Terms Flashcards
Pharmacodynamics
what the DRUG does to the BODY
- Determines how drug is classified
Pharmacokinetics
what the BODY does to the DRUG
- How the drug is absorbed, distributed, metabolized, & eliminated from body
- Important for determining kind of drug
Effector Mechanism
Drug alters cell communication
- Communicates effect of DRUG-TARGET interaction to the cell
Orphan Receptors
Unknown ligands = potential drug discoveries
Types of Effector Systems
- Regulatory proteins
- Enzymes
- Structural proteins
- Transport proteins
Conformational Change
Drug binding to protein target
- Affects of protein SHAPE and FUNCTION
Drug binding can cause effect…
Directly or Indirectly
Targets exist in two states:
- Inactive = Ri
- Active = Ra
Both forms are always in equilibrium
Constitutive Activity
Mostly in active state, in absence of ligand
Inert Binding Site
Drug binding to non-regulatory target
- No effect on biological function
Selectivity
Receptors will decide what the drug does
Drug-Target interactions are determined by concentration
The more drug concentration C, the more drug effect E.
- Effect increases as dose increases
Emax
The max. effect that can be produced by a drug
- Very close to toxicity
EC50
The concentration of drug that produces 50% of the max. effect
- Calculates the dose
Bmax
Fraction of the free receptors decreases with increasing drug/ligand, until saturation occurs
- Number of free receptors
Kd
Equilibrium Dissociation Constant
Concentration of free drug (mol/L) when receptors are 50%
Low Kd
High affinity
High Kd
Low affinity
Log Scale
Small changes in concentration makes a big change in effect
Indirect = Enzymes
Biological response may reach the max, before full saturation
Direct = Ion Channels
Effect depends on how many drug molecule binds to how many receptors
Occupancy-Response Relationship
Max. response may occur without max. occupancy of the receptors
- A lot of spare receptors will make EC50 not the same as Kd
Spare Receptors
Good potential for increasing dose
Endogenous Ligand
Produced in the body and acts on receptors
Full Agonist
Activates all targets, shifts equilibrium to saturate all receptors pool (Ra - D)
Competitive Antagonist
Competes with endogenous ligand to bind to the same pocket
- Does not have any effect if no endogenous agonist (there must be competition)
- Stabilizes receptors in their inactive form
To increase chance to win competition against antagonist…
The concentration of natural ligand should be increased
- If equal number of molecules, the one with the higher affinity will win
Non-Competitive Antagonist
Doesn’t bind to receptor at binding site. Binds to another spot and deactivates it
Two types of distribution
Localized distribution or widespread distribution (more side effects possible)
Increasing lipid solubility means…
harder to move between environments
First Order Elimination
When the body eliminates half of the concentration in a particular period of time.
Higher concentration, higher rate of elimination
Exponential Decay
Zero Order Elimination
When the body breaks down particular amounts of drug per unit of time
Linear Elimination
Glucuronidation
UDP - UGT
Adds a glucuronosyl
Attacks nucleophiles
Sulfation
SULTs
Adds a sulfate group
Attacks nucleophile - alcohol / amine
Glutathione
GSH or GST
Adds a glutathione (GSH)
Attacks electrophiles
Delayed Drug Effects
Delay can be caused by the time required for distribution to tissues;
dissociation of drug from target
Cumulative Effects
Irreversible anti-cancer agents
Action = irreversible binding; drug binds to target immediately after absorption
Delayed Effect = blocks cell division leading to cell death
Response = slowing tumour growth
Hydrophilic (water soluble) drugs are easily eliminated, however, lipid soluble drugs must undergo…
Metabolism to enhance drug elimination by turning lipid soluble to water soluble
Phase 1 (Oxidation)
Add small polar groups to drug and removing lipophilic groups to increase water solubility of drug
If product from Phase 1 undergoes Phase 2, that means…
The product is toxic
Phase 2
Adds specific (usually large and bulky) polar functional groups on drug or Phase 1 toxic product
Both phases (1 and 2) mostly takes place in the…
Liver
Tylenol Metabolism is an example of…
Glutathione (GSH) transferase (GST)
Factors that affect drug metabolism:
Genetic Factors;
Diet & Environment;
Age & Sex;
Drug-Drug Interactions
Diseases
Prodrug
Compound is metabolized after administration to turn into its active form;
Will not act as a drug until changed through metabolism
Prodrugs helps…
Compounds permeate through target tissue walls if parent drug cannot on its own;
Increases absorption
Synergism Interaction
Effects of two chemicals taken together is greater than the sum of their separate effect at the same dose;
Increases effect when both are taken together
Pharmacokinetic Principles
Absorption; Distribution; Metabolism; Elimination
ADME
Drug Permeation
Intercellular, Lipid, Special Carriers, Endocytosis and Exocytosis
Intercellular Diffusion
Must be small, water soluble
Lipid Diffusion
Lipid soluble molecules
Special Carriers
Transporter proteins for water soluble molecules
Endocytosis and Exocytosis
For larger molecules that do not have any transporter proteins to carry them
First Pass Effect
Initial metabolism of drug in the liver that reduces drug concentration
High effect for oral administration
Area Under the Curve (AUC)
Total drug exposure over time;
proportional to dose and extent of bioavailability.
What does larger AUC mean?
Body is exposed to high amount of drug for a longer period of time; longer duration of drug elimination.
