Pharm - CH 2: Pharmacodynamics

Pharmacodynamics

• actions of drug on the body

  • drugs interact w/ receptors on cell surface/within cell to create an effect

  • drug receptor complex —> alterations in biochemical/molecular activity

Drug-Receptor Complex

Produce a biological response

Produces a signal transduction —> biological response

Ligand

• Refers to s small molecule that binds to receptor protein

  • can be naturally occuring or a drug

  • can initiate a series of rxns that result in biological response 

• Examples: ACH, NE, Epi, Dopamine

Affinity

measure of how tightly a drug bind to the receptor

Intrinsic activity

The ability of the drug-receptor complex to produce maximum functional biologic response

Note: not the same as affinity, which is the ability to bind to the receptor

Agonist

• Affinity for receptor = binding to active site

• Activates site —> cause intrinsic activity

= affinity + intrinsic activity

Antagonist

• Affinity for receptor = binding to active site

• Activates site —> no intrinsic activity

= affinity + no intrinsic activity

Major Receptor Families in Our Body

1. Transmembrane Ligand-Gated Ion Channel Receptor

2. Transmembrane G-Protein Coupled Complex

3. Enzyme Linked Receptor 

4. Intracellular Receptors

Transmembrane Ligand-Gated Ion Channel Receptor

• Regulates ion flow across membrane

• changes in membrane or ionic concentration w/n cell (Cl-/Na+)

Ex. nicotinic receptors for neurotransmission, cardiac conduction, muscle contraction

Transmembrane G-Protein Coupled Receptor

• Extracellular domain binds to ligand

• Intracellular domain of receptor linked to G-protein —> activates second messenger

  • Second messengers = molecules that relay signals from receptors on cell surface to target molecules inside cell, cytoplasm, nucleus

  • Often activated adenyl cyclase —> cAMP

  • everything between g-protein receptor and biological response is second messenger

• protein phosphorylation

Ex. alpha and beta receptors, muscarinic receptors

Enzyme Linked Receptors

• Transmembrane receptor w/ enzyme as integral part as receptor

  • binding activates/inhibits intracellular enzyme 

• protein + receptor phosphorylation

Ex. insulin receptor

Intracellular Receptor

• Receptor entirely intracellular = must diffuse into cell to interact w/ receptor

  • lipid soluble

• protein phosphorylation + altered gene expression

Ex. steroid hormones

Potency

• measure of drug necessary to produce an effect 

Efficacy

• ability of drug to elicit a respons

Dose Response Relationships

1. graded dose response relationship

2. quantal dose-response curve (ED50/TI)

Graded Dose Response Relationship (EC50)

• Determines EC50

  • Effective Conc. 50 = drug dose that shows 50% of max response in an individual

  • Used to determine potency

    • smalled EC50 = more potent

• constructed for one patient

• conc. of drug increases —> magnitude of pharmacologic effect

• dose and effect vary BUT SUBJECT IS CONSTANT (1)

  • since dose and effect varies

Which drug is more potent?

Drug A b/c less amt is needed to produce an effect

• However, A and B have equal efficacy (biological effect)

The lower the EC50., the less conc. needed to produce 50% of max effect and higher potency

Which drug has the least efficacy?

Drug C = lower biological effect

Which is therapeutically more beneficial, a drug that is more potent, or a drug that has  greater efficacy?

Drug w/ greater efficacy

• A more potent drug requires a smaller dose to reach 50% of its maximum response (lower EC₅₀), but that doesn’t mean it can produce a stronger or better therapeutic outcome.

• In contrast, a drug with greater efficacy can produce a higher maximal response regardless of how much drug is needed to get there.

  • Therefore, from a clinical standpoint, efficacy determines the therapeutic usefulness of a drug, because it reflects the maximum effect that can be achieved in the body, not just the dose required to achieve it

Competitive (reversible) Antagonists

• The dose response curve is shifted to the right

• antagonist and agonist bind and compete for the same site

  • Antagonism - w/ competitive antagonist, is reversible

    • can be overcome by adding more agonist drug to the equation

  • capacity to reach maximal response still exists

• The EC50 of the agonist increases and shifts to the right in the presence of competitive antagonists

Non-Competitive (irreversible) Antagonist

• Addition of non-competitive antagonist causes a downward shift of the maximum biological effect seen by the agonist

  • no shift of curve on dose of EC50

• irreversible antagonists cannot be overcome (or competed w/) by adding more agonist to the equation

• no increase in EC50

• In the presence of a noncompetitive antagonist, the maximum effect is unattainable. increasing the dose of the agonist

Ex. Q-drug for opioid OD

Quantal Dose-Response Curve (ED50)

• plots fraction of the pop. that responds to a given dose of a drug

  • not one person

• describes conc. of a drug that produces a given effect in a pop.

• dose and pop. vary BUT EFFECT IS CONSTANT

  • compared to the graded dose response curve where dose and effect vary but subject was constant

• ED50

  • effective dose 50 = dose of drug required to produce therapeutic effect in 50% of a certain pop.

• Useful for determining drug dose to which MOST of the pop. responds to

  • also used to calc. therapuetic index

Therapeutic Index (TI)

• Measure of drug’s safety

  • determined by measuring the frequency of the desired response + toxic response at various doses of the drug

  • larger value = wider margin b/n dosed that are effective + toxic

• TI = TD50/ED50

  • doses that produce therapeutic effect and toxic effect in 50% of the pop:

    • ED50 = dose that produces therapeutic effect in 50% of the pop.

    • TD50 = dose that produces toxic and undesirable effect in 50% of the pop.

      • unwanted adverse effect

      • TD50: drug dose that produces toxic efcet on ½ pop.

      • ED50: drug dose that produces therapeutic/desired response in ½ pop.

  • measure of toxic dose (TD50)/therapeutic effect dose (ED50)

    • ratio that produces toxixity of the dose that produces a clincically desire of effective response in pop. of indivduals

Therapeutic Index =TD50/ED50  

Drug Example # 1: 1000mg/10mg= TI of 100

Drug Example # 2:  100mg/10mg= TI of 10

Q- Which drug is more safe?

Example 1, the higher the TI ratio, the safer the drug……!!!!!!!