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183 Cards in this Set
- Front
- Back
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What body enzyme metabolizes epinephrine (endogenous) as well as tyramine (exogenous)?
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Monoamine oxidase metabolizes epinephrine (endogenous) as well as tyramine (exogenous).
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Why do the clinically useful agents (i.e., drugs) need to be hydrolyzed/metabolized by the body?
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The lipophilic nature of the drugs makes them poorly excreted, and thus they need to be made less lipophilic (i.e. more polar) by Phase I and Phase II reactions in order to be excreted by the kidneys.
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Which types of reactions comprise both Phase I and Phase II reactions?
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Phase I reactions: HOR – Hydrolysis, Oxidation (most common, mediated by CYPS—most commonly CYP3A4), Reduction
Phase II reactions: SAGGMeth – Sulfation, Acetylation, Glucuronidation (most common), Glutathione, Methylation |
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What is the application and mechanism of action of Midazolam?
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Midazolam is a benzodiazepine that induces sedation by increasing inhibitory transmission via GABA(A) receptors, which incorporate chloride channels and open more frequently in the presence of a benzodiazepine for increased hyperpolarization.
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What is the application and mechanism of action of succinylcholine?
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Succinylcholine is used to relax skeletal muscles at the beginning of surgery prior to intubation and for rapid intubation when the urgent need for airway is present. It prevents the neurotransmitter acetylcholine from exciting skeletal muscle.
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What is the function of epoxide hydrolases?
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Epoxide hydrolases protect the body from cancer-causing epoxides.
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What is the therapeutic use and mechanism of action of propranolol?
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Propanolol is an antihypertensive, anti-anginal, anti-arrhythmic, and has uses for stage fright. It blocks beta1 adrenoreceptors that mediate increase in heart rate and cardiac contraction.
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What is the therapeutic use and mechanism of action for cimetidine (Tagamet)?
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Cimetidine suppresses acid secretion (used for heartburn) by competitively inhibiting histamine at the H2 receptor.
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What is the therapeutic use and mechanism of action of diphenhydramine (Benadryl)?
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Diphenhydramine’s used to treat mild allergic reactions, and it works by competitively inhibiting histamine at H1 receptors, which are responsible for mild allergic reactions produced by histamine released from mast cells.
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What is the therapeutic use of the methylxanthines (caffeine and theophylline)?
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Caffeine is a stimulant, and theophylline treats disorders of the bronchioles (asthma, COPD). They work by competitively inhibiting adenosine at adenosine receptors.
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What is the therapeutic use and mechanism of action of diazepam (Valium)?
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Diazepam is used to treat seizures, anxiety, muscle spasms, and other disorders. It’s a benzodiazepine that increases the frequency of opening of GABA(A) receptors.
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What two drugs is diazepam metabolized to?
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Diazepam’s first metabolized to Nordazepam by an N-dealkylation; nordazepam is a long-acting agent. It’s then metabolized to oxazepam by a hydroxylation. It’s finally completely activated in the urine.
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What is the metabolite of codeine?
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Codeine (weak agonist) gets metabolized to morphine (full agonist).
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What two enzymes are important for alcohol processing by the liver?
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Alcohol dehydrogenase is found in liver and stomach. Aldehyde dehydrogenase is also found in the liver.
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Besides alcohol processing, what’s an example of P450-independent oxidation in drug metabolism?
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Amine oxidases (e.g. Monoamine oxidase)
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What is the mechanism of action of warfarin?
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Warfarin blocks the carboxylation of coagulation factors.
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What is the most important CYP that inactivates warfarin?
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CYP2C9 is the most important CYP that inactivates warfarin.
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What’s the therapeutic use and mechanism of action of terbutaline? Furthermore, what inactivates terbutaline?
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Terbutaline is a beta-2 agonist used to treat asthma and premature labor. It relaxes smooth muscles by increasing cyclic AMP. Sulfate conjugation inactivates terbutaline.
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What is the therapeutic use and mechanism of action of isoniazid? Furthermore, how is it inactivated?
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Isoniazid is the most active drug against TB. It inhibits mycolic acid synthesis in the membranes of the mycobacterium. It’s inactivated by acetylation.
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Which is the most common Phase II reaction?
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Glucuronidation is the most common phase II reaction. The enzymes are in the SER and require UDP glucuronic acid.
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Which drugs are inactivated by glucuronidation (that we spoke about in lecture)?
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All benzodiazepines are inactivated by glucuronide conjugation (e.g., lorazepam “Ativan”). Acetaminophen is inactivated by both sulfation and glucuronidation.
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Which reaction that we spoke about in lecture declines slowly as you grow older?
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Glucuronidation declines minimally in the elderly, and hence lorazepam (inactivated by glucuronidation) is a good drug for the elderly.
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Besides its role in cellular detoxification, what has glutathione been implicated in?
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Glutathione has been implicated in chemoresistance, as it’s been found in high levels in many tumors.
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Which CYP polymorphisms are the most common, and what are some common substrates of the most common CYP polymorphism?
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CYP2D6 are the most common polymorphisms, and common substrates are: 1) codeine 2) metoprolol 3) tricyclic antidepressants.
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Why is diazepam metabolism slower in Asians as compared to Caucasians?
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About 15-25% of the Asian population have a high frequency of CYP2C19 mutant alleles, making for poor metabolizers of diazepam (half-life can be 4x longer than normal).
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What causes the Asian flush when drinking alcohol?
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The Alcohol dehydrogenase reaction is enhanced, causing a more rapid accumulation of acetaldehyde, producing tachycardia and flushing, and the aldehyde dehydrogenase cannot keep up. Furthermore, aldehyde dehydrogenase is deficient in 30-50% of people of Chinese and Japanese ancestry.
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What is responsible for toxicity of environmental pollutants?
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Induction of CYP1A enzymes is responsible for toxicity of environmental pollutants (e.g. cigarette smoke, etc.).
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Which CYPs does grapefruit juice inactivate?
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GFJ inactivates CYP 3A4 and CYP2E1.
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Which environmental “toxins” induce CYP1A?
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Charcoal broiled foods, cruciferous veggies, and caffeine induce CYP1A and can reduce the effectiveness of warfarin.
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If someone is on oral contraceptives and still gets pregnant, what natural remedy could be the culprit?
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St. John’s wort induces CYP3A4, 2C9 and 2E1 and enhances the metabolism of oral contraceptives and other agents.
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What drugs and CYP does Ginkgo affect?
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Ginkgo induces CYP2C19 and increases metabolism of omeprazole and warfarin.
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Which CYPS does Echinacea affect?
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Echinacea inhibits CYP1A2 and induces CYP3A4.
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What drug is both a substrate and inhibitor of CYP2C19?
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Omeprazole is both a substrate and an inhibitor of 2C19. It gets there and stays there and inhibits other molecules from interacting with 2C19.
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What is the most important pathway for drug transport across the cell membrane?
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The most important pathway for drug transport across the cell membrane is lipid diffusion, because the lipid bilayer is the major barrier separating two aqueous compartments, and the vast majority of drugs are lipid soluble. The rate of diffusion is proportional to the concentration gradient of the drug and its lipid/water partition coefficient.
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Which molecules comprise the majority of uptake transporters?
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Members of the solute carrier (SLC) family, which carry out secondary active transport. Couples transport of a solute that flows down its gradient with a solute going uphill against electrochemical gradients (and thus doesn’t need ATP directly).
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Which molecules comprise the majority of efflux transporters?
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Members of the ATP-binding cassette (ABC) family, which carry out primary active transport. ABC transporters couple the energy from ATP hydrolysis to translocate a solute across biological membranes. The system is saturable and can be inhibited by metabolic inhibitors. Two most important ABC transporters: MDR1/Pgp/ABCB1 and MRP1/ABCC1 pump drugs out of cells.
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How does insulin get past the blood-brain-barrier to enter the brain?
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Insulin uses receptor-mediated transport to overcome the BBB.
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How are albumin molecules transported across the cell membrane?
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Albumin transport via caveolae (small lipid raft invaginations present in the cell membrane).
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What’s an important component of tight junctions, especially those formed in the BBB?
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Claudins
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Where does the majority of absorption of drugs occur?
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The majority of drug absorption occurs in the intestines due to large surface area and long transit time.
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What is the “first pass” effect?
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The pre-systemic degradation of drug that occurs in the gut or liver and results in reduced effectiveness of the drug is referred to as the first pass effect.
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What common household agent inhibits absorption of fexofenadine (Allegra), and what’s the mechanism of inhibition?
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Grape fruit juice inhibits the organic anion transport polypeptides (OATP), reducing absorption of fexofenadine. GFJ can also inhibit CYP3A4 drug metabolism.
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What’s an advantage of rectal administration in terms of the first pass effect?
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The lower rectal area drains directly into systemic circulation bypassing the liver and thus has a decreased first pass effect. Well, 50% of the venous drainage of the rectum bypasses the liver.
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What does bioavailability mean?
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Bioavailability is defined as the relative amount of an administered drug dose that reaches the systemic circulation or site of action unchanged.
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What’s the difference between pharmaceutical equivalence and bioequivalence?
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Pharmaceutical equivalence is when two drugs have the same active ingredient and are identical in strength, route of administration, and dosage form. Bioequivalence is when the two drugs have the same bioavailability of the same ingredient.
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Which type of molecules can get into the CSF from the blood?
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Only lipid-soluble drugs can get into the CSF from the blood due to the CSF-brain barrier.
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What is the most common drug-binding protein in the plasma?
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Albumin; it has a particular affinity for organic anions.
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What is a biliary mechanism for enhanced drug efficacy, and how does it work?
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Enterohepatic recirculation works by drugs secreted in whole form or metabolite form into the bile and being reabsorbed in a recycling process.
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What is the major means of excretion of charged drugs?
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Polarized drugs are excreted largely through the tubular secretion mechanism.
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What could the result of a mutation in the MDR3 gene lead to?
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MDR3 gene mutations: lead to absence or low level of phospholipids in the bile. The elevated cholesterol-to-phospholipids ratio promotes lithogenicity (forming calculi/stones) of the bile with crystallization of cholesterol. Heterozygotes for either nonsense or missense mutations in the MDR3 gene are associated with several diseases
• Intrahepatic cholestasis (a condition in which little or no bile is secreted or the flow of bile into the digestive tract is obstructed) in pregnancy (ICP) • Progressive familial intrahepatic cholestasis • low phospholipid-associated cholelithiasis (The presence or formation of gallstones in the gallbladder or bile ducts.). |
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What condition do mutations in either ABCG5 or ABCG8 genes cause?
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Mutations in either ABCG5 or ABCG8 genes cause sitosterolemia, an autosomal recessive disorder characterized by the accumulation of plant-derived toxic sterols (phytosterols) and cholesterol in blood and other variety of tissues (increased intestinal absorption and decreased bile secretion).
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What is the prototypical example of CYP3A4 oxidation followed by Phase II-glucuronide metabolism?
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Midazolam and other zolams are the prototypical example of CYP3A4 oxidation followed by Phase II-glucuronide metabolism.
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What is the prototypical H2 blocker that inhibits a lot of CYPs? (sounds like the Shaft theme)
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Cimetidine (you damn right)
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This enzyme is inhibited by flavonoids in grapefruit juice, induced by St. John’s wort, induced by Echinacea, and important for acetaminophen toxicity. What is it?
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CYP3A4 is inhibited by flavonoids in grapefruit juice, induced by St. John’s wort, induced by Echinacea, and important for acetaminophen toxicity.
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This CYP has as substrates: metoprolol (a beta blocker), opioids (codeine and hydrocodone), and tricyclic antidipressants. What is it?
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CYP2D6 has as substrates: metoprolol (a beta blocker), opioids (codeine and hydrocodone), and tricyclic antidipressants.
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This CYP has important polymorphisms, but not as much as CYP2D6 and is induced by ginkgo. It has as important drug substrates: -zepam benzos. PPIs (e.g., prazoles like omeprazole). What is it?
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CYP2C19 has important polymorphisms, but not as much as CYP2D6 and is induced by ginkgo. It has as important drug substrates: -zepam benzos. PPIs (e.g., prazoles like omeprazole).
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This CYP metabolizes high doses of ethanol and is induced by high doses of ethanol and is important for acetaminophen toxicity. Furthermore, It’s induced by St John’s wort. What is it?
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CYP2E1 metabolizes high doses of ethanol and is induced by high doses of ethanol and is important for acetaminophen toxicity. Furthermore, It’s induced by St John’s wort.
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What is the mechanism of action for sulfonamides?
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Sulfonamides resemble PABA and competitively inhibit dihydrofolate synthesis.
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Why are sulfonamides less effective in abscesses?
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Abscesses have a lot of PABA and other compounds that compete with sulfonamides and render them ineffective.
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What is the mechanism of action of trimethoprim?
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Trimethoprim is a folate analog (it is a structural analog of the pteridine moiety of folic acid) that depletes tetrahydrofolate by blocking dihydrofolate reductase. The step of converting FH2 to FH4 is blocked by Trimethoprim. Pyrimethamine has the same action.
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What are some advantages of drug combinations like that of trimethoprim + sulfamethoxazole, which work along the same pathway?
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• Synergism
• Dosage for each drug can be reduced, reducing toxicity. • Probability of developing resistance to both drugs together is much less compared to that of the each drug alone. |
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What is the mechanism of action of fluroquinolones (quinolones)?
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Quinolones target DNA gyrase in G(-) bacteria and topoisomerase IV in G(+) bacteria.
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Which fluroquinolones would be useful in anephric patients?
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Moxifloxacin has a primary route of excretion that is non-renal. So does Trovafloxacin, but it has hepatotoxicity.
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What is a potentially serious adverse event related to the fluroquinolone levofloxacin?
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Levofloxacin can rupture tendons and has joint toxicity/arthropathy.
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Why doesn’t Flucytosine harm mammalian cells?
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Mammalian cells lack cytosine deaminase, which converts 5-Flucytosine to 5-FU. Without that conversion, there’s no activity, and thus mammalian cells are spared.
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What is the mechanism of the azole drugs?
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Azoles inhibit fungal cytochrome P450-dependent enzyme which is involved in the synthesis of ergosterol from lanosterol. The fungal cell membranes become leaky and die, and there’s a greater affinity of the drugs for fungal than mammalian P450 enzymes.
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What is the mechanism of action of Caspofungin?
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Caspofungin noncompetitively inhibits 1,3-beta glucan synthase, blocking glucan synthesis.
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What is the mechanism of action of Terbinafine?
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Terbinafine inhibits fungal ergosterol synthesis by inhibiting the non-P450 squalene oxidase, leading to accumulation of squalene, which is toxic to fungal cells.
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How is isoniazid processed for excretion?
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Isoniazid is acetylated and excreted by the kidneys. (75-95% of dose excreted in urine in 24 hr, mostly as a metabolite.)
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What is the mechanism of action of Rifampin?
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Rifampin blocks beta subunit of prokaryotic DNA-directed RNA polymerase stopping mRNA transcription & translation of polypeptides.
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What is the application and mechanism of action of ethambutol?
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Ethambutol, used to treat TB, inhibits arabinosyl transferase, blocking synthesis of arabinogalactan, destabilizing cell wall. A side effect is it causes optic neuritis with red-green color blindness.
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What would you choose to treat Giardia Lamblia?
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Metronidazole is effective.
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What is the mechanism of action of metronidazole?
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Metronidazole inhibits nucleic acid synthesis by disrupting the DNA helix with its nitro group reduced by pyruvate-ferredoxin oxidoreductase.
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What is the mechanism of action of Albendazole?
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Albendazole inhibits tubulin polymerization.
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What would you use to treat Chagas’ disease, and what’s the mechanism of action?
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Nifurtimox can treat Chagas’ disease, and it works by futile redox cycling: NADH-dependent nitrogen and oxygen radical species--intracellular generation of radical anions that damage the cells.
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What would you use to treat ascaris lumbricoides, and what’s the mechanism of action?
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Piperazine can treat ascaris lumbricoides, and it is an agonist at GABA-gated chloride channels on nematode muscle. The roundworms are paralyzed and expelled per rectum.
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What would you use to trea Onchocerca volvulus?
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Ivermectin (it can also treat strongyloidiasis)
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What would you use to treat schistosomiasis?
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Praziquantel can treat schistosomiasis; it increases Ca++ permeability.
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What combination of sulfonamides would you use to treat UTIs?
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Sulfisoxazole and sulfamethoxazole
(remember--put a sox on it) They are useful for UTI, because they have the highest water solubility (so that they do not precipitate out in the kidney) and are excreted in an intact, unmetabolized form (as opposed to acetylated and inactive metabolites of other sulfonamides). |
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Which sulfonamide would be used to treat meningitis?
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Sulfadiazine readily crosses into CSF and can be used for meningitis
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Which sulfonamide combination would be used for the threatment of acute toxoplasmosis?
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Sulfadiazine+pyrimethamine
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Which sulfonamide would be used to treat burns (external use)?
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Silver sulfadiazine
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Which sulfonamide would be used for the treatment of ulcerative colitis?
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Sulfasalazine is used in ulcerative colitis (Crohn's disease), enteritis, and other inflammatory bowel disease.
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Which sulfonamide would be used for the treatment of infections of the eye or ear?
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Sulfacetamide
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Which sulfonamide would be used for the treatment of chloroquine-resistant Plasmodium falciparum (malaria)?
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Long acting sulfadoxine+pyrimethamine (Fansidar)
(could also use Mefloquine) |
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Do antibiotics that inhibit cell wall synthesis tend to be bacteriostatic or bactericidal?
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Antibiotics that inhibit cell wall synthesis tend to be bactericidal.
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Do antibiotics that inhibit protein or nucleic acid synthesis tend to be bacteriostatic or bactericidal?
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Antibiotics that inhibit protein or nucleic acid synthesis tend to be bacteriostatic.
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Why are G(-) bacteria resistant to narrow spectrum penicillins?
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G(-) bacteria resistant to narrow spectrum penicillins, because they cannot penetrate the outer membrane surrounding the G(-) bacterial cells.
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Sulfonamides inhibit folate biosynthesis and block the production of what molecules?
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Sulfonamides inhibit folate biosynthesis and block the production of purines, thymidine, methionine, and serine.
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What are three mechanisms of bacterial resistance?
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1) Efflux pumps
2) Enzymatic inactivation of drug 3) Modification of the drug/decreased affinity of target for drug 4) Increased expression of target 5) Increased metabolite concentration that competes with drug (e.g., sulfonamides in abscess) |
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What are the beta-lactamase inhibitors?
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1) Clavulanic acid
2) Sulbactam 3) Tazobactam |
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What is a super infection, and which pathogens would be difficult to eradicate in the case of a superinfection?
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A superinfection is when the normal flora is eliminated, allowing the proliferation of another pathogen. If this pathogen is Enterobacteria, Pseudomonas, Candida, or other fungi, it would be difficult to eradicate.
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Why does imipenem have a short biological lifetime?
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Imipenem is a carbapenem (binds PBPs and disrupts bacterial cell wall synthesis), and it has a short biological lifetime, because it’s easily hydrolyzed by dehydropeptidase-1, which is present in the brush border of the proximal tubule cells of the kidney.
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What are side effects of Imipenem?
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Imipenem may cause seizures. Common side effects are nausea and vomiting.
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Could you use Aztreonam to treat Streptococcus pyogenes? Why or why not?
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Aztreonam, although active against G(-) rods, is not active against G(+) bacteria and anaerobes.
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Are Aztreonam and Aminoglycosides effective against G(+) or G(-) bacteria?
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Aztreonam and Aminoglycosides are effective against G(-)
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Are tetracyclines and later generation beta-lactams effective against G(+) or G(-) bacteria?
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Tetracyclines and later generation beta-lactams are effective against G(+)
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What drug does the combination of clavulanic acid + amoxicillin produce?
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clavulanic acid + amoxicillin = Augmentin
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What drug does the combination of clavulanic acid + ticarcillin produce?
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clavulanic acid + ticarcillin = Timentin
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What drug does the combination of sulbactam + ampicillin produce?
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sulbactam + ampicillin = Unasyn
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What drug does the combination of tazobactam + piperacillin produce?
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tazobactam + piperacillin = Zosyn
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What is the mechanism of action of penicillin?
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Penicillin inhibits transpeptidase, blocking the cross-linking of peptidoglycan—the final step in cell wall synthesis. Beta-lactam resembles the alanyl-alanyl bond recognized by the transpeptidase and acrylates the active site of the enzyme.
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Would Penicillin G be effective against Staph aureus? Why or why not?
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Penicillin G would not be effective against Staph aureus, because it has a beta lactam that’s sensitive to beta-lactamase, and most staph aureus have beta lactamases. Most bacteria are resistant to Penicillin G.
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Could penicillin G be used for oral administration? What about penicillin V?
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Penicillin G could not be used for oral administration, because it’s labile in acidic pH. Penicillin V is stable in acid due to a small change in its side change (the addition of phenoxymethyl.
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What are possible consequences of high doses of penicillin G and the mechanism of the side effects?
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At high doses of penicillin, you can see neurological effects and seizures due to inhibition of GABA-gated chloride ion influx.
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What is the mechanism of the Class B lactamase?
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Class B lactamase is a Zn enzyme, which hydrolyzes penicillin
directly, without the formation of penicilloyl enzyme complex. Clavulanic acid and congeners are not able to inhibit this enzyme. |
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What can be added to penicillin to block active renal excretion of penicillin?
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Probenecid can be added to penicillin to block the active renal excretion and prolong the half life.
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Which penicillin derivative has the broadest spectrum?
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Piperacillin + tazobactam = Zosyn
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Why might a patient initially get worse upon antibiotic use?
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Beta-lactam antibiotics, in the process of lysing the bacteria, can cause a release of toxins/virulence factors.
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What function does clavulanic acid have?
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Clavulanic acid can be added to penicillin to inhibit penicillinases.
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What is the action of vancomycin?
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Vancomycin blocks crosslinking or transpeptidation as well as glycosylation or chain elongation
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Could you use vancomycin to treat pseudomonas aeruginosa?
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Vancomycin is bactericidal against only G(+) bacteria. It has no effect against G(-) organisms (it gets blocked by the outer cell membrane).
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When would vancomycin be given orally?
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It would be given orally for treating staphylococcal enterocolitis and Clostridium difficile. Otherwise it’s given IV.
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When does “red man” syndrome occur, and what is the mechanism?
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Red man syndrome occurs when vancomycin is infused over a very short amount of time (e.g., 90 seconds). Histamine is released and you get urticarial (hives), flushing, tachycardia, and hypotension.
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What drug could you use against vancomycin-resistant enterococci and MRSA?
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You could use Linezolid
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What is the mechanism of action of fosfomycin?
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Fosfomycin inhibits enolpyruvate transferase and is effective against G(+) and G(-) bacteria and good for UTIs.
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What is the mechanism of action of bacitracin?
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Bacitracin works against G(+) organisms and Neisseria. Bacitracin inhibits cell wall synthesis by blocking the dephosphorylation of bactoprenol diphosphate, depriving the bacterial cell of bactoprenol monophosphate which serves as the anchoring site for UDP-N-acetylmuramic-pentapeptide.
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What is the mechanism of action for cycloserine?
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Cycloserine inhibits alanine racemase and D-analyl-Dalanine ligase. It’s used almost exclusively for TB but can be used for G(+) and G(-) bacteria.
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What pathogens is colistimethate used for?
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Colistimethate is used for MDR G(-)
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Which drugs concentrate in the urinary tract and are especially useful for treating UTIs?
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Fosfomycin, nitrofurantoin, cycloserine, and quinolones
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What pathogens is bacitracin restricted to treating, and what is an important side effect?
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Bacitracin is restricted to G(+) organisms and Neisseria. Due to serious nephrotoxicity, it’s restricted to topical application.
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What drugs does Neosporin contain?
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• Bacitracin (active against G(+) organisms)
• Neomycin (an aminoglycoside active against G(-) organisms) • Polymixins (active against G(-) organisms by acting as detergent on bacterial outer membranes) |
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Why do G(+) organisms have a higher intracellular pressure than G(-) organisms?
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G(+) have higher amino acid content.
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What class of lactamases are the lactamase inhibitors not effective against?
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Lactamase inhibitors are not effective against class B lactamases.
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Why might it not be a good idea to use a tetracycline while drinking milk or taking an antacid?
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The presence of di- or tri-valent metal ions (Ca++, Mg++, Fe+++, Al+++) interferes with absorption due to chelate formation.
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What is the mechanism of action for tetracyclines?
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Tetracycline Inhibits bacterial protein synthesis by binding to 30S ribosomal subunit, blocking peptide chain elongation by binding to acceptor site for aminoacyl-tRNA.
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What is the usual mechanism of resistance to tetracycline?
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Usual resistance to tetracycline is impaired active transport: decreased influx and increased efflux of the drug. Genes are carried by plasmid and inducible.
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What are adverse effects of tetracycline?
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• Deposited in bones during gestation and childhood: 40% depression of bone growth in premature infants.
• Permanent staining of growing teeth. Should not be given to pregnant women or children. • Superinfection is a serious problem (broad spectrum activity) • Liver dysfunction (symptoms: lethargy, jaundice) at high doses. |
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Doxycycline can cause erosion of the esophagus, so it’s best to take it while standing up right and with a lot of water. What else should one be careful about when using doxycycline?
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Avoid extended exposure to sun.
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Why is azithromycin used more now than erythromycin?
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When erythromycin is combined with a strong inhibitor of CYP3A4, risk of sudden cardiac death is increased 5-fold. Therefore, erythromycin is now superseded by newer macrolides like azithromycin.
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What is the mechanism of action of macrolides, and what are they most effective against?
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Macrolides bind to the 50S ribosomal subunit and interfere with the binding of chloramphenicol, which inhibits a translocation step. It’s most effective against aerobic G(+) cocci and bacilli and useful against Mycoplasma pneumonia and Legionella pneumophila. It can also be used to substitute penicillin for patients who are allergic to beta-lactams.
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What are side effects of macrolide antibiotics?
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• Low degree of toxicity – high therapeutic index.
• GI disturbance: Erythromycin may act on motilin receptor of the GI tract and stimulate motility. Abdominal cramps, nausea, vomiting, and diarrhea. • Cholestatic jaundice may be attributable to extended treatment with the estolate form. Usually reversible when drug is withdrawn. • Hypersensitivity reactions are rare. For patients who are allergic to penicillin class, macrolides are good substitute. • Erythromycin inhibits cytochrome P450, leads to inhibition of metabolism of other drugs. • When erythromycin is combined with strong inhibitor of CYP3A, risk of sudden cardiac death is increased 5 fold. Erythromycin is now superseded by newer macrolides. |
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What protein-synthesis inhibitor antibiotics bind to the 50S ribosomal subunit?
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CLOMS (Clindamycin Lincosamides Oxazolidinones Macrolides Streptogramins)
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What can an oxazolidinone like linezolid be used against?
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Oxazolidinones (e.g., Linezolid) has chief use against MRSA and Vancomycin Resistant Enterococcus. Clinically, it has faster onset of action than vancomycin, and it has high oral bioavailability. It can be used safely with SSRIs.
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Which drug can be used as a topical anti-G(+) and for impetigo?
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Topical mupirocin (it’s rapidly degraded in human plasma, so can really only be used topically).
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What are examples of macrolide antibiotics?
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Erythromycin, clarithromycin, azithromycin (prototype = Erythromycin)
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Aminoglycosides should be given together with what antibiotic for efficacy?
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There’s synergy between penicillin and aminoglycoside. The penicillin inhibits the cell wall synthesis which allows the normally impermeable aminoglycoside access to the inside of the bacteria (e.g., E. faecalis).
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What is the most commonly resisted class of antibiotics, and what is the mechanism of resistance?
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Aminoglycosides are most commonly resisted, and the most common mechanism of resistance is enzymatic modification and inactivation of aminoglycosides.
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Why can’t aminoglycosides be given orally, and how are they excreted?
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Aminoglycosides are not absorbed when administered orally. They are not metabolized, so they’re excreted by glomerular filtration in their active form.
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What are common side effects of aminoglycosides?
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Aminoglycosides exhibit
• Ototoxicity: damages cochlear and vestibular hair cells. • Nephrotoxicity (especially Neomycin which is no longer used systemically) • Neuromuscular blockade: blocks Ca++ channels in nerve terminals and nAChR channels, so there’s a presynaptic and post-synaptic effect. |
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Would it be safe to use Streptogramin with Warfarin?
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Streptogramin inhibits CYP3A4, so there would be potential drug interactions with the use of warfarin.
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Which aminoglycoside is least susceptible to enzymatic modification?
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Amikacin is least susceptible to enzymatic modification.
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What are examples of aminoglycosides, and what is the mechanism of action?
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-mycins (e.g., Streptomycin, kanamycin, tobramycin, neomycin)
-micins (e.g., Gentamicin, sisomicin, netilmicin, Amikacin is a synthetic derivative of kanamycin) Aminoglycosides irreversibly inhibit bacterial protein synthesis by binding to the 30S ribosomal subunit. |
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What side effect should you be careful of in the use of gentamicin with myasthenia gravis patients?
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Gentamicin is an aminoglycoside which can cause neuromuscular block for both the presynaptic and postsynaptic aspect of ACh neurotransmission (presynaptic effect is greater).
The order of potency for this effect: neomycin > kanamycin > amikacin > gentamicin > tobramycin |
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What bacteria are resistant to tetracyclines, and are tetracyclines bacteriocidal or bacteriostatic?
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Pseudomonas aeruginosa and Proteus are resistant to tetracyclines. Tetracyclines are bacteriostatic.
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What is the cause of pseudomembranous colitis, a side effect from clindamycin use?
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Pseudomembranous colitis is caused by the toxin from Clostridium difficile (symptoms: abdominal pain, diarrhea, fever, and mucus and blood in the stool).
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Can you coadminister Linezolid with SSRIs?
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You can coadminister Linezolid (an oxazolidinone) with SSRIs.
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What molecules comprise Bactrim?
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Bactrim is Sulfamethoxazole + trimethoprim.
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What are side effects of fluroquinolones?
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Generally well tolerated. Most common = GI upset (3-17%): nausea, vomiting, diarrhea. Occasional CNS, potentiated by NSAIDs due to the augmentation of the displacement of GABA from its receptors by quinolones.
Trovafloxacin associated w/ bad liver stuff (acute hepatitis, hepatic failure). |
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Why does antifungal therapy generally require a longer course of drug treatment?
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Fungal metabolism is slower than bacteria.
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What is the mechanism of action for Amphotericin B/nystatin, which is closely related?
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Amphotericin B binds to ergosterol in the cell membrane of fungi and forms a complex and creates pores in the membrane, causing death. One side of the molecular ring is hydrophobic (interacts with the membrane lipids), and the other side is hydrophilic (creates an aqueous channel).
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What are adverse effects of amphotericin B?
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1) Infusion related: chills, fever, muscle spasms, vomiting, headache, hypotension
2) Delayed toxicity: nephrotoxicity: renal tubular acidosis, severe K+ and Mg++ wasting, azotemia a. Prerenal component: reversible, associated with decreased renal perfusion b. Renal component: irreversible, due to damage of tubular cells |
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Which azole has the widest therapeutic index?
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Fluconazole has the widest therapeutic index of the azoles. Ranking of the differential: Fluconazole>itraconazole>ketoconazole.
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What is the drug of choice for the treatment of non-falciparum and sensitive falciparum malaria?
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Chloroquine; it preferentially accumulates in parasitized erythrocytes. Mechanism not fully understood.
1) interacts w/ DNA via intercalation, followed by inhibition of nucleic acid synthesis 2) Concentrates in lysosomes and may inhibit hydrolases in plasmodial digestive vacuoles 3) Forms chloroquine-ferriprotoporphyrin IX complex from plasmodial digestion of Hb, the complex causes lysis of parasite membrane |
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What are adverse effects of chloroquine?
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• Chloroquine could cause headache, visual disturbances, GI upsets, pruritus.
• With prolonged treatment, you can have lichenoid skin eruptions. • Can cause hemolytic anemia in patients with G6PD • Contraindicated in patients with psoriasis or porphyria, where it can worsen those conditions. |
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What would primaquine be used for, and what is the mechanism of action?
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Treats malaria
• Effective against exo-erythrocytic forms of P. vivax • Exerts gametocytocidal activity against all four species that infect man • Drug of choice for getting rid of dormant liver forms of P. vivax and P. ovale Mechanism uncertain, but it binds to DNA. It may also enter plasmodial mitochondria and cause swelling and vacuolization. |
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What are adverse effects of primaquine?
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• Recommended doses=well tolerated
• Large doses: cramps, epigastric distress, mild anemia, cyanosis (methemoglobin) and leukocytosis • Prima-quine sensitive hemolytic anemia occurs in patients with G6PD deficiency (should test patients before prescribing primaquine) |
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What are uses of quinine?
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• Quinine has suppressive effects against erythrocytic forms of malaria but not against liver stages; some gametocytocidal activity (P. vivax, P. malariae)
• Valuable in treating multiresistant strains of P. falciparum. |
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What are adverse effects of quinine?
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• Cinchonism – tinnitus ( ringing in the ear), headache, nausea, dizziness, flushing, and visual disturbance (blurring of vision)
• Cardiac depressant; at high doses stimulates then depresses respiration • Stimulates uterine contracts, especially in the 3rd trimester • May stimulate release of insulin resulting in hypoglycemia • Hemolytic anemia (esp. w/ G6PD deficiency) |
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What drug(s) could be used against chloroquine-resistant falciparum?
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• Fansidar (sulfadoxine+pyrimethamine )
• Mefloquine |
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Why is Fansidar no longer recommended for chemoprophylaxis?
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Fansidar may cause uncommon but severe cutaneous reactions: erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis
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What is Artemisinin used for?
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Artemisinin is effective against schizont of nearly all strains of Plasmodium falciparum and Plasmodium vivax.
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What is diloxanide furoate used for?
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Diloxanide furoate is used as a direct and effective luminal amebicide, but it’s not active against tissue trophozoites. It is the drug of choice for asymptomatic infections. Flatulence is common. (This drug not available in the U.S.)
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What is Iodoquinol used for, and what are adverse effects?
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• Iodoquinol is used for luminal amebae, but not tissue trophozoites. It’s an alternative to diloxanide furoate for asymptomatic amebiasis or in combination with metronidazole for other forms of amebiasis.
• 90% of the drug is not absorbed, and the 10% absorbed has problems relating to iodine. o May increase protein bound serum iodine o May cause dermatitis, urticarial, pruritus, fever due to iodine intoxication o Hypersensitivity reactions |
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What is paromomycin sulfate used for, and what are adverse effects?
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• Administered orally, it’s an effective amebicide. Not absorbed in the GI tract.
• Occasional adverse effects: abdominal distress and diarrhea. Can also cause nephrotoxicity. |
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What is the drug of choice for cestodes?
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• Niclosamide is the drug of choice for most cestodes. It kills cestodes on contact due to inhibition of oxidative phosphorylation as well as to ATPase stimulating activity.
• Should be given in the morning on an empty stomach. Tablets should be chewed thoroughly and swallowed w/ water. • Potential for release of larval forms of pork tapeworm into tissues |
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What drugs are the drugs of choice for nematodes (roundworms), and what is the mechanism of action?
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• Thiabendazole, mebendazole, and albendazole would be used for nematodes.
• The primary action is to inhibit microtubule polymerization by binding beta-tubulin. They also inhibit mitochondrial fumarate reductase and reduce glucose transport and uncouple oxidative phosphorylation. |
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What is the drug of choice for filariasis, loiasis, and tropical eosinophilia, and what are adverse effects?
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Diethylcarbamazine is the drug of choice for filariasis, loiasis, and tropical eosinophilia. It works by immobilizing microfilariae and enhances the parasite’s susceptibility to the immune system.
Adverse effects: Headache, weakness, malaise, nausea, vomiting |
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What are mechanisms of resistance to sulfonamides?
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• Production of a dihydropteroate synthase with decreased affinity for sulfonamides (plasmid-mediated).
• Decreased bacterial permeability or active efflux of the drug. • Increased production of PABA (less common) |
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What are adverse effects of sulfonamides?
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• Crystalluria:
• Crystalluria was a major problem with older sulfonamides, this is less of a problem with more soluble agents (e.g., sulfisoxazole). However, the acetylated metabolites of sulfamethoxazole and sulfadiazine tend to precipitate in the kidney tubules. • Adequate water intake or administration of sodium bicarbonate is needed to reduce the risk of crystalluria. • Hematopoietic disorders: Acute hemolytic anemia, agranulocytosis and aplastic anemia may occur, but very rare. • Hypersensitivity reactions: rashes, erythema, drug eruption, accompanied by fever, malaise, and pruritus. |
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What are adverse effects of Rifampin?
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Rifampin turns urine red, causes hepatotoxicity, induces CYP2C9 & CYP3A4 and causes dyspnea.
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What are adverse effects of Ethambutol?
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Causes optic neuritis with red-green color blindness
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How do the class A, C, and D lactamases work?
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Class A, C, and D lactamases have serine as the active site,
which mediates formation of a transient covalent penicilloyl- enzyme intermediate. Hydrolysis rate = 2,600/sec |
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Which penicillins are useful against Pseudomonas aeruginosa?
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Group IV penicillins are active against Pseudomonas: carbenicillin, carbenicillin indanyl, ticarcillin, mezclocillin, piperacillin (all sensitive to penicillinase).
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Which one is acid stable, amoxicillin or ampicillin?
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Amoxicillin is acid stable and completel absorbed by the GI tract.
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Why wouldn’t you use a cephalosporin as a primary agent for an established infection?
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Cephalosporins shouldn’t be used as primary agents for the majority of established infections, since other drugs are less expensive and less likely to cause superinfections.
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Why isn’t tetracycline used to treat routine infections of G(+) cocci?
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Tetracycline resistance is frequent, and other narrower-spectrum, less-toxic agents are available (e.g., penicillins).
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What are symptoms of pseudomembranous colitis?
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Abdominal pain, diarrhea, fever, and mucus and blood in the stool.; proctoscopic examination shows white to yellow plaques on the mucosa of the colon.
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What is postantibiotic effect?
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Postantibiotic effect is a phenomenon unique to aminoglycosides where there’s residual bactericidal activity persistent after serum concentrations of the drug have fallen below the MIC. Occurs in a concentration-dependent fashion.
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What is the name of the bacterial enzyme that catalyzes the incorporation of PABA into folate that is missing from the human cells?
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Dihydropteroate synthase
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What is the mechanism of CNS stimulant side effects of fluoroquinolones (insomnia, delirium, even seizures)?
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Occurred in patients using theophylline; quinolones inhibit metabolism of theophyllines, which results in an increase in methylxanthine.
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Why is it that concurrent administration of an NSAID may potentiate the CNS stimulant effect of fluoroquinolone?
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NSAIDs may augment displacement of GABA from its receptors by the quinolones.
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Why are fluoroquinolones contraindicated for use in pregnant women?
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Quinolones can cause arthropathy in children.
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