Lecture 1 - Pharmacodynamics

Define the term pharmacodynamics and distinguish it from pharmacokinetics

Pharmacodynamics = effect of a drug on the body

(think dynamic is drug 1st)

Pharmacokinetics = effect of the body on a drug (ADME)

Understand how the physical properties of drugs and receptors determine their interactions

Drug + Receptor = Lock & Key = conformation determines function

RECEPTORS - interact with drug and initiate response

• Physiological = bind to endogenous ligands made in body (B-andregenic)

• Generalized = drug can bind but is not normally a receptor (Na+ channels)

DRUGS - interact with system to cause physiological effects

• Small molecules = most traditional drugs (ibuprofen)/Lipinski 5

• Large molecules/biologicals = peptides and antibodies (GLP1s)

Describe the types of bonds in drug receptor binding

most commonly hydrogen bonds, rarely covalent bonds

Define the term selectivity and describe its relationship to drug dose and side effects

Selectivity - drug’s ability to bind to specific receptors

• most drugs bind to one receptor in multiple tissues

• OR bind to different receptors as [ ] increases

• necessary to determine the dose that will maximize beneficial effects while minimizing adverse ones

Define affinity and K_D and the relationship between the two

Affinity - how strong attraction is between drug and receptor

K_D - equilibrium dissociation constant; [ ] where 50% of receptors are bound by drug

• Low K_D = high affinity = high attraction

• High K_D = low affinity = low attraction

Understand the differences between full and partial agonists

Full agonist - binds with full potential

Partial agonist - can decrease full agonist if given together

Understand the differences between competitive and irreversible non-competitive antagonists

Competitive antagonist - surmountable, more drug needed for effect

Irreversible non-competitive antagonists - insurmountable, covalent binding

Describe the difference between orthosteric and allosteric drugs and describe positive and negative allosteric modulators

• Orthosteric - bind to primary agonist site of a receptor

• Allosteric - bind to secondary agonist site of a receptor, up or down regulate binding/efficacy

  • PAM = more effective

  • NAM = less effective

Understand that many receptors can exist in an active signaling conformation in the absence of agonists and describe how inverse agonists work

Constitutive signaling - low levels of activation that happen without agonists

• Agonists keep R* active conformation

• Antagonists do no action but keep agonists from changing conformation

• Inverse agonists promote R inactive = no constitutive signaling

Understand the relationship between drug-receptor interactions and the pharmacological effects of drugs in terms of potency and efficacy

Potency - how much [drug] is needed for desired effect?

Efficacy - how large is the effect?

Describe the function of second messengers in cellular communication

Second messengers = signal cascade = amplification relay

Interpret dose-response curves in terms of the relationship between a drug and its pharmacological effects

Define the terms effective dose 50 (ED₅₀) and E_MAX and describe how they relate to drug potency and efficacy

ED₅₀/EC₅₀ - [ ] or dose needed to reach 50% of max effect (potency)

E_MAX - max effect produced by the drug or endogenous agonist (efficacy)

Determine ED₅₀ from a dose response curve

ED₅₀ on a given graph is the [ ] on the x-axis where the y-axis is at 50%

Rank drugs in terms of efficacy and potency based on their dose response curves

POTENCY - less drug for response is more potent

• more left = more potent

• more right = less potent

EFFICACY - height of graph

• lower max peak = less effective

• higher max peak = more effective

Relate drug effects to receptor binding: how does affinity/K_D relate to potency/ED₅₀

• Low K_D = Low ED₅₀

• High K_D = High ED₅₀

Classify drugs as full, partial or inverse agonists based on dose response curves

• Full agonist should hit 100% (E_MAX)

• Partial agonist should be below 100%

• Antagonist alone should be no response or 0%

• Inverse agonist should reverse the response

Distinguish between quantal and graded dose responses

Quantal dose response - all or nothing effects

• Y-axis is % of people responding

Graded dose response - effect has a scaling response

• Y-axis is response E/E_MAX

Recognize and interpret quantal dose response curves when plotted cumulatively or non-cumulatively

Quantal dose will have % population instead of % response (wrong in image)

Define the terms median effective toxic and lethal doses (ED₅₀ TD₅₀ and LD₅₀) determine their values from quantal dose response curves and use them to calculate a therapeutic index (TI) and margin of safety (MOS)

• ED₅₀ - median effective dose - [ ] needed to induce effect of drug in 50% of population

• TD₅₀ - median toxic dose - [ ] needed to induce adverse effects of drug in 50% of population

• LD₅₀ - median lethal dose - [ ] needed to kill in 50% of population

CALCULATIONS

• TD₅₀ or LD₅₀ / ED₅₀ = TI

• TD₁ or LD ₁/ED_{99 = MOS}
  

Rank drugs in terms of safety based on TI and margin of safety

Higher TI and MOS values = safer drug

Define tolerance, tachyphylaxis and sensitization and depict them in shifts on dose response curves

• Tachyphylaxis/Tolerance - decreased response with multiple of the same doses

  • Densitize = receptor is phosphorylated » bind B-arrestin

  • Inactivation = long term change, remove receptor from membrane

• Regulation - change # of receptors (ex. downregulation leads to tolerance)