| How is the drug-receptor binding relationship? | When a drug or an endogenous ligand binds a receptor, this will result in a response (molecular level)
When a sufficient number of receptors bind receptors on a cell, the cumulative effect will become apparent in the cell, and if all receptors are occupied, this is a maximal response (cellular level)
When response occurs on many cells, it can be seen at the level of an organ or a patient. |
| Give an example of drug-receptor binding. | Pantoprazole PPI
Binds H+K+ ATPase pump acts on gastric parietal cells inhibiting acid production and thus decreasing acidity of the stomach relieving GERD (acid reflux) |
| How is the drug-receptor binding relationship? | When a drug or an endogenous ligand binds a receptor, this will result in a response (molecular level)
When a sufficient number of receptors bind receptors on a cell, the cumulative effect will become apparent in the cell, and if all receptors are occupied, this is a maximal response (cellular level)
When response occurs on many cells, it can be seen at the level of an organ or a patient. |
| What is the dissociation constant in drug-receptor binding curve? | It represents the affinity of a ligand to the receptor, defined by the dose of drug given in order for half of the receptors to be occupied.
If a drug has a lower Kd than the other, it will have a higher affinity and in case of competition it will bind faster to the receptor |
| How do we assess the dose-response relationship? | It is related closely to the drug-receptor binding
Two major types, graded dose-response (effect on an individual) and quantal dose-response (effect on a population) |
| What is the graded dose-response relationship? | It resembles very much the drug-receptor binding curve, EC50 (potency- amount of drug needed to exert a certain effect) replaces the Kd, and Emax (efficacy- ability to elicit a physiologic response, more important than potency) replaces receptor max occupation
The drug that has a higher efficacy is better therapeutically than the one with a higher potency. |
| Give an example of two drugs with different efficacy and potency. | Candesartan and Irbesartan (ACE inhibitors for HTN)
Candesartan is more potent (dose range 4-32 mg while other is 75-300mg) |
| What is quantal dose-response relationship? | Seen on a population of individuals, Three main parameters seen, ED50 (50% of individuals exhibiting a therapeutic response- effectiveness), TD50 (50% toxic response- toxicity) and LD50 (50% die- lethality)
ED50 (50% therapeutic individuals) EC50 (50% of maximal response) |
| What is the therapeutic index? | It is the therapeutic window, calculated as TD50/ED50
If it is higher, then it gives us a better range of dosage of the drug, if low then we have a narrow therapeutic window and must be closely monitored after giving a drug |
| Give two examples of drugs with wide and narrow therapeutic window. | Warfarin (small TI)
Penicillin (large TI) |
| What are the main drug-receptor interactions? | Agonists, antagonists, partial agonists (activates in a small fraction the response) and inverse agonist (induces an effect opposite to the agonist - not blocking) |
| What are the agonists response | binds to the receptor and stabilizes it in a conformation which is active usually, they may be drugs or endogenous ligands |
| What are antagonists? | inhibit action of an agonist with no action in the absence of the agonist (not a reverse agonist)
They are classified as receptor antagonists (bind on active site or allosteric site (non-competitive but stops response) of agonist- prevent conformational changes, may be reversible (competitive, shift dose-response curve to right decreasing potency maintaining efficacy) or irreversible (decreases efficacy)) and nonreceptor antagonists (chemical anatagonists (inactivate agonist neutralization), physiologic antagonists reverse effect)) |
| Give examples of non-receptor antagonists? | Chemical (Calcium sodium edetate forming complex with arsenic/lead)
Physiologic (Glucagon and Insulin -opposite effects) |
| What are partial agonists? | binds to receptor binding site and produces a partial response only, even if bound to all receptors.
So it can reduce the action of a full agonist if it binds on the binding sites |
| What are inverse agonists? | Reverses the intrinsic activity of free receptor
Like GABAA receptors (benzodiazepines) create a sedative effect, whereas the inverse agonists have a convulsive effect (beta-carbolines) |
| What is desensitization of receptors? | This is the phenomenon of tachyphylaxis.
When a receptor is contiuously getting activated by agonists, their response will change to prevent cellular damage, diminishing the effect of the agonist, so the receptors are still found on the cell surface but irresponsive. |
| Give examples on receptor down and up-regulation? | Downregulation in case of prolonged agonists (chronic use of salbutamol (adrenergic agonist) down regulated beta-receptors- decreased effect of salbutamol in asthmatic pt))
Upregulation in case of prolonged antagonist effect (withdrawal of beta blockers (propranolol) suddenly, causes withdrawal symptoms anxiety palpitation tachycardia, htn, |
