【Pharmacology】Pharmacodynamics

Pharmacodynamics

1. Definition

Pharmacodynamics is the study of a drug's molecular, biochemical, and physiologic effects or actions.

When a drug enters into body, it then starts interacting with cell receptors which in turn leads to a formation of signal and this signal through series of different reactions ultimately results in some

biological effect.

2. Receptor type

a. Ligand-gated ion channels

when the ligand binds to ligand binding site, the channel opens very briefly which allows ions such as sodium potassium chloride calcium etc to pass through the membrane.

b. G protein-coupled receptors

Also known as seven-transmembrane receptor

passes through the cell membrane seven times

composed of three subunits: alpha beta and gamma 👉G protein
Inactive: alpha subunit has GDP attached
Active: when ligand binds to the receptor,

the affinity for GTP increases,
so then GTP replaces GDP.
This causes the alpha subunit to dissociate from beta-gamma complex and
then both of these complexes go to interact with other enzymes or proteins which they can alter and regulate.
ultimately leading to some kind of response

Gs: stimulative g-protein that activates enzyme called adenylyl cyclase which produces cyclic AMP from ATP. cyclic AMP is a very important second messenger

Gi: inhibitory G protein which inhibits adenylyl cyclase thus lowers levels of cAMP in the cell

Gq: activates class of enzymes called phospholipases C (PLC).

PLC produces two second messengers: diacylglycerol (DAG) & inositol triphosphate (IP3)

***G protein-coupled receptors & most enzyme-linked receptors have ability to amplify signals

One stimulated G protein receptor can activate many adenylyl cyclases, which will result in more cyclic AMP molecules produced and ultimately amplified response

c. Enzyme-linked receptors

have extracellular binding site where ligand typically hormone or growth factor can attach and thus stimulate enzymatic activity inside the cell
most enzyme-linked receptors are of tyrosine kinase type

display kinase activity and that there is a amino acid tyrosine involved in

Active: When ligand binds to two of these receptors, it causes

conformational change that results in aggregation of both receptors
once the dimer is formed, the tyrosine regions get activated and cause ATP to become ADP
which results in auto phosphorylation of the receptors
once each tyrosine picks up phosphate group, different inactive intracellular proteins come up and attach themselves to phosphorylated tyrosine
This causes conformational change in the attached protein
ultimately leading to cascade of activations that produces cellular response

d. Intracellular receptors

located entirely inside the cell
Active: ligand has to first cross lipid membrane and

then once bind to the receptor
the activated ligand receptor complex can move into the nucleus bind to DNA and regulate gene expression
ultimately leading to synthesis of specific proteins

Life cycle of receptors:

Each cell's DNA contains code that's used to synthesize proteins from which different receptors are assembled
once assembled, the receptors get embedded into the cell membrane and can receive and respond to signaling molecules

👉If cells receive too much stimulation which can potentially damage

Cells have the ability to downregulate receptors
--take them out of the membrane and recycle them
--leads to fewer number of expressed receptors
--thus decreased sensitivity to signaling molecules

👉If most of cell's receptors get blocked and cell receives very weak signals

Cells have the ability to upregulate receptors
--more receptors can get inserted into the membrane
--thus increasing cell sensitivity to signaling molecules

3. EC50 & Emax

Signaling molecule is actually some kind of a drug

Concentration of that drug ↑, its pharmacologic effect also↑, until we reach the point at which all the receptors are occupied

Determine EC50 from the graph:

EC50: The concentration of a drug that produces 50% of the maximal effect. It tells us how potent the drug

From graph: Drug "A" is not only more potent but also more efficacious

Drug "A" is more potent because it has lower EC50.

simply less drug is needed to get half of the max response

Drug "A" has higher Emax (maximum efficacy)

drug "B" doesn't reach the same level of pharmacological effect as drug "A"

Emax: Assume that all the receptors are occupied by the drug and higher concentrations of it don't produce larger effect

4. Agonists

Intrinsic activity: Ability of a drug to produce maximal effect.

Basal activity: Receptors show some kind of activity when there is no agonist around

Full agonist: an agent that maximal effect, comparable to effect produced by our bodies own endogenous ligand

Partial agonist: an agent that unable to produce maximal effect even if it occupies all the receptors

Inverse agonist: an agent that eliminates basal activity (Instead of activating, it stabilizes receptors in their inactive form)

5. Antagonists

Antagonist: A ligand that can bind to receptor and block it thus reducing agonist activity

Both agonist and antagonist that can bind to the same side on the receptor 👉 compete for that side

Competitive antagonist: antagonist that binds and prevents agonist from binding

characteristic: shifts dose response curve of the agonist to the right

Irreversible antagonists: some antagonists can form covalent bonds with active site on the receptor and thus irreversibly block it. This is non-competitive process because irreversible antagonists can't be displaced by agonist which leads to reduction in Emax.

From graph:

Agonist + competitive antagonists:

require higher concentrations of drug to EC50
potency is reduced

Agonist + irreversible antagonists:

reduction in Emax
reduction in agonist efficacy

Allosteric antagonist: bind to the site different from agonist binding site and induce conformational change which prevents agonist from activating the receptor

Reduction in Emax but no change in EC50

6. Therapeutic index

Therapeutic index: Range of doses at which a drug provides benefits without causing major toxicity

--helps to measure the relative safety of a drug for a particular treatment

Therapeutic index formula:

simply the ratio of the dose of a drug that produces toxicity in 50% of the population (TD50) to the dose of a drug that produces effective response in 50% of the population (ED50).

Graph: determine the curve that represents positive therapeutic response and the curve that represents negative toxic response

7. Reference

https://youtu.be/tobx537kFaI

【Pharmacology】 Pharmacokinetics

Medical student's note

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