming a dimer –> Activates the tyrosine-kinase parts of the dimer –> each phosphorylates (using ATP) the tyrosines on the tail of the other polypeptide –> receptor proteins are now recognized by relay proteins inside the cell –> relay proteins bind to the phosphorylated tyrosines (may activate 10 or more different transduction pathways)
–Ex: tyrosine kinase receptor; insulin receptor

46
Q

Nuclear receptor

A

Ligand binds to the receptor in the cytoplasm –> ligand-receptor binding leads to conformational change and nuclear localization –> nuclear receptor binds to DNA to increase transcription and the consequent protein expression
–Ex: Hormone receptor; glucocorticoid receptor

Pharmacology (6 decks)

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