Pharmacodynamics: Drug-Receptor Interactions Flashcards
Pharmacokinetics v. Pharmacodynamics
- Pharmacokinetics = the study of what body does to a drug to affect the movement of drug into, through, and out of the body (ADME)
- Pharmacodynamics = the study of the mechanisms of drug action and the relationship between drug concentration and effect
Components of pharmacodynamics
- Drug-receptor interaction
- Mechanism of drug action
- Efficacy/toxicity
Effective dose (ED)
= the amount of drug (mg, gram, grains) administered that results in drug plasma concentrations within the therapeutic range
ED50
= the dose needed to produce the desired therapeutic effect in 50% of the population of animals to which it is given
–Starting point for therapeutic index
Therapeutic index (TI)
= a measure of drug safety; the ratio of the dose that produces toxicity to the dose that produces a therapeutic response in 50% of the individuals
TI = TD50/ED50
Therapeutic window
High TI = big therapeutic window = safer drug
Type of drug effect
- Stimulation
- Inhibition
- Replacement
- Irritation
- Cytotoxicity
Mechanism of drug action
Non-receptor mediated:
- Osmotic diuretics/purgatives
- Heavy metal chelating agents
- Local antacids
Receptor mediated:
-Majority of targeted drug therapy
Drug is designed based on the ligand-receptor response
Ligand/drug binds to receptor –> send cell signal –> cellular event
Major site of action - Receptor
A macromolecular component (usually protein) of a cell with which a drug interacts to produce a response:
- Membrane proteins
- Enzymes
- Nucleic acids
- Others: lipids and polysaccharides
Macromolecular types of protein receptors
- Transport proteins (ex: Na/K ATPase ion channel targeted by Digoxin (cardiac drug))
- Catalytic enzymes (ex: Dihydrofolate reductase targeted by methotrexate (anti-cancer drug))
- Structural proteins (ex: Tubulin targeted by colchicine (anti-gout drug))
- Regulatory proteins (ex: Glucocorticoid receptor targeted by glucocorticoids (anti-inflammatory drug))
Receptor Functions
- Interaction with specific ligand (ligand binding domain)
- Transduction of signal into response (effector domain)
Characteristics of ligand-receptor response
- Receptors must have structural features that permit ligand affinity and specificity
- Receptors must be biologically important molecules with selectivity of response
- The biological response is proportional to ligand bound receptors with sensitivity (predictable amount of response when it binds to that receptor)
Receptor occupation theory
Effect (E) is proportional to the fraction of occupied receptors (DR) - determined by drug concentration (D) and receptor binding ability (K); receptor (R)
K1
D + R DR –> E
K2
Efficacy
Potential maximum drug response (E)
Affinity
Propensity of a drug to stay binding to the receptor (K)
Potency
Amount of drug needed to produce an effect (D)
more potent –> less drug needed
Functional types of ligands
- Agonist
- Antagonist
Agonist
Has affinity for binding to the receptor and efficacy for eliciting the response (Induces active conformation of the receptor protein and elicits a response)
- Agonist alone elicits full efficacy
- Example: epinephrine
Antagonist
- Has affinity but no intrinsic efficacy (does not trigger an intrinsic response, even though it fits in the binding site)
- Blocks the action of agonist
- Action only observed in presence of agonist
(Occupies receptor without conformational change –> no response)
-Example: Adrenergic receptor beta-blocker
Competitive Antagonist
Agonist efficacy can be fully rescued by increasing agonist at the cost of potency
- If competitive antagonist is > agonist –> limited response
- If agonist is > competitive antagonist –> can overcome and produce a significant response
- *Decreased potency –> more drug needed –> reach full efficacy
Non-competitive Antagonist
Agonist efficacy cannot be rescued by increasing agonist
*Agonist cannot compete against a non-competitive antagonist (irreversible binding) –> decreased efficacy
Potency v. Efficacy
- Maximal effect % (y axis) v. log concentration (x axis): logarithm compresses and proportionate doses at equal intervals
- EC50: the agonist concentration that can produce 50% of maximal effect
- Lower EC50 indicates higher potency
Agonists differ in efficacy
Highest % response has the greatest efficacy
Agonists differ in potency
The more potent drug takes smaller drug concentration to achieve the max % response
*Compare EC50 - smaller EC50 has the greatest potency
Competitive antagonists decrease agonist potency
Agonist + competitive antagonist take more drug concentration to achieve the max % response
Non-competitive antagonists decrease agonist efficacy
Agonist + non-competitive antagonist decreases the drug response at the same drug concentration
Partial agonist
Has affinity but lower efficacy and potency than a full agonist
*Can have both full agonist and partial agonist present at the same time
Two state receptor theory
- Full agonist binds to active receptor - sustained activation
- Antagonist binds equally to both active and resting receptor - balanced
- Inverse agonist binds to resting receptor - sustained inactivation
Inverse agonist
- An inverse agonist binds to the receptor to exert the opposite pharmacological effect of an agonist
- -Ex: Histamine H2 blocker - Cimetidine reduces basal cAMP level
- Different from an antagonist, which binds to the receptor but does NOT reduce basal activity of the receptor
Agonist v. antagonist v. inverse agonist
- Agonist –> positive efficacy
- Antagonist –> zero efficacy
- Inverse agonist –> negative efficacy
Receptor occupancy and biological response
- Biological stimulus
- -Threshold effect (0% response)
- -Max effect (100% response)
- Receptor occupancy
- -Threshold effect (20% occupancy)
- -Max effect (70% occupancy; with receptor reserve - 100% occupancy)
-In some systems, maximal effect does not require occupation of all receptors by agonists (=spare receptor)
Effect of spare receptor on partial agonist
In the presence of spare receptor, increasing partial agonist can reach maximal effect
- Full agonist - full intrinsic efficacy
- Partial agonist - lower intrinsic efficacy
Tolerance
Reaction to a drug is reduced, requiring an increase in concentration to achieve the desired effect
- Innate
- Acquired
- Acute
- Cross
Innate tolerance
Lack of sensitivity to a drug due to genetic variation
Acquired tolerance
- Pharmacokinetic tolerance: repetitive administration causes a decrease in drug absorption or an increase in drug metabolism
- Pharmacodynamic tolerance: decrease in the number/sensitivity of receptors
Acute tolerance (Tachyphylaxis)
Acute development of tolerance after a rapid and repeated administration of a drug in shorter intervals
-Ex: Sympathomimetic ephedrine depletes noradrenaline from the nerve terminal
Cross tolerance
Among drugs that belong to the same or similar pharmacological category
-Ex: Anti-anxiety drug-hypnotics-anesthetics
Desensitization and Down-regulation
- Prolonged/continuous use of an agonist: Decreased receptor sensitivity (activity on signaling transduction) or receptor number
- Ex: Bronchodilator beta2-agonist - NOT for continuous use - Inhibition of ligand degradation
Sensitization and Up-regulation
- Prolonged/continuous use of a receptor blocker: Increased receptor sensitivity (activity on signaling transduction) or receptor number
- Ex: Anti-arrhythmic Beta-blocker - DO NOT discontinue abruptly
- -Body tries to compensate with sympathetic nervous system by releasing epinephrine –> increased number of receptors are open for epinephrine binding –> extreme tachycardia - Inhibition of ligand synthesis or release
After ligand/drug receptor interaction
–> Activation of the receptor to induce downstream signaling transduction
Functional types of receptors
- Ligand-gated ion channel
- G protein-coupled receptor
- Enzyme-linked receptor
- Nuclear receptor
Ligand-gated ion channel
- Ligand-binding and pore-forming proteins in the cell membrane
- Signal molecule binds as a ligand at a specific site on the receptor –> conformational changes open the channel allowing ions to flow into the cell –> the change in ion concentration within the cell triggers cellular responses
- -Ex: Na/K ATPase ion channel
G protein-coupled receptor
- Seven-transmembrane polypeptide helices
- Receptor interacts with G protein at the cytoplasmic side of the helices upon ligand binding
- Ex: Adrenergic receptor
Enzyme-linked receptor
Ligands bind to both receptors –> the two receptor polypeptides aggregate forming a dimer –> Activates the tyrosine-kinase parts of the dimer –> each phosphorylates (using ATP) the tyrosines on the tail of the other polypeptide –> receptor proteins are now recognized by relay proteins inside the cell –> relay proteins bind to the phosphorylated tyrosines (may activate 10 or more different transduction pathways)
–Ex: tyrosine kinase receptor; insulin receptor
Nuclear receptor
Ligand binds to the receptor in the cytoplasm –> ligand-receptor binding leads to conformational change and nuclear localization –> nuclear receptor binds to DNA to increase transcription and the consequent protein expression
–Ex: Hormone receptor; glucocorticoid receptor
