Pharmacology - Pharmacodynamics

What is pharmacodynamics?

The study of the biochemical and physiological effects of drugs and their mechanisms of action

What do agonists do?

Activate receptors. Primary agonists interact with the same recognition site as endogenous compounds (orthosteric binding site)

What do antagonists do?

Block binding of agonists to receptors

What do inverse agonists do?

Produce the opposite action of agonists at receptors

What do allosteric modulators do?

Modify receptor activity at allosteric sites (modify agonist activity). Allosteric binding sites are distinct from orthosteric binding sites

What are orthosteric sites?

A site for endogenous ligand. Competitive inhibitors, highly conserved amino acid residues

What are allosteric sites?

Sites that modulate binding to orthosteric site. May also directly activate or inhibit receptors. Less highly conserved

What is the difference between a full and partial agonist?

Full agonists push equilibrium in which active sites predominate while partial agonists only activate some of the sites

What is pharmacophore?

The chemical properties required for optimal receptor interactions (size, shape, position, and orientation of functional groups)

What is the purpose of G protein-coupled receptors?

Mediate slow onset, long duration drugs

What is the sequence of activation of G protein-coupled receptors?

1. Agonist binding to receptor (active state) 2. Exchange of GDP for GTP on G protein 3. Dissociation of G𝛼 -GTP subunit from G𝛽𝛾 subunits

4. Activation or inhibition of second messengers (e.g., Gs𝛼 activates adenylyl cyclase, Gi𝛼 inhibits adenylyl cyclase)

5. Intrinsic GTPase activity of G 𝛼 subunit results in inactivation and recombination with G𝛽𝛾 subunits

What is the purpose of Gi receptors?

Inhibit adenylyl cyclase

What is the purpose of Gs receptors?

Stimulate adenylyl cyclase

What is the purpose of Gq receptors?

Stimulates phospholipase C

What is the purpose of G olf receptors?

Olfactory G protein mediates olfactory sensation

What is the purpose of Gt receptors?

Transducin, mediates sensitivity to light

What is the purpose of muscarinic M1, M3, and M5 receptors?

Activate Gq family of G proteins. Promote phosphoionositide metabolism

What is the purpose of muscarinic M2 and M4 receptors?

Activate the Gi/o family of G proteins. Inhibit adenylyl cyclase, decreases cAMP

What is the purpose of the adrenergic 𝛽1 , 𝛽2 and 𝛽3 receptors?

Activate the Gs family of G proteins. Stimulate adenylyl cyclase, increase cAMP

What is the purpose of the adrenergic 𝛼1A, 𝛼1B and 𝛼1D receptors?

Activate the Gq family of G proteins. Promote phosphoionositide metabolism

What is the purpose of the adrenergic 𝛼2A, 𝛼2B and 𝛼2C receptors?

Activate the Gi family of G proteins. Inhibit adenylyl cyclase, decrease cAMP

What are ion channels?

Free standing ion channels that regulate the flow of ions into and out of the cell

What are some examples of drugs that target voltage-gated ion channels?

Lidocaine (inhibit Na+ channels), nifedipine, verapamil (inhibit Ca2+ channels)

What are ligand-gated ion channels?

Channels that regulate ion flow in response to extracellular signals. Can be excitatory or inhibitory depending on ion flow

What are some examples of ligand-gated ion channels?

Nicotinic receptors (Na+ channel)

Mediate fast-onset, short duration responses to acetylcholine

GABA A receptors

(Cl- channel)

Predominant inhibitory receptor in the CNS

What are transient receptor potential channels (TRP)?

Regulate physiological and sensory processes including perception of pain, heat and cold, and chemical stimulation

What are receptors as enzymes?

Receptors that have catalytic activity (tyrosine kinases, phophatases). Influence long term changes

What is the purpose of cyclic GMP signaling?

Important pathways for maintaining normal blood pressure

Nuclear transcription?

Hormone receptors regulate gene transcription within the nucleus (steroid receptors, retinoic acid receptors). Response elements alter rates of gene transcription

What is the purpose of a dose response curve?

Determines binding affinity and drug activity in a quantitative measure

How can drug affinity and potency be measured?

Kd and EC50 values

How can binding and activity be measured?

Bmax and Smax values

At what point will 50% of receptors be occupied by a drug?

When [D] = KD (equilibrium dissociation constant)

What is the KD equation?

KD = [D][R]/[DR] = k2/k1

What are competitive antagonists? What do they do to agonist dose response curves?

Indicated when agonist (A) and antagonist (I) compete for the same binding site on the receptor. Push agonist dose response curves to the right

What are irreversible antagonists? What do they do to agonist dose response curves?

Indicated when antagonist (I) dissociates slowly from receptor. Shifts dose response curves to the right

What are allosteric antagonists? How do they affect agonist receptor affinity?

Antagonist (I) or allosteric modulator (NAM) binds at a different site on receptor. Decreases apparent affinity of agonist for receptor (may also depress maximal response). Noncompetitive

What are allosteric enhancers? How do they affect agonist receptor affinity?

Potentiator or positive allosteric modulator (PAM) binds at a different site on receptor. Increases apparent affinity of agonist for receptor (enhances agonist potency and may also enhance agonist maximal response - increase efficacy). Noncompetitive

LOOK OVER EQUATIONS

What are cholinergic receptors activated by?

Acetylcholine

What are muscarinic receptors activated by?

G-protein coupled receptors

What are nicotinic receptors activated by?

Ligand gated ion channels

What are adrenergic receptors activated by?

Epinephrine and norepinephrine

What are receptors with an unknown endogenous compound?

Orphan receptors