PCOL 1: DRUG RECEPTORS & PHARMACODYNAMICS

Component of cell or organism that interacts with

the drug leading to an effect

RECEPTORS

Receptors must be ______ to ligand-binding characteristic and also be modifiable when they bind a drug molecule

selective

TYPES OF RECEPTORS (4)

• Regulatory proteins

• Enzymes

• Transport proteins

• Structural proteins

3 ASPECTS OF DRUG RECEPTOR FUNCTIONS

• Determinants the quantitative relationship

between d_____ and e____

• R______ proteins and components of signaling mechanisms that provides target for the drugs

• Key determinants of t____& t_____ of drugs

dose and effect; Regulatory, therapeutic and toxic effects

Molecules that translates the drug-receptor

interaction into change in cellular activity

EFFECTORS

Often a channel, transporter, or enzyme molecule, may be a part of the receptor molecule.

EFFECTORS

RELATIONSHIP BETWEEN DOSE & CLINICAL

RESPONSE (2)

G___ DOSE-RESPONSE RELATIONSHIP

Q___ DOSE-RESPONSE RELATIONSHIP

GRADED; QUANTAL

Response of a particular receptor-effector system against increasing concentration of drug

GRADED DOSE-RESPONSE RELATIONSHIP

Relationship of drug concentration and effect

GRADED DOSE-RESPONSE RELATIONSHIP

GRADED DOSE-RESPONSE RELATIONSHIP: ____ and ____ parameters can be derived

Efficacy; Potency

Maximal effect a drug can produce

EFFICACY

Efficacy is represented by _____

Emax

Amount of drug required to produce a specific

effect (___%)

POTENCY; 50

Represented by ____ (dose that causes 50% of maximal effect) in graded dose-response and ED50 in quantal dose-response curve

EC50

Potency: The ____ the EC50, the more potent the drug is

lower

Minimum concentration needed to produce a specific response in each member of a population

QUANTAL DOSE-RESPONSE RELATIONSHIP

QUANTAL DOSE-RESPONSE RELATIONSHIP can derive (3)

Median effective dose (ED50), Median toxic dose

(TD50), and median lethal dose (LD50)

Median effective dose abv

ED50

Median toxic dose abv

TD50

median lethal dose abv

LD50

Maximal effect of drug is not determined (vs.

Graded dose-response)

QUANTAL DOSE-RESPONSE RELATIONSHIP

Ratio of TD50 and ED50

THERAPEUTIC INDEX

Range between TD50 and ED50

THERAPEUTIC WINDOW

NARROW THERAPEUTIC INDEX DRUGS

(WALA Cyang PaPaVasTeD pa!) (9)

• Warfarin

• Aminoglycosides

• Lithium

• Amphotericin B

• Carbamazepine

• Phenytoin

• Phenobarbital

• Vancomycin

• Theophylline

• Digoxin

Receptors are postulated to exist partially in the inactive, nonfunctional form (Ri) and partially inactivated form (Ra)

MODEL OF DRUG-RECEPTOR INTERACTION

MODEL OF DRUG-RECEPTOR INTERACTION: Even in the absence of any agonist, some of the receptors pool must exist in Ra → may produce the same physiologic effect (_____ Activity)

Constitutive or Basal

Ra >> Ri

FULL AGONIST (Da)

Stabilizes Ra configuration → maximal effect is

produced

FULL AGONIST (Da)

Ra > Ri

PARTIAL AGONIST

Do not stabilize Ra configuration → significant

receptors exist in the Ri-D pool

PARTIAL AGONIST

can also prevent access by full

agonist on receptor sites

PARTIAL AGONIST

Ra = Ri → prevents binding of agonist

ANTAGONIST

Ra < Ri → prevents conversion to Ra state → lowers constitutive activity

INVERSE AGONIST

Binds to the agonist receptor site in a reversible way without activating it

COMPETITIVE ANTAGONIST

Can be overcome by increasing the agonist

concentration

COMPETITIVE ANTAGONIST

Diazepam (agonist) VS. Flumazenil (antagonist)

COMPETITIVE ANTAGONIST

Binds to the agonist receptor site in a irreversible way without activating it or

NONCOMPEPTITIVE ANTAGONIST

the bind reversibly to different binding site

NONCOMPEPTITIVE ANTAGONIST

Cannot be overcome by increasing the agonist

concentration

NONCOMPEPTITIVE ANTAGONIST

Norepinephrine (agonist) VS. Phenoxybenzamine (noncompetitive antagonist)

NONCOMPEPTITIVE ANTAGONIST

Substances that bind to different receptor and

produces an opposite effect

PHYSIOLOGIC ANTAGONIST

Histamine VS. Epinephrine

Glucagon VS. Insulin

PHYSIOLOGIC ANTAGONIST

Substances that interact directly to the agonist

(inactivation) or

CHEMICAL ANTAGONIST

prevent in from binding directly to

its receptor

CHEMICAL ANTAGONIST

Protamine SO4 VS. Heparin

CHEMICAL ANTAGONIST

Dimercaprol VS. Lead

CHEMICAL ANTAGONIST

Substances that binds to the same receptor as the drug it inhibits

PHARMACOLOGIC ANTAGONIST

Beta blockers VS. Epinephrine/Norepinephrine

PHARMACOLOGIC ANTAGONIST

Once an agonist is bound to its receptor, some

effector mechanism is activated

TRANSMEMBRANE SIGNALING

TRANSMEMBRANE SIGNALING: The receptor, its cellular target, and intermediary

molecules are referred to as ________ or ____

Receptor-Effector system or Signal Transduction pathway.

Frequently, the proximal cellular effector protein is not the ultimate physiologic target but rather is an enzyme, ion channel, or transport protein called ________

secondary messengers

Consist of seven-transmembrane or serpentine

receptors that spans across the plasma membrane

G PROTEIN-COUPLE RECEPTORS

G PROTEIN-COUPLE RECEPTORS: Compose of 3 separate components: R__,G___,S___

Receptor, GTP binding protein, secondary messenger

G protein is composed of an ____

subunits

α subunit and βγ subunits or alpha and betay

Gα subunit falls into 4 families

Gs,Gi,Gq,G12/13

What subunit activates Adenylyl cyclase

(AC)

Gs α

What subunit inhibits AC

Gi α

What subunit activates Phospholipase C β

(PLCβ)

Gq α

Ion Gated Channels (3)

LIGAND-GATED CHANNELS,VOLTAGE-GATED CHANNELS,

Drugs often mimic or block the actions natural

agonist (Acetylcholine, Serotonin, GABA, and

glutamate)

LIGAND-GATED CHANNELS

Allows certain ion to flow down its concentration

gradient into the cell → changes in electrical

potential ▪ Nicotinic acetylcholine receptor (2 α, 1β, 1 γ, 1 δ subunits)

LIGAND-GATED CHANNELS

Ligand-Regulated Transmembrane enzyme

RECEPTOR TYROSINE KINASE

Insulin, Epidermal growth factor (EGF), PDGF, ANP,TGF-B

RECEPTOR TYROSINE KINASE

Binding of ligand to receptor causes dimerization ofthe receptors → phosphorylation ad activation ofthe receptor → phosphorylation of signaling proteins → effect

RECEPTOR TYROSINE KINASE

JAK-STAT

CYTOKINE RECEPTORS

GH, Erythropoietin, Interferons

CYTOKINE RECEPTORS

Ligand binds to the receptor → dimerization of the receptor → activation of JAK → phosphorylation of the receptor → binding and dimerization of STAT → STAT dissociates and regulates transcription of specific genes on the nucleus

CYTOKINE RECEPTORS

Intracellular nuclear receptors and For lipid-soluble agents

INTRACELLULAR RECEPTORS

Steroids (Corticosteroids, Mineralocorticoids, Sex

steroids, Vitamin D), & thyroid hormone

INTRACELLULAR RECEPTORS

In absence of a ligand, nuclear receptors are

inactive because they are bound to a chaperone

protein (HSP90)

INTRACELLULAR RECEPTORS

Binding of ligand promotes dissociation of

chaperone protein → entry of receptors into the

nucleus → hetero- or homodimerization of

receptors → interaction with DNA of target proteins

INTRACELLULAR RECEPTORS