Week 4 - Pharmacodynamics Flashcards
Define Pharmacology
Pharmacology is the study of substances (“drugs”) that interact with living systems through chemical processes
Define Toxicology
Classically, toxicology is viewed as a branch of pharmacology that deals with adverse effects on living systems (the “science of poisons”)
All substances can under certain circumstances exert toxic effects
Define Pharmacodynamics
The actions a drug has upon the body
Pharmacologic Dogma
Receptor
Agonist
A drug produces its effect by interacting with a macromolecule within or expressed at the surface of a cell, a receptor
An “agonist” is a drug that activates molecular, biochemical, and physiological events associated with that interaction (we’ll talk about antagonists later)
Function of a receptor
- Recognition - receptor recognizes drug, the drug must fit perfectly into receptor (lock and key)
- Signal Transduction - receptor then transmits signal to cell and something happens
A drug may…
A DRUG MAY INCREASE OR DECREASE CELL FUNCTION BUT DOES NOT INITIATE NEW CELLULAR FUNCTION
Selectivity and Specificity
- Recognition imparts selectivity ofdrug binding (the drug binds one or a small number of receptor types)
- The tissue localization of different receptor types imparts specificity of drug action (the drug exerts a distinctive influence on the body)
Do you think that there are many drugs which bind covalently to their receptors? (hint: think about this of perspective of controlling drug responses, particularily when things go wrong)
True
False
False
Covalent interactions are LONG LIVED.. So drug would take receptor out perminantly..Not good if want to reverse effects. Body would have to synthesize more receptors.
Some (a very few) drugs DO bind covalently, must be very careful.
Most drugs act though weak forces and must have a very high specificity for the receptor…
Chemical Nature of receptors
- Most are proteins
- Enzymes (most)
- Ion Channels
- Structural
- Regulatory
- Nucleic acids
Transduction does what in a cell after the drug binds?
- It PROPAGTATES a signal
- Alters receptor funciton
- Generates a 2nd messenger (GMP, cAMP, etc)
- 2nd messengers may generate another messenger
- Some cases the receptor will impact gene transcription (protein synthesis of some sort)
Transduction Mechanisms
(dont need to know details on test)
G Protein-coupled Receptor Signaling
- Drug binds to G protein, then receptor dissociates through membrane and transducucts a signal to an effector
- About half of all drugs use this mechanism
- hundreds of these types in body - dont know what many of them do or what ligand binds to them
Ligand gated Ion Channel
- Ligand binds and opens up ion channel, can cause depolorization of membrane
Receptors as Enzymes
- Once ligand (drug) binds to the receptor it acts as an enzyme to phosphorylize or dephosphorylize
Receptors mediating Nuclear Transcritpion
- Steroid hormones act on these
- These are in cytoplasm or nucleus (rest are membrane bound)
Attributes of receptor - mediated processes
(this will be on test)
- Highly compartmentalized - some located on cell membrane, some in cytoplasm
- Self-limiting on relatively short time scales - so when a G-protein receptor is activated they initiaiate their own deactivation very quickly.. ion channels will close back up very quickly
- Organized into opposing systems - pathway for upregulatiing something, there will also be a pathway to downregulate somethign. Phosphorilization, dephosphylization
- Provide opportunities for signal amplification - The signal can get amplified very quickly from a very breif interaction of drug and receptor
- Operate through a relatively small number of 2nd messenger systems - The total number of receptors GREATLY out numbers the 2nd messenger systems** A drug interacts with receptors but there are many many other receptors and indogenous ligands acting at the same time
Many drug-drug interactions can be explained by this distingcit attribute of receptor mediate biologica processes. Which is responsible for this phenominon?
Receptor based processes tend to be organized into opposing systems
Receptor medicated processes tend to be highly compartmentalized
decrease in receptor numbe ofgen occurs over time in response to sustained stimulation of the system
A large number of different receptors may operat through a much smaller number of 2nd messenger systems
Teh response of a receptor to a logan generally long lived due to the self perpetuation nature of these systems
**A - True - Opposing systems, special case of D (good response) **
B - true - but no opportunity for drug-drug interactions
C- true - tolerance but not a drug drug interaction
D - True - (good response)
E - false
Drug-drug interaction questions will be on exam**
What important groups of drugs that do not interact with receptors?
- Drugs interact chemically with small molecules - EDTA, dimercaprol
- Drugs producing physicochemical effects – mannitol, antacids, volatile anesthetics, compounds that impact pH etc
- Drugs that target rapidly dividing cells -
Cell cycle - specific drugs: target cells that are dividing
- Toxic to cells that are cycling (dividing or preparing to divide)
- Includes structural analogs of endogenous compounds (“antimetabolites”) that act by interfering with DNA/RNA synthesis – e.g., methotrexate, 6-mercaptopurine, 5-fluorouracil
- Others bind to DNA causing strand breaks – e.g., the antibiotic bleomycin
- Still others target the cellular machinery needed for cell division – e.g., vinblastine (a plant alkaloid), which inhibits tubulin polymerization
Cell cycle-nonspecific drugs: resting or cycling cells are the targets (Non receptor mediated mechanisms)
- Toxic to cells that are cycling as well as cells that are resting (G0)
- Many damage and/or bind to DNA interfering with normal cell function
- Examples include alkylating agents (e.g., nitrosoureas) and some antibiotics (e.g., doxorubicin)
Occupancy Theory - What does it assume?
Effect of drug is proportional to receptor occupancy*
….and that these interactions are monovalent (one receptor binds to one ligand)*
(law of mass action explains this)
What is teh occupancy theory at equilibrium?
Association Rate
Dissociation Rate
At equilibrium
x is molar concentration of drug
r is molar concentration of receptor
rx is product
k1 and k2 are constants
Kd - ratio of on rate constant to off rate constant (units are concentration)
Know this equation**
Deriving occupancy theory at equilibrium…
Fractional occupancy rx/rt
Deriving occupancy theory at equilibrium…
Assume response (or effect E) is proportional to RECEPTOR OCCUPANCY
So.. fraction of total responase is equal to fraction of total occupied.. assume that system responds at HALF maximal action… then we get that concentration of drug is equal to Kd. (dissociation constant)
This is called the EC50, concentration of drug that produces half maximal response* it is equal to Kd
Explaine a Dose-Response Curve
Plot of dose against response…
Plotted are both log dose and dose (log dose is on left) makes it easier to get EC50 much easier.
Define Affinity, how does it effect the Log-Dose Curve?
- Ability to form complex with receptor
- Characterized as 1/KD
- The greater the affinity the lower the drug concentration required to produce an effect
- Basis of receptor classification
Kd for X is much lower than the Kc for Y - so X has a much HIGHER affinity for receptor that drug Y
Define Potency
Potency - relative position of dose-response curve
Drug X is more potent than Drug Y because it takes LESS of drug X to elicit a response
Efficacy or Intrinsic Activity
Full Agonist (X)
Partial Agonist (Z)
How do this effect the log-dose curve?
Efficacy or Intrinsic Activity
- Capacity to produce response
Full Agonist (X)
- Maximal Response
- Has full efficacy (alpha = 1)
Partial Agonist (Z)
- Produces less than maximal response
- Has partial efficacy (1>alpha>0)
*Alpha is term to define efficacy, 1 is full effacacy, 0 is no efficacy
So - we want to know what affinity is and efficacy is***
‘Pure’ Antagonist
- Has Affinity for receptor
- Inhibits Action of Agonist
- Has no efficacy (alpha = 0)
Classicll receptor occupancy theor explains the observed behavior of many drug receptor systems.. choos teh one correct statement
receptor occupancy increasees linearly with drug conc.
occupancy of a small percentage of receptors may elicit a full response of system
response to a drug is proportional to receptor occupancy
one receptor can bidn two drugs simultaniously
response to a drug is proportional to the aomunt of drug added
A - NOT linear - add more and more drug but it will eventually saturate - it cannot be literally
B - Spare receptors - it is a violation of theory
C - response to a drug is proportional to receptor occupancy
D - clear violation of theory (monovalent)
E - is a restatement of A, response will saturate
Competitive Antabonist (one of two types of antagonist)
How does it change dose response Curve?
- Reversible (binds to receptor and unbinds.. both atropine and acetiycholine do this)
- Dose-response shifts to right
- Apparent affinity of agonist is reduced (EC50, Kd shift towards right)
- Slope does not change
- Maximal response can be produced if add enough agonist, just takes a lot to outcompete antagonist..
Non-Competetive Antagonist
- Irriversible (this is the covalent type reaction, or off rate is very long)
- Maximal response reduced
- Slope reduced
- Apparent affinity change a litte if at all
- Apparent numnber of receptors decreased*
- Cannot get maximal response* no matter how much of agonist is added…
Log dose response curves are obtained for A and B. A has higher potency than B. What attribute of these two curves can be used to support this claim
Max response of syst to A exceeds that in response to B
Addition of B falis to antagonized effects of A
Curve for B is left of curve for A
Max resp of sys to B exceeds that to the response A
Curve for A is well to left compared to B
A - potency has nothing to do with max response
B - Has nothing do do with question
C - direct opposite
D - Potency has nothing to do with max response
E - Curve is well to left for A
A is non-competetive antagonist of B. Which is true?
Adding fixed amount of A shifts B curve to left
Adding fixed amount of A reduses response to system to a fixed dose of B, but a full response to b can be obtained by increaseing dose
adding a fised amount of a reduces the resonse of the system to a fixed dose of b, and the addition of moer b will not bring back the full response
fadding a fixed dose of a has no effedct of slope of curve for b
adding fixed amound of a substancially increases teh apperant affinity of A
A - Antagonism will never move it to left
B - No, adding more B will not increase it (that would be for competitive antagonist)
C - this is characteristic of non-competitive
D - this is consistent with competetive antagonist
E - No, curve wont shift right
Define Physiological Antagonism
- Distinct from competitive and non-competitive antagonism (drug-receptor)
- Distinct from the type of antagonism just described insofar as it involves interactions among regulatory pathways mediated by different receptors
- In this case a drug that impacts one pathway is used to “antagonize” (ie., counteract) an effect caused by a different pathway. E.g., insulin/glucocorticoids
Using one drug to deal with side effects of another drug*
Partial Agonist
Efficacy: 1>alpha>0
In the presence of a full agonist, it may act as an antagonist…
Morphines response is in resp depression.. Give fixed dose of morphine that will give a full response, but then give morphine at same dose, but increase the dose of buprenorphine (it binds to the same recpetor as morphine) and iff we add enough buprenorphine, it will outcompete morphine, and the system will transition from a morphine response to a buprenorphine response
Inverse Agonist
Actually getting a depressin in response with inverse agonist…
If add a agonist and an inverse agonist nothing will really happen.
This is completely different from occupancy theory
Two State Theory
Receptors act in two different forms, inactive and active, in equal amounts.
An agonist will stabilize the active form of the receptor (moves equilibrium to right)
Inverse Agonism will interact with inactive form of receptor (moveing equilibrium to left) - reduces amount of receptor available to produce effect
Pure antagonist has equal affinity for both active and inactive forms (no net effect) - but does decrease the number of receptors to bind to agonists
Partial agonist will move equilibrium to right but not as much as a full agonist
(no questions on two state theory)
Spare Receptors
Occupancy vs Response, Kd is different than EC50… so 5% occupancy elicits a 100% response… this is an extreme case.
Quantal Dose Effect
- All or None
- Population Response
- MEdian effective dose (ED50) - Dose producing effect of 50% of population
- CANT be used to deterimine Kd or maximal efficacy
- Individual responsivenes
- Hyperreactive if respond to dose <
- Hyporeactive if respone to dose >> ED50
So this graph explaines the efficacy of a drug on a total population… half the population is effected by a certain dose of the drug..
Tolerance
Tachyphylaxis
- Tolerance – a form of hyporeactivity induced by repeated administration
- Tachyphylaxis – a form of hyporeactivity induced rapidly after only a few doses
Therapeutic Index (TI)
- Measure of realative safety
- Ratio of LD50 to ED50
- TI = LD50/ED50
- Certain Safety Factor (CSF)
- Ratio of LD1 to ED99
- CSF = LD1/ED99
In this example TI = 2000/100 = 20
CSF = 1000/210 = 4.7
LD50 concentration to kill half of patients
ED50 concentration that will produce 50% efficacy in half of pts
LD1 concentration to kill 1% of pts (very hard to obtain)
ED99 concentration to be effective in 99% of pts (very hard to obtain)
TI is a measure of central tendancy. TI dose not factor in slope over lap, but CSF does (more conservative).. if slopes over lap it is a dangerous drug!
TI and CSF, bigger numbers are better! This separates teh curves more.
Chemotherapty, response you want is toxicity, narrow TI. Some chemo drugs TI is in single digits….
Diphenhydramine
- Active ingredient in Benadryl, Sominex, Tylenol PM, other OTC medications.
- at low doses it is a H1 (histamine) receptor antagonist, but also (hight doses) blocks serotonin reuptake and has anticholinergic activity
- at high doses it is a strong sleep agent
Look at structures of the following..
Look at the strucure simiarities and appreciate how it can be an antagonist / agonist for some of these compounds and their receptors
Managing pharmacological effects
- Many drugs possess “side effects” that relate to their activities at different receptor types (implies imperfect selectivity)
- These activities may vary; thus, a drug may be an agonist for one receptor, a partial agonist for a second, and an antagonist for a third
- The “predominant” activity at any given time may be highly dependent on dose due to differences in affinity (i.e., KD values) for the different receptors with which the drug interacts.
Managin pharmacologica effects in a complex sytemt cont..
- Thus, high dose levels may “unmask” undesired side effects that are not evident at lower dosages
- Alternatively, dose may be adjusted by the clinician to emphasize a particular pharmacological effect
- Q: how do we manage dose? A: we use the science of pharmacokinetics
