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
What drug blocks L-type calcium channels?
Verapamil
How does Verapamil effect the SA and AV node and what does it help treat?
SA: lowers heart rate
AV: lower conductivity
helps treat atrial and supraventricular arrhythmias
How does Verapamil effect cardiomyocytes and what does it help treat?
decreases contractility and oxygen demand
helps treat Angina pectoris
How does Verapamil effect vascular smooth muscle and what does it help treat?
relaxes smooth muscle
helps treat hypertension
How does Verapamil effect non-vascular smooth muscle and what is a side-effect that it can cause?
can cause muscle relaxation in the gut
can lead to constipation
