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Which Principle deals with the actions of the drug on the human body?
How do you plot Pharmacodynamics?
- Concentration vs. Effect
- Dose vs. Response
Which Principle deals with the actions of the human body on the drug?
How do you plot Pharmacokinetics?
Concentration vs. Time
What is another name for a drug molecule in the body?
What two actions must take place in order to activate a receptor?
- 1) The drug molecule or ligand must fit into the binding site.
- 2) The drug molecule or ligand must form chemical bonds in that binding site (make the right connections.
If these two things take place, a pharmacological effect
What is another name for Drug Selectivity?
What is the relationship between Drug Selectivity and Drug Specificity?
Drug Selectivity (aka "Selective Binding") of a drug refers to the number of receptor types the drug binds to in the body.
Many drugs are "selective" as they will bind to only a few receptor types or subtypes in the body.
Drug Specificity, on the other hand, refers to the number of effects (both therapeutic and toxic) that the drug is capable of producing in the body.
Because no drug causes only one single effect, there is not such thing as a "specific" drug.
Therefore, drugs are only Selective in their actions; they are not Specific.
Can the stereochemistry of a molecule be changed?
No. Stereochemistry is a constant and cannot be manipulated. However, the drug can be changed.
What are some specific examples of drugs that bind covalently?
- Beta Lactams
- Chemotherapeutic drugs
Which bonds are most selective in their binding?
Non-covalent bonds are more selective than covalent bonds.
Why? Because covalent bonds produce a very strong irreversible reaction, whereas the weaker non-covalent bonds must get very intimate in the drug pocket to produce an effect. Not every drug will intimately fit and bind in that drug pocket, and therefore, non-covalent bonds are more selective.
What is a racemic mixture? What is an Enantiomer?
A racemic mixture is a mixture of optical isomers, or enantiomers. In a racemic mixture there is an S enantiomer and an R enantiomer. The two enantiomers are identical except for their 3D rearrangement in space: enantiomers are mirror images of each other and contain one or more asymmetric centers and have opposite stereochemistry at all centers.
What are some examples of drugs on the market that are racemic mixtures?
*Each of these drugs have both an S & R enantiomer
What is an example of a drug that is marketed as a pure enantiomer?
Keep in mind that in most cases, one drug enantiomer is much more potent than the other, reflecting a better 'fit' to the receptor molecule
For example, the dextrorotatory isomers
(the (+) enantiomers
) in the morphine series of drugs, such as dextromethorphan, are cough suppressants that possess the anti-tussive properties of codeine (which has a levorotatory, (-)
, stereochemistry), without the analgesic, addictive, central depressant, and constipating features
exhibited by the (-) form
. The (+)
form simply does not bind to the receptors involved in analgesic, constipative, addictive, and other actions exerted by the (-)
form. As a result, dextromethorphan
has largely replaced many older antitussives
, including codeine
, in prescription and nonprescription cough preparations.
- Another example is the local anesthetic levobupivacaine, which is the (S) isomer of bupivacaine. Bupivacaine is available on the market; it is the racemic mixture of the (R) and (S) isomers. Both the (R) and (S) isomers have good local anesthetic activity, but the (R) isomer causes
- myocardial depression and ventricular arrhythmias. In contrast, the (S) isomer shows much less cardiotoxicity. Consequently, the pure (S) isomer of bupivacaine is now available on the market because of its superior safety profile.
Name all possible types of drug-receptor interactions.
- AgonistsFull AgonistPartial Agonist
- Inverse Agonist
- Allosteric Agonist
- Pharmacologic Antagonist (Noncompetitive and Competitive)
- Allosteric Antagonist
When would partial agonists be used?
- Partial agonists are used:
- 1) When we settle without a full agonist available.
- 2) When we want to use it as a competitive antagonist (used as blockers to compete with the full agonist so that full agonist doesn't activate the receptor).
Give an example of an endogenous agonist and an exogenous agonist?
GABA works endogenously on the same receptor that Benzodiazepines (which are exogenous) do.
Is there any way to extend/amplify the pharmacological effect without binding to a receptor?
Yes! Some drugs mimic the effect of a receptor agonist by inhibiting the molecules responsible for terminating the action of an endogenous agonist.
For example, phosphodiasterase inhibitors do not activate a receptor, but they are able to keep the physiological effect going. When phosphodiesterase, an enzyme, is inhibited, it allows cAMP to continue being active because phosphodiesterase breaks down cAMP.
Acetylcholinesterase inhibitors are able to prevent neurotransmitters from being broken down to be recycled by the synaptic cleft that released it, and therefore, they allow more neurotransmitters to be transmitted through neurons. Thus, acetylcholinesterase inhibitors are another example of something extending pharmacological effect without binding to a receptor.
What type of receptor exhibits high intrinsic efficacy?
What type of receptor exhibits low intrinsic efficacy?
True or False: Intrinsic efficacy is dependent on affinity.
False. Intrinsic efficacy is independent from affinity.
You could have high affinity, but low intrinsic efficacy, or vice versa.
Think of the tickle analogy: you could be tickling someone (making connections, bonding in the drug pocket), but the person isn't laughing (the drug molecule, although binding, is not making the right connections to produce a pharmacological effect).
Which type of receptor will bind and produce opposite effects of the agonist, binding in a non-functional state?
What are other names for pharmacologic antagonists?
- Receptor Specific Antagonists
Which type of receptors are dependent on concentration or dose?
Competitive antagonists which compete with the agonist (whether it be endogenous or exogenous) for the binding site.
Who wins? Whoever is in greater concentration.
What is constitutive activity?
Constitutive activity is the effect produced in the absence of agonist (which is a small observable effect).
What factors determine the constitutive activity?
- The equilibrium between Ri and Ra conformations.
- Receptor density
- The concentration of coupling molecules (if a coupled system).
- The number of effector molecules in the system.
Which state is favored in the absence of a ligand?
The Ri form of the receptor is favored in the absence of a ligand, but a small percentage still exist in the Ra (active) form.
Which state of equilibrium is a Full Agonist in?
Which state of equilibrium is a Partial Agonist in?
Ra-Dpa + Ri-Dpa
Which state of equilibrium is a Pharmacologic Antagonist in?
Ra-Dant + Ri-Dant
(slightly favored) = constitutive activity
Which state of equilibrium is a Inverse Agonist in?
Will you see any constitutive activity with an inverse agonist?
No. An inverse agonist
holds the receptor in the Ri form
. Constitutive activity is an equilibrium of Ri
What's the difference between a drug binding to a receptor and binding to an inert binding site?
A Receptor is usually an endogenous regulatory molecule that must be selective in binding to ligands (drug molecules and other xenobiotics), and must change its function upon activation (binding) in order to alter the biologic function or response.
Binding of a drug to a nonregulatory, inert molecule in the body (e.g., albumin in plasma) will not alter the biologic function or response; these inert endogenous molecules that can bind to drugs are known as Inert Binding Sites. Although this type of drug binding does not result in a pharmacological effect, it is of great pharmacokinetic significance because it affects drug distribution in the body and the amount of ‘free’ drug that is available in the general circulation.
Drug Receptors: What are some examples of regulatory proteins?
- Regulatory proteins mediate the actions of endogenous chemical signals. Examples include:
Drug Receptors: What is an example of an enzyme?
Dihydrofolate reductase enzyme is the receptor for the anticancer drug methotrexate.
Drug Receptors: What is an example of a Transport Protein?
Na+/K+ ATPase is the membrane receptor for the cardiotonic digitalis glycosides.
Drug Receptors: What is an example of a structural protein?
Tubulin is a receptor for colchicine.
What three important things are receptors responsible for?
Receptors are largely responsible for establishing the quantitative relationships between dose or concentration of the drug and its pharmacologic effects
- Receptors are responsible for selectivity of
- drug action.
Receptors mediate the actions of both Agonists and Antagonists
What is the relationship between affinity and selective binding?
The higher the affinity of the drug, the more likely it will be selective in binding.
What is the relationship between affinity and drug potency?
Potency is a concentration, or amount of the drug required at the receptor site to produce a pharmacologic effect.
Increased affinity = increased potency, and vice versa.
What is the relationship total number of receptors in a tissue or cell, and pharmacologic effect??
The more receptors you have, the more likely you are to have a pharmacologic effect.
What is an example of a narrow-spectrum antibiotic?
What is a mathematical way to determine whether an antibiotic is synergistic, indifferent or antagonistic?
The Fractional Inhibitory Concentration (FIC) Index
Explain the mechanism of action for Septra (also called Bactrim).
Septra or Bactrim is composed of a combination of Trimethoprim and Sulfamethoxazole. The two drugs work together to block sequential steps in a metabolic sequence of bacterial cells. Therefore, the mechanism of action of Septra is synergistic.
What is a beta lactamase?
A beta lactamase is an enzyme produced by a bacterial species that evolved to destroy the beta lactam ring in beta lactam antibiotics.
Explain the mechanism of action for Penicillin (which is susceptible to beta lactamases) and Clavulonic acid (which resists beta lactamases).
Penicillin and Clavulonic acid have a synergistic mechanism that allows them to defeat bacterium that produce beta lactamases. In fact, Penicillin and Clavulonic acid together has the drug name Augmentin.
Their mechanism of action is such that it does not allow the bacterial enzymes (beta lactamases) to inhibit the action of the antibiotic. In other words, Clavulonic acid acts as a "body guard" for penicillin so penicillin can do its job.
Is the combination of penicillin and an aminoglycoside synergistic or antagonistic?
This combination is synergistic because of their different mechanisms of action working together. Penicillin allows the increased uptake of aminoglycosides by the microbes.
Is the combination of amphotericin B and flycytosine synergistic or antagonistic?
This combination is synergistic because amphotericin B, an antifungal agent, will essentially poke holes in the fungal cell walls, which allows increased uptake of flucytosine. Now flucytosine can do its job (which is to inhibit the DNA/RNA synthesis of the cell). Thus we can see how two different mechanisms of action can work together synergistically.
Describe the mechanism of action for a penicillin and a tetracycline.
This combination is antagonistic because the static agent (the tetracycline) inhibits the cidal agent (the penicillin) from working. Recall that a cidal species must have replicating cells to work, but the static agent will stop the cells from dividing, thus, they antagonize each other's effects.
Note, however, that this mechanism of action does not always occur with static/cidal agents.
Is the combination of tetracycline and an aminoglycoside antagonistic?
No...this combination is not antagonistic.
Which class of antibiotics are potent inducers of beta lactamase production? (Recall a beta lactamase is an enzyme produced by some bacterial cells to evade destruction by an antibiotic).
Beta lactam antibiotics, such as imipenem, cefoxitin and ampicillin, are potent inducers of beta lactamase.
What happens when a beta lactam antibiotic (such as imipenem, cefoxitin or ampicillin), which are potent inducers of beta lactamase production, is combined with an antibiotic that is sensitive (or vulnerable) to beta lactamases (such as pipercillin)?
An antagonistic effect is produced. So for example, if imipenem and pipercillin were combined, the two drugs would antagonize each other as imipenem would essentially produce more beta lactamases, which would destroy the pipercillin.
What does MDR stand for?
- Multi Drug Resistance.
- MDR is caused by microbial resistance.
Which class of drugs do beta lactamases destroy?
Beta lactam antibiotics
What is Target Modification?
Target Modification is a very common mechanism that bacteria evolve to evade antibiotics.
Essentially, the bacterial species will change the chemistry of the binding site so that the antibiotic will no longer be able to bind to it. If the antibiotic can't "catch" the bug, then it can't inactivate or kill it.
Target modification happens by chromosomal mutations, which is a spontaneous mutation on the gene of the chromosome.
Which classes of drugs are susceptible to Target Modification?
- Beta Lactams
What is Alteration in Target Accessibility?
Alteration in Target Accessibility is a mechanism that bacteria use to evade antibiotics.
Essentially, in Alteration in Target Accessibility, the bacteria reduce permeability of the antibiotic, or increase efflux of the antibiotic.
Which classes of drugs are susceptible to Alteration in Target Acessibility?
Some bacteria have developed a completely new and different metabolic pathway to evade a certain class of drugs. Which class of drugs would this be?
Can bacteria use more than one mechanism to evade antibiotics?
Yes! A combination of two or more mechanisms can definitely happen. Bacteria are clever and will evade antibiotics any way they can.
Give an example of a microorganism that exhibits microbial resistance by a non-genetic origin (non-multiplying organisms).
The classic example would be TB (Tuburculosis).
The idea behind TB's mechanism of action is that if the bacterial cell is not dividing, then we can't kill it with an antibiotic or stop it (because it's already stopped).
TB stays dormant in the lung tissue from anywhere from months to years. Then, when the host is immunocompromised, the TB seizes the opportunity to strike when the host is weak and begins multiplying again.
Describe the steps leading up to Chromosomal Resistance.
- The bacterial cell has a spontaneous mutation.
- The spontaneous mutation leads to target modifications. (Target modifications = chromosomal resistance).
- Target modifications lead to the production of enzymes that inactivate the antibiotics.
ASK if this slide is correct....a bit confused on this!
What is a plasmid?
A plasmid, also called an R-Factor, is a self-replicating piece of DNA.
What are the four mechanisms of the Transfer of R-Factors?
What is Transformation?
Transformation is when an R-factor inserts itself? (inserts itself into what??)
What is Transduction?
Transduction is when an R-factor is transferred from one bacterial cell to another via a virus.
What is Conjugation?
Conjugation is by far the most important mechanism of the Transfer of R-factors that contributes to microbial resistance.
Conjugation is basically sexual intercourse of two bacterial cells. This causes big problems of microbial resistance when two bacterial cells of different species mate because of the potential diversity of the super bug that may result!
What is Transposition?
Transposition is the transfer of R-factors via transposones = "jumping genes."
Transposition can only be used when genes that encode for resistance are transposones.
If a transposone is carried on a plasmid (R-factor), then the genes can "jump" and move onto a chromosome on another DNA.
If genes are not transposones, transposition will not occur.