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Pharmacology - PMC 621 > Exam 1 > Flashcards

Exam 1 Flashcards

1
Q

What are the four reasons for an increase in fungal infections?

A
  1. Advances in antibacterial therapies
    * Antibiotics kill bacteria, which gives fungi the opprotunity to grow
  2. Predisposing procedures
    * Placement of indwelling catheters
  3. Predisposing treatments
    * Chemotherapy
  4. Predisposing diseases
    * Leukemia, AIDS
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2
Q

What are the general principles for prescribing/using antifungal topical therapies?

A
  • Use creams, ointments and liquids are primary therapy. Powders are adjunctive therapy unless the condition is mild
  • Creams/solutions - preferred for fissured or inflamed areas, such as toe webs, groin or scrotum
  • Powder - confined to mild lesions or preventive therapy in tinea pedis (Athele’s Foot)
  • Sprays - not recommended for face
  • Most therapy lasts 2+ weeks. Treatment for tinea pedia is 4+ weeks
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3
Q

Drug: Flucytosine

  1. Does it penetrate the CSF?
  2. Adverse Effects (and management)
  3. Associated with resistance?
  4. Therapeutic use
A
  1. Yes
    • Bone marrow hypoplasia (anemia, leukopenia, thrombocytopenia) - especially in prolonged therapy or when in combo with Amphotericin B
    • Elevated serum levels of hepatic enzymes (5%) - decrease dose in pts with decreased renal function
  3. Resistance can be a problem when used alone, so combo therapy is recommended
    • Serious infections of candida and cryptococcus
    • Cryptococcal meningitis in AIDS patients
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4
Q

Drug: Ketaconazole

  1. Drug Interactions
  2. Does it penetrate the CSF?
  3. Therapeutic use
A
  1. Azole drug class interactions
  2. No
    • Histoplasmosis, Coccidioidomycosis, Candidiasis, Tinea, Vulvovaginal candidiasis
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5
Q

Drug: Itraconazole

  1. Does it penetrate the CSF?
  2. Adverse Effects (and management)
  3. Therapeutic use
  4. Drug Interactions
A
  1. No (not much)
    • Diarrhea, abdominal cramps, anorexia, nausea
    • Hepatotoxicity (usually occuring in the first three months)
    • Increased aminotransferases
    • Stevens-Johnson Syndrome
    • Hypokalemia
    • Adrenal insufficiency
    • Lower limb edema, hypotension
    • Contraindicated in pregnancy
    • Oral therapy for histoplasmosis and blastomycosis
    • Useful in some pts with candidiasis, cryptococcosis, coccidioidomycosis
    • Ringworm
  4. Azole drug class interactions
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6
Q

Drug: Fluconazole

  1. Pharmacokinetics
  2. Does it penetrate the CSF?
  3. Adverse Effects (and management)
  4. Drug interactions?
  5. Therapeutic use
A
    • Absorption: GI tract (F > 90%)
    • Elimination: Renal excretion (60-80% excreted unchanged in urine)
    • Plasma concentrations are essentially the same regardless of administration method
  2. Yes
    • Nausea, headache, rash, vomiting, abdominal pain, diarrhea
    • Alopecia
    • Hepatotoxicity
    • Stevens-Johnson Syndrome
    • Skeletal and cardiac deformities in infants
    • Contraindicated during pregnancy
  4. Azole drug class interactions
    • Candidiasis, meningitis (cryptococcal and coccidioidomycosis)
    • Drug of choice for meningitis due to excellent CSF penetration and less morbidity than Amphotericin
    • Prophylaxis and empirical therapy in immunocompromised host
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7
Q

Drug: Voriconazole

  1. Pharmacokinetics
  2. Does it penetrate the CSF?
  3. Adverse Effects (and management)
  4. Drug Interactions
  5. Therapeutic use
  6. Contraindications
A
    • Absorption: Bioavailability = 96%, decreased by high fat meals
    • Elimination: metabolized in liver, t1/2 = 6 hours
    • Metabolized by and inhibits CYPs (2C19 > 2C9 > 3A4)
    • Monitor CP serum levels
  2. Yes
    • Hepatotoxicity, cardiac arrthymia, rash
    • Visual disturbances (30%) - blurred vision, color changes
    • Contraindicated in pregnancy
  4. Azole drug class interactions
    • Invasive aspergillosis, esophageal candidiasis
    • P. boydii, Fusarium infections
    • Cerebral fungal infections
    • Decreases Voriconazole bioavailability - Rifampin, Carbamazepine/Phenobarbital
    • Increases drug concentrations - Quinidine, Sirolimus, Ergot Alkaloids, Omeprazole
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8
Q

Drug: Posaconazole

  1. Does it penetrate the CSF?
  2. Pharmacokinetics
  3. Adverse Effects (and management)
  4. Therapeutic use
A
  1. Poorly, inconsistently
    • Oral bioavailability enhanced by food
    • Drugs that decrease gastric acid, decrease posaconazole exposure
    • GI effects, headaches
    • Can elevate liver function tests
    • Candida and Aspergillus infections in severly compromised patients
    • Oropharyngeal candidiasis (but fluconazole preferred)
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9
Q

Drug: Clotrimazole

  1. Does it penetrate the CSF?
  2. Administration
  3. Adverse Effects (and management)
  4. Therapeutic use
A
  1. Used mainly as topical
  2. Cream, powder, lotion, aerosol solution, tablets (not often)
  3. Skin irritation, burning sensation in vagina, GI irritation, lower abdominal cramps
    • Dermatophyte infections (ringworm)
    • Vulvovaginal and oropharyngeal candidiasis
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10
Q

Drug: Caspofungin Acetate

  1. Mechanism of Action
  2. Does it penetrate the CSF?
  3. Adverse Effects (and management)
  4. Therapeutic use
A
    • Drug class: Echinocandin
    • Blocks fungal cell wall synthesis
    • Glucan synthesis inhibitor (not found in mammalian cells)
  2. No
    • Phlebitis (vein inflammation), headache, fever
    • Increased LFTs, SrCr - monitor both while taking
    • Invasive Aspergillosis (used for pts that are intolerant to other agents)
    • Candida infections
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11
Q

Drug: Griseofulvin

  1. Mechanism of Action
  2. Does it penetrate the CSF?
  3. Administration
  4. Adverse Effects (and management)
  5. Therapeutic use
A
  1. Disrupts the cell mitotic spindle structure and arrests cell division in metaphase
  2. No
    • Oral administration, not effective topically (given after topical agents fail)
    • Absorption is reduced by barbiturates
    • Nausea, vomiting, diarrhea, headache, dizziness
    • Hypersensitivity, rash
    • Hepatotoxicity, nephrotoxicity
    • Hematologic effects
    • CYP450 inducer
    • Dermatophytosis
    • Tinea corporis, pedis, barbae, capitus
    • Unguium
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12
Q

Drug: Terbinafine

  1. Mechanism of Action
  2. Does it penetrate the CSF?
  3. Adverse Effects (and management)
  4. Therapeutic use
  5. Pharmacokinetics
A
    • Synthetic allylamine derivative
    • Inhibits squalene epoxidase (key enzyme in ergosterol biosynthesis in fungi)
  2. No
    • Nausea, diarrhea, headache
    • Hypersensitivity, rash, erythema multiforme, toxia epidermal necrolysis
    • Liver enzyme abnormalities, neutropenia, pancytopenia
    • Not recommended with liver or renal dysfunction, or pregnancy
    • Onychomycosis
    • Tinea capitis
    • Ring worm
    • Dermatophytes
    • Bioavailability = 40%
    • Drug accumulates in skin, nails, fat
    • t1/2 = 12 hours, after CSS achieved it goes to 200-400 hours
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13
Q

Drug: Nyastatin

  1. Does it penetrate the CSF?
  2. Administration
  3. Adverse Effects (and management)
  4. Therapeutic use
A
  1. No
    • Topical or oral solution
    • Should be swished and swallowed
    • Not absorbed in GI tract
  3. Well tolerated, not many side effects or allergy reactions
    • Oropharyngeal candidiasis
    • Treatment of oral thrush in neonates and infants
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14
Q

Terbinafine Drug Interactions

A
  • Cimetidine - Terbinafine clearance decreased by 33%
  • Rifampin - Terbinafine clearance increased 100%
  • Cyclosporine - Increased clearance of cyclosporine
  • Warfarin - Warfarin clearance may be decreased, but unknown (through CYP 2C9/2D6)
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15
Q

Amphotericine B deoxycholate (C-AMB)

  1. Therapeutic use
  2. Adverse Effects
A
    • Invasive candidiasis and aspergillosis
    • Blastomycosis
    • Histoplasmosis
    • Coccidioidomycosis
    • Mucormycosis
    • Sporotrichosis
    • Empirical therapy in immunocompromised host
    • Significant nephrotoxicity (azotemia, renal tubular acidosis, hypochromic, normocytic anemia)
    • Infusion-related reactions (infusion related fever and chills)
    • C-AMB better tolerated by premature neonates than older children and adults
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16
Q

Amphotericin B: ABCD, L-AMB, ABLC

  1. Therapeutic uses
  2. Adverse Effects
A
  1. Invasive aspergillosis (for pts intolerant of treatment with conventional amphotericin B)
    • Less nephrotoxic than C-AMB
    • Infusion related reactions: highest with ABCD, lowest with L-AMB
    • Nephrotoxicity, hematological effects
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17
Q

What is the main mechanism of action for Amphotericin B and Azole (class) drugs?

A
  • Disrupts/inhibits ergosterol synthesis in fungi
  • Ergosterol - key component in fungi cell membrane
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18
Q

After initial Amphotericin B therapy, what should be the follow-up therapy for these diseases?

  1. Deep-seated candidiasis
  2. Cryptococcal meningitis
  3. Disseminated coccidioidomycosis
A
  1. Deep seated candidiasis - Fluconazole or flucytosine
  2. Cryptococcal meningitis - Fluconazole
  3. Disseminated coccidioidomycosis - Fluconazole or Itraconazole
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19
Q

After initial Amphotericin B therapy, what should be the follow-up therapy for these diseases?

  1. Paracoccidioidomycosis
  2. Blastomycosis
  3. Histoplasmosis
A
  1. Paracoccidioidomycosis - Sulfonamide
  2. Blastomycosis - Itraconazole
  3. Histoplasmosis - Itraconazole
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20
Q

What antifungal therapy is used for Histoplasmosis and Blastomycosis in severe, moderate and mild cases?

A
  • Severe: AmpB
  • Moderate: Itr > Flu
  • Mild: Itr > Flu
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21
Q

What antifungal therapy is used for Candidiasis in severe, moderate and mild cases?

A
  • Severe: AmpB
  • Moderate: AmpB, Flu, Cas
  • Mild: Flu or Cas
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22
Q

What antifungal therapy is used for Coccidioidomycosis (meningeal, disseminated and pulmonary) in severe, moderate and mild cases?

A
  • Meningeal: Severe- AmpB or Flu, Mild/Moderate - Flu
  • Disseminated: Severe - AmpB > Flu, Mild/Moderate - Azole
  • Pulmonary: Severe - AmpB > Flu, Mild/Moderate - Azole
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23
Q

What antifungal therapy is used for Aspergillosis in severe, moderate and mild cases?

A
  • Severe: AmpB
  • Moderate: AmpB > Itr
  • Mild: Itr > AmpB
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24
Q

What antifungal therapy is used for Cryptococcal Meningitis in severe, moderate and mild cases?

A
  • Severe: AmpB or 5-FC
  • Moderate: Flu or AmpB
  • Mild: Flu
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25
Q

What are the three main physiochemical properties of drugs?

A
  1. Molecular size - determined by the number and type of atoms, and the stereochemistry (how the atoms are arranged)
  2. Solubility - determined by overall polarity of the drug, measured using the parition coefficient
  3. Charge - determined by the acidic, basic or neutral characteristics of the drug
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26
Q

What is the partition coefficient (P.C.)?

A
  • PC is measured experimentally using water and 1-octanol
  • PC > 1 = hydrophobic
  • PC < 1 = hydrophilic
  • PC = [Drug]fat / [Drug]water
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27
Q

How does the charge of a drug affect it?

A
  • Ionized (charged) drugs tend to be hydrophilic and stay in the plasma
  • Unionized (uncharged) drugs tend to be hydrophobic and diffuse into plasma
  • Both acids or bases can diffuse into plasma, if they are unionized (ex: a weak acid is unionized in a very low pH)
  • Ionized/unionized character largely depends on pH of the solution
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28
Q

What is the Henderson-Hasselbach equation?

A
  • HA <–> H+ + A-
  • Equilibrium with weak acids involve an equilibrium constant (Keq) and are pH dependent
  • [A-] / [HA] = ionized / unionized
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29
Q

How do drugs cross biological membranes?

A
  1. Filtration through pores - all forms
  2. Passive diffusion (simple and carrier facilitated) - unionized, nonprotonated, uncharged
  3. Active transport - charged, ionized, protonated
  4. Minor endocytosis - not used often
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30
Q

What are the routes of drug administration?

A
  1. Enteral - absorbed in GI tract
    * Oral, sublingual, rectal
  2. Parenteral - absorbed somewhere other than GI tract
    * Subcutaneous, intramuscular, intravenous (IV), intraarterial, inhalation, intrathecal
  3. Topical - drug placed on surface of tissue
    * Patches, intravaginal, dermatological/ophthalmic applications
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31
Q

What are the 5 factors that affect drug distribution?

A
  1. Physiochemical properties of the drug
  2. Biological membranes encountered
  3. Protein binding and storage
  4. Blood perfusion
  5. Disease states
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32
Q

What is ionic trapping?

A
  • Basic drugs enter tissues by passive diffusion, then become protonated (ionized)
  • Ionic form of basic drug can’t diffuse out and “ion trapping” occurs
  • Happens to basic drugs in acidic environments (stomach, prostate gland, etc.)
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33
Q

What is the importance of protein binding in “storage and redistribution”?

A
  • Protein binding occurs in plasma and tissues
  • Free drug - unbound drug, able to move freely
  • Drugs bound to proteins (like albumin) cannot move and diffuse as easily
  • Another substance (such as another drug) may compete and bind to the protein, thus increasing the free drug concentration
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34
Q

How is redistribution different from initial distribution?

A
  • Initial distribution: depends primarily on blood flow to a body region
  • Redistribution: can terminate actions of drugs (particularly hydrophobic drugs), depends on factors other than blood flow
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35
Q

What is biotransformation, and what are the results?

A
  • Biotransformation: drug metabolism, a change in chemical structure caused by a living system
  • Primarily occurs in the liver
  • Product is a metabolite - more polar, more water soluble, excreted faster
  • Results: activates an inactive drug, inactives an active drug, active drug to active metabolite, safe metabolite or drug to toxic one
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36
Q

What are the classes of biotransformation reactions?

A
  • Phase I - oxidation, reduction, hydrolysis
  • Phase II - conjugation or synthesis
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37
Q

Where can drugs be stored in the body?

A
  • Fat - lipid soluble drugs, environmental chemicals, anesthetics
  • Bone - tetracyclines (and other calcium replacement), metals (lead)
  • Kidneys - aminoglycosides, cephalosporins
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38
Q

What are microsomal enzymes and what is their role?

A
  • Located in smooth ER
  • Catalyzes biotransformations
  • To be metabolized by microenzymes, substrates must be hydrophobic
  • Acetaminophen, ethanol –> metabolized by CYP 2E1
  • Different types: MFO, CYP
  • Activity is inducible:
  • Tobacco smoke induces CYP 1A2
  • Ethanol –> CYP 2E1
  • Antiepileptic drugs –> CYP 3A4
  • Grapefruit juice –> inhibits CYP 1A2 + 3A4
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39
Q

What reactions are catalyzed by microsome enzymes?

A
  • Side chain/alkyl hydroxylation
  • Aromatic ring hydroxylation
  • N-/O-/S- demethylation
  • Oxidative deamination
  • Sulfoxide formation
  • N-oxidation or hydroxylation
  • Dehalogenation
  • Glucuronide formation
  • Reduction of nitro and azo groups
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40
Q

What are non-microsomal enzymes?

A
  • Located in the cytosol, mitochondria, blood (esterases)
  • Activity is generally not inducible
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41
Q

What reactions are catalyzed by non-microsomal enzymes?

A
  • Alcohol/aldehyde dehydrogenase
  • MAO
  • Esterases
  • Amidases
  • Conjugations of sulfate, acetylation, glycine, methylation, glutathione
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42
Q

What factors affect the rate of biotransformation?

A
  • Enzyme activity inducers (drugs, smoking, etc.)
  • Enzyme inhibitors
  • Age
  • Liver function
  • Nutritional state
  • Genetics (polymorphisms)
  • Gender
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43
Q

What is hepatic excretion?

A

Path:
1. Absorption
2. Portal vein/general circulation, hepatic artery
3. Sinusoid in liver
4. Hepatocyte
* Back to blood
5. Bile canaliculus
6. Bile ductule
7. Gallbladder
* MW = 0-220 –> urine
8. MW = 300+ –> bile
9. Small intestine
* Enerocyte to liver (again) - enterohepatic cycle
* General circulation
* Excretion

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44
Q

What is renal excretion?

A
  1. Filtration of drugs through pores in glomerular capillary membrane
  2. Active transport of anionic and cationic forms of drugs in the proximal portion of the nephron
  3. Non ionic back diffusion of uncharged drugs occurs in the distal portion of the nephron
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45
Q

How is the effect of a drug related to blood concentration?

A
  • A change in [blood] = change in the effect of the drug
  • Usually, an increase in the dose = increase [plasma] = increase effects
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46
Q

What is the one compartment model?

A
  • 1 body = 1 compartment
  • Drug rapidly equilibrates between plasma and tissues
  • Change in [plasma] reflects a proportional change in [tissue]
  • On a semi-log plot, a one-compartment model is a straight line.
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47
Q

What is the two compartment model?

A
  • 1 body = 2 compartments (central and peripheral)
  • Drug takes longer to equilibrate
  • Elimination happens from central compartment
  • 2 phases: initial distribution phase and elimination phase
  • On a semi-log plot, the two compartment model is one line with 2 straight segments
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48
Q

What is first order kinetics?

A
  • Rate of decrease in [drug] is directly proportional to the amount of drug in the body
  • A constant fraction of drug is eliminated. The constant fraction is dose independent.
    • 10% of drug is eliminated per hour
    • Starts at: 100 mg
    • 1st hour: 90 mg
    • 2nd hour: 89 mg
    • 3rd hour: 80.1 mg
  • Most drugs follow first order kinetics
  • On a linear plot, first order kinetics are curved. (Semi-log plot, first order is linear)
  • C = (dose / Vd)e-kt
    • ke –> elimination rate constant
    • C –> concentration
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49
Q

What is zero order elimination kinetics?

A
  • Enzymes are saturated.
  • A constant amount of a drug is eliminated, independent of the dose
    • Example: 10 mg eliminated per hour
    • Starts at: 100 mg
    • 1 hour: 90 mg
    • 2 hours: 80 mg
    • 3 hours: 70 mg
  • On a linear plot, zero order kinetics is a straight line
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50
Q

What is bioavailability (F)?

A
  • Fraction of unchanged drug that reaches systemic circulation following administration
  • IV drugs have F = 1, all other drugs are less than (or equal to) 1.
  • To determine F:
    • Administer drug via IV and measure [plasma] over time
    • Administer same dose by different route and measure [plasma] over time
    • The area under the curve (AUC) is an index of the extent of the drug that enters the bloodstream and body
  • F = (AUCoral)/(AUCIV)
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51
Q

What is half-life of elimination (t1/2)?

A
  • The time for total plasma drug concentration to decrease by 50%, expressed in hours or minutes
    • After 1st half life - 50% remains
    • 2nd half life - 25% remains
  • Depends on both CL and Vd
  • Four half lives rule: A drug is considered essentially eliminated after 4 half lives (6% remains in body)
  • t1/2 = (ln 2)/(ke) = (0.693)/(ke)
  • Fraction of drug remaining = 1/2n, n = # half lives
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52
Q

What is the volume of distribution (Vd)?

A
  • The apparent volume that a drug is distributed within the body once an equilibrium is established between the tissue and plasma, expresses in L or L/kg body weight
  • Vd can be greater than total body weight
    • Warfarin Vd = 9 L (99% protein bound)
    • Thiopental Vd = 140 L
    • Morphine Vd = 245 L
  • Vd = (DoseIV) / (C0)
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53
Q

What is clearance (CL)?

A
  • The volume of blood from which a drug is totally removed in a given time, expressed as L/hr or mL/min
  • Due to metabolism and excretion
  • If Vd remains constant and t1/2 increases, then CL will decrease
  • CL = (ke)(Vd)
    • ke = (ln 2) / (t1/2
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54
Q

How is plasma concentration related to the dose?

A
  • Following a single dose administration, the [plasma] is proportional to the dose administered
  • A = (C)(Vd)
    • A = dose administered, C = concentration
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55
Q

What is steady state concentration (CSS)?

A
  • The average [plasma] when a balance is achieved between drug intake and elimination
  • To achieve CSS, a drug must be given at regular intervals
  • It takes 4 half lives to attain CSS
  • CSS = (MD) / (CL)
    • MD = maintenance dose
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56
Q

What are maintenance doses (MD)?

A
  • Drugs are often given for intervals of 7-10+ days.
  • During this time, [drug] has peaks and troughs
    • Peaks - highest concentration
    • Troughs - lowest concentration, right before next dose
  • The longer the dosing interval, the greater the variation between the peak and trough values
  • ** MD = (dose * F) / (dosing interval) = CSS * CL**
  • If drugs are given via IV, substitute MD for infusion rate.
    • ** CSS = (Infusion rate) / (CL)**
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57
Q

What is a loading dose?

A
  • A single large dose, administered via IV, given to achieve CSS in a short period of time
  • Loading dose is followed by an MD to maintain CSS
  • **Loading dose = (CSS * Vd) / F
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58
Q

What is a dose-response relationship?

A
  • Dose: the amount of drug administered
  • Response: a change in biological activity
  • Dose response relationship: relationship between amount of drug administered and observed changes in biological function
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59
Q

What are the two receptor response theories?

A
  1. Occupation theory: magnitude of a response is proportional to the number of receptors occupied by a drug
  2. Rate theory: magnitude of a response is proportional to the rate of formation of the drug-receptor (D-R) complex
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60
Q

What is a dissociation constant? What is affinity?

A
  • Dissociation constant (KD): the tendency of a substance to reversibly dissociate in a solution
    • KD = (k2) / (k1)
    • k’s are association rate constants
  • Affinity: the ability of a drug to bind to a receptor
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61
Q

What is intrinsic activity? Efficacy? Potency?

A
  • Intrinsic activity: ability of a drug to produce a biological effect
  • Efficacy: maximal effect produced by a drug
  • Potency: determined by the dose needed to produce a particular effect of a given intensity
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62
Q

What do specificity and selectivity mean?

A
  • Specificity: ability of a drug to act through a single mechanism of action
  • Selectivity: ability of a drug to induce one effect in preference to another effect
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63
Q

On a logarithmic-dose graph, with % efficacy on the y-axis and dose on the x-axis, what can you deduce about agonist drugs?

A
  • An increase in efficacy is up the y-axis
  • An increase in potency is to the left on the x-axis
  • Partial agonists will not reach the same efficacy (same height on the y-axis) as full agonists
  • The most potent drug will be furthest to the left.
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64
Q

What are the two types of antagonists?

A
  1. Competitive
    * Maximum efficacy remains the same
    * Curve shifts to the right (lower potency)
  2. Non competitive
    * Maximum efficacy decreases (shift down)
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65
Q

What are agonist vs antagonist drugs?

A
  • Agonist: a drug with affinity and intrinsic activity
  • Antagonist: a drug with affinity, but no intrinsic activity. Decreases either the potency or the efficacy of an agonist
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66
Q

What is the difference between grades and quantal dose response relationships?

A
  • Graded: a drug’s concentration vs magnitude of effect in a single individual
    • The y-axis can go above 100%, because it shows the increase in desired effect of a single individual
  • Quantal: a drug’s concentration vs the percent of people in a population who experience a certain level of effect (e.g., can sleep)
    • The y-axis cannot go above 100% because you can’t have more than 100% of the population experiencing something
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67
Q

What is an ED50? What is an LD50?

A
  • ED50 (median effective dose): dose required to produce a therapeutic effect in 50% of test subjects
  • LD50 (median lethal dose): dose required to produce death in 50% of test subjects
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68
Q

What are therapeutic indexes? What is a certain safety factor?

A
  • Therapeutic index or ratio (TR or TI): the difference in an effective dose and a toxic dose
    • TI = (LD50) / (ED50)
  • Certain safety factor (CSF) = (LD1) / (ED99)
    • If CSF > 1, then no overlap between the therapeutic and toxic curves
    • If CSF < 1, then the therapeutic and toxic curves overalp
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69
Q

What are the three decreased dose response relationships?

A
  • Tolerance: decrease in efficacy with repeated drug administration (e.g., narcotics)
  • Tachyphylaxis: acute tolerance to rapid, repeated drug administration (e.g., nitroprusside)
  • Resistance: a decrease or complete lack of responsiveness to drugs that normally inhibit growth or cause cell death (e.g., chemotherapeutics)
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70
Q

What are the three increased dose response relationships?

A
  • Additive effect: the total effect equals the sum of the effects of drug A + drug B
    • Cancer chemotherapeutic agents
  • Synergy: the total effect > effects of drug A + drug B
    • Penicillin + Amino glycoside
  • Potentiation: drug A has little to no intrinsic activity, but increases the effects of drug B.
    • Cocaine + NE
    • Moves dose response curve to the left
71
Q

What is pharmacokinetics vs pharmacodynamics?

A
  • Pharmacokinetics: what the biological system does to the drug (absorption, distribution, etc.)
  • Pharmacodynamics: what the drug does to the biological system (mechanism of action, effects, etc.)
72
Q

What are inverse agonists?

A
  • Inverse agonists are agents that stabilize a receptor in its inactive conformation
  • Losartan - AngII receptor blocker
  • Famotidine - H2 receptor blocker
73
Q

How are receptors classified?

A
  • Receptors are classified based on the effects and potencies of select agonists/antagonists, and on molecular biology
  • Cholinergic receptors
    • Nicotinic & Muscarinic (M1-4)
  • Adrenergic receptors
    • Alpha (A1, A2) & Beta (B1-3)
74
Q

What are the four general drug-effector mechanisms?

A
  1. Membrane receptors associated with enzymes
  2. Intracellular receptors
  3. Receptors on membrane ion channels
  4. Receptors linked to effectors via G-proteins
75
Q

What are some types of enzyme-associated receptors?

A
  • Protein kinases (e.g., tyrosine kinases)
    • Insulin, growth hormones
  • Protein kinase-associated receptors
    • Cytokines, interferon gamma receptors
  • Guanylyl cyclase
    • Membrane bound (ANP, BNP), soluble (nitric oxide)
76
Q

What are some key principles of receptors on ligand-gated ion channels?

A
  • Includes receptors for several neurotransmitters
    • Nicotinic ACh, GABAA, Glutamate, Aspartate, Glycine
  • Alters ion movement across cell membrane
  • Alters membrane electrochemical potential
77
Q

What are some key principles of intracellular receptors?

A
  • Ligand must be hydrophobic and able to passively diffuse through cell membranes
  • Once bound to the receptor, usually DNA transcription is altered to increase or decrease the rate of protein synthesis
  • Examples: steroids, retinoids, thyroid hormones
78
Q

What are some key principles of G-protein coupled receptors?

A
  • GCPRs are the largest superfamily of receptors
  • GCPRs have 7 helical domains that span the membrane
    • On the outside, they bind the ligand
    • On the inside, they bind a G-protein, with alpha, beta, and gamma subunits
    • The alpha unit contains a GTP binding site.
  • To trigger a G-protein signal transduction:
    1. A ligand binds to the extracellular portion of the GCPR.
    2. The intracellular G-protein undergoes a conformational change.
    3. The alpha subunit swaps its bound GDP for a GTP.
    4. The G-protein dissociates into a beta-gamma subunit and an alpha subunit.
    5. The alpha subunit triggers a cascade to carry and amplify the “message”
79
Q

What are the types of G-proteins? What activates them (receptor type), what is the effector, what is the second-messenger response and what is the final result?

A
  • Gq
    • M1, M3, A1, serotonin
    • Activates Phospholipase C
    • Increases IP3 and DAG
    • Increases Ca2+ and protein kinase activity
  • Gs
    • B-adrenergic, D1, histamine
    • Stimulates adenylyl cyclase
    • Increases cAMP
    • Increases Ca2+ influx and enzyme activity
  • Gi
    • A2, M2, opioids
    • Inhibits adenylyl cyclase
    • Decreases cAMP
    • Decreases Ca2+ influx and enzyme activity
    • Increases K+ efflux
80
Q

What is cAMP and how is it used?

A
  • Made by adenylyl cyclase
    • 1 active AC = multiple cAMP produced
  • Regulates activity of PKAs
    • PKAs can phosphorylate targets such as insulin, glucocorticoid receptor, etc.
  • Inactivated by PDE (phosphodiesterase)
81
Q

What is cGMP and how is it used?

A
  • Made by different forms of guanylyl cyclase (GC)
    • Nitric oxide stimulates soluble GC
    • Natriuetic peprides + guanylins stimulate particulate GC (membrane spanning)
  • Regulates activity of PKGs
  • Important effects: smooth muscle relaxation, platelet inhibition
82
Q

What is Ca2+ and how is it used?

A
  • Both cAMP and cGMP can activate ligand gated channels for Ca2+
  • PLC (phospholipase C) cleaves PIP2 into DAG and IP3
    • DAG –> activates PKC
    • IP3 –> releases Ca2+ from the ER
  • Changes in [Ca2+] and activation of PKC regular many cellular functions
83
Q

What is desensitization (down-regulation)?

A

Long term administration of agonist –> continuous stimulation –> tachyphylaxis and tolerance

84
Q

What is supersensitization (up-regulation)?

A

Long term administration of an antagonist –> chronic reduction of receptor stimulation –> super response

85
Q

What are some examples of non-receptor mediated drugs?

A
  • Antacids: CaCO3, Al(OH)3, Mg(OH)2
  • Osmotic diuretics: Mannitol (laxative)
  • Cholesterol binding resins: WelChol
  • Antibiotics (have target receptors in bacteria but not in humans)
86
Q

What is precision medicine?

A
  • Medical care based on specific biological characteristics of the disease process in individuals
  • First case- breast cancer
    • Treatment (Herceptin) interfered with the overexpression of HER2 gene that was causing the cell proliferation and cancer
    • Other treatments just targeted all the cells as a whole, rather than the specific element of a cell causing the cancer
87
Q

What is genomics?

A

The study of the structure, content and evolution of genomes

88
Q

What are some sources of genetic differences?

A
  1. Length polymorphisms - insertions/deletions (indels), microsatellites
  2. Sequence variation - SNPs
89
Q

What are loci? Alleles?

A
  • Loci (locus): a single position on a chromosome (may be that of an allele, gene, segment, etc.)
  • Alleles: alternate “forms” of DNA at a specific locus
    • “Forms”: sequence variations, length polymorphisms, protein expressions, etc.
90
Q

What is homozygous vs heterozygous?

A
  • Homozygous: 2 identical alleles at a given locus
  • Heterozygous: 2 different alleles at a given locus
91
Q

What is a genotype vs phenotype?

A
  • Genotype: genetic constitution of an organism
  • Phenotype: observable physical properties
92
Q

What is dominant vs recessive? What is a wildtype?

A
  • Dominant: heterozygote phenotype = homozygote phenotype
  • Recessive: heterozygote phenotype is not the same as the homozygote phenotype
  • Wildtype: most common phenotype
93
Q

What are genetic polymorphisms?

A
  • The presence of 2+ alleles at a given locus for a population
  • More alleles = more polymorphism = more chance an individual is heterozygous for that locus
94
Q

What are cytochrome P450 (CYP) proteins and what are they responsible for?

A
  • CYPs are the most common drug metabolizing enzyme in humans
  • CYPs are responsible for:
    • synthesis of cholesterol, steroids, prostacyclins, thromboxane A2, and other important lipids
95
Q

What is allelic vs locus heterogeneity?

A
  • Allelic heterogeneity: two or more different alleles (genetic variants on the same gene) that result in the same phenotype
  • Locus heterogeneity: two or more different genes result in the same phenotype
96
Q

What types of mutations are CYP3A4 *1S\, *6\, and *20\?

A
  • *1S\ –> deletion of AT, loss of function
  • *6\ –> insertion of A, frameshift
  • *20\ –> insertion of A, frameshift
97
Q

When given the location of a gene, how do you read the location?
Example: 7q22.1

A

7th chromosome, q = long arm, region 22.1

98
Q

When given the variant or mutation of a gene, how do you read it?
Example: CYP3A4*1B\ is the allele, with a gene variation of -392A>G

A
    • means upstream of the gene
  • 392 is the number of base pairs
  • Most have A nucleotide base, but some have G
99
Q

What is the wildtype of the CYP3A4 allele?

A

CYP3A4 *1A\

100
Q

What is the codeine/morphine story, from absorption to elimination?

A
101
Q

What are phenocopies?

A
  • A variation in phenotype caused by environmental conditions (not genetics)
  • Example: Statins inhibit CYP 2D6 –> affects codeine/morphine pathway –> codeine has less of an effect
102
Q

What happens if someone has a mutation of CYP 2D6 and takes codeine?

A
  • No CYP2D6 (gene deletion) –> poor metabolizers –> codeine does not become morphine –> little to no pain relief
  • Lots of CYP2D6 (gene duplication) –> extensive metabolizers –> codeine quickly turns to morphine –> toxic levels of morphine
103
Q

When a person has a mutation, why is knowing if a drug is a prodrug or active agent important?

A
  • Extensive metabolizer
    • Prodrug –> super effect (toxic levels, turns active too quickly)
    • Active agent –> No effect (no response to the drug, it’s eliminated too fast)
  • Poor metabolizer
    • Prodrug –> No effect (isn’t turned into an active form)
    • Active agent –> Super effect (toxic levels, not eliminated efficiently)
104
Q

What are the three classes of pharmacogenes?

A
  1. Drug metabolizing enzymes (CYP)
  2. Drug transporters
  3. Drug targets
105
Q

What happens to a patient taking Warfarin if CYP 2C9 has reduced function?

A
  • CYP2C9: S-Warfarin (active) –> hydroxywarfarin (inactive)
  • Reduced function of CYP2C9 = Warfarin not eliminated = high exposure to active drug (toxic levels) = greater risk of bleeding
106
Q

What happens to a patient taking thiopurine drugs if TPMT has reduced function?

A
  • TPMT (thiopurine-S-methyltransferase): phase II enzyme that catalyzes S-methyltransferase of thiopurine drugs (inactives them)
  • Reduced function of TPMT = drug reaches toxic levels
107
Q

What happens to a patient taking Tamoxifen if CYP2D6 has reduced function?

A
  • Tamoxifen is a selective estrogen receptor modulator. It is the less active form of the drug
  • CYP2D6: Tamoxifen —> Endoxifen (more active form)
  • Reduced function of CYP2D6 = less response from drug
108
Q

What happens to a patient taking Simvastatin if SLCO1B1 has reduced function?

A
  • SLCO1B1 transports Simvastin to liver cells for metabolism
  • Reduced function of SLCO1B1 = takes longer to eliminate Simvastin, increases effects, greater risk of myopathy
  • Pt outcomes are more complicated to predict due to:
    • Multiple different transporters for a drug
    • Rarely do transporters or enzymes have a total loss of function (usually only partial loss)
109
Q

What happens to a patient if VKORC1 has an allele resistant to Warfarin?

A
  • S-Warfarin (active) inhibits VKORC1
  • VKORC1 plays a key role in the Vitamin K pathway (which partialy controls clotting)
  • If VKORC1 is resistant to Warfarin –> decreased Warfarin effect
110
Q

What are the three CYP3A5 SNPs? Three ABCB1 SNPs?

A
  • CYP3A5:
    • *3\ - transition substitution
    • *6\ - transition substitution
    • *7\ - insertion/deletion
  • ABCB1:
    • 1236 - silent
    • 2677
    • 3435 - silent
111
Q

What is Tacrolimus and what is its “story”? Why is the dosing closely monitored?

A
  • Tacrolimus (immunosuppressant): rapidly absorbed and extensively bound to erythrocytes in the blood stream
  • Highly metabolized in the liver and small intestines by CYP3A5
  • Genetic variation in CYP 3A5 –> causes variability in Tacrolimus clearance
112
Q

Why do silent site substitutions matter?

A
  • Silent site substitutions do not cause phenotype variation on their own
  • However, they are often part of a haplotype block and are closely linked with other mutations
  • Haplotype block - a set of DNA variations (polymorphisms) that tend to be inherited together
113
Q

What are eicosanoids?

A
  • Members of a family of oxygenated products of polyunsaturated long-chain fatty acids
  • Leukotrienes (LTs)
  • Prostaglandins (PGs)
  • Thromboxanes (TXs)
114
Q

What is arachidonic acid?

A
  • Most abundant and most important precursor of eicosanoids
  • Synthesized in liver from linoleic acid
  • 20 carbons with 4 unsaturated (double) bonds
115
Q

How are membrane phospholipids converted to LTs, PGs, and TXs?

A
  1. Membrane phospholipids are converted to arachidonic acid by phospholipase A2
  2. Arachidonic acid is converted to LTs by lipoxygenase, in a linear pathway
  3. Arachidonic acid is converted to PGs and TXs by PGH synthase (COX-1 and COX-2) in a cyclic pathway
116
Q

What is the basic lipoxygenas pathway?

A
  1. Arachidonic acid is converted to 5-HPETE by 5-lipoxygenase
  2. 5-HPETE —> LTA4
  3. LTA4 —> LTC4 by glutathione
    • Can also be converted to LTB4 by hydrolase
  4. LTC4 —> LTD4, LTE4
117
Q

What are the lipoxygenase products?

A
  • 5-HETE (5-HPETE), LTB4
    • Chemotactic agents
    • LTB4 can produce hyperalgesia
    • Human colonic epithelial cells synthesize LTB4. Patients with IBD have substantial amounts of LTB4.
  • LTC4, LTD4, LTE4
    • Chemoattractant for eosinophils
    • Potent bronchoconstrictors
    • Increase vascular permeability
    • Components of slow reacting substances of anaphylaxis
118
Q

What are the eicosanoid receptors that go with each lipoxygenase product?

A
119
Q

What drugs alter lipoxygenase products?

A
  • Zileuton: 5-Lipoxygenase inhibitor
  • Zafirlukast, Montelukast: Competitive LTD4 receptor antagonist
120
Q

What are the mechanism of action of Zafirlukast and Montelukast? What are they used for?

A
  • Competitive, reversible LTD4 receptor antagonist
  • Inhibits the LT mediated effects on bronchoconstriction and vascular permeability
  • Used for:
    • Prophylactic treatment for asthma
    • Allergic rhinitis
    • Aspirin sensitivity induced asthma (Montelukast only)
121
Q

Why do some asthmatic patients respond extensively to aspirin/NSAIDs?

A
  • 5-10% of people with asthma respond to very small doses of aspirin and NSAIDs
  • Results in bronchoconstriction and symptoms of systemic release of histamine, such as flushing and abdominal cramps
  • NSAIDs block the COX pathway, forcing arachidonic acids to shift to the lipoxygenase pathway and form LTs
  • Montelukast can be used in these patients
122
Q

What are the adverse effects and drug interactions for Zafirlukast?

A
  • Adverse effects:
    • Headache, pharyngitis
    • Increased liver enzymes - rare
  • Drug Interactions:
    • Inhibits CYP 3A4 and 2C9
    • Creates numerous drug interactions
123
Q

What are the drug interactions and contraindications for Zileuton?

A
  • 4-5% patients have elevated hepatic transaminase
  • Zileuton increases the response of: Theophylline, Warfarin, Propanolol
  • Contraindicated in liver disease
124
Q

What are COX-1, COX-2 and COX-3?

A
  • COX-1
    • Constitutive form
    • House keeping functions, always present, widely distributed
  • COX-2
    • Inducible form
    • Elevated by inflammation and cytokinds
    • Immediate early response gene product in inflammatory/immune cells
  • COX-3
    • New isoform
125
Q

What is the mechanism of action of prostanoid?

A
  • Acts localy, short half life
  • Activates G proteins (increase cAMP, decrease Ca2+) OR phosphatidylinositol metabolism (increase Ca2+)
  • Major effects are on four types of smooth muscle - vascule, gastrointestinal, airway, reproductive
126
Q

How does PGI2 (Prostacyclin) affect different body systems?

A
  • Vascular
    • Powerful vasodilator
  • Platelet
    • Inhibits platelet aggregation by all recognized agonists
  • Airway
    • Powerful bronchdilator
    • Used clinically to treat pulmonary and portopulmonary hypertension
  • GI
    • Inhibits gastric acid secretion
    • Increases mucus secretion
  • Renal
    • Increases GFR and renal blood flow
    • Increases water and sodium excretion
  • Reproductive
    • Relaxes uterine muscles
  • Pain
    • Induces pain
  • Receptors
    • IP (Gs - increases cAMP)
127
Q

How does PGE2 (Prostaglandin) affect different body systems?

A
  • Vascular
    • Vasodilator
  • Platelet
    • At low concentrations - enhances platelet aggregation
    • At high concentrations - inhibits aggregation
  • Airway
    • Powerful bronchdilator
  • GI
    • Inhibits gastric acid secretion
    • Increases stomach mucus secretion
  • Renal
    • Increases GFR and renal blood flow
    • Increases water and sodium excretion
  • Reproductive
    • Contracts uterine muscles
  • Pain + fever
    • Induces pain
    • Induces fever
  • Receptors
    • EP1-EP4 (Gs, Gq)
128
Q

How does TXA2 (Thomboxane) affect different body systems?

A
  • Vascular
    • Potent vasoconstrictor
  • Platelet
    • Major product of platelet COX-1
    • Stimulates platelet aggregation
  • Airway
    • Bronchoconstrictor
  • Renal
    • Intra-renal vasoconstriction
    • Decline in renal function
  • Reproductive
    • Contracts uterine muscles
  • Receptors
    • TP (Gq-PLC)
129
Q

How does PGF2a (Prostaglandin F2a) affect different body systems?

A
  • Vascular
    • Vasoconstrictor
  • Airway
    • Contacts airway smooth muscle
  • Reproductive
    • Contacts uterine muscles
  • Eye
    • Decreases intraocular pressure
  • Receptors
    • FP (Gq-PLC)
130
Q

What are the clinical uses of Misoprostol (PGE1)?

A
  • Adjunct to NSAID therapy - to reduce ulcer formation
  • Inhibits gastric acid secretion
  • Contraindicated in pregnancy - may cause contractions
131
Q

What are the clinical uses of Latanoprost (PGF2a)?

A
  • Ophthalmic preparation
  • Used for open angle glaucoma to lower intraocular pressure
132
Q

What are the clinical uses of Alprostadil (PGE1)?

A
  • Temporarily maintains patent ductus arteriosus in newborns until surgery can be don
  • Improves blood oxygenation
133
Q

How do PGs play a role in fetal development?

A
  • Ductus arteriosus (DA) in fetus carries blood from pulmonary artery to aorta (since lungs are collapsed before birth)
  • PGE2/1 and PGI2 keep the DA open in the fetus
  • After birth, PGE2/1 and PGI2 decrease, and the DA closes
  • If the DA does not close, Indomethacin can be used
  • If the DA must be kept open for surgery, Alprostadil is used
134
Q

What are the common therapeutic uses for aspirin and traditional NSAIDs?

A
  • Antipyretics - inhibit PG synthesis in hypothalamus to lower temperature
  • Analgesics - reduction of mild to moderate pain associated with inflammation
  • Good anti inflammatory properties - inhibits PG synthesis in localized areas
135
Q

What are the common side effects associated with aspirin and tNSAIDs?

A
  • Increased risk of GI ulcers and pain
  • Increased risk of bleeding
  • Inhibits PG mediated effects in the kidney, causing sodium and water retention
  • Aspirin - hypersensitivity
136
Q

What are the drug interactions of aspirin and tNSAIDs?

A
  • ACE inhibitors
  • Glucocorticoids
  • Warfarin
137
Q

What is the mechanism of action of aspirin?

A
  • Irreversible inhibitor of COX 1 and COX 2
  • Acetylates the enzymes (Ser 530 in COX-1 and Ser 516 in COX-2)
  • Irreversibly inhibits platelet COX-1
138
Q

What are the traditional NSAIDs?

A
  • Ibuprofen, Naproxen - Proponic acid derivatives
  • Ketorolac - Heteroarylacetic acid derivative
  • Diclofenac - Phenylacetic acid derivative
  • Indomethacin - indole derivative
  • Celecoxib - selective COX-2 inhibitor
139
Q

Ibuprofen and Naproxen

  1. Mechanism of action
  2. Use
A
  1. Competive, reversible active site inhibitors of COX-1 and COX-2
    • Both: analgesic, antipyretic, anti inflammatory, treats symptoms of rheumatoid and osteoarthritis
    • Ibuprofen: fever, dysmenorrhea, acute migraines
    • Naproxen: acute gout, ankylosing spondylitis (spine joint pain)
140
Q

Ketorolac

  1. Use
  2. Adverse reactions
  3. Contraindications
A
  1. Seasonal allergy, recovery from cataract surgery, analgesic
  2. GI bleeding, ALT/AST level change, elevated creatinine
  3. Do not use : with history of peptic ulcer or GI bleeding, with other NSAIDs, in renal disease, during labor/delivery or lactation. Stop using before surgeries
141
Q

Diclofenac

  1. Uses
  2. Adverse effects
  3. Combination drug
A
  1. Rheumatoid, osteoarthritis, ankylosing spondylitis, primary dysmenorrhea, for postoperative pain and inflammation following cataract surgery
  2. GI pain, nausea, cramps, diarrhea, modest elevation of ALT in plasma
  3. Diclofenac + Misoprostol = Arthrotec - used in patients with a risk of gastric or duodenal ulcers
142
Q

Indomethacin

  1. Uses
  2. Adverse effects
  3. Contraindications
A
    • Oral: acute gouty arthritis, rheumatoid and osteoarthritis, tendinitis, ankylosing spondylitis
    • IV: Closes DA in newborns
  2. GI pain, severe frontal headache, displacement of bilirubin from albumin, decreased urine output
  3. Hyperbilirubinemia, renal failure
143
Q

Celecoxib

  1. Mechanism of action
  2. Uses
  3. Drug interactions
  4. Adverse effects
  5. Positives to using it
A
  1. Selective COX-2 inhibitor (less effect on COX-1)
  2. Rheumatoid and osteoarthritis, primary dysmenorrhea, ankylosng spondylitis
  3. Metabolized by CYP 2C9 (interacts with drugs that inhibit CYP 2C9), inhibits CYP 2D6
  4. GI pain (high dose), nausea
  5. Lower incidence of GI pain compared to other NSAIDs
144
Q

What are some general considerations for the use and selection of NSAIDs?

A
  • All have basically same mechanism, but different sensitivities to COX inhibition
  • If sensitive to aspirin, do not use NSAIDs
  • Most common side effect is GI bleeding and ulceration
  • Do not use in last trimester of pregnacy (premature closure of DA, increased uterine bleeding during delivery, inhibits uterine motility)
  • Do not combine NSAIDs
  • Switch between dose and type of NSAID used
145
Q

How do prostaglandins affect the kidney?

A
  • PGI2 and PGE2: increase GFR and renal blood flow
  • PGE2: inhibits Cl- reabsorption

(NSAIDs lower PGs)

146
Q

How do prostaglandins affect hyperkalemia and water retention?

A
  • PGE2: inhibits effects of ADH
  • PGI2 and PGE2: stimulates renin release

(NSAIDs lower PGs. This causes water retention and K+ retention)

147
Q

Acetaminophen

  1. Mechanism of action
  2. Drug interactions
  3. Adverse effects
  4. Uses
A
  1. Weak COX-1 and COX-2 inhibitor, acts on peroxide site of enzyme, exact mechanism unknown, possibly modifies COX-3
  2. Alcohol
  3. Hepatic toxicity - #1 cause of drug induced liver failure in US
  4. Antipyretic, analgesic, weak anti inflammatory agent
148
Q

What are DMARDs?

A
  • Immune modulators believed to restore normal immune environment within the joint synovium
  • Used for active rheumatoid arthritis when not responding to NSAID treatment
  • Prevents joint damage and preserves structure/function of joints
149
Q

How do DMARDs compare to NSAIDs?

A
150
Q

What are the major regions of the adrenal gland?

A
  • Medulla
    • Inner section produces Epi and NE
  • Cortex
    • Zona glomerulosa - Aldosterone
    • Zona fasciculata & Zona reticularis - Cortisol, androgens
151
Q

How are steroids synthesized?

A
  • Cholesterol is building block
  • Biosynthesis occurs in zona fasciculata and zona reticularis
152
Q

What do mineralocorticoid receptors (MR) do?

A
  • Upregulates Na+K+ATPase, which regulates Na+ handling by the kidney
  • Promotes hypertension
153
Q

How is the HPA axis and cortisol production regulated?

A
  • Cortisol levels are regulated by circadian rhythm (high in morning, low in afternoon/night)
  • Hypothalamus produces CRH, which stimulates ACTH
  • ACTH promotes cortisol production in adrenal gland
  • Regulated by feedback loops
154
Q

What do Glucocorticoids do?

A
  • Nervous System
    • Bad for Psychiatric disorders
  • Cardiovascular System
    • Bad for CV disease
  • Immune System
    • Good for organ transplants
  • MSK System
    • Good for rheumatoid arthritis
    • Bad for osteoporosis
  • Visual System
    • Good for Uveitis, Keratitis
    • Bad for Glaucoma
  • Respiratory System
    • Good for asthma and COPD
  • Glucose & liver metabolism
    • Bad for obesity and hyperglycemia
  • Reproductive System
    • Good for preterm birth
    • Bad for Gonadal virilization
  • Integumentary System
    • Good for Psoriasis and Eczema
155
Q

What happens if you have excess or low glucocorticoids?

A

Excess - Cushing’s Syndrome
Low - Addison’s Disease

156
Q

What are the main non-endocrine uses for glucocorticoids?

A
  • Increases lipcortin levels by inhibiting phospholipase A2 activity
  • Reduces NF-kappa B levels, which leads to reduced levels of:
    • Proteolytic enzymes
    • Vasoactive enzymes
    • Chemotractant cytokines
    • COX-2
    • NOS
157
Q

What are the absorption, transport and metabolism properties of glucocorticoids?

A
  1. Absorption
    • Many orall active
    • Water soluble esters given via IV to give rapid high concentrations
    • More prolonged effect when given IM
    • Absorption from local sites is possible
  2. Transport
    • 90% cortisol in plasma is protein bound by CBG and albumin
  3. Metabolism
    • Hepatic conjugation with glucoronides/sulfates
    • First pass effect varies
    • Renal excretion
158
Q

What are the routes of administration for glucocorticoids, and which drugs use which routes?

A
159
Q

How can you reduce the long-term effects associated with glucocorticoids?

A
  • Use short term
  • Use highly localized
  • Reduce withdrawal effect by tapering off dose after prolonged therapy
160
Q

What are some of the symptoms of Cushing’s Syndrome?

A
161
Q

What are the withdrawal effects of glucocorticoids?

A
  • Long term use suppresses HPA axis
  • Decreased ACTH induced coritsol secretion
  • Leads to secondary adrenocortical insufficiency
162
Q

What are some general therapeutic uses for glucocorticoids?

A
  • Rheumatic disorders
  • Rheumatoid arthritis
  • Respiratory diseases, like asthma and COPD
  • Allergies
  • Respiratory distress syndrome
  • Inflammatory dermatoses
  • COVID-19 (low dose dexamethasone recommended for patients on ventilator)
163
Q

What are the contraindications and precautions for using corticosteroids?

A
  • Pregnancy, breast feeding - potential for growth and development inhibition
  • Can mask viral and fungal infections
  • Congestive heart failure or hypertension
  • Can induce osteoporosis, long bone fractures, femoral/humoral necrosis
  • Can exacerbate psychiatric disorders
164
Q

What are the drug interactions for corticosteroids?

A
  • Can induce CYP 3A4 and reduce levels of other drugs (estrogens, antivirals, etc.)
  • Hepatic microsomal enzyme induces will promote metabolism
  • Estrogens increase CBPs, which increases the half-life but reduces the free concentration of corticosteroids
165
Q

Is atropine an agonist or antagonist? Of what receptor?

A

Antagonist for muscarinic acetylcholine receptor

166
Q

Is propanolol an agonist or antagonist? Of what receptor?

A

Antagonist for beta adrenergic receptor

167
Q

Is muscarine an agonist or antagonist? Of what receptor?

A

Agonist for muscarinic

168
Q

Is isoproterenol an agonist or antagonist? Of what receptor?

A

Agonist for beta adrenergic receptor

169
Q

Is buspirone an agonist or antagonist? For what receptor?

A

Partial agonist for serotonin receptor

170
Q

Is losartan an agonist or antagonist? For what receptor?

A

Inverse agonist for AngII receptor (blocker)

171
Q

Is famotidine an agonist or antagonist? For what receptor?

A

Inverse agonist for H2 receptor (blocker)

172
Q

Insulin (T2DM) and Imatinib act on what family of receptors?

A

Protein kinases (receptors as enzymes), specifically inhibiting tyrosine kinases

173
Q

What family of receptors do Glibenclamide and minoxidil act on?

A

Ligand-gated ion channels

Pharmacology - PMC 621 (3 decks)

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