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79 Cards in this Set

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Define Pharmacology
It is the study of substances/chemicals that interact with living biological systems through chemical processes (particularly by binding to regulatory molecules) and alter (activate or inhibit) biologic function or response.
Define Pharmacodynamics
Pharmacodynamics refers to the actions of the drug on the human body (what the drug does to the body).
Define Pharmacokinetics
Pharmacokinetics literally ‘the movement of a drug’, refers to the actions of the human body on the drug (what the body does to the drug). It is the study of the Absorption, Distribution, and clearance (Metabolism/Excretion) of a drug (or the ADME properties of the drug) with respect to time, and the establishment of a relationship between drug concentration and time.
What must it take for a drug to bind to its receptor?
a drug molecule must have the necessary properties to be transported from its site of administration to its site of action. It must also have the right size, electrical charge, shape, and atomic composition in order to fit into and bind to the active site of its receptor.
Explain selective binding
• Selectivity is determined by 3d structure, size, and weight of the molecule. When molecules are between 100-1000 their binding ability is determined by 3d structure.
Explain covalent binding
covalent binding is, in most cases, irreversible. Drugs capable of forming a covalent bond with the receptor are usually ‘highly reactive’ molecules and do not require a perfect fit with the receptor
Explain electrostatic binding
Electrostatic bonds are weaker than covalent bonds; they (electrostatic bonds) vary from relatively strong ionic bonds between charged ionic molecules, to weaker hydrogen bonds, and very weak induced dipole interactions such as van der Waals forces. Drugs that form these bonds are short acting.
Explain hydrophobic binding
These bonds are very weak but they are important in the interactions of highly lipophilic drugs with the phospholipid bilayers of cell membranes; they are also important in the interaction of drugs with the active site or ‘pocket’ of the receptor. These drugs are short acting as well due to bond weakness.
What happens when a drug binds to a receptor?
The binding of the drug to the receptor cause a conformational change which will induce a pharmacological response.

Once the drug dissociates from the receptor the receptor will return to its original shape. And eventually the drug concentration will reach 0 and pharmacological effects will cease.
Explain Diastereomeric and Enantiomeric structures
Diastereomeric structures contain two or more asymmetric centers and have opposite stereochemistry (R vs S) at one or more, but not all, of these centers. Enantiomeric structures, on the other hand, contain one or more asymmetric centers and have opposite stereochemistry at all centers. Enantiomers, which are mirror images of each other, have the same physical properties; diastereomers have different physical properties (solubility, polarity, melting point, boiling point, …)

Remember, the more chiral a drug is the more selective it is
Why do stereoisomer drugs show different biological properties?
Active transport mechanisms involve asymmetric carrier molecules, which means that there will be preferential binding of one stereoisomer over others.

When differences in physical properties exist between stereoisomers, the distribution of drug isomers between body fluids and tissues where the receptors are located will differ. Differences in physical properties exist only among drug ‘diastereomers’ (not ‘enantiomers’) (e.g., the diastereomers ephedrine and pseudoephedrine)
Drug-metabolizing enzymes are asymmetric and stereoselective, which means that one drug enantiomer will often be more susceptible than the other to drug metabolism.
What is a racemic mixture?
a racemic mixture is a 50:50 mixture of the (-) and (+) enantiomers, one of which may be inactive or toxic.
What are conformational and steric factors?
Conformational and Steric Factors (as determined by the stereochemistry of the receptor site surface and that of the drug molecules) (only one enantiomer will have a perfect fit to the receptor) are of primary importance in establishing the nature and the efficiency of the drug-receptor interaction.
What are partial agonists?
PARTIAL AGONISTS are drugs that bind and activate the receptor; however, the evoked response or effect is not as high as the effect obtained from the binding of a ‘full’ agonist. Consequently, a partial agonist may act as either an ‘agonist’ (in the absence of a full agonist) or as an ‘antagonist’ (in the presence of a full agonist). It does not initiate the correct conformational change in the receptor which makes it less efficient. Drugs that are partial-agonists are not used as agonist, we use them as antagonist’s.
How are drug actions at the receptor level terminated?
1) Dissociation of the drug from the receptor. In some cases, dissociation will automatically terminate the pharmacological effect of the drug; in other cases, the effect may persist for a period of time following dissociation (when, for example, a coupling molecule is still present in an activated form).

2) Biosynthesis of new receptor molecules. In the case of drugs that bind covalently to the receptor, the effect may persist until the drug-receptor complex is destroyed and new receptor molecules are biosynthesized.
Explain the importance of 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.
Explain the two ways a drug permeates through the body
1) Passive Diffusion in an aqueous or lipid medium.

2) Active Transport by selective carrier molecules, less selective membrane carriers (P-glycoprotein or MDR transporters), endocytosis, or exocytosis. Unlike passive diffusion, transporters and carrier molecules involved in the active transport process (also known as ‘Facilitated Diffusion’) are saturable and inhibitable.
Explain the three practical consequences of the receptor
1) Receptors are largely responsible for establishing the quantitative relationships between dose or concentration of the drug and its pharmacologic effects.

(The receptor’s affinity for binding to the drug molecule determines the concentration of the drug required to produce a significant number of drug-receptor complexes, which will influence drug effect)

2) Receptors are responsible for selectivity of drug action.

3) Receptors mediate the actions of both Agonists and Antagonists.
What is Emax?
Maximal response that can be produced by the drug (a measure of drug efficacy) (Emax for an antagonist is 0)
What is EC50?
The Concentration of the drug that produces 50% of the maximal effect.(a measure of drug potency) (the higher EC50 the lower the potency)
What is Bmax?
Total concentration of receptor sites that are bound to the drug at infinitely high concentrations of free drug. (max number drug-receptor complexes that can be formed) (determined by the number of receptors available)
What is KD?
‘Equilibrium Dissociation Constant’ is the concentration of free drug at which 50% of maximal binding is observed. (50% of Bmax) (it is a measure of affinity) (if KD is high then the binding affinity is low) (high affinity means that you only need a small amount of a drug to produce a pharm. effect)

The EC50 and KD may be identical, but they don’t have to be. (total number of receptors in the tissue plays a role in the type of pharm effect b/c a certain number of receptors might be needed in order to produce the full affect of the drug)
What determines the efficiency of the coupling process (process between occupancy of receptor molecules and drug response)?
1) Initial Conformational Change in the receptor. As a result, the conformational change (occupancy) that results from binding of a full agonist leads to a much more efficient occupancy-response coupling than the conformational change that results from binding of a partial agonist.

2) Biochemical Events that transduce receptor occupancy into a cellular response and how efficient (or complicated) these events are.
What are spare receptors?
For a particular pharmacologic response, ‘Spare Receptor Molecules’ are present when the maximal effect or response can be produced by an agonist at a concentration that does not result in occupancy of all of the available receptor molecules.

• The sensitivity of a cell or tissue to a particular concentration of the agonist depends on both: The affinity of the receptor for binding to the agonist (which is characterized by KD ) and the degree of spareness of the receptor.

It is possible to change the sensitivity of tissues with spare receptors by changing the receptor concentration.
Explain Competitive (reversible) Antagonists
Competitive antagonism is concentration-dependent. Increasing concentrations of a competitive antagonist, in the presence of a fixed concentration of the agonist, will result in a gradual decrease or inhibition of the agonist effect; high concentrations of the competitive antagonist will completely abolish the agonist effect. (does not form covalent bonds) (it has to compete with agonists)
Explain Irreversible Antagonists
Some antagonists bind irreversibly to receptors. In some cases, this is attributed to an extremely high affinity of the antagonist for binding to the receptor; as a result, the receptor is practically unavailable for binding to the agonist. In other cases, antagonists bind irreversibly because they form covalent bonds with the receptor. *the only way to separate is to create a new receptor*

If Spare Receptors are present, a low dose of the irreversible antagonist will likely leave enough unoccupied receptor molecules for the agonist to exert a maximal effect (although a higher agonist concentration will be required).

The duration of action of an irreversible antagonist largely depends on the rate of turnover of receptor molecules (not the rate of its own elimination).
Explain Partial Agonists
Partial agonists produce a lower response, at full receptor occupancy, than do full agonists. The inability of a partial agonist to produce a maximal effect at full receptor occupancy is determined by its mode of interactions with the receptor, ie, the initial conformational change in the receptor (it is not due to decreased affinity for binding to the receptor). (it is also determined by the types of bonds formed with the receptor due to the chemical structure of the drug)

Many of the drugs that are used clinically as competitive antagonists are weak partial agonists.
Explain Chemical antagonism
Chemical antagonism occurs when one drug antagonizes the actions of a second drug by binding to and inactivating the second drug (e.g., protamine is a chemical antagonist of the anticoagulant drug heparin; protamine is used clinically to counteract the effects of heparin) (Protamine will bind chemically to heparin and terminate its effect)
Explain Physiologic Antagonism
Another way to antagonize the effects of a drug or an endogenous substance (substance found in the body) is to take advantage of the Physiologic Antagonism that already exists between endogenous regulatory pathways in the body (e.g., the use of insulin to antagonize the hyperglycemic effects of glucocorticoid therapy). However, when compared to the effects of receptor-specific antagonists, the effects of physiologic antagonists are much less specific and more difficult to control.
Explain Intracellular Receptors for Lipid-Soluble Agents
In this particular mechanism, a very good lipid-soluble ligand (or drug) crosses the plasma membrane and acts on an intracellular receptor (which may be an enzyme or a regulator of gene transcription). Examples of ligands that exert their effects via this pathway include nitric oxide, corticosteroids, mineralocorticoids, sex hormones, thyroid hormone, and vitamin D.
Explain Ligand-Regulated Transmembrane Enzymes (Including Receptor Tyrosine Kinases)
The receptors in this pathway are transmembrane proteins consisting of an extracellular ligand-binding domain and a cytoplasmic (intracellular) enzyme domain (which may be a protein tyrosine kinase, a serine kinase, or a guanylyl cyclase). The two domains are connected by a hydrophobic segment of the polypeptide that crosses the lipid bilayer of the plasma membrane.

The chemical signal (ligand) binds to the extracellular domain of the transmembrane receptor protein, thereby activating (allosterically regulating) the enzymatic activity of its intracellular domain.

Examples of ligands that exert their effects via this pathway include insulin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), transforming growth factor- (TGF-), and many other trophic hormones.
Explain Cytokine Receptors
The mechanism for the cytokine receptors is very similar to the mechanism of receptor tyrosine kinases. However, in the case of the cytokine receptor, the protein tyrosine kinase activity is not intrinsic to the receptor molecule; instead, a separate protein tyrosine kinase, from the Janus-kinase (JAK) family, binds noncovalently to the receptor.

Examples of ligands that bind to and activate cytokine receptors include growth hormone, interferons, and other regulators of growth and differentiation.
Explain Ligand-Gated Ion Channels
In this particular class of receptors, a ligand-gated transmembrane ion channel is induced to open or close by the binding of a ligand.

Examples of natural ligands that regulate the flow of ions through plasma membrane channels, by binding to these channels, include the neurotransmitters acetylcholine, serotonin, -aminobutyric acid (GABA), and the excitatory amino acids (e.g., glycine, aspartic acid, and glutamic acid). Many important drugs act by either mimicking or blocking the actions of endogenous ligands that regulate ion channels.
Explain G Proteins
G proteins use a molecular mechanism that involves binding and hydrolysis of GTP to amplify the transduced signal. Amplification of the original signal (which is the result of binding of the ligand to its membrane receptor) is attributed to the fact that the active GTP-bound G protein remains in its active state for a relatively long time (tens of seconds) (20-30 sec). The duration of activation of adenylyl cyclase, for example, depends on the duration of activation of the G protein (not on the receptor’s affinity for binding to the ligand or the duration of that binding) (it amplifies the signal by phosphorilation and dephosphorilation) (After depolarization the G-protein will stay active for many seconds).

The corresponding G protein, Gs, stimulates adenylyl cyclase after being activated by ligands that act via a specific receptor; examples of these ligands include catecholamines (-adrenoceptors), histamine (H2 receptors), serotonin (5-HT4 receptors), vasopressin (V2 receptors), glucagon, FSH, LH, thyrotropin, parathyroid hormone, …etc.

Receptors coupled to G proteins belong to a family of proteins known as ‘Serpentine Receptors’ or ‘7-Transmembrane Receptors’; all serpentine receptors transduce signals across the plasma membrane in the same fashion.
Explain Second Messengers
Three well-studied intracellular Second Messenger Signaling Pathways are known: cyclic adenosine monophosphate (cAMP), calcium and phosphoinositides, and the cyclic guanosine monophosphate second messenger pathways.

cAMP exerts most of its effects by stimulating cAMP-dependent protein kinases. The specificity of cAMP’s regulatory effects is attributed to the distinct protein substrates (usually enzymes) of the kinases that are expressed in different cells.
Explain the two functions of reversible phosphorylation found in second messenger signaling
Amplification of the original regulatory signal by recording a molecular memory that the pathway has been activated, and by performing dephosphorylation to erase the memory. Keep in mind that dephosphorylation takes a longer time than is required for dissociation of an allosteric ligand, which contributes a great deal to the amplification of the initial signal.

Flexible Regulation by the second messengers. The different protein kinases (differing from one cell type to another) that are regulated by second messengers have different substrate specificities; this allows second messengers to use the presence or absence of particular kinases or kinase substrates to produce different effects in different cell types. These differences also provide, depending on the cell type, branch points in signaling pathways that may be independently regulated.
Explain Desensitization
Desensitization (receptor molecule restores its 3d structure after drug molecule dissociates from receptor) (after this the receptor is ready for another drug molecule) and it is usually reversible; a second exposure to the agonist, few minutes following the termination of the first exposure, affords a response similar to the initial response.
Explain Down Regulation
Down-Regulation is another important process that regulates receptor-mediated responses. Down-regulation decreases the number of receptor molecules present in the cell or tissue. It is a much slower process than rapid desensitization and is less readily reversible.

Down-regulation involves degradation of receptor molecules present in the cell (usually by ligand-induced endocytosis and delivery to lysosomes), and requires the biosynthesis of new receptor molecules for recovery (unlike the process of rapid desensitization which involves reversible phosphorylation of existing receptors). Down-regulation occurs only after prolonged or repeated exposure of cells to the agonist (hours to days).
Explain Internalization of receptors
In this particular process, receptor molecules are recycled intact to the plasma membrane via endocytic vesicles. This rapid cycling of receptor molecules facilitates their dephosphorylation and increases the rate of restoring fully functional receptors in the plasma membrane.
Explain drug potency
Potency of a drug depends on the affinity (KD) of receptors for binding to the drug and the efficiency of the occupancy-response coupling process.

Keep in mind that clinical effectiveness of a drug depends on its maximal therapeutic efficacy and its ability to reach its site of action (not on its pharmacologic potency). Reaching the site of action can depend on the route of administration and the pharmacokinetic (ADME) properties of the drug.

In selecting one of two drugs to administer to a patient, one must make that selection based on the relative effectiveness rather than the relative potency of the two drugs. However, pharmacologic potency is going to largely determine the administered dose of the selected drug.
Explain Median Effective Dose (ED50)
Median Effective Dose (ED50), is the drug dose at which 50% of individuals exhibit the specified quantal (therapeutic) effect.
Explain Median Toxic Dose (TD50)
Median Toxic Dose (TD50), is the drug dose required to produce a particular toxic effect (adverse effect) in 50% of individuals or laboratory animals. If the toxic effect is death of the laboratory animal, a Median Lethal Dose (LD50) can be experimentally defined. Toxic dose that kills 50% of the animals
Explain Therapeutic Index
Therapeutic Index of a drug, also known as the Therapeutic Window, relates the dose of a drug required to produce a desired effect to the dose of the drug which produces an undesirable effect. In animal studies, the therapeutic index is defined as the ratio of TD50 / ED50 for a particularly relevant therapeutic effect.
Explain an Idiosyncratic drug response
An Idiosyncratic drug response is an unusual response that is infrequently observed in most patients. This type of response is usually attributed to genetic differences in drug metabolism or immunologic mechanisms, including allergic reactions.
Explain Drug Tolerance
With a number of drugs, the intensity of the response to a given dose decreases as a consequence of continued drug administration, producing a state of relative tolerance to the drug’s effects. When responsiveness diminishes rapidly after administration of the drug, the response is said to be subject to tachyphylaxis: opposite of tolerance
Explain the four mechanisms that contribute to drug responsiveness
1) Alteration in Drug Concentration at the Receptor Site due to pharmacokinetic differences (in drug absorption, distribution, metabolism, or excretion) among patients, which leads to variability in the clinical response.

2) Variation in Concentration of an Endogenous Receptor Ligand. This particular mechanism leads to a great deal of variability in responses to drug antagonists and partial agonists.

3) Alterations in the Number or Function of Receptors. An increase or decrease in the number of receptor sites or alterations in the efficiency of the occupancy-response coupling can cause variability in drug responsiveness. Alteration in the number of receptor sites is sometimes caused by other hormones. Genetic factors can also contribute to altering the number or function of specific receptors.

4) Changes in Components of Response Distal to the Receptor

Drug response in a patient depends not only on the drug’s ability to bind to the receptor, but also on the functional integrity and efficiency of the biochemical processes in the cell (occupancy-response coupling) and the physiologic regulation by interacting organ systems.

Changes in these postreceptor events represent the most important mechanism that causes variation in responsiveness to drug therapy. Factors that influence these events include age and general health of the patient and, most importantly, the severity and pathophysiologic mechanism of the disease that is being treated.
Explain drug selectivity
Selectivity of a drug can be measured by comparing binding affinities of the drug to different receptors or by comparing the ED50s for different effects of the drug in the body. Clinically, selectivity of a drug is considered by separating drug effects into two categories: Beneficial or therapeutic effects versus toxic effects (toxic effects are sometimes called side effects).
What is an antibiotic?
An antibiotic is a molecule (synthetic or a natural product) capable of selectively inhibiting the growth or survival of one or more species of microorganisms at low concentrations.
What is the MIC value of an antibiotic?
The MIC value of an antibiotic is the Minimum Inhibitory Concentration of the antibiotic which completely prevents the growth or survival of a microorganism in a standard assay.
What is the clinical dose of an antibiotic?
The clinical dose is usually expected to achieve a plasma concentration of ~ 4 to 8 times the MIC value of the antibiotic. The clinical dose must be associated with minimum or no toxicity to the patient. (the higher the MIC the less potent) (this dose is tailored for each patient)
What is a bacteriostatic antibiotic?
An antibiotic which exhibits a bacteriostatic effect at the clinical dose is referred to as a ‘Bacteriostatic Antibiotic’. (inhibits growth of the bacteria)

When administered at the clinical dose, a bacteriostatic antibiotic inhibits cell division (growth) of the microorganism. As a result, the microorganism survives but will stop multiplying. (needs help from the bodies immune system in order to kill the bacteria) (make sure that the patient is immunocompotent)

Drugs that are classified as static means that their cidal dose is toxic. Bacteriostatic antibiotics should be used for the treatment of mild infections.
What is a bactericidal antibiotic?
An antibiotic which exhibits a bactericidal effect at the clinical dose is referred to as a ‘Bactericidal Antibiotic’. (kills the bacteria)

When administered at the clinical dose, a bactericidal antibiotic inhibits the survival of the microorganism (kills the microorganism). (does not need help from the bodies immune system to help kill the bacteria)

Patients with severe or life-threatening infections should be treated with bactericidal antibiotics.
Name the different bacteriostatic antibiotics
1) Tetracyclines
2) Sulfanomides
Name the different bactericidal antibiotics
1) Penicillins
2) Cephalosporins
3) Aminoglycosides
4) Polypeptides
5) Quinolones
Is it possible for all antibiotics to exhibit a bactericidal effect regardless of their mechanisms of action?
YES, only if there is a high enough concentrations of the antibiotics.
Is it possible for an antibiotic to exhibit both bacteriostatic and bactericidal effects against a bacterial strain?
YES, an antibiotic has both effects at certain doses.
Is it possible for an antibiotic to exhibit only a bactericidal effect against a bacterial strain (no static effect even at lower concentrations)?
YES, only in a small percent of antibiotics like betalactam and polypeptide antibiotic due to their mech of action, it is so lethal the effect is cidal all the time.
Is it possible for an antibiotic, which is known to be ‘bactericidal’ against a particular bacterial species, to suddenly become ‘bacteriostatic’ against a strain of that species at the same clinical dose?
YES, resistance is the cause, it only happens when the antibiotic has two targets or binding sites and one develops a resistance, this will cause the effect of the antibiotic will drop from cidal to static.
What is a narrow-spectrum antibiotic?
A narrow-spectrum antibiotic is effective only against a limited number of bacterial species/strains. The use of narrow-spectrum antibiotics contributes significantly to minimizing the emergence of microbial resistance to antibiotic therapy (they should always be recommended whenever possible). (Pen-G) (Best to use a narrow)
What is a broad-spectrum antibiotic?
A broad-spectrum antibiotic is effective against a large number of bacterial species/strains, which usually would include both Gram-positive and Gram-negative bacteria. To help minimize the emergence of microbial resistance, broad-spectrum antibiotics should be used only when it is absolutely necessary. (Tetracycline) (when we use these we are favoring the growth of stronger bacteria, contributing to bacterial resistance or bacterial selection)
Explain the clinical uses of combination antibiotic therapy
1) To provide a broad-spectrum Empiric (Initial) antimicrobial therapy in seriously ill patients.

2) To treat polymicrobial (mixed) infections such as intra-abdominal abscesses. (caused by two or more bacteria)

3) To decrease the emergence of resistant strains of the organism that is causing the infection (e.g., treatment of TB).

4) To decrease dose-related toxicity by using reduced doses of one or more components of the drug combination regimen.

5) To obtain enhanced antimicrobial activity against a specific infection (Synergism). The agents used in the combination must have different mechanisms of action or different targets in the bacterial cell.
What are the disadvantages of combination antibiotic therapy?
1) Increased overall toxicity.

2) Increased cost to patient.

3) Antagonism (some combinations may be antagonistic).

4) Emergence of microbial resistance through selection of resistant bacterial species/strains. By eliminating bacterial competition
Explain antibiotic synergism
Synergism is marked by a fourfold or greater reduction in the MIC or MBC (Minimum Bactericidal Concentration) of each drug when used in combination versus when used alone.

The interaction between two antimicrobial agents can be expressed by the Fractional Inhibitory Concentration (FIC) Index (FIC A + FIC B)

FIC = MIC of drug A in combination / Drug A alone

Synergism for combinations of two drugs requires an FIC or FBC index of 0.5 or less. (quite useful)
Explain antibiotic antagonism
Antagonism occurs when the combined inhibitory or killing effects of two or more antimicrobial agents are significantly less than expected from their effects when used individually. Antagonism for combinations of two drugs is marked by an FIC or FBC index of 4 or more. (definitely not useful)

Indifference is when the sum of the two effects is no better then the drug separated.(not useful)
Explain the mechanisms of synergistic actions
1) Blockade of Sequential Steps in a Metabolic Sequence (e.g., trimethoprim-sulfamethoxazole combination). (one antibiotic is inhibiting a sequential step in a metabolic pathway)

2) Inhibition of Enzymatic Inactivation (e.g., combinations of Penicillins and b-Lactamase Inhibitors) (one drug inhibits the enzymatic activation of the bacteria self-defense)

3) Enhancement of Antimicrobial Agent Uptake (e.g., combinations of Penicillins or other antibiotics that inhibit bacterial cell wall synthesis and Aminoglycosides; the combination of the antifungal agents amphotericin B and flucytosine) (one antibiotic increases the uptake of another antibiotic by the bacteria)
Explain the mechanisms of antagonistic actions
1) Inhibition of Cidal Activity by Static Agents (e.g., combinations of bacteriostatic agents and bactericidal cell wall-active agents). In general the static will inhibit the cell division therefore inhibit the effect of the cidal on the bacteria.

2) Induction of Enzymatic Inactivation. For example, some Gram-negative bacteria possess inducible b-lactamases. b-Lactam antibiotics, such as imipenem, cefoxitin, and ampicillin, are potent inducers of b-lactamase production. If an inducing agent is combined with a b-lactam antibiotic which is b-lactamase-sensitive (such as piperacillin), antagonism may result.
Explain the mechanisms of microbial resistance to antibiotics
1) Drug Inactivation by Enzymes (e.g., b-Lactams, Aminoglycosides). (bacteria are able to secrete enzymes capable of destroying the antibiotic)

2) Target Modification (e.g., b-Lactams, Aminoglycosides, Quinolones, Trimethoprim). (bacteria can mutate and change their 3d structure of the target/receptor causing the drug not to bind to it)

3) Alteration in Target Accessibility by reducing permeability or increasing efflux of the drug (e.g., Tetracyclines, Aminoglycosides). (bacteria can deny the anti access to target either by decreasing permeability or increase active efflux of anti)

4) Development of Altered Metabolic Pathways in order to bypass the metabolic reaction inhibited by the drug (e.g., Sulfonamides) (inhibit one step). (bacteria can change it’s steps in the metabolic pathway in order to achieve the same results as before)
Explain nongenetic microbial resistance
Nongenetic Origin (e.g., nonmultiplying organisms) (has nothing to do with the genetic resistance of the bacteria) (TB can stop multiplying and lie dormant for many years and avoid destruction)
Explain genetic microbial resistance
1) Chromosomal resistance is caused by a spontaneous mutation that occurs on the bacterial chromosome. This type of resistance becomes predominant in the microbial population through the process of Selection of resistant strains (which results from the use of antibiotics). Chromosomal mutations lead mainly to ‘Target Modification’ as the resistance mechanism. This is the one main mechanism of action.

2) Extrachromosomal resistance is caused by the transfer of R-Factors from one bacterial cell to another. R-Factors (Resistance) are plasmids which contain genes that encode for resistance. Transfer of R-Factors leads mainly to ‘Drug Inactivation by Enzymes’ as the resistance mechanism.

As the R-factors move from bacteria to bacteria they gain more and more resistance genes
Explain microbial Cross-resistance
1) Classic cross-resistance is a single resistance mechanism confers resistance to a single class of antimicrobials. (very specific)(resistance to pen, means that it is resistant to all types of penicillin)

2) Cross-resistance between two or more antimicrobials.

Overlapping Targets - For example, methylation of a single adenine residue in ribosomal RNA confers resistance to three classes of antibiotics which are chemically unrelated (Macrolides, Lincosamides, and Streptogramins), due to overlapping targets on the bacterial ribosome. (Binding sites are very close) (resistance in one area makes it resistant to all the other receptors due to the closeness of the receptors)

Active Efflux - This energy-dependent export system confers low-level resistance to a wide variety of antimicrobials. The broad substrate specificities of the pumps account for decreased susceptibility to Tetracyclines, Aminoglycosides, b-Lactams, Fluoroquinolones, and Sulfonamides, among others. (This is non-specific) (it can be resistant to multiple types of antimicrobials) (usually resistant to two or more antibiotics)
Explain microbial Co-Resistance
Results from the presence of several resistance mechanisms, in the same strain, each conferring resistance to a given class of antimicrobials. (hardest form of resistance to deal with) (the genes that code for this resistance are linked and co-express meaning that when one gene express’ resistance the other’s express and the same time) (all you can do is try different antibiotics until you find one that works)

Because of the co-expression of the various genes, the use of any antibiotic that is a substrate for one of the resistance mechanisms will co-select for resistance to other classes of antimicrobials and thus for maintenance of the entire gene set.
What antibiotics are Inhibitors of Bacterial Cell Wall Synthesis (best against gram positive bacteria)?
These drugs inhibit the production of peptidoglycan to form the cell wall:

1) b-Lactam antibiotics (e.g., Penicillins, Cephalosporins, ..etc)
2) Vancomycin
3) Cycloserine
4) Bacitracin
5) Fosfomycin
Describe the peptidoglycan polymer in bacterial cell walls
The peptidoglycan polymer, also known as murein or mucopeptide, is a complex, cross-linked (rigid) polymer consisting of polysaccharides and polypeptides.

The linear peptido-polysaccharide chains of the polymer contain alternating aminosugars, N-acetylglucosamine and N-acetylmuramic acid. A five-amino-acid peptide is linked to the N-acetylmuramic acid sugar. This peptide terminates in D-alanyl-D-alanine. The peptide side chains in the polymer are cross-linked, which gives the bacterial cell wall its structural rigidity. The exact amino acid composition of the peptide side chains in the polymer varies among bacterial species. In Staph. aureus, the pentapeptide side chains are linked to each other by pentaglycine bridges (see below).

The linear polymeric chains in peptidoglycan must be cross-linked (last step) by transpeptidation of the peptide side chains in order to achieve the necessary strength and rigidity of the peptidoglycan polymer for cell viability. These chains form a net to form the cell wall. The cell will die if there is no cross-linking
Explain the mechanism of action for Cycloserine and Fosfomycin
These antibiotics the formation of the NAG/NAM pentapeptides in the cells cytoplasm
Explain the mechanism of action for Vancomycin and Bacitracin
Vancomycin: inhibits the attachment of the liner chain to the cell wal

Bacritracin: inhibits the attachment of the NAM-pentapeptide to the phospholipid membrane (the cell membrane)
Explain the mechanism of action for beta-Lactams
They inhibit the cross-linking of linaer peptidoglycan strands

b-lactam antibiotics and the other inhibitors of bacterial cell wall synthesis are bactericidal only if bacterial cells are actively growing (multiplying/dividing) and synthesizing new cell walls.
PBPs catalyze the transpeptidation (penicillin binding protein) reaction (cross-linking) in the biosynthesis of peptidoglycan by removing the terminal D-alanine residue from a peptide side chain to form a crosslink with another nearby peptide side chain. This cross-linking reaction is inhibited by b-lactam antibiotics.

A ‘PBP’ is a D-alanyl-D-alanine carboxypeptidase/transpeptidase enzyme that creates a cross-link between two linear chains in the peptidoglycan net. PBPs are found in the cell membrane of all bacteria.

b-lactam antibiotics are structural analogs of the natural [D-Ala-D-Ala] substrate for the PBPs. b-lactams bind covalently to the active site of PBPs, inhibiting the transpeptidation reaction. Consequently, peptidoglycan synthesis is inhibited and the bacterial cell dies. The exact mechanism responsible for cell death is not completely understood, but autolysins (bacterial enzymes that remodel and break down the cell wall) are involved.
List the antibiotics who inhibit bacterial cell wall synthesis
1) b-Lactams
2) Vancomycin
3) Cycloserine
4) Bacitracin
5) Fosfomycin
List the antibiotics that inhibit protein synthesis
1) Tetracyclines
2) Aminoglycosides
3) Macrolides
4) Lincosamides
5) Chloramphenicol
6) Streptogramins
7) Linezolid