Lecture 68 Flashcards
Fundamental Principles of Pharmacodynamics
pharmacokinetics
- how does the body affect the drug?
- ADME
- drug-drug/drug-herb interaction: a drug/herb alters another drug’s pharmacokinetics (absorption, distribution, metabolism, excretion)
pg 1757-1758
pharmacodynamics
- how does the drug affect the body?
- drug-drug/drug-herb interaction: a drug/herb alters another drug’s action (increase or decrease)
pg 1757-1758
pharmacokinetic drug interactions: absorption
a drug can alter another drug’s absorption by:
- formation of unabsorbable complex
- delaying gastric emptying → slows down drug absorption from the intestine
- changing the pH of the GI → affects drug solubility and absorption
pg 1768
pharmacokinetic drug interactions: distribution
a drug can alter another drug’s distribution by:
- displacement at plasma protein binding sites
- changing volume of distribution of a drug (e.g.: diuretic changes Vd of lithium)
pg 1768
pharmacokinetic drug interactions: metabolism
a classic example of what can go wrong is CYP inducers and inhibitor
pg 1768
pharmacokinetic drug interactions: excretion
a drug can alter another drug’s renal excretion by:
- changing urine pH (urine alkalinization → increases reabsorption of alkaline drugs/increases excretion of acidic drugs)
- interference with reabsorption and secretion carriers/transporters
pg 1768
pharmacodynamic drug interactions: addition
1 + 1 = 2
drugs administered together have the same effect as if they were administered separately
pg 1769
pharmacodynamic drug interactions: synergism
1 + 1 > 2
result of interaction is greater than the sum of the drugs used alone “supra-additive effect” (help each other work better)
pg 1769
pharmacodynamic drug interactions: potentiation
1 + 0 > 1
a drug’s effect is increased by another agent that doesn’t really have an effect
pg 1769
pharmacodynamic drug interactions: antagonism
the two drugs may or may not act on the same receptors
pg 1769
receptor occupancy theory
response is directly proportional to the number of occupied receptors
drug + receptor → drug-receptor complex → biologic effect
pg 1772
affinity
- does the drug “like” the receptor?
- can it fit?
- how well does it bind?
- Key-lock model analogy: does the key fit the lock?
pg 1773
affinity vs intrinsic activity
- binding is needed to elicit a response, but it doesn’t mean an action will definitely follow
- for an action to follow, it needs to create the structural/conformational changes in the receptor that will elicit a response
- key-lock model analogy: after the key fits, is it going to turn the lock?
- affinity determines if the drug and receptor will form the drug-receptor complex
- intrinsic activity determines if the drug-receptor complex will elicit a biologic effect
pg 1774
agonist vs antagonist
- natural ligand: key fits in (has affinity) and turns (has intrinsic activity) the lock (receptor)
- agonist: mimicked key fits in (has affinity) and turns (has intrinsic activity) the lock (receptor)
- antagonist: has the ability to bind a receptor (has affinity), but doesn’t elicit a response (NO intrinsic activity)
pg 1775
agonists
- an agonist can bind to the primary site (where the natural ligand binds) and mimic its action
- OR
- it can bind to a different site on the same receptor (allosteric/secondary site)
- binding the allosteric site results in: increased affinity of ligand to primary site OR increased effect that results from the binding
- an agonist that binds the allosteric site is called a PAM (positive allosteric modulator) or allosteric activator
pg 1776
antagonists
- antagonists themselves produce NO response (NOT a negative response
- they ONLY prevent/block the natural ligand/agonist from binding
- antagonists can be: competitive, non-competitive (irreversible inhibitors, allosteric inhibitors), functional
pg 1781
competitive antagonists
- a competitive antagonist binds to the same primary site as the natural ligand/agonist
- fair competition → if the competitive antagonist has higher conc and/or affinity, it can displace the natural ligand/agonist from the primary binding site (and vice versa)
- the “winner” is the molecule that has higher concentration at the binding site and/or higher affinity to bind the receptor
pg 1782
non-competitive antagonists
- a non-competitive antagonist cannot be displaced by higher concentrations of the agonist
- irreversible antagonist: strong bond with the primary site → once bound, cannot be displaced
- allosteric inhibitor (NAM): higher concentration of the agonist at the primary binding site will not displace the negative modulator at the allosteric site
pg 1783
functional antagonists
natural antagonists
- histamine binds histamine receptors leading to bronchoconstriction
- epinephrine binds beta-receptors leading to bronchodilation
pg 1784
partial agonists
- partial agonists cannot produce maximal response even at maximal receptor occupancy
- partial agonists display a “mixed agonist-antagonist” effect
- in the presence of a full agonist, a partial agonist precipitates withdrawal (forcing the molecules to release)
- in the absence of a full agonist, a partial agonist prevents/treats withdrawal (once molecules have released, they make the body happy by binding some)
pg 1787-1788
partial agonists example
- buprenorphine used in treatment of opioid use disorder (OUD)
- due to its agonist action, it provides some pain relief and prevents opioid withdrawal symptoms
- but it does NOT produce the “high” that a full agonist, such as morphine, is capable of producing
pg 1791
constitutive activity theory
- traditionally, unoccupied receptors were considered to be inactive
- we now know that some receptors can be active WITHOUT a ligand (have constitutive activity)
- that receptor has two forms that exist in equilibrium (Ra is active form and Ri is inactive form)
pg 1794
inverse agonist - mechanism of action
- inverse agonist: stabilizes the inactive form of the receptor, shifting equilibirum towards formation of more Ri; response: negative (does opposite function)
- antagonist: equal affinity to both forms; NO response (just blocks agonist binding)
- agonist: stabilizes the active form of the receptor, shifting equilibrium towards formation of more Ra; response: positive
pg 1795
