Flashcards in PDA Block 1 Deck (141):
What is PHARMACODYNAMICS?
the way a drug affects the human body; must look at mech of action, therapeutic uses and adverse effects
What is pharmacokinetics?
the way the body affects the drug; must take into account absorption, distribution, metabolism and elimination
The mechanisms of drug action result from interactions with __________ of the organism.
functional macromolecular components
Drugs ______ ongoing functions of the body (they do not ____ effects).
______ is one type of functional macromolecular component with which drugs interact
What are the 2 types of ligands that bind receptors?
1. endogenous ones (NE, 2AG, etc.)
What is the difference between a receptor and an enzyme?
the ligand comes off the receptor as the same molecule as when it bound to it whereas a substrate turns into a product with an enzyme
What is the OCCUPANCY THEORY?
it is the occupancy of the ligand on the receptor that produces an effect
What does CURARE block? Why does this poison kill prey but then poison dart frogs can eat the prey (Bernard)?
-nicotinic ACh receptors
-because curare binds receptors causing paralysis/muscle weakness in breathing via a ligand
What is the chemotherapeutic index (Ehrlich)?
way to understand doses for the effect you want vs. toxicity
Why is there no "Magic Bullet" (Ehrlich)?
because agents bound to receptors cause a cascade of different interactions of other molecules (multiple effects)
In which space do CURARE and NICOTINE act? What are their respective effects?
-in NMJ (Langley)
-curare blocks nAChR while nicotine activates nAChR
What are some functional macromolecular mechanisms, other than receptors, by which drugs can produce effects?
-ion channel inhibitors
-binding of clotting factors (Heparin)
_______ binds to angiotensin converting enzyme
_____ competitively binds dopamine uptake carriers
_____ blocks the potassium ATP channel and increases insulin release from the pancreas
The interactions with proteins and/or receptors involves ________ binding.
Why are receptors awesome drug targets?
1. specificity (subset of receptors)
2. selectivity (coupling to different pathways)
3. sensitivity (amplification of signal in cell)
By what are pharmacological receptors classified?
-receptor names based on ligand
By what are biochemical receptors classified?
transduction mechanisms (GPCRs vs. ionotropic)
By what are molecular/structural receptors classified?
families of similar gene products
Describe the LAW OF MASS ACTION.
the amount of complex that is formed is related to the concentration of the reactant, the rate constant for association and rate constant for dissociation
What is the equation for L + R LR at equilibrium (steady state)?
k1 [L]x[R] = k2 [LR]
What are the units for the association constant? Dissociation constant?
-k1 units = 1/(sec*M)
-k2 units = 1/sec
What is Kd?
the equilibrium dissociation constant; the ratio of k2/k; describes the "goodness of fit" between L and R
What does a low Kd indicate?
more complex is bound (increase in [LR]); high affinity
What does a high Kd indicate?
there is more unbound ligand (increase in [L] and [R]); low affinity
How does Kd relate to affinity of L for R?
Kd is inversely related to affinity
What are the units for Kd?
What is an antagonist?
a blocker of a receptor
If you wanted a drug with high specificity for your new drug (instead of endogenous ligands), what would you look for?
the highest Kd for the ligand you do NOT want to bind to the receptor and lowest Kd for the ligand you DO want to bind to the receptor
What is Rt?
the total number of receptors available for binding; Rt = [R] + [LR]
Draw a rectangular hyperbolic curve showing [LR] vs [L] and: Rt, 1/2Rt, Kd
When [L] is very large, what happens to [LR]?
[LR] ~ Rt
When does [L] = Kd?
when [LR] = 1/2Rt
Describe ionic binding of L to R.
1. strongest bond
2. receptors with charged amino acids
3. many ligands are weak acids/bases and are charged at physiological pH
4. major determinate of k1
Why is ionic binding of L to R a major determinate of k1?
because the bond is strong, R can influence L from farther distances apart
Describe hydrogen bonding of L to R.
when H+ bound to electronegative atom (O/N), the H+ will have a slight positive charge
Describe Van der Waals interactions of L to R.
1. weakest bond, therefore species must be very close to the receptor
2. hydrophobic interactions
3. stabilizes ligand by strengthening the binding interaction; major determinant of k2
Which types of interaction of L to R are the strongest when L is far away? Close?
-hydrogen bonding (k1)
-Van der Waals (k2)
What is the Rate Theory?
it is not the number of ligands that produce the magnitude of effect, but the number of formed LR complexes
What is the formula for the Rate Theory?
E/Emax = LR/Rt
When does Emax occur?
when ALL receptors are occupied; E/Emax = 1
What is EC50 (Kact)?
the [L] at which you get 50% Emax (maximum EFFECT in a tissue)
What is the equation corresponding to [L] vs. Effect of [L]?
Some compounds are intrinsically able to produce an effect/activate a receptor while others are not. Explain why choline esters with a methyl group has a greater effect than a propyl/butyl group (never gets to Emax)?
the choline ester with the methyl group has a greater affinity for the receptor while the propyl/butyl have lesser affinity for the receptor
Why in choline esters will methyl and ethyl side chains reach Emax while propyl side groups will not?
because the receptor binds better with smaller hydrocarbons, up to an ethyl group, which has less affinity for the receptor but can still bind (same intrinsic activity, different amounts of L to produce Emax)
What is intrinsic activity (∂)?
What does ∂=1 indicate? ∂=0? 0<1?
What is a partial agonist?
can bind receptor, but doesn't have the full agonistic/antagonistic effect
Taking into account intrinsic activity, what is the new equilibrium equation for the effect of L on R?
An antagonist usually has _____ receptor binding with ______ effect.
What is the relationship between ligand affinity (Kact) and intrinsic activity (∂)?
they are independent parameters
What is the MODIFIED occupancy theory?
because there are spare receptors, decreasing the amount of receptors can still cause Emax (due to limited EFFECTOR molecules, to a point), but it takes increasing [L] to create Emax response as you decrease spare receptor # (EC50 would go up)
What does the MODIFIED occupancy theory prove?
that EC50 (effect) ≠ Kd (dissociation constant) due to fractional occupancy of the receptor
Taking into account fractional occupancy (f) and (∂), what is the new equilibrium equation for the effect of L on R?
When there is a higher number of receptors (same number of effectors and ligands as another cell with fewer receptors), how will the cell respond?
with increased sensitivity (LR complex is dependent on Rt!)
What is one way cells can modulate the effects if they cannot change ligand concentration?
change the number of receptors on the plasma membrane (FRACTIONAL OCCUPANCY)
You have a drug with a positive charge that binds a protein with a negative charge to inhibit the effects of an agonist. What kind of antagonist is this?
You have a drug that activates SNS to override PNS in order to inhibit the effects of an agonist. What kind of antagonist is this?
Describe what a pharmacological agonist is.
it blocks the EFFECT of an agonist of a receptor
Describe the mechanism of a competitive pharmacological antagonist.
acts at the same binding site to occupy and occlude the binding of endogenous agonist
Draw the equilibrium between a drug (D) and its competitive pharmacological antagonist
for the effect of the drug, ∂=1
for the effect of the antagonist, ∂=0
What determines the total effect on the system that an antagonist can effect?
proportion of [D]/[A]
The more you increase EC50 when using an antagonist, the more you you ________
increase the amount of inhibition
What kind of antagonist is used when the effect is dependent upon both agonist and antagonist? Why?
competitive antagonist; antagonist with higher affinity for the receptor will produce greater inhibition
What kind of antagonist is used when the effect is dependent upon the antagonist only? Why?
competitive IRREVERSIBLE antagonist because there ends up being no spare receptors and so amount of effectors activated are overall decreased
What is an unsurmountable response?
cannot overcome antagonist by increasing agonist (competitive irreversible antagonist)
Suppose you have a log curve graph showing the effects of an antagonist. With antagonist, the curve shifts to the right, increasing Ki, but maintaining the Emax. What kind of antagonist is it?
either competitive reversible OR competitive irreversible; you must get rid of all spare receptors in order to figure out which type of receptor it is
What two major characteristics of irreversible antagonists?
1. the only way to overcome this type of antagonist is to synthesize new receptors
2. inhibition produced is not influenced by agonist present
Give an example of an irreversible antagonist to treat HTN.
PHENOXYBENZAMINE = inhibits ∂-adrenergic receptor whose effect is vasoconstriction; in pheochromocytoma (adrenal medullary tumors), a huge increase in catecholamines bind ∂-adrenergic receptors, causing increased vasoconstriction-->HTN
Which type of antagonist causes an effect that is independent both on agonist concentration and number of spare receptors?
noncompetitive antagonist; allosteric binding to an EFFECTOR (not receptor) can calm down an effect without stopping it because these antagonists can bind nonselectively at the receptor level, targeting more effectors
What are the two major characteristics of a partial agonist?
1. when PA is present alone (no endogenous ligand), it acts as an agonist
2. when PA is present with endogenous ligand, it acts as a partial antagonist because it limits the effect of the endogenous ligand
Give some examples of useful partial agonists for:
(b) Parkinson's disease
(a) SARALASIN = binds angiotensin II receptors
(b) BROMOCRIPTINE = binds presynaptic dopamine receptors
What constitutes a tonically active receptor? What will an agonist do to that receptor? an inverse agonist? a partial agonist?
-a receptor is constantly flipping between the open/closed states, and tonically active receptors are mostly in the active state
-agonist will increase the probability that the receptor is in the active state by stabilizing it
-an inverse agonist will increase the probability that the receptor is in the inactive state by stabilizing that conformation
-a partial agonist is not as good at stabilizing the receptor in the active state
On a log concentration curve, draw what an agonist, partial agonist, antagonist and inverse agonist will do to the Ra/Ri (active/inactive receptors).
What is the difference between an ANTAGONIST and an INVERSE AGONIST?
Inverse agonists evoke responses (opposite to endogenous agonist) but while antagonists block the agonist, they do not evoke a response at all. Antagonists possess NO INTRINSIC ACTIVITY.
Why is a partial agonist also a partial antagonist?
depends on if the endogenous ligand is present or not
What is the fundamental tenet of therapeutics?
there is a relationship between the dose of a drug and administered/therapeutic effect
Describe an idealized dose-response curve.
mirrors the concentration-effect one obtains in laboratory settings-->S-shaped curve
Define dose vs. concentration.
dose =the amount per kg body weight given
concentration = amount per volume
How does Emax and EC50 change with a partial agonist/antagonist?
Emax decreases, EC50 increases
When looking at a dose-response curve, what is EFFICACY?
the maximum effect produced by a particular drug; similar to Emax
the relationship of the amount of drug administer to produce its effect
Define ED50 and how it is related to potency.
ED50 is the dose value at which the effect is 50% of the maximum effect (efficacy); it is inversely related to potency
The higher the ED50 the _____ amount of drug you must give to the patient; this drug is [very/not very] ______ potent.
What are the determinants of potency?
1. affinity for the site of action
2. ability to reach the site of action quickly
What are 3 drugs that act as agonists of opiate receptors? List the most potent from greatest to least.
What is an analgesic agent?
one that causes an elevation in pain threshold
In the picture below, PROPRANOLOL and ATENOLOL have about the same potency and SOTALOL is the most potent as an antihypertensive. Why is this?
propranolol and atenolol undergo the 1st pass effect, where is is absorbed in the stomach then immediately degraded by the liver
Potency is a major determinant for prescriptions. T/F?
FALSE; efficacy is!
What are the determinants of efficacy?
1. the intrinsic activity for a receptor ligand (type of agonist)
2. characteristics of effector
3. limitations on amount of drug that can be administered, due to adverse effects
What is ASPIRIN's efficacy for pain threshold compared to analgesic agents? Why?
it is lower because it acts through a different mechanism (blocking cylcooxidase); analgesic agents have additive, synergistic effects, causing a steeper curve and greater Emax and lower ED50
What is the standard measure to cover the range from 0 to 100% maximal effect for a drug?
-must be depended upon the law of mass action (ability of drug to bind receptor)
-3 log units of drug dose
What results in deviations in the dose-response curve?
1. additive effects of the drug (slope)
2. threshold effects (have to measure the change in person because can't measure small, weak effects)
3. antagonist effects
What dose-response curve is most difficult to get therapeutic Tx just right? Give an example of a class of drugs that exhibits this.
-very steep, upsidedown U-shaped curve
-antidepressants because if you give too much drug, it won't work and if you give too little, it won't work
Suppose you give a patient 100mg SERATRALINE (an antidepressant) and they have no response. Should you give more or less of the drug?
You don't know because it could be on the right/left of the U-shaped curve, showing threshold; therefore it might be too little or too much; you must adjust and monitor the patient
Name some characteristics about dose-response relationships among populations.
1. biological variability among individuals
2. determination of individual dose-response curve rarely done (time/$), so look at statistics
3. usually responses of POPULATION of people are calculated to determine drug doses
4. the distribution of a specific response as a function of dose is looked at (usually normal distribution)
When looking at the distribution of a particular drug dose on response frequency in a POPULATION, describe what kind of data you are looking at.
-quantal (yes effect/no effect); ex) looking at how dose of drug causes patients to have relief from pain
-mean (ED50) is the frequency of "yes"s
What is a CUMULATIVE FREQUENCY distribution? What does ED50 represent in this curve?
-tells what % of total individuals have had this response or a lower response (S-curve)
-ED50 represents the dose at which 50% of the POPULATION has had a positive response to the drug (helped with pain)
Describe the reasons for variation in response among individuals.
1. differences in pharmacokinetics (ex: smokers are less responsive to some drugs)
2. variation in endogenous agent (ex: propranol and HR)
3. different number/function of target (ex: tolerance to BARBITURATES)
4. differences in component distal to target
What are BARBITURATES?
Name some types of biological variability (5)
1. idiosyncratic drug response (unexpected based on mechanism)
2. hypo and hyper-reactive (at tails of D-R curve); need more or less dose to produce an effect
3. hypersensitivity = allergic or inflammatory response--> BAD
4. tolerance = SLOWLY developing resistance due to receptor metabolism level
5. tachyphylaxis = RAPIDLY developing resistance to drug (ex. nicotine)
Describe a QUANTAL dose-response curve.
-aka cumulative frequency D-R curve
1. Y-axis is quantal effect (yes/no)
2. ED50, LD50 (lethal dose) or TD50 (toxic dose) values are obtained depending on response measured [lower __D50, the higher ___]
3. Shape of curve shows variability in population response
When looking at ED50 and TD50/LD50 of a single drug, what is your ideal graph?
one in which ED50 and ED99 (99% of population has desired effect) does not overlap the toxic/lethal dose curve at all
What is the THERAPEUTIC INDEX?
TD50/ED50 of a particular drug
What two characteristics determine the rate of passive diffusion?
1. partition coefficient of drug (into oil from water)
2. concentration gradient across membrane
What kind of molecules are most drugs?
weak acids/weak bases
When will a drug that is a weak acid/base passively diffuse across the PM?
when it is in its neutral charge (either HA or B)
Describe ion trapping.
Acidic drugs accumulate on the BASIC side of the membrane and basic drugs accumulate on the ACIDIC side of the membrane
How does MORPHINE, a weak base, become detected in the stomach contents following IV overdose?
even though BH+ is in blood, enough B is present and will diffuse down its gradient into the stomach and will get protonated and trapped
Name the 3 purposes of carrier-mediated transport.
1. move hydrophilic molecules through bilayer
2. can move molecules against [ ] gradient
3. provides specificity
Name the characteristics of facilitated diffusion. Give an example.
-no requirement for the input of energy
-ex) GLUT transporters = selective
Name the characteristics of active transport. Give an example of primary and secondary active transport.
-moves solutes AGAINST [ ] gradient
-primary = P-glycoprotein ABC carrier/pump
-secondary = symporters/antiporters, like Na+ dopamine uptake
Describe the mechanism of transport of P-glycoprotein ABC carrier/pump.
binds lipophilic drugs that have entered via passive diffusion to mediate efflux from the cell; primary active transport; mechanism encoded by human genes for multidrug resistance (kicks meds out of infected cells)
Which ions are most generally coupled with secondary active transporters?
Na+ or H+ moving down [ ] gradient
aka "F"; the fraction of the administered dose of drug that reaches the circulation; IV-administered results in F = 1
Why do orally-administered drugs usually have a bioavailability of less than 1?
IV-administered drugs result in F=1; orally-administered drugs usually have either:
1. incomplete absorption
2. first pass effect (propranolol)
What are the two routes of the first pass effect?
1. metabolized by liver
2. excreted back into intestine through biliary excretion during it's first pass through the liver (never reaching systemic circulation)
1. same drug
2. same route of administration
3. same amount of drug enters the circulation
4. same rate of drug entering circulation
How are orally administered drugs absorbed?
into circulation from GI tract; mostly via passive diffusion; favors absorption of UNIONIZED drugs (week acids in HA form and weak bases in B form)
Name characteristics of stomach vs. intestinal absorption.
-Stomach = acidic (pH1-2), lined with mucous, small surface area, limited absorption
-Intestine (upper) = pH about 7; large absorptive surface area (200 m^2); MORE ABSOPTION
Where is the vast majority of drug absorption? Why?
in the UPPER INTESTINE because the equilibrium is not reached due to the constantly moving blood; therefore you gradually absorb more and more drug down its concentration gradient even though most of it is ionized (because some is NOT ionized)
Describe how gastric emptying affects the rate of absorption.
increased gastric emptying increases rate of absorption
What, besides gastric emptying can affect the rate of absorption?
dissolution of a solid drug --> coatings, particle size, etc.
Describe controlled-release drugs and their advantages and disadvantages.
-accomplished by coatings (the more coatings, the longer that will take to dissolve)
-pros = slower absorption causes decreased frequency of dosing and more uniform [drug] in blood
-cons = greater variability among patients and TOXICITY if the drug is released all at once (chewing, etc.)
Define enteric coatings.
used to protect drug from the stomach acid and the stomach from the drug; serves to provide better taste
What are the benefits of sublingual/buccal drug administration? Give an example of a drug.
venous drainage from mouth to superior vena cava protects drug from immediate metabolism in the liver; good for highly lipophilic drugs (but small surface area)
(ex) nitroglycerine (to treat angina)
What are the benefits/drawbacks of rectal administration?
pros = if patient cannot/won't swallow; 50% less first pass than when taken orally
cons = variable absorption; irritating to rectal mucosa
What are the benefits of transdermal administration?
pros = nearly complete barrier to non-lipophilic substances, but is permeable to lipophilic drugs; best if hydrated; long-term, steady approach
(ex) nicotine, estrogen/progesterone
What are the benefits/drawbacks of parenteral injection administration?
1. IV = directly into bloodstream; F=1, rapid action and highly-controlled/adjusted; less irritating due to blood volume
2. subcutaneous/intramuscular = depots (not completely bioavailable) occur by dimple diffusion to nearby capillaries; hydrophilic molecules
cons = can be distributed to lung first (excretion of volatile agents or temporarily stored in the lungs)
What are limitations of lipophilic and large hydrophilic drugs?
lipophilic = limited by surface area of capillaries and solubility in interstitial fluid; potentially stored and then redistributed in lungs
hydrophilic =proteins enter circulation slowly via lymphatic system (vaccinations)
When giving IV drugs, which organ do those drugs first encounter?
What factors must you take into account when administering drugs subcutaneously?
drugs must be non-irritating; can add vasoconstrictors to delay absorption (reducing capillary blood flow)
What factors must you take into account when administering drugs intramuscularly?
absorption depends on blood flow to the muscle; if you work out right after, your body will absorb the drug faster
Describe some characteristics of pulmonary absorption.
used to deliver volatile agents; rapid access to circulation
Describe some characteristics of topical application to mucous membranes/eye.
-mucous membrane drugs are common
-eye = usually absorption through cornea; systemic absorptions can occur from nasolacrimal canal (bad taste); must prepare drug to increase duration of action using inert ointments/etc.
Describe 3 novel methods of drug delivery.
1. drug eluting stents would increase blood flow by eluting anticoagulants
2. targeting of drugs coupled with antibodies (cancer, for example)
3. activation of drugs at site of action (enzymatic trigger)
The extent and rate of drug delivery depend on:
1. regional blood flow
2. capillary permeability of drug (endothelial junctions)
3. drug binding to plasma proteins, like albumin (+) for acids and ∂1-acid glycoprotein (–) for bases
4. tissue accumulation of drugs (fat = reservoir for lipophilic drugs and bone = reservoir for divalent metal chelating agents, like tetracyclines)
Describe what happens when during drug binding to proteins and what affects this process.
1. protein binding prevents drug from leaving circulation
2. drug responses, toxicity, metabolism are all a function of the drug that is free
3. at equilibrium, amount of free drug is constant
4. equilibrium can be perturbed if [plasma proteins] change or there are long-term changes in exogenous/endogenous competitors for binding sites