Pharm Lecture 3: Cellular Receptors and Drug Action

What is the K1 Association constant

the rate of drug receptor complex formation

what is the k-1 dissociation constant

the rate of drug dissociation from the receptor

Kd dissociation constant

• kd = k-1/k1

• drugs with a low Kd have a high affinity for the receptor (greater potency)

drug affinity

• tells us how well the drug binds to the receptor, but does not tell us anything about the action of the drug at the receptor

what are full agonists

Drugs that bind to the same receptor site as the endogenous ligand (ligands that our bodies already make) and produce the same biological effect as the endogenous ligand at that receptor

cortisol full agonist

dexamethasone which is a glucocorticoid drug

what are partial agonists

drugs that bind to the same receptor as the endogenous ligand but only a part of the biological effect is produced

dopamine partial agonist

aripripazole produces a weaker biological effect at the dopamine receptor compared to dopamine

what are inverse agonists

• drugs that bind to the same receptor as the endogenous ligand but induce the opposite response

• only occurs when receptors have an intrinisc level of activity

• considered to have “negative efficacy”

what are antagonists

• drugs that bind to the same receptor site as the endogenous ligand to prevent it from binding

• do not stimulate the receptor

• reversible and irreversible antagonists

reversible antagonist types

competitive antagonist

noncompetitive antagonists

• most are competitive and reversible

competitive reversible antagonists

Always dissociates from the receptor (binds and let go, binds and lets go)

non-competitive antagonists

• Binds to a site other than the endogenous ligand receptor site “allosteric modulation”

• Prevents the endogenous ligand from binding at the receptor binding site

are non-competitive antagonists or competitive antagonists preferred

competitive because non-competitive antagonists can have unpredictable effects, generally preferred to administer competitive

irreversible antagonists

antagonists that bind to the receptor site and do not dissociate from the receptor

irreversible antagonists dissociation constant and drug affinity

• k-1 = 0

• drug affinity is very high

uses of irreversible antagonists

• aspirin

• omeprazole (gastroesophageal reflux)

• biological weapons (nerve gases)

what type of signaling mechanism does insulin use

insulin is water soluble and must use a receptor located on a membrane spanning enzyme

what types of receptors would lipid soluble hormones use

intracellular receptors because they can cross the cell membrane

how do G protein coupled receptors work

G proteins stimulate effectors to produce intracellular changes

• ligands bind to a receptor site to stimulate G protein

• G protein stimulates effectors

cardiac atrial muscarinic receptor process

1. acetylcholine binds at a receptor site which stimulates the G protein

2. G protein stimulates opening of a potassium ion channel

3. potassium leaves the cell which slows heart rate

Gs proteins effect on adenylyl cyclase

• Gs proteins stimulate adenylyl cyclase which is the effector

• Adenylyl cyclase converts ATP into cAMP

• cAMP is a second messenger that binds to and activates protein kinases

• protein kinases activate enzymes by adding a phosphate group to have a biological effect

Gi proteins effect on adenylyl cyclase

• inhibits adenylyl cyclase

• decrase in CAMP = less protein kinase = fewer biological effects

what is albuterol/salbutamol

• Drug that is a beta 2 (lungs, think beta 2-2 lungs) adrenergic receptor partial agonist

• It is a bronchodilator

albuterol/salbutamol action

• when it binds to the receptor, it stimulates adenylyl cyclase through its associated Gs protein

• Leads to an increase in cAMP

biological effects of albuterol

• increase in cAMP activates enzymes that sequester calcium and inactivate inactivate myosin light chain kinase

• decreased levels of calcium and MLCK lead to relaxation of bronchial smooth muscle (bronchodilation

what is misoprostol

peptic ulcer drug

mistoprostol G protein coupled receptor

• mistoprostol binds to the Gi linked EP3 receptor

• Receptor binding causes Gi protein to inhibit adenylyl cyclase

• cAMP decreases, protein kinases not activated

biological effects of mistoprostol

• Enzymes and pumps that help produce stomach acid are no longer activated

• The production of stomach acid decreases

why is mistoprostol never given in pregnancy?

it can induce labour and cause uterine contractions because reduced cAMP means less calcium sequestered and more muscle contraction

Gq proteins

• always associated with phospholipase C

• phospholipase cleaves PIP

what does the cleaving of PIP yield

yields 2nd messengers: IP3 and DAG

what does IP3 do

binds to the sarcoplasmic reticulum to stimulate the release of calcium into the cytoplasm

what does DAG do

bidns to the calcium channels on the cell membrane to facilitate the movement of extracellular calcium into the cell

biological effect of Gq proteins

calcium influx into the cytoplasm causing muscle contraction

what is ergonivine

Drug that binds to Gq proteins linked to E1 receptors in the uterus and alpha 1 adrenergic receptors in the blood vessels.

what does ergonivine binding to Gq protein do

• receptor stimulates PLC to cleave PIP to produce IP3 and DAG

• causes calcium release inot the cytoplasm

biological effect of ergonivine

induces contraction of the uterus and the blood vessels

clinical use of drugs that bind to Gq proteins

• used to manage postpartum hemorrhage

• facilitates formation of healthy clots to limit blood flow

• oxytocin is the preferred version because ergonivine increases BP

what signaling mechanism does dopamine, epinephrine, histamine use?

they are polar, cell surface receptors and regulate intracellular second messengers through G-protein coupled receptors

what is the most common cause of adverse drug effects in the elderly

renal function/drug clearance