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)
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| Related link: 【Covid-19】Causes & mechanisms that promote thromboinflammation in COVID-19 |
***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
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| 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
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| 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
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