Lecture 3: Intro to Pharmacodynamics Flashcards
What is the major difference between Pharmacokinetics and Pharmacodynamics?
PK = effects of the body on drugs (ADME)
PD = effects of the drugs on the body
- receptors, response curves, drug action mech.
What do Emax and ED50 on a logarithmic dose-response curve tell us?
Emax (on y-axis) is the maximal effect that can be produced by the drug
ED50 (on x-axis) is the dose of drug that produces 50% of its maximal effect
What does a Graded vs Quantal Dose-Response curve answer?
Graded answers: “How much?”
- usually the mean value in a pop. or single subject
Quantal answers: “Does the response occur or not?” and “How many?”
- usually all-or-none, yes/no, or binary responses
- examines frequency of a response in large pop.
What is the difference between a Non-Cumulative vs Cumulative Quantal Dose Curve?
- non-cumulative shows number/% of pts responding to drug dose ONLY at that dose
- cumulative shows number/% of pts responding to drug dose and at all doses lower than that dose
What is the Therapeutic Index and how is it calculated?
TI = TD50 / ED50 (higher TI = safer drug)
TD50 = median toxic dose ED50 = median effective dose
What is Drug Potency and how is it related to median effective dose? (ED50)
- the amount of drug required to produce a specific pharmacological effect
- lower ED50 means the drug is MORE potent and helps determine the drug does that will be used clinically
What is Drug Efficacy and how is it related to Emax?
- describes the pharmacological effect that a drug can produce (represented as Emax)
- greater Emax means the drug is MORE efficacious and is related to the total number of receptors available to bind a drug
- determines magnitude of clinical effect
What is the difference between a Covalent bond and Non-Covalent bond?
Covalent: irreversible; requires re-synthesis of receptor or enzymatic removal of the drug
Non-Covalent: reversible; most drugs bind to receptors this way
What are the 3 major Non-Covalent bonds from strongest to weakest?
Ionic (electostatic interactions)
Hydrogen
Hydrophobic
What is the difference between a high affinity and low affinity drug?
- HIGH affinity drugs have strong receptor binding and require less drug to produce a response
- LOW affinity drugs have poor receptor binding and require more drug to produce a reponse
What is the Equilibrium Dissociation Constant (Kd) and why is it important for drug interaction?
- Kd represents the drug concentration at which 50% of the drug receptor binding sites are occupied
- LOWER Kd = HIGHER affinity of drug for receptor
- HIGHER Kd = LOWER affinity of drug for receptor
How is drug selectivity measured? How is selectivity related to adverse effects?
- via Kd ratio = Kd (off target) / Kd (on target)
- higher Kd ratio means the a drug is more selective
- more selective drugs have fewer adverse effects, while less selective drugs have more adverse effects
What is Intrinsic Activity and how does it relate to drug Agonists and Antagonists?
- the ability of a drug to change receptor function and produce a physiological response when bound
Agonists - have intrinsic activity
Antagonists - have NO intrinsic activity
bind to receptor but do NOT change its function
What is the difference between Full Agonists, Partial Agonists, and Inverse Agonists?
Full - fully activate receptors (maximal intrinsic activity)
Partial - partially activate receptors (sub-max effects)
Inverse - produce opposite effect to other agonists
- dec. receptor signaling
What is the difference between Pharmacological, Chemical, and Physiological Antagonism?
Pharm - antagonism at receptors
Chemical - chemical antagonist makes other drug unavailable
Phys - endogenous pathway blocks other pathway
What is the difference between Irreversible and Allosteric Non-Competitive antagonists?
- Irreversible bind to agonist site on receptor with COVALENT bonds
- Non-Competitive bind to site other than agonist and prevent agonist binding/receptor activation
How does Agonist EC50 and Emax change in the presence of a competitive and non-competitive antagonist?
Competitive - EC50 inc., Emax does not change
Non-comp - Emax dec., EC50 does not change
What does Gs, Gi, Gq, and G12/13 activate in their pathways when activated?
Gs –> adenylate cyclase ACTIVATION
Gi –> adenylate cyclase INHIBITION
Gq –> Phospholipase C ACTIVATION
G12/13 –> Rho GTPases = cytoskeletal rearrangements
How does G protein receptor resensitization occur using GRK, Beta-arrestin, and P’ase?
- GRK phosphorylates receptors, preventing interaction with G subunit and allows Beta-arrestin binding
- Beta-arrestin binds to coated pits, allowing for receptor internalization
- agonist dissociation dec. Beta-arrestin affinity, allowing P’ase to dephosphorylate receptors
- receptor is returned to the plasma membrane
prolonged or repeated agonist exposure leads to lysosomal breakdown of receptor
What is the second messenger in the G protein pathway and what creates it? What breaks it down?
- cAMP
- created by adenylate cyclase from ATP
- Phosphodiesterase converts cAMP into 5’-AMP
What 5 molecules activate the JAK-STAT pathway? (GELII)
- growth hormone (somatotropin)
- erythropoietin
- leptin
- interferons
- interleukins 2-10, 15
What 6 molecules activate the RTK pathway? (IIVENP)
- IGF-1 (insulin-like growth factor 1)
- insulin
- VEGF (vascular endothelial growth factor)
- EGF (epidermal growth factor)
- NGF (nerve growth factor)
- PDGF (platelet-derived growth factor)
Ras GTPase activation via Receptor Tyrosine Kinase
- adaptor protein binds to phosphorylated tyrosine in cytoplasmic receptor domain
- Ras activating protein binds to adaptor protein to activate Ras GTPase
- Ras GTPase activate Raf –> MEK –> ERK 1/2
What are 5 common activators of nuclear receptors? (STDAL)
- usually lipophilic molecules that are able to cross the cell membrane
- steroid hormones, thyroid hormones, vitamins A and D, and lipid mediators (FFAs)
- heat-shock proteins bind to receptor in absence of ligand to prevent unwanted folding
