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DD & BL Unit 1 > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Preclinical drug testing

A

In vitro studies to determine a lead compound from biologic products or chemical synthesis, followed by animal testing to determine efficacy, selectivity, and mechanism of drug action as well as safety concerns including dosing, toxicity, and mutagenicity

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2
Q

Phase I new drug testing

A

20 - 100 healthy patients; intended to determine pharmacokinetics in humans, safe & effective dosing, and toxicity

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3
Q

Phase II new drug testing

A

100 - 300 patients with disease; Investigational New Drug (IND) application describes the specific disease (indication); single blind comparison to placebo or established treatment

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4
Q

Phase III new drug testing

A

1,000 - 3,000 patients with disase; double blind, randomized trial to control for placebo effect and observer bias; approval of New Drug Application (NDA), FDA allows sale as Rx or OTC agent approved for specific indications

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5
Q

Phase IV new drug testing

A

Postmarketing surveillance of drug effects under actual conditions of use in a large number of patients; monitors rare & serious side effects

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6
Q

Dietary Supplement Regulation

A

According to the DSHEA Act of 1994, dietary supplements do not need to be tested for safety / efficacy by the FDA; any health claims made on the label must include disclaimer “not evaluated by FDA, not intended to prevent, diagnose, or treat” but burden to show unsafe lies on FDA

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7
Q

Generic equivalency

A

Bioequivalent drug products are pharmaceutical equivalent drug products (same active ingredient, same dosage formulation, same ROA, same strength / concentration) that also display the same biologic effects (rate and extent of absorption into plasma)

Generic product is bioequivalent to brand name if Cmax, Tmax, and AUC are equivalent

It is assumed that, in the absence of other evidence, bioequivalence = therapeutic equivalence

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8
Q

Pharmaceutical equivalents vs. Pharmaceutical Alternatives

A

Pharmaceutical equivalents - same active ingredients, same dosage formulation, same ROA, same strength/concentration

Pharmaceutical alternatives - same therapeutic moiety but different preparation or dosage formulation (oral vs. IV, rapid vs. extended release)

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9
Q

Controlled Substance Regulation (Federal & Colorado)

A

The Controlled Substances Act requires DEA licensing to prescribe controlled substances:

Schedule I - no accepted medical use, high abuse potential, cannot be prescribed
Schedule II - accepted medical use, high abuse potential; Rxs must be hand written in prescriber’s hand writing, cannot be telephoned to pharmacist, cannot be re-filled
Schedule III, IV, and V (in Colorado) may be telephoned to pharmacist and re-filled up to 5 times in 6 months

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10
Q

Oral ROA Considerations

A

Bioavailability (AUCoral / AUCiv) can vary from 0 to 100%

Weak acids are absorbed better in the stomach pH 1 - 2); weak bases are absorbed better in the upper intestine (pH 3 - 6)

Increased GI mobility increases speed of absorption by allowing drug to reach the greater surface area of the small intestine

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11
Q

Bioavailability (F)

A

Defined as the fraction of unchanged drug reaching systemic circulation following administration by any route

Described by the area under the curve (AUC) of a graph of Cp vs. time obtained following a single dose given by any route, compared to the graph following a single dose by IV

F = AUCroute / AUC iv

Generally only a consideration for oral ROA; most other ROAs have bioavailability approaching 100%

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12
Q

Volume of Distribution (Vd)

A

Describes the size of the compartment necessary to account for the total amount of drug in the body if present at the same concentration as in plasma

The greater the tendency for a drug to remain in the plasma, the smaller the value of Vd

Vd = Dose / Cp

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13
Q

Phase 1 Metabolism

A

CYP450 enzymes catalyze oxidation reactions on lipid-soluble molecules to increase solubility

Other reactions: reduction, hydrolysis (mediated by esterases, amidases, etc.)

Mostly occurs within the smooth ER of liver cells

Phase I enzymes are subject to induction / inhibition

Genetic polymorphisms exist; individuals may be ultrarapid metabolizers or poor metabolizers

CYP3A4 participates in the phase I metabolsim of 50% of all commonly used drugs

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14
Q

Phase II Metabolism

A

Mainly conjugation reactions carried out by transferase enzymes, ex: glucuronyl transferase, N-acetyltransferase, glutathione transferase, sulfotransferase

Tends to increase ionization and increase size

Pathways are generally saturable due to limited supply of conjugation reactants

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15
Q

Induction of Phase I drug metabolism

A

Inducers are generally TFs that increase production of CYP enzyme protein; generally takes 48 - 72 hours to see effect

Examples of inducers: Rifampin, ethanol, St. John’s Wort, Tobacco smoke, phenytoin, phenobarbital

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16
Q

Enterohepatic Recirculation

A

Drug and metabolites with MW > 300 may be absorbed into portal circulation, stored in the gallbladder, excreted via the bile duct and delivered to the intestines where it is reabsorbed and returns to the liver; this process reduces drug elimination and prolongs duration of action by keeping the drug in the body but out of the plasma

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17
Q

Drug Clearance (CL)

A

CL is defined as the volume of plasma (Vd) that is completely cleared of drug in a given period of time by all processes

Clearance is proportional to the elimination constant

Hepatic clearance varies with blood flow to the liver and hepatic metabolic activity; renal clearance varies with kidney function, necessitating “renal dosing”

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18
Q

Half Life (t 1/2)

A

The time required to eliminate 1/2 of the drug present in the body, regardless of total amount

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19
Q

Elimination constant (Ke)

A

The fraction of drug leaving the body, per unit time, via all elimination processes

Ke is the slope of the B elimination phase in a graph of ln Cp vs. time

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20
Q

First order elimination kinetics

A

Rate of drug elimination is proportional to the concentration of the drug in the plasma

Virtually all drugs are eliminated by first order elimination kinetics at therapeutic dosage levels

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21
Q

Zero order elimination kinetics

A

The rate of elimination of a drug from the body is independent of the amount of drug in the body; most often occurs due to saturation of hepatic metabolic processes (i.e. Phase II conjugations)

Occurs at therapeutic doses for aspirin, ethanol, and with toxic doses for many hepatically eliminated drugs

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22
Q

Dose fluctuation

A

Depends on the number of drug half-lives within the dosing interval (tau)

Magnitude of fluctuation is given by 2 ^ n where n = number of half-lives in the dosage interval

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23
Q

Dose-response curve

A

Plots the percent of the maximum response possible (e/Emax) on the y-axis vs. dose (D) on the x-axis

Hyperbolic curve is relatively linear at low doses indicating that, below EC50, response is proportional to dose

Curve is level at high doses indicating that dose-response is saturable

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24
Q

Drug Potency

A

The plasma concentration of a drug required to produce 50% of that drug’s individual maximum effect (EC50)

Depends on the affinity (Kd) of receptors for binding the drug

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25
Q

Maximal Efficacy / Power

A

Used to compare the efficacy of different drugs by comparing Emax values; full agonists have an Emax of 100% whereas partial agonists have an Emax < 100%

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26
Q

Competitive Reversible Antagonist

A

A class of pharmacological antagonist; binds reversibly to the active site of the same receptor as the agonist, blocking the agonist from binding and maintaining the receptor in its inactive conformation

Reduces apparent agonist affinity for receptor (decrease in EC50) because more drug must be administered in order to see the same effect; dose-response curve shifts to the right, Emax is unchanged

Ex: Metoprolol / Propanalol are competitive reversible antagonists of NE at beta 1 adrenergic receptors in the heart –> lowers HR

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27
Q

Noncompetitive Irreversible Antagonist

A

A class of pharmacological antagonist; binds irreversibly or pseudoirreversibly to the receptor active site, removing functional receptors from the system

Emax is reduced

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28
Q

Noncompetitive Allosteric Antagonist

A

A class of pharmacological antagonist; binds irreversibly to a different site on the receptor than the agonist, inhibiting the receptor from responding to an agonist

Emax is reduced

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29
Q

Physiological antagonist

A

Activates or blocks a different receptor than is bound by the agonist, usually mediating a physiologic response that is opposite to that of the action of the agonist at its receptor

Ex: The effect of histamine via histamine receptors to produce constriction of bronchiolar smooth muscle, and the antagonist action of epinephrine via adrenergic receptors to produce bronchiodialation when used in the treatment of anaphylactic shock

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30
Q

Chemical antagonist

A

Binds to the agonist directly, preventing its action

Ex: antacid neutralizing stomach acid

31
Q

Quantal dose-response curves

A

Plotted as the fraction of a population that experiences an all-or-nothing response at each dose of a drug vs. the log of the dose

ED50 refers to the dose at which half of the individuals experienced the all-or-nothing effect

32
Q

Therapeutic Index (TI)

A

The factor by which the dose that is effective in 50% of individuals (ED50) must be increased in order to cause death in 50% of individuals (LD50)

33
Q

Standard Safety Margin (SSM)

A

The percent by which the dose that is effective in 99% of the population (ED99) must be increased in order to cause death in 1% of the population (LD1)

Useful when patient response to a drug varies widely

34
Q

Mechanism of acetaminophen toxicity

A

Normally, 70 - 80% of Ac is conjugated through Phase II reactions and 5 - 10% proceeds through a phase I oxidation by CYP2E1, producing the chemically reactive Ac* metabolite which is further detoxified via Phase II

At toxic doses (> 4g/day), saturation of Phase II pathways shunts more Ac toward Phase I, producing higher levels of Ac* and leading to eventual depletion of cellular glutathione –> hepatotoxicity

Treatment: N-acetylcysteine serves as a precursor for glutathione synthesis and also functions as a nucleophile to capture Ac*

35
Q

Effect of alcohol on acetaminophen toxicity

A

Alcohol induces CYP2E1, causing increased production of Ac*, and also decreases hepatic glutathione, leading to greater hepatotoxicity

Chronic alcoholics should not exceed 2g/day

36
Q

Mechanism of methanol / ethylene glycol toxicity

A

Methanol is metabolized to formic acid, which causes visual disturbances followed by sudden death from respiratory suppression

Ethylene glycol is metabolized to oxalic acid, which causes kidney damage from calcium oxalate crystals leading to acute renal failure

Treatment: Giving ethanol to a BAC of .100 - ethanol competitively inhibits alcohol dehydrogenase, reducing production of toxic metabolites - or - administration of fomepizole, followed by hemodialysis to remove methanol / ethylene glycol and toxic metabolites; sodium bicarbonate to correct metabolic acidosis

37
Q

Aspirin

A

Mechanism: Irreversible inhibition of COX1 and COX2

Effects: Analgesic, Anti-pyretic, anti-inflammatory, anti-platelet

Side effects: GI, Bleeding, Renal, delayed Labor,

Other: Reyes syndrome (contraindicated in children with viral infection), hypersensitivity allergy in 5-10% of asthmatics

38
Q

Mechanisms of therapeutic uses of NSAIDS

A

Analgesia - inhibition of COX2 at sites of injury
Anti-pyresis - inhibition of COX2 in the hypothalamus
Anti-inflammatory - inhibition of COX2 at sites of inflammation
Anti-thrombogenesis - inhibition of COX1 in platelets

39
Q

Mechanisms of NSAID side effects

A

GI irritation (ulceration, bleeding, nausea) - inhibition of COX1 in gastric cells

Increased bleeding - inhibition of COX1 (TXA2) in platelets

Renal failure - inhibition of COX1 and COX2 in kidney cells

Delayed labor - inhibition of COX2 in uterine smooth muscle

Thrombosis - inhibition of COX2 (PGI2) in vascular endothelial cells

40
Q

tNSAIDS

A

i.e. Ibuprofen, Naproxen, etc.

Mechanism: Reversible inhibition of COX1 and COX2

Effects: Analgesia, anti-pyresis, anti-inflammation

Side effects: GI, bleeding, renal, delayed labor

41
Q

Acetaminophen

A

Mechanism: Inhibition of COX2 in the CNS

Effects: Analgesia, anti-pyresis; NO anti-inflammatory or platelet action

Side effects: Mild; minimal renal effects, safe in pregnancy

> 4g/day leads to hepatotoxicity; acute OD treated with N-acetylcysteine

42
Q

Celecoxib

A

Mechanism - Selective, reversible inhibition of COX2

Effects: Analgesia, anti-pyresis, anti-inflammation

Side Effects: Renal failure, increased thrombosis, delayed labor,

43
Q

COX1

A

Constitutively expressed

GI tract: decreases acid production, increases mucous and bicarbonate (cytoprotective)

Platelets - Pro-aggregatory (TXA2)

Kidneys: - increases renal blood flow, promotion of diuresis

Pain

44
Q

COX2

A

Expression is induced at sites of inflammation by cytokines

Hypothalamus - Fever (PGE2)

Pain

Vascular endothelium - vasodilation and platelet anti-aggregation (PGI2)

Inflammation

Uterine contraction

45
Q

Mechanism of Aspirin anti-platelet effect

A

Low dose aspirin is essentially selective for platelet COX1 because it inhibits irreversibly and platelets, which are anucleate, cannot synthesize new COX1 enzyme; TXA2 synthesis is inhibited, reducing clotting

The largest concentration of ASA is contained in the presystemic (portal) circulation where it can have a greater effect on circulating platelet COX1 (versus its effect on endothelial cell COX2) and so the anti-platelet effect of COX1 inhibition is amplified relative to the pro-aggregation effect of COX2 inhibition

46
Q

Legally required components of a prescription

A

Date

Prescriber name, address, professional degree, telephone number

Patient name, address

Drug name, strength, quantity, formulation

Dosage regimen, including amount of drug to be taken; time, frequency, and route of administration; duration of therapy

Refill information - one year limit on original prescription, regardless of # refills written

Prescriber signature, DEA number

47
Q

Factors affecting oral bioavailability

A

Ability of drug to survive in GI environment

Ability of drug to cross GI membranes (lipid solubility, size, % unionized)

Efficacy of drug metabolism by gut wall or liver (first pass effect)

Drug formulation (extended release vs. liquid)

48
Q

Considerations of rectal ROA

A

Useful when oral route is precluded by vomiting, unconsciousness, or GI injury/irritation

First pass metabolism is less than for oral ROA as approximately 50% of dose will bypass the liver

49
Q

Considerations of sublingual / buccal ROA

A

Venous drainage from the mouth is to the superior vena cava; therefore less first pass metabolism plus faster onset of action

Useful for drugs that are lipid soluble and relatively potent due to the smaller surface area for absorption

50
Q

Considerations of intramuscular ROA

A

Onset and extend of absorption affected by local blood flow at site of injection but can approach equivalence with IV route

Depot forms suspended in oil or other preparations exhibit slower, more sustained absorption

51
Q

Considerations of subcutaneous ROA

A

Usually provides slower, constant rate of absorption; rate of absorption can be intentionally altered by varying particle size, protein complexation, etc.

Only for non-irritating drugs

52
Q

Considerations of inhalation ROA

A

Systemic effects: Rapid and complete absorption due to large surface area and high blood flow in pulmonary tissue; comparable to IV

Local effects: Application of aerosolized particles at site of action in lungs; effect depends on particle size

53
Q

Considerations of Transdermal ROA

A

Systemic effects: Prolonged drug levels can be achieved for systemic effects; first pass metabolism is avoided

Local effects: Via skin or mucous membranes for treating inflammation, infection, etc. Generally minimal systemic absorption.

Drug must be potent, able to permeate skin sufficiently, non-irritating

54
Q

Where do tight junctions limit drug absorption?

A

GI mucosa - limits absorption of drug into blood through oral ROA

Blood Brain Barrier - limits distribution of drug from blood into brain

Placenta - limits distribution of drug from blood into fetal circulation

Renal Tubules - following filtration, limits reabsorption of drug back into the blood, enhancing excretion

55
Q

Clinical significance of ion trapping

A

Alteration of urinary pH to ion trap weak acids or bases and hasten renal excretion; i.e. alkalinization of urine can trap weak acid aspirin in overdose situations

Greater potential to concentrate basic drugs (i.e. opioids) in more acidic breast milk

56
Q

Plasma protein binding

A

Reduces concentration of active, free drug in circulation

Hinders metabolism and rate of excretion; increases half life & prolongs drug action

Decreases Vd

Decreases ability to enter CNS across BBB

Acidic drugs bind primarily to albumin; basic drugs bind primarily to alpha-1-acid glycoprotein

57
Q

Cytochrome P450 independent oxidations

A

Phase I reactions mediated by enzymes other than CYP450, most often dehydrogenases, oxidases

Ex: Monoamine oxidase, important in neurotransmitter metabolism

Alcohol dehydrogenase

58
Q

Inhibitors of Phase I metabolism

A

Inhibitors work by many mechanisms (competitive, non competitive, etc.) but generally take effect as soon as sufficient hepatic concentration is reached

Examples of inhibitors: erythromycin, ketoconazole, fluoxetine and other SSRIs, grapefruit juice, omeprazole, HIV protease inhibitors

59
Q

P-Glycoproteins

A

ATP-fueled active transporters located on intestinal, renal, and hepatic epithelial cells; function to move xenoiotics, including drugs, out of the cell at sites of entry into the body; in the intestine they function to decrease absorption whereas in the liver and kidney they function to enhance elimination

Inhibitors of p-glycoproteins increase drug plasma levels

Inducers of p-glycoproteins decrease drug plasma levels

60
Q

How are drugs excreted by the kidney?

A

Glomerular Filtration - drugs smaller than albumin will be filtered at a rate of 120ml/min; glomerular filtration rates are affected by renal blood flow & function

Active tubular secretion - drugs are transported directly from blood into urine at a rate of 120-600mL/min

61
Q

HPA Axis

A

Stress stimulates the release of corticotropin releasing hormone (CRH) in the hypothalamus; CRH stimulates the release of adrenocorticotropic hormone in the hypothalamus which stimulates the production of cortisol and aldosterone in the adrenal gland.

Cortisol produced from the adrenal gland negatively regulates the production of both CRH and ACTH in the hypothalamus

62
Q

Metabolic effects of glucocorticoids - Carbohydrates

A

Stimulates gluconeogenesis, leading to increased blood sugar and subsequent insulin release

Can lead to a diabetes-like state

63
Q

Metabolic effects of glucocorticoids - Protein

A

Decreases protein synthesis, and increases breakdown of protein to glucose (gluconeogenesis)

Can result in peripheral muscle wasting

64
Q

Metabolic effects of glucocorticoids - Fat

A

Increased breakdown of triglycerides into free fatty acids; elevated insulin caused by increased blood sugar stimulates the uptake of free fatty acids into triglycerides in the central body

Can lead to centripetal obesity

65
Q

Mineralcorticoid effects of glucocorticoids

A

Mimic the effects of aldosterone on mineralcorticoid receptors in response to reduced blood flow

Increased reabsorption of Na+ and H2O coupled with loss of K+ and H+ can lead to hypertension, edema, hypokalemia, and metabolic alkalosis

66
Q

Cellular & Vascular effects of glucocorticoids

A

Vascular effects: reduced vasodilation, decreased fluid exudation

Cellular effects: Decreased activation and chemotaxis of neutrophils in areas of acute inflammation; decreased activity of monocytes and lymphocytes, decreased angiogenesis and fibrosis at areas of chronic inflammation

67
Q

Glucocorticoid Metabolism

A

11-keto glucocorticoids (i.e. Cortisone, Prednisone) are prodrugs that must be activated by 11B hydroxysteroid dehydrogenase I (11B-HSD I) in the liver to form active 11-hydroxy glucocorticoids (i.e. Cortisol, Prednisolone)

11-hydroxy glucocorticoids are inactivated in the kidney by 11B-HSD2, which converts them back to 11-keto glucocorticoids

68
Q

Hydrocortisone

A

11-keto glucocorticoid pro-drug, must be activated to cortisol by 11B-HSDI in the liver; activated upon first pass metabolism when given orally (no topical activity)

Drug of choice for replacement therapy, i.e. Addison’s Disease

Glucocorticoid and mineralcorticoid action

69
Q

Prednisone

A

11-keto glucocorticoid, must be activated to prednisolone by 11B-HSDI in the liver; activated by first pass metabolism when given orally (no topical action)

Most commonly used oral agent for steroid burst therapy

70
Q

Methylprednisolone

A

Major parenteral (IV) agent for steroid burst therapy

Glucocorticoid action only; no mineralcorticoid activity

71
Q

Dexamethasone

A

Most potent anti-inflammatory agent; no mineralcorticoid action

Used when water retention is undesirable, as in cerebral edema

72
Q

Triamcinolone

A

No mineralcorticoid action; used topically

73
Q

Fludrocortisone

A

Drug of choice for mineralcorticoid effects

74
Q

Lipid:water partition coefficient

A

Describes the ratio of concentrations of a compound in a mixture of two immiscible phases at equilibrium

Drugs with a high lipid:water partition coefficient are highly lipid soluble

DD & BL Unit 1 (6 decks)

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