Drug Mech: Exam 1 Review

Pharmacodynamics

• Concentration vs. Effect
• Dose vs. Response

Pharmacokinetics

Concentration vs. Time

Ligand

• 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 will happen.

Selective Binding

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.

No. Stereochemistry is a constant and cannot be manipulated. However, the drug can be changed.

• Aspirin
• Plavix
• Beta Lactams
• Chemotherapeutic drugs

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.

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.

• Ibuprofen
• Warfarin
• Verapamil

*Each of these drugs have both an S & R 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.

• Agonists
• Full Agonist
• Partial Agonist
• Inverse Agonist
• Allosteric Agonist

• Antagonists
• Pharmacologic Antagonist (Noncompetitive and Competitive)
• Allosteric Antagonist

• 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).

GABA works endogenously on the same receptor that Benzodiazepines (which are exogenous) do.

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.

Full Agonist

Partial Agonist

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).

Inverse Agonists

• Blockers
• Receptor Specific Antagonists

Competitive antagonists which compete with the agonist (whether it be endogenous or exogenous) for the binding site.

Who wins? Whoever is in greater concentration.

Constitutive activity is the effect produced in the absence of agonist (which is a small observable effect).

• 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.

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.

Ra-Da

Ra-Dpa + Ri-Dpa

Ra-Dant + Ri-Dant (slightly favored) = constitutive activity

Ri-Di

• 

No. An inverse agonist holds the receptor in the Ri form. Constitutive activity is an equilibrium of Ri and Ra forms.

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.

• Regulatory proteins mediate the actions of endogenous chemical signals. Examples include:
• neurotransmitters
• autacoids
• hormones

Dihydrofolate reductase enzyme is the receptor for the anticancer drug methotrexate.

Na+/K+ ATPase is the membrane receptor for the cardiotonic digitalis glycosides.

Tubulin is a receptor for colchicine.

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.

The higher the affinity of the drug, the more likely it will be selective in binding.

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.

The more receptors you have, the more likely you are to have a pharmacologic effect.

Penicillin-G

The Fractional Inhibitory Concentration (FIC) Index

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.

A beta lactamase is an enzyme produced by a bacterial species that evolved to destroy the beta lactam ring in beta lactam antibiotics.

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.

This combination is synergistic because of their different mechanisms of action working together. Penicillin allows the increased uptake of aminoglycosides by the microbes.

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.

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.

No...this combination is not antagonistic.

Beta lactam antibiotics, such as imipenem, cefoxitin and ampicillin, are potent inducers of beta lactamase.

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.

• Multi Drug Resistance.
• MDR is caused by microbial resistance.

Beta lactam antibiotics

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.

• Beta Lactams
• Aminoglycosides
• Quinolones
• Trimethoprim

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.

• Tetracyclines
• Aminoglycosides

Sulfonamides

Yes! A combination of two or more mechanisms can definitely happen. Bacteria are clever and will evade antibiotics any way they can.

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.

• 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!

A plasmid, also called an R-Factor, is a self-replicating piece of DNA.

• Transformation
• Transduction
• Conjugation
• Transposition

Transformation is when an R-factor inserts itself? (inserts itself into what??)

Transduction is when an R-factor is transferred from one bacterial cell to another via a virus.

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!

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.