Pharmacodynamics

3-D structure of drug/receptor, chemical reactivity, and affinity for lipids/water

What influences drug-receptor interactions? (3)

Reversible (Drug-R Bonds)

Hydrogen, ionic, hydrophobic/VdWaals

(Reversible or irreversible?)

Irreversible (Drug-R Bonds)

Covalent bonds, rare

(Reversible or irreversible?)

Agonists (I)

Drug class binds to and alters activity of receptor, mimicking endogenous ligand

Full, partial, inverse

(3) subtypes of agonists

Full agonist

Agonist produces maximal effect similar to endogenous ligand

Partial agonist

Agonist produces submaximal effect similar to endogenous ligand

Reversibly, full agonist

Partial agonist

• Bind __ (reversibly/irreversibly) to agonist site

• ONLY do their function in absence of a __ __ (drug)

Inverse agonist

Agonist produces negative effects by inhibiting constitutive activity; Stabilize the inactive receptor conformation

Antagonists (I)

Drug class binds to and inactivates receptor “blockers/inhibitors”

(General class)

Competitive and non-competitive

(2) subtypes of antagonists

agonists, action

Antagonists prevents the action of __, but DO NOT have an __ on their own (like agonists)

Competitive antagonist

Antagonist binds to active site reversibly

Agonists, can, right, agonist potency, efficacy

Competitive Antagonist

• Compete with __ for binding to receptor active site

• Blockage __ (can/not) be overcome by increasing concentrations of agonist (E50)

  • Such increase in E50 shifts dose-response curve to the __

  • Reduces __ __

  • __ unchanged

right, no change

Competitive antagonist curve

• Parallel shift in EC50 to the __

• With __ __ in maximum response

Competitive Antagonists

Competitive/Non-C Antagonists

Non-competitive Antagonists

Competitive/Non-C Antagonists

Irreversibly, reversibly, irreversibly

Non-Competitive antagonists: 

• Either bind to active site __

• bind at allosteric site __ or __

(Reversibly/irreversibly)

Pseudo-irreversible

Non-competitive antag. binding without a covalent bond may be reversible, however tight bind means dissociation is very slow

Not, efficacy

Non-Competitive Antagonists

• Blockage __ (can/not) overcome from increasing concentrations of agonist

  • Decreases __

Downward, no change

Non-competitive antagonist curve

• __ shift in maximal response /efficacy

• __ __ in EC50

Neutral Antagonists

Most of this drug class have no intrinsic efficacy (cannot activate Rs)

Allosteric Modulators

Enhance/inhibit agonist action at different site than agonist binding site

Activator, inhibitor, not

Allosteric Modulators

• Allosteric __ = facilitate agonist action, allosteric

• Allosteric __ = Inhibit agonist action, allosteric

• *Effects __ (can/not) be overcome by increasing concentration of agonist

Constitutive Activity

Basal level of physiologic response in absence of agonist

Constitutive Activity drug curve

Effect of receptor alone, baseline activity

Intrinsic Activity

Ability of drug to stabilize active state and produce a response

Intrinsic Activity drug curve

Effect of drug + receptor

Neutral Antagonism

Indicates antagonists have 0 intrinsic efficacy

Intrinsic Activity drug curve

No response from antagonists alone

Concentration, maximal

Receptor Occupancy Theory

• As drug __ increases: 

  • Drug effect increases until some __ effect occurs

EC50

Drug concentration necessary for which half-maximal effect/response occurs

Kd

Drug concentration which half-maximal R binding occurs

Binding, low, binding

Receptor Occupancy Theory

• __ of drug to Rs increases until all of Rs are occupied

• Higher affinity = __ Kd

  • lower concentrations of drug needed to have drug __ to R

Graded Log Dose-Response Curves

Indicate maximal efficacy of drug in single person (curve)

Action/response, continuous

Graded Log Dose-Response Curves

• Y-axis - __/__ as a __ variable

Efficacy

Magnitude of a response a drug causes when it interacts with receptor

Independent, complexes

Efficacy

• __ (dependent/independent) of binding affinity

• Dependent on number of drug-receptor __ formed and intrinsic efficacy of drug

Dependent, coupling, more

Potency

• __ (dependent/independent) of binding affinity

• Dependent on number of drug-receptor __ to physiologic response (intrinsic efficacy)

  • Lower EC50 = __ potent

Potency

Amount or concentration of drug necessary to produce particular effect

antagonist, inverse agonist, full agonist, partial agonist

Agonists vs antagonists

Quantal dose-response curves

Indicate the potential variability in responsiveness of individuals relative to populations

Binary, ED50, TD50, LD50

Quantal dose-response curves

• Defined response is __ (does or does not occur pattern)

• Used for determining __ (median effective dose), __ (median toxic dose), __ (median lethal dose)

% of individuals responding to drug

Y-axis of Quantal dose-response curves

Therapeutic Index (TI)

Indicates relative safety of drug

TD50/ED50

TI =

Safer drug

Higher TI means a….

Therapeutic Window

Dose range between minimal therapeutic response and minimal toxic response are observed

Tolerance

Gradual reduction in drug effects over days/weeks of drug exposure

Higher, clearance, endocytosis

Tolerance

• __ dose required to produce given response

• Mechanisms - Enhanced __, __

Tachyphylaxis

Rapid desensitization to drug effects in seconds to minutes

Not, molecular, phosphorylation, 3D, uncoupled, depletion

Tachyphylaxis

• Higher dose may __ improve responsiveness, cells make __ adjustments

• Mechanisms

  • Receptor __

  • endocytosis, __ modification

  • __ 2nd messenger

  • __ of vesicle

Down, desensitization, up, sensitization

• Chronic agonist exposure results in receptor __-regulation or __

• Chronic antagonist exposure results in receptor __-regulation or __

Receptor trafficking

Movement of receptors between plasma membrane and internal membrane-bound compartments

Lysosomes, plasma membrane

From receptor trafficking:

• Internalized Rs may be degraded in __ or shuttled back to the __ __