Flashcards in topic 6 Deck (29):
What are two types of dose response relationships?
Graded-Plotted with the dose increasing on the x-axis and intensity of effect on the y axis
Quantal-plotted with the dose increasing on the x-axis and the fraction of a population that a dose works for on the y-axis. Good for all or nothing effects of drugs
What does a typical dose effect curve look like? Where do most drugs aim to be on curve?
Threshhold-When the drug first starts to take effect
Slope-linear relationship where larger dose leads to larger effect. (1st order)
max effect-line evens out, larger dose doesn't lead to greater effect
Most drugs aim to be just above the threshhold dose
What is the difference between efficacy and potency? How are they measured
Efficacy refers to the maximum effect a drug can have regardless of size or dose. It is measured by Emax
Potency refers to the quantity of drug necessary to achieve a certain effect. It is measured by ED50 or EC50, which is the amount of a drug required to cause 50% of the max. effect.
What is the importance of a slope of a dose response plot
If the slope is steep, it means that a slight change in dose could lead to large changes in response which means that it will more easily become toxic. A flatter slope is easier to dose (less chance of toxicity).
What is a full agonist? Partial agonist?
A full agonist is a drug that gives the maximum effect once bound to a receptor. A partial agonist gives a less effective response than the full agonist and thus when both are give, a partial agonist can act as an antagonist.
What is a dose-percent curve? What is the difference between a cumulative frequency distribution and a frequency distribution?
The dose-percent curve is a quantal dose-effect curve. It plots the dose vs. the percent of individuals affected. A frequency distribution plots only the percentage of people that were first affected a certain dose. A cumulative frequency distribution plots all the people that were affected at a certain dose even if they were previously affected by a lesser dose (it resembles
a graded dose response curve).
How do you calculate the therapeutic index and the margin of safety for a drug.
Therapeutic index=LD50 (lethal dose)/ED50
Margin of safety can be more accurate especially when dealing with different slopes.
Margin of safety=LD1/ED99
What are the 4 levels of drug response and mechanism?
systems-effect on system function(autonomic, etc.)
tissue-effect on tissue function
molecular-receptor, ion channel enzyme, carrier molecule, etc.
What are 3 general ways that drugs work?
Antagonize/block inhibit endogenous proteins
activate endogenous proteins
Other unconventional ways
What are some examples of drugs with unconventional mechanisms of action?
Enzymes such a streptokinase (from bacteria) for thrombolysis
Drugs that exert actions due to physical properties (mannitol-osmotic diuretic)
What are 4 ways in which drugs can selectively inhibit enzymes (examples?)
Selective toxicity through inhibition of a unique metabolic pathway-sulfonamides work on an enzyme that bacteria have but humans don't.
Selective toxicity through species differences in enzyme selectivity-more drug is needed to inhibit the human enzyme than the bacteria enzyme (antibacterial/anti-malarial drugs-trimethoprim/pyrimethamine).
counterfeit incorporation-add an analog to a macromolecule (substrate) and make it so the enzyme doesn't recognize it. Anti-cancer drugs.
Inhibitors of enzyme activity in specialized cells-target pathways specific to certain cells. Inhibitors of tyrosine hydroxylase
How do drugs target ion channels?
They can either directly or indirectly bind to the channel but allosterically. There are numerous places in which different drugs can bind and the effects can be numerous. They might make the opening of the channel faster or slower or might block the channel or keep the channel open longer, etc.
What are some examples of drugs affecting carrier proteins
NE uptake-Tricyclic antidepressants block the carrier molecule that brings it back into the cell, cocaine does the same.
Penicillin reuptake-Probenicid (targets the carrier protein that leads to excretion in kidney).
What are 4 key characteristics of receptors
Specificity, Affinity, Intrinsic activity (causes some affect), saturability
What are 4 types of receptors (physiological targets)? How quickly do they work?
Ionotropic-receptor operated channels-milliseconds
G-protein coupled (metabotropic)-seconds to minutes
Kinase Linked (tyrosine kinase, serine/threonine)-minutes
DNA Linked (nuclear)-hours
How do g protein coupled receptors work? Which subunit determines the effect?
Ligand binds, 7 alpha helices changed configuration, alpha, beta/gamma subunits change conformation, GDP unbinds from alpha subunit and GTP binds to it, alpha/gtp go to an effector and beta/gamma goes to an effector
The alpha subunit determines the effect
What are the effects of the different alpha subunits?
Gs=activates adenylate cyclase-->cAMP
Gi (1/2/3)=inhibits adenylate cyclase-->less cAMP
Gq=activates Phospolipase C
What is the difference between EPI's effect at SM and cardiac muscle
At cardiac muscle epinephrine binds to a B1 receptor which is a Gs so adenylate cyclase then protein kinase A is activated which leads to phosphorylation of troponin which leads to contraction
At smooth muscle, E binds to B2, then PKA phosphorylates myosin light chain kinase which inhibits myosin which leads to relaxation of muscle.
What is the mechanism of phospholipase C
NE, E, ACh bind, g protein (Gq) activates PLC which cleaves PIP2 into IP3 which opens a Ca channel on SER and DAG which activates PKC.
What does activation of Phospholipase A2 result in?
Arachidonic acid which can result in prostaglandins or thromboxanes.
What are most tyrosine kinase receptors involved in?
Growth. Epidermal growth factor (EGF) receptor is the most targeted drug. These drugs are usually anticancer drugs.
Insulin receptors are also tyrosine kinases.
What is the mechanism for tyrosine kinase receptor activation?
Ligand binds, receptors dimerized. Dimerization leads to activation of tyrosine kinase aspect of receptors which leads to autophosphorylation of tyrosine groups which allows them to act as scaffolding for target proteins.
What is occupancy theory?
The effect is proportional to the fraction of receptors occupied.
What is th spare receptor theory?
Maximal response can be achieved by binding only a fraction of the receptors (amplification).
Response depends not only on the occupancy of the receptors but on the rate of binding and dissociation. K=K2/K1
K2=rate of dissociation
K1=rate of association
What are simple definitions for agonist, antagonist, and partial agonist?
Agonist-Affinity and intrinsic activity
Antagonist-affinity but no intrinsic activity
partial agonist-affinity but less intrinsic activity
What categories of antagonists are there?
Active site binding-reversible (compet), irreversible (non-compet); allosteric binding-reversible (non compet), irreversible (non-compet).
What are characteristics of a competitive antagonist?
competes with agonist for receptor
surmountable with increasing agonist concentration
dose response curve goes to the right
Reduces apparent affinity of the agonist for the receptor (increases Kd and EC50)