Pharmacodynamics - Cellular Receptors and Drug Action

What is drug association?

The rate that a drug binds to a receptor to form a drug-receptor complex.

A drug has a higher affinity for the receptor if it associates quickly

What is drug dissociation?

The rate that a drug stays and removes itself from a receptor.

A drug has a higher affinity for the receptor if it dissociates slowly

What is K1?

Rate of drug association

The rate that a drug binds to a receptor to form a drug-receptor complex.

A drug has a higher affinity for the receptor if it associates quickly

What is K-1?

Rate of drug disassociation

The rate that a drug stays and removes itself from a receptor.

A drug has a higher affinity for the receptor if it dissociates slowly

What is the rate of association and disassociation for a drug with a high affinity for a receptor?

Quick association - K1

Slow disassociation - K-1

What is the rate of association and disassociation for a drug with a low affinity for a receptor?

Slow association - K1

Quick disassociation - K-1

What is the dissociation constant?

aka Kd

The ratio of a drug's rate of disassociation to it's rate of association. A higher kd signifies that the drug has a lower affinity to the receptor

What is kd?

The dissociation constant.

The ratio of a drug's rate of disassociation to it's rate of association. A higher kd signifies that the drug has a lower affinity to the receptor

What is the relationship between affinity and the dissociation constant?

An inverse relationship

A drug that has a low dissociation constant has a higher affinity for the receptor

The reverse is also true

What are drug agonists?

Drugs that directly bind to a receptor to stimulate an effect

Full agonist - full stimulation - same as normal ligand

Partial agonist - partial stimulation - weaker than normal ligand

Inverse agonist - causes opposite effect of receptor

What are drug antagonists?

Drugs that stop ligands from binding to the receptor either by directly blocking the receptor or binding to an allosteric site

Reversible antagonist - able to bind to and dissociate from receptor

Competitive antagonist - binds directly to receptor, competing with ligand

Noncompetitive antagonist - binds to allosteric site

Irreversible antagonist - binds to receptor, unable to dissociate

What are full agonist drugs?

Drugs that bind to the same receptor site as an endogenous ligand (produced by the body) and produces the exact same biological effects as the endogenous ligand once it binds to the receptor site.

These drugs have high efficacy

How is dexamethasone a full agonist?

Dexamethasone, a glucocorticoid drug, once bound to a receptor, exerts the same therapeutic effect as cortisol

What are partial agonist drugs?

Drugs that bind to the same receptor site as an endogenous ligand (produced by the body) and only produces partial effect compared to the endogenous ligand once it binds to the receptor site.

These drugs have a lower efficacy compared to full agonists

They are used to weaken the biological effect caused by the endogenous ligand (ex; psychosis, excessive dopamine is produced. If full antagonist used, patient will have Parkinson like symptoms)

These drugs have lower efficacy compared to the endogenous ligand and full agonists

How is aripiprazole a partial agonist?

Aripiprazole produces a weaker biological effect compared to dopamine.

This is useful in patient with schizophrenia who have excessive dopamine, and where using a full antagonist will result in Parkinson's like symptoms

What are inverse agonists?

Drugs that bind to the same receptor site as the endogenous ligand, but induce the opposite response. This only occurs on receptors that exert a biological effect WITHOUT binding to an endogenous ligand

Which type of agonist drug has the highest efficacy?

Full agonists, exert the full effect of the original endogenous ligand

What are reversible antagonist drugs?

Drugs that are able to bind to and dissociate from receptor

Include competitive and noncompetitive antagonists

What are competitive antagonist drugs?

A type of reversible antagonist that compete for the same receptor binding site as endogenous ligands, blocking the endogenous ligand from binding to it

What are noncompetitive antagonist drugs?

A type of reversible antagonist that binds to an allosteric site to produce an enzyme that blocks endogenous ligands from binding to the receptor.

Often includes recreational drugs (PCP and ketamine)

What are irreversible antagonists?

A drug that binds to a receptor and dose not dissociate from it. The body is required to make more receptors to return to normal function

What is the k-1, Kd, and affinity for irreversible antagonists?

K-1 = 0 because the drug cannot dissociate

Kd is very low because K-1 = 0 (k-1/k1)

Affinity is very high because Kd is very low (inverse)

What is a drawback of using noncompetitive antagonist drugs?

These drugs depend on enzyme function to initiate it's antagonist effect. Enzyme function is variable in different paitents and can only be pushed so much, resulting in a non-linear response

What is a drawback of irreversible antagonist drugs?

Once these drug bind to the receptors, they cannot be used anymore. The body is required to produce more receptors to return to normal function, which may not happen depending on patient factors

What is the "most" effective antagonist drug?

Reversible competitive antagonists, drug effects can be neutralized easily, and produces a linear response (more drugs = greater response)

What are intracellular receptors?

Receptors that are located inside of the cell, past the cell membrane. Drugs must be non-polar to access these receptors due to having to pass through the cell membrane

What are membrane spanning receptors?

Receptors that span across the cell membrane, interacting with the extracellular environment

Membrane spanning receptors that activate janus kinase are most involved with action of cytokines

What are G-protein coupled receptors?

Receptors that activate a G-protein once bound to a ligand or drug, and produces intracellular changes

How do ion channels that are linked to g-proteins work?

A ligand binds to a receptor, which activates a g-protein.

The g-protein then binds to an ion channel, which induces the opening of the ion channel

How do cardiac atrial muscarinic receptors work?

A ligand (Ach) binds to a muscarinic receptor, causing the stimulation of a G-protein.

The G-protein then binds to a potassium ion channel, which allows potassium to exit out of the cell, resulting in hyperpolarization of the cell membrane.

This causes the heart rate to slow down

How do Gs proteins work?

Gs proteins bind to adenylyl cyclase, which stimulates them to convert ATP to cAMP.

cAMP then activates protein kinases, which then attach a phosphate group to an enzyme, activating them and producing variable biological effects

What is adenylyl cyclase?

An enzyme that, once stimulated by a g-protein, converts ATP into cAMP. cAMP then activates protein kinases, which add a phosphate group to enzymes and produce variable biological effects

What are protein kinases?

Enzymes that are activated by cAMP and bind to enzymes, activating them and producing variable biological effects

What is cAMP?

A molecule produced by adenylyl cyclase once it is activated by a Gs protein.

cAMP activates protein kinases, which attaches a phosphate group to enzymes, resulting in variable biological effects

How does Albuterol/salbutamol work in relation to it's G-protein?

Albuterol/salbutamol is a beta2-adrenergic receptor agonist that causes bronchodilation

Beta2- exerts its effect on the lungs

Agonist - exerts same effect as the endogenous ligand

Albuterol binds to a g coupled receptor, which stimulates the release of a Gs protein. The Gs protein binds to adenylyl cyclase, resulting in the conversion of ATP into cAMP. cAMP binds to a protein kinase, which attaches a phosphate group to enzymes that sequester Ca2+ and inactive MLCK.

Lower Ca2+ levels and an inactive MLCK causes relaxation of the bronchial smooth muscle, resulting in bronchodilatation

How do Gi proteins work?

Gs proteins bind to adenylyl cyclase, which inhibits them from converting ATP to cAMP.

This results in decreased cAMP and decreased activity of protein kinases, resulting in less enzymes being activated and resulting in variable biological effects

How does Misoprostol work in relation to it's G-protein?

Misoprostol is a Gi-linked prostaglandin EP3 receptor that reduces stomach acid to treat peptic ulcers

Misoprostol binds to a g-coupled receptor, which stimulates the release of a Gi protein. The Gi protein binds to adenylyl cyclase, resulting in inhibited conversion of ATP to cAMP.

This results in lower activity of enzymes and pumps that produce stomach acid, resulting in decreased stomach acid.

Misoprostol also results in uterine contraction as lower cAMP levels causes decreased sequestration of calcium, resulting in muscle contraction

Why is Misoprostol contraindicated in pregnancy?

Misoprostol is a drug that reduces stomach acid production to treat peptic ulcers by reducing cAMP levels and resulting in lower enzyme activity

Misoprostol also results in uterine contraction as lower cAMP levels causes decreased sequestration of calcium, resulting in muscle contraction.

This same mechanism is the reason why Misoprostol is also used for medical abortions

How do Gq proteins work?

Gq proteins activates phospholipase C (PLC) which cleaves PIP. The cleaved PIP results in two messenger molecules, IP3 and DAG.

IP3 binds to the sarcoplasmic reticulum and causes release of Ca2+ into the cytoplasm

DAG binds to calcium channels on the cell membrane, allowing calcium to move into the cell, which produces variable biological responses.

What is PLC in the Gq protein pathway?

aka phospholipase C, activated by a Gq protein to cleave PIP, resulting in the production IP3 and DAG, which both allow calcium movement into a cell

What is PIP in the Gq protein pathway?

PIP is cleaved by PLC (activated by Gq protein) and results in the production of IP3 and DAG, which both allow calcium movement into a cell

What is IP3 in the Gq protein pathway?

IP3 is one of two messenger molecules produced when PIP is cleaved by PLC (activated by Gq proteins). IP3 binds to the sarcoplasmic reticulum and causes release of Ca2+ into the cytoplasm, allowing calcium movement into the cell and resulting in variable biological responses

What is DAG in the Gq protein pathway?

DAG is one of two messenger molecules produced when PIP is cleaved by PLC (activated by Gq proteins) DAG binds to calcium channels on the cell membrane, allowing calcium to move into the cell and resulting in variable biological responses.

How does Ergonovine work in relation to it's G-protein?

Ergonovine is a drug that causes contraction of the uterus and blood vessels to manage postpartum hemorrhage by binding to g-protein linked prostaglandin E1 receptors in the uterus and Gq-protein linked a1 adrenoceptors in the blood vessels

Ergonovine binds to a Gq protein receptor, which stimulates the release of a Gq protein. The Gq protein activates PLC, which cleaves PIP, resulting in the production of DAG and IP3. Both DAG and IP3 result in increase movement of calcium into the cell, resulting in muscle contraction