A.2 Flashcards
Qualitatively described reponse
Plots % of a population responding to a specific drug drug effect vs. drug dose.
It shows us variation in drug sensitivity in a given population, and permit estimation of median effective dose -> effective dose in 50% of a population.
- ED50 -> 50% of individuals responding.
therapeutic index
Quantitive measurement of the relative safety of a drug.
- Safe drug: high toxic dose and much lower effective dose
- if ED and TD are close → administration of drug is dangerous (aminoglycosides, theophulline, warfarin, digoxin, lithium has a narrow Therapautic index
How can TI be measured?
Therapautic index (TI)= Toxic dose in 50% of the individuals(TD50)/Effective dose in 50% in individuals (ED50).
- The higher therapautic index the better!
What is therapautic window?
Therapautic window = TD-ED (Dosage range between the minimum effective therapautic dose and the minimum toxic dose
Drug-receptor interactions:
- Agonist
- Partial agonist
- Inverse agonist
- Antagonist (competitive/noncompetitive)
- Agonist
Maximal effect is ahchieved when it is bound to the receptor. Intrinsic activity = 1 (e.g. morphine)
- partial agonist
Drug that binds to its receptor, but produces a smaller effect than a full agonist. In the presence of a full agonist, the partial agonist will act as an inhibitor (displaces the full agonist from the receptor). Has affinity, intrinsic activity <1 (e.g. buprenorphine)
- inverse agonist
Causes opposite effect of the full agonist. Drug binds to the non-active state of the receptor and decreases its constitutive activity. Intrinsic activity =-1 (e.g. Flumazenil)
- antagonist
Results in inhibition of receptor activation
Competitive antagonist: (e.g. Ticagrelor):
Drugs that bind to the agonist receptor site in a reversible way, without activating the effector system for that receptor. The antagonist can be overcome by increasing agonist concentration. The dose-response curve for an agonist is shifted to higher doses, but the same maximal effect may still be reached
Irreversible antagonist: non-competetive antagonist (e.g. Abciximab)
Effect cannot be overcome by adding more agonist. Causes a downward shift of the maximum effect. ED50 is not increased unless spare receptors are present
the molecular targets of drugs
- Receptors: GPCR, Ligand gated ion channels, tyrosine kinase, intracellular cytoplasmic etc.
- Enzymes: COX, ACE, ACh-esterase, dihydrofolate reductase
- Transporters: Serotonin, NE, dopamine reuptake inhibitors
- Voltage gated ion channels: Na+ , K+, Ca2+ , Cl- channels
- Non-receptorial drug targets: Nuclei acids, cholesterol, acids etc
6: Other (novel targets): RNA, miRNA
potency
EC50 or ED50
The concentration or dose of a drug producing 50% of maximum effect- It tells us the quantity of drug required to produce a given effect.
- If we have lower EC50 → higher potency!
Mainly determined by the affinity of receptor to the drug+ number of available receptors
Efficacy - Emax
Maximal effect an agonist can produce by the highest tolerated dose level
- It´s a measure of effectiveness → how well a drug produces a response
classical receptor theory
Ligands bind to receptors in a reversible fashion and reaches an equilibrium: R+L -> RL
Kd
Dissociation constant Kd denotes the concentration of a drug required to bind 50% of the available receptor sites; measure of affinity of a drug molecule to its receptor. The smaller the Kd the greater the affinity of the drug for its receptor.
Kd=[L]*[R]/[LR]
spare receptor theory
Receptors are said to be ´´spare´´ for a given pharmacologic response, if it is possible to elicit a maximal biological response at a concentration of agonist that DOESN´T bind all of the available receptors → No need to occupy all receptors to achieve maximal effect. Presence of spare receptors increases the sensitivity to the agonist, because the likelihood of a drug-receptor interaction increases in proportion to the number of receptors availabe.
Due to 2 mechanisms:
1.Duration of effector activation may be much greater than the duration of the drug-receptor interaction
2.Number of receptors may exceed the number of effector molecules available
wo-state receptor theory
That ligand binding results in a change of receptor state from an inactive state to an active state, based on receptor conformation change
the point of receptor theory
Application of receptor models to explain drug behavior
Where does a orthosteric drug bind?
On the active site
Where does an allosteric drug bind?
Elsewhere on the receptor than the active site, and changes the conformation of the protein binding sit
