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Foundations 2 - Week 5 > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

What is a graded dose response curve?

A

Looks at effect on individuals, looks at magnitude of response (plots intensity vs. dose)

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2
Q

What is a quantal dose response curve?

A

Looks at effect on populations, looking for absence or presence or particular phenomenon (plots population % vs. dose)

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3
Q

What is LD50?

A

lethal dose for 50% of the population

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4
Q

What is ED50?

A

effective dose for 50% of the population

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5
Q

What is TI (therapeutic index)?

A

LD50/ED50

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6
Q

What is margin of safety and what are its implications?

A

LD1/ED99 Larger number = safer drug

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7
Q

What is TLV?

A

threshold limit value (part of occupational toxicology)

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8
Q

What is TLV-TWA?

A

Time weighted average values, safety of compound a worker is exposed to over an 8 hr day over a 40 hr week (person can be exposed to compound at that limit as long as there is an equal amount of time below that limit)

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9
Q

What is TLV-C?

A

Ceiling value, concentrations you cannot exceed, even instantaneously

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10
Q

What is PEL?

A

permissible exposure limits, federal regulations, not changed unless the law is changed

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11
Q

What is bioaccumulation?

A

Increasing concentration of a persistent environmental chemical in the tissues of an organism as a result of the chemical physiochemical properties (part of environmental toxicology)

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12
Q

What is biomagnification?

A

Increasing concentration of chemical w/ each progressive link of food chain (part of environmental toxicology)

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13
Q

What are 4 ways a toxicological response can be modified?

A
  1. Potentiation or supra-additive effects
  2. Physical and chemical characteristics (eg. sensitivity to pH, stability, solid vs. liquid vs. gas forms)
  3. Routes of administration (IV, oral, skin, inhalation)
  4. Metabolism
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14
Q

How can pharmacokinetic drug interactions affect toxicity during absorption (3 ways + examples)?

A
  1. Direct interaction
    1. tetracyclines (antibiotic) precipitate sulfonamides (antibiotic) –> less sulfonamide will be available for absorption
    2. carbenicillin (antibiotic) reacts w/ aminoglycosides (gentamicin) to form amides –> inactivation of aminoglycosides
  2. GI absorption
    1. Altering tract function:
      1. laxatives increase motility –> decrease absorption - antibiotics decrease gut flora –> decrease vit K synthesis –> affects clotting –> increases response to oral anticoagulants
    2. Altering contents
      1. tetracyclines chelate Ca2+ (eg. Antacids) –> tetracycline is unabsorbable - H2 blockers increase pH/decrease acid secretion –> changes dissolution properties
      2. Resins (cholestyramine) binds vitamins and digoxin (fat soluble)
  3. Dermatomucosal absorption
    1. DMSO solvent allows permeation of skin by drugs - Patches (fentanyl, nicotine) absorbed by potential oils in skin
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15
Q

How can pharmacokinetic drug interactions affect toxicity during distribution (2 ways + examples)?

A
  1. Plasma protein binding (acid drugs bind to albumin)
    1. Salicylates displace warfarin and phenytoin –> more free drug –> toxicity
  2. Displacement from tissue binding sites
    1. Quinidine (anti-arrhythmic) displaces digoxin –> available toxicity elsewhere
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16
Q

How can pharmacokinetic drug interactions affect toxicity during metabolism (2 ways + examples)?

A
  1. Induction- slowly induces/increases metabolism of a drug - Phenobarbital (anti-epileptic, tranquilizer) - Rifampin (antibiotic) - Pollutants (polycyclic aromatic hydrocarbons PAH) - Chronic ethanol 2. Inhibition- high enough concentration rapidly inhibits activity of drug, covalent binding can be irreversible - Chloramphenicol - Ketoconazole- inhibits CYP3A4, anti-fungal - Cimetidine (Tagamet)- inhibits propranolol and theophylline metabolism, beta-blocker
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17
Q

How can pharmacokinetic drug interactions affect toxicity during excretion (3 ways + examples)?

A
  1. Block transport mechanism: weak acids transport in proximal tubules - Probenicid blocks penicillin –> increases half life (blocks availability of transport mechanism of penicillin out of body, so keeps it in body longer) –> don’t have to dose as often 2. Alter pH of urine (through ion traffic) - Bicarb increases pH –> increases elimination of weak acids (important for OD of phenobarbital) - Ammonium chloride and ascorbic acid decrease pH –> increases elimination of weak bases 3. Diuretics - Cisplatin: decreases tubular concentration of toxic compounds –> decreases renal toxicity - Thiazides: decrease K+ (essential for normal cardiac function) –> toxicity w/ digoxin
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18
Q

What is potentiation?

A

A compound that has little/no activity yields an order of magnitude response when added to another compound

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19
Q

What is synergy?

A

2 drugs added together produce a greater response than expected

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20
Q

What are some examples of agonists and antagonists?

A
  • Naloxone- antagonist to opiates - Tamoxifen: antagonist to estrogen positive receptors in breast tumors, but acts like estrogen (agonist) for bone - Cimetidine, Ranitidine- H2 blockers
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21
Q

How can pharmacodynamic drug interactions cause physiologic alterations?

A
  • Hydralazine decreases peripheral resistance (decreases BP) –> causes reflex tachycardia (affects heart) –> give propranolol (beta-blocker) to decrease response on heart - Ethanol increases fluidity of plasma membrane –> increases Cl- influx (chloride channels) –> affects GABA (inhibitory NT)
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22
Q

Why is it dangerous to give NSAIDs to a patient who is taking gingko biloba?

A

Both inhibit platelet aggregation –> increase risk for bleeding

23
Q

Why are patients who are taking calcium channel blockers (like Verapamil) advised to not drink grapefruit juice?

A

Grapefruit juice contains furanocoumarins, which inhibit CYP3A4 (so anything metabolized by CYP3A4 can be inhibited by grapefruit juice) –> leads to higher levels of drugs –> toxicity - Verapamil (for angina) increases 30% in concentration when furanocoumarins inhibit CYP3A4 –> leads to hypotension and myocardial depression

24
Q

What does ketoconazole do?

A

Ketoconazole inhibits CYP3A4 (so anything metabolized by CYP3A4 can be inhibited by ketoconazole) –> leads to higher levels of drugs –> toxicity - Verapamil (for angina) increases 30% in concentration when furanocoumarins inhibit CYP3A4 –> leads to hypotension and myocardial depression

25
Q

What does phenobarbital do and what happens when it is combined with warfarin?

A

Phenobarbital induces the warfarin enzyme When combined with warfarin (anti-coagulant), phenobarbital causes prothrombin time to decrease (i.e. warfarin doesn’t work anymore) b/c enzyme induces warfarin metabolism

26
Q

Why is acetaminophen especially dangerous to patients who chronically abuse alcohol?

A

Acetaminophen is metabolized through many pathways, including by CYP2E1, to a toxic intermediate –> normally, glutathione conjugation in this pathway reduces this toxic intermediate to normal metabolites HOWEVER, ethanol metabolism pushes acetaminophen metabolism through a different, toxic pathway –> glutathione stores are reduced and toxic intermediates bind to cell macromolecules –> causes cell necrosis and death * Chronic alcohol abusers have already induced the CYP2E1 pathway and produced very high levels of the toxic intermediate –> acetaminophen will now catalyze the toxic pathway to a greater extent

27
Q

Describe the steps for management of a poisoned patient.

A
  1. Maintain vital functions (ABCD) - Airway- no obstruction - Breathing- well ventilated - Circulation- pulse, BP - Dextrose-thiamine (if alteration of CNS state) 2. Decontamination - Syrup of ipecac (unless there’s no gag reflex, or unless there’s corrosives or hydrocarbons) - Activated charcoal (high surface area, absorbs lots of molecules, but can also absorb antidote) 3. Enhancement of elimination - Manipulation of urine pH (bicarb OR ammonium chloride and ascorbic acid) - Hemodialysis or hemoperfusion 4. Antidotes (eg. Naloxone)
28
Q

What are the symptoms, mechanisms, and treatment for acetaminophen poisoning?

A

Symptoms: - Early in toxicity: nausea, vomiting, abdominal pain - Increased liver enzymes (liver damage) - Late: jaundice Mechanisms - Depletion of glutathione stores - Covalent binding to cell macromolecules - Lipid peroxidation –> superoxide formation Treatment - Syrup of Ipecac - N-acetylcysteine (Mucomyst) w/in 15-24 hrs (binds metabolite, increases glutathione stores) - Monitor levels

29
Q

What are the symptoms, mechanisms, and treatment for cyanide poisoning?

A

Symptoms - Flush appearance - Dizziness, confusion, anxiety - Resp distress –> arrest Mechanisms - Binds tightly to heme iron in cytochrome oxidase –> prevents aerobic oxidation, metabolism, and phosphorylation Treatment - Stabilize patient (hypobaric oxygen) - Amyl nitrite and/or IV sodium nitrite, followed by sodium thiosulfate (produces Met-hemoglobinemia –> CN binds more tightly to MetHb than cytochrome oxidase –> thiosulfate reacts w/ rhodonase (from liver) –> gets rid of CN by producing relatively non-toxic metabolites)

30
Q

What are the symptoms, mechanisms, and treatment for iron poisoning?

A

Symptoms - Vomiting, diarrhea (often bloody) –> massive blood and fluid loss - Remission - Shock, seizures, liver failure, death Mechanisms - Corrosive effect on mucosal tissue - Cellular dysfunction– acidosis and liver necrosis Treatment - Treat shock - Deferoxamine (chelating agent)– if serum Fe > TIBC (total iron binding capacity) - Monitor urine color (orange b/c concentration of free Fe is decreasing) - Monitor serum Fe levels

31
Q

What are the symptoms, mechanisms, and treatment for chronic lead poisoning?

A

Symptoms - Nausea, constipation or diarrhea, abdominal pain - Basophilic stippling (deposits of Pb in cells) and microcytic, hypochromatic anemia - Increased urinary excretion of coprophyrin and aminolevulinic acid - Mental retardation, change in personality (irritable) - Blue lead line on gums - Peripheral neuropathy (wrist drop, foot drop) Mechanisms - Binds sulfhydryl groups –> interferes w/ enzymatic processes - Decreases Hb synthesis and RBC life span (blocks protoporphyrin IX synthesis relating to excretion of these compoudns) - Segmental demyelination of peripheral nerves Treatment - Maintain urinary output - Chelate w/ dimercaprol and/or calcium EDTA

32
Q

What are the symptoms, mechanisms, and treatment for ethylene glycol poisoning?

A

Symptoms - Intoxication - Increased osmolar gap leading to anion gap acidosis - Hyperventilation - Reversible renal failure Mechanisms - Metabolized to toxic organic acids (ethylene glycol (like ethanol) is metabolized by alcohol dehydrogenase –> glycolic, glyoxylic, and oxalic acids) - Deposition of calcium oxalate crystals –> causes tissue necrosis Treatment - Hemodialysis - Ethanol- competitive antagonist - Fomepizole- inhibits alcohol dehydrogenase

33
Q

What are the symptoms, mechanisms, and treatment for ricin?

A

Symptoms - Delayed GI irritation (nausea, vomiting, diarrhea, abdominal pain) - Remission - Hemorrhagic gastritis and dehydration - Tissue necrosis –> death Mechanism - Disrupts protein synthesis by binding 60S ribosomal subunit (2 chains of ricin: B chain binds to extracellular receptor –> ricin is internalized, A chain breaks off and binds to 60S ribosomal subunit –> cell death) Treatment - Activated charcoal - Treat fluid and electrolyte loss

34
Q

What are the symptoms, mechanisms, and treatment for amanita mushrooms?

A

Symptoms - Nausea, vomiting, diarrhea, abdominal pain - Remission (dangerous b/c people don’t go to ER) - Increased liver enzymes - Metabolic acidosis - Jaundice Mechanism - Cyclopeptides inhibit RNA polymerase II –> decreases protein synthesis –> cellular necrosis Treatment - Treat fluid and electrolyte loss aggressively - Activated charcoal - Liver transplant

35
Q

What are the 4 groups of Cell Cycle (CSS) specific Anti-tumor drugs?

In general, what does each group of drugs inhibit?

A
  1. Antimetabolites - inhibits DNA/RNA metabolism
  2. Vinca Alkaloids / Taxanes - inhibit microtubules (growth and destruction)
  3. Epipodophyllotoxins - inhibit topoisomerase II
  4. Camptothecins - inhibit topoisomerase I
36
Q

How does methotrexate interfere with cell replication?

A

Methotrexate inhibits DNA and RNA synthesis by binding to the enzmye dihydrofolate reductase (DHFR). This enzyme is required to convert Folic Acid to tetrahydrofolate, which is required to make pyrimadines and purines.

37
Q

How does 5-flourouracil interfere with cell replication?

A

In vivo, 5-flourouracil is converted into a couple of different metabolites. In general, the drugs acts as a pyrimadine analog. It can become incorporated into RNA, which inhibits RNA processing. It can also inhibit the production of Thymadine which is required for production.

38
Q

How do Vinca Alkaloids and Taxanes affect microtubles.

Name 2 drugs for each drug class.

A
  1. Vinca Alkaloids destabilze microtubules - Vincristine, Vinblastine
  2. Taxanes stabilze microtubules - Docetaxel, Paclitaxel (aka - taxol)

If you pay your taxes, you are stable!!

39
Q

What are the 3 main drug classes that make up cell cycle non-specific agents (CCNS)?

What are some drugs associated with these classes?

In general, how do these drugs interfere with cancer cells?

A
  1. Antibiotics - anthracyclins, bleomycins
  2. Alkylating Agents - Nitrogen mustards, nitrosoureas
  3. Platinum Co-ordination complexes - cisplatin

These drugs form DNA adducts/damage that eventually leads to apoptosis.

  • Cross-linking DNA
  • Mispairing gaunine and thymine residues
  • Depurination of guanine residues
  • Fragmentation of DNA
40
Q

How does Nuclear Hormone Receptor targeted therapy work?

A

Many hormonal growth factors (estrogen and testosterone) are up regulated in cancer. Blocking these signals can reduce cancer.

  • Selective Estrogen Receptor Modulators (SERMs) - antagonize estrogen receptors on breast cancer (eg - tamoxifen)
  • Selective Androgen Receptor Modulators (SARMs) - antagonize androgen (testosterone) receptors on prostate cancer (eg - bicalutamide)
41
Q

How do Monoclonal Antibodies work on cancer cells?

What 3 letters do they typically end in?

What is a one drug that attaches to the HER2/Neu receptors on breast cancer cells?

A

Monocolonal antibodies attach to cell surface proteins much like regular antibodies. Cancer cells sometimes up regulate growth factor receptors. This makes them a good target of anti-tumor drugs.

Monoclonal antibody drugs typically end in -MAB. (trastuzumab, rituximab, Bevacizumab, etc…)

Herceptin (Trastuzumab) is used to fight HER2/NEU positive breast cancer.

42
Q

Kinase inhibitors, monoclonal antibodies, proteosome inhibitors, nuclear hormone receptor inhibitors, epi-genomic, and immodulation are all forms what what type of cancer therpy.

A

Targeted Cancer therpy

43
Q

How does epi-genetic targeted cancer therapy work?

A

Epi-geneitc targeted therapy works by turning ON and/or OFF certain genes.

  • DNA Methylation turns off genes (ie - turn off an anti-apoptotic genes)
  • Histone Acyelation turns on genes (turn on tumor suppressor genes)
44
Q

How does proteosome cancer therapy work?

A

Many cancer cells inhibit the production of tumor suppresor genes by upregulating proteosomes. Inhibiting those proteosomes would increase tumor supporesor genes which would lead to apoptosis.

45
Q

How does immunodulation thearpy work?

A
  1. Cancer Vaccines - like HPV or Provenge.
  2. Activation of the immune system - Ipilimumab is a drug directed against CTLA-4 on T-cells. Inhibiting CTLA-4 leads to an incrase in T-cells which can help fight the cancer.
46
Q

What does Gleevac inhibit?

What type of cancer does it effect?

A

Gleevac is a kinase inhibitor. It effects the bcr-abl receptor which is a result of a t(9;22) translocation (philadelphia chromosome).

It mostly treats chronic myeloid leukemia (CML).

47
Q

Kinase Inhibitors typicallyl end with what 3 letters?

A

NIB (ie - imantinib, sorafinib, sunitinib, etc.)

48
Q

How doe angiogenesis inhibitors work?

A
  • Target VEGF - antibodies target this cytokine
  • Target VEGFR - inhibit the kinase receptor
49
Q

In Cost-Minimization analysis (CMA), what is assumed about outsomes? What is the objective of this method with regards to outcomes?

What is a disadvantage of this method?

What is an advantage?

A
  • Assumption - Outcomes are equal.
  • Objective - To pick the least costly.
  • Distavangates - It is limiting because no outcomes are perfectly equivalent.
  • Advantages - It is simple.
50
Q

What does Cost-minimization Analysis (CMA) measure?

What is Average Cost-Effectiveness Ratio (CER)

What is incremental Cost Effectiveness Ratio (ICER)

What units are outcomes typically measured by?

A
  • CMA measures the extra costs associated with each additional unit of outcome.
  • CER is the cost per outcome (eg - $5 per life year gained)
  • ICER is the incremental cost per outcome. Used when comparing two outcomes.

Natural Units (life years gained, mmHg blood pressure, mMol/L of Glucose, etc…)

51
Q

What does Cost-utility Analysis (CUA) measure?

What is Average Cost-Effectiveness Ratio (CUR)

What is incremental Cost Effectiveness Ratio (ICUR)

What units are outcomes typically measured by?

A
  • CUA measures the outcomes based on years of life that are adjusted by “utility” weights. The most common utility is quality adjusted life years (QALY), which is based on patients preferences about quality living.
  • CUR measures the cost to gain 1 additional quality adjusted life year. (eg - Drug A costs $50,000 to gain 1 QALY. Is that worth it? who knows)
  • ICUR measures the incremental cost per QALY when comparing two interventions.
52
Q

What is Cost-Benefit Analysis?

A

CBA is used to analyze a single interventaion compared to the status quo. Or it is used when comparing two different interventions. It basically analyzes how much benefit (ie - profit) you will gain if you implement a certain intervention.

Results are typically presented as: Net benefit, Benefit-to-cost ratios, internal rate of return, or break-even points.

53
Q

What are the best practices to following when performing a pharmacoeconomic study?

A
  1. Use 2 pharmaceutical interventions (even if one is to “do nothing”)
  2. Conduct an analysis (CMA, CEA, CUA, CBA)
  3. Pick a perspective - Societal (all costs), Payer (medicare, medicaid, private insurance, patient, etc.), or Institutional (hostipal, clinic, pharmacy, etc.)
  4. Discount costs and benefits - make sure future and past costs/benefits are adjusted to current market values. (“time value of money”)
  5. Conduct a Sensitivity Analysis - see what changes to your assumptions impact your results (bigger change = more sensitive).

Foundations 2 - Week 5 (6 decks)

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