Pharmacology - General Flashcards
What pharmacokinetic variables affect drug levels
-absorption:
route, nature of absorption surface, blood flow, drug solubility (small bowel abnormalities)
-distribution:
volume of distribution and bioavailability (reduced albumin)
-biotransformation:
metabolism in liver, lungs, kidneys, skin, intestine (reduced hepatic enzyme function in baby)
-elimination:
rate of clearance (impaired liver function)
What pharmacodynamic variables affect drug dosing
-therapeutic index:
ratio of TD50 to ED50
-tachyphylaxis:
response diminishes rapidly after administration
-bioaccumulation:
accumulation of substances in an organism
What factors contribute to the variation in drug response
age gender body mass disease states polypharmacy tachyphylaxis
What mechanisms are involved in variation of drug response
- alteration in concentration of drug that reaches receptor: absorption, clearance
- variation in concentration of endogenous receptor ligand: high levels of endogenous catecholamines
- alteration in number or function of receptors: downregulation or upregulation
- changes in response components distal to the receptor
What is the difference between a full and partial agonist
-full agonist:
can activate the receptor-effector system to the maximum effect
-partial agonist:
binds some receptors but does not evoke as great a response
When can a partial agonist act as an antagonist
in the presence of a full agonist (ex. buprenorphine)
What is EC50 and what are spare receptors
EC50 = the concentration of a drug required to produce 50% of the drugs maximal effect
spare receptor = maximal biological response is possible without full occupancy of all receptors
2 mechanisms:
temporal - prolonged effect after transient binding
numerical - limited substrate with excess receptors
What is an antagonist and give an example
- a drug that binds to a receptor, does not activate it and competes with binding of other molecules
- example: naloxone, flumazenil, beta-blockers
What is the difference between competitive and non-competitive antagonists and what type is naloxone?
- non-competitive antagonist binds via irreversible covalent bonds or so tight that the receptor is not available to the agonist
- competitive antagonist has less affinity for the receptor than irreversible antagonists
at higher concentrations of agonist there will be a given effect - naloxone is a competitive antagonist
Define potency, efficacy and dose response curves
-potency is the amount of drug required to produce 50% of maximum effect
ED50 = dose of a drug required to produce 50% maximum effect
EC50 = concentration of a drug required to produce 50% maximum effect
-efficacy is the maximum effect a drug can bring about
What factors affect a drugs efficacy
affinity of receptor for drug drug-receptor interaction route of administration absorption distribution clearance
What are the steps in activating a second messenger
- method of transmembrane signalling
- binding of extracellular ligand to G-protein-coupled receptor causes activation of cytosolic G-protein
- activation of GTP-binding protein leads to increase in 2nd messengers
- second messenger then produces an active intracellular element
-examples of second messengers:
cAMP activated via adenylyl cyclase->- mobilises fats/carbs, conserves water in kidneys, increases HR/contractility, calcium regulation
cGMP - relaxes vascular smooth muscle
calcium/phosphoinositides - smooth muscle contraction
Discuss the events in cAMP activation
- extracellular ligand binds to GPCR –> conformational change
- alpha subunit exchanges GDP for GTP and is released from the complex, activating adenyl cyclase (AC)
- AC converts ATP to cAMP which is the second messenger
- cAMP activates downstream pathways such as PKA, ion channels (CNG), EPAC, Popdc
What are some ligands that work via second messengers
adrenaline noradrenaline acetylcholine on muscarinic receptor opioids nitric oxide
What are some mechanisms of transmembrane signalling?
- lipid-soluble ligand crossing membrane to act on intracellular receptors
(ex. steroids, thyroid hormones) - ligand-gated ion channel
(ex. GABA, acetylcholine on nicotinic receptors) - transmembrane receptor binding to intracellular protein tyrosine kinase
(ex. insulin) - voltage gated ion channel
(ex. verapamil) - second messenger
(ex. glucagon, dopamine, adrenaline, serotonin, acetylcholine on muscarinic, nitric oxide)
What influences the extent and rate by which a drug is absorbed
route of administration nature of absorbing surface blood flow drug solubility drug formulation
What routes of drug administration are there
sublingual, buccal, oral, rectal, subcutaneous, intramuscular, intravenous, intrathecal, epidural, inhalational, topical
What factors affect rate of absorption from the small intestine
-ionisation status:
alkaline pH favours absorption of un-ionised basic drugs
-intestinal motility:
increased motility leads to reduced transit time and less absorption
-gut surface area, blood flow, formulation or drug
Why is aspirin absorption enhanced by low pH in the stomach
aspirin is acidic and is more in the uncharged and lipid soluble state at acidic pH
How does the ionisation of a drug affect its solubility
- drugs exist as acids or bases in the body
- ionised (charged, polar) drugs are water soluble and do not cross membranes easily
- unionised (uncharged, nonpolar) drugs are lipid soluble and cross membrane easily
What is first pass metabolism
- when drugs are metabolised before they enter the systemic circulation
- after administration of an orally ingested drug, the portal system delivers the drug to the liver
- metabolised in gut wall, portal blood, liver or excreted into bile before reaching systemic circulation
- reduces bioavailability of the drug, impacts on the efficacy of the orally administered drugs
