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105 Cards in this Set

  • Front
  • Back
According to the WHO's definition of ADR, what factor is different?
Must be unintentional. Excludes intentional overdose and therapeutic misadventure
Define tachyphylaxis
Actue tolerance in mins to hours. Ffrequent albuterol administration to an acute asthma pt in the ER. After the first two doses, subsequent nebs may not be effective.
What is the main factor in normal variability?
Genetic factors are the major determinants of the normal variability of drug effects and are responsible for a number of striking quantitative and qualitative differences in pharmacological activity.
A common mutation in pharmacogenomics is called...
If the mutation is relatively common (more than 1%) it creates a polymorphism (ie, the distribution of the trait has multiple forms)
What is a missense mutation?
a substitution of one nucleotide for another changes the codon so that a different amino acid is incorporated into the protein.
What is a silent mutation?
a substitution of one nucleotide for another changes the codon, but does not change the amino acid (because more than one codon can specify a single amino acid). This type of mutation is not detrimental to the protein since the amino acid sequence stays the same; however, it can be used as a “marker.”
What is a silent mutation?
a substitution of one nucleotide for another changes the codon, but does not change the amino acid (because more than one codon can specify a single amino acid). This type of mutation is not detrimental to the protein since the amino acid sequence stays the same; however, it can be used as a “marker.”
What is a nonsense mutation?
a substitution of one nucleotide for another changes an amino acid codon into a stop codon, creating a truncated protein.
What is a frameshift mutation?
a deletion or insertion of one or more nucleotides shifts the codons, so that incorrect amino acids are specified from the point of deletion of insertion onward in the protein.
Other polymorphisms result from:
insertions of one or more extra bases at a specific location, or deletion of one or more bases at a specific location.
a variable number of tandem repeats
Chromosomal abnormalities (ie, duplications; translocations)
What is a poor metabolizer?
Has two defective alleles and lacks functional enzyme.
What is an intermediate metabolizer?
heterozygous for one functional and one deficient allele
has two partially defective alleles that cause reduced metabolism
What is a silent mutation?
a substitution of one nucleotide for another changes the codon, but does not change the amino acid (because more than one codon can specify a single amino acid). This type of mutation is not detrimental to the protein since the amino acid sequence stays the same; however, it can be used as a “marker.”
What is a nonsense mutation?
a substitution of one nucleotide for another changes an amino acid codon into a stop codon, creating a truncated protein.
What is a frameshift mutation?
a deletion or insertion of one or more nucleotides shifts the codons, so that incorrect amino acids are specified from the point of deletion of insertion onward in the protein.
Other polymorphisms result from:
insertions of one or more extra bases at a specific location, or deletion of one or more bases at a specific location.
a variable number of tandem repeats
Chromosomal abnormalities (ie, duplications; translocations)
What is a poor metabolizer?
Has two defective alleles and lacks functional enzyme.
What is an intermediate metabolizer?
heterozygous for one functional and one deficient allele
has two partially defective alleles that cause reduced metabolism
What is an extensive metabolizer?
two normal alleles
often majority of population
“normal” metabolizers
What is an ultra rapid metabolizer?
duplicated or multiduplicated functional alleles with extremely high metabolic capacity.
What enzyme metabolizes codeine?
Conversion of codeine to morphine is dependent on the polymorphic gene CYP2D6. Genotype of CYP2D6 affects the analgesic effect of codeine. Codeine an example of a prodrug? Morphine is the active metabolite of codeine. Has enhanced effect in rapid metabolizers
What mutation causes coumadin resistance?
Patients carrying mutations in VKORC1 are usually warfarin resistant and require dose adjustment.
Which two polymorphisms cause coumadin variability?
>50% of the variability in the warfarin dose may be explained by polymorphisms in CYP2C9 and VKORC1
What mutation causes severe, if not deadly, skin rxs with carbamazine?
HLA-B*1502. 
This allele occurs almost exclusively in patients with ancestry across broad areas of Asia, including
Describe synthesis and storage of histamine
Storage in cells and basophils
Synthesis and release in epidermal cells; gastric mucosa; CNS; and in regenerating or rapidly growing tissues
Histidine Histamine
Describe funtion of endogenous histamine
Allergic (hypersensitivity responses)
IgE-mediated release from mast cells and basophils
Release inhibited by cromolyn sodium, nedocromil; moderated by beta-2 agonists
Non-immune release by organic bases including venoms and several drugs
Name gastric, CNS, and WBC functions of histamine
Gastric acid secretion via H2 receptors on gastric parietal cells.
Gastric carcinoid tumors and conditions associated with proliferation of mast cell and basophils
CNS neurotransmitter; myenteric plexus
Hematopoetic cell function?
Name histamine receptors and their locations
H1-vascular/extravascular smooth muscle, nerves, glands; some CNS
H2 -some vascular smooth muscle; gastric parietal cell; cardiac; some CNS
H3 –CNS; dampening; negative feedback
H4 -white blood cells
Name cardiac effects of histamine
Vasodilation
Increased “capillary” permeability
“Triple response” of Lewis (wheal and flare)
Cardiac stimulation; arrhythmias
Name extravascular effects of histamine
Bronchoconstriction
Intestinal smooth muscle contraction (longitudinal)
Nerve endings
-itch -pain
Name effects of antihistamines
Currently available drugs block H1 or H2 receptors
H1 blockers are divided into older (1st) generation and newer (2nd) generaiton agents
2nd generation agents penetrate CNS poorly and are “nonsedating”
H2 blockers (OTC) are used to decrease gastric acid secretion
Name effects of H1 antagonists
Reversible, competitive inhibitors of the H1receptor.
1st generation (sedative; anticholinergic) and 2nd generation (less or no sedation) agents
-Sedation (varies)
-Anticholinergic; some with alpha and 5-HT blocking action
-Central antinausea and antiemetic effects (some agents may
irritate GI-tract)
-Mild antiparkinsonian effects (anticholinergic)
-Local anesthetic effects (structural features of local anesthetics)
-Drug allergy from topical administration
Name clinical uses of H1 antagonists
Allergies; allergic reactions; pruritus & itching
Motion sickness and vestibular disturbances
OTC sleep aid
Name effects of H2 antagonists and their names
Block histamine-induced gastric acid secretion; larger effect on nocturnal acid secretion.
All drugs in this class are now available over-the-counter to reduce gastric acid secretion
Cimetidine: Inhibits P450 and may cause confusion in elderly patients receiving larger doses
Ranitidine: Less effect on P450
Famotidine: Less effect on P450
Nizatidine
What causes kinin release?
Tissue damage, allergic reactions, viral infections, and other inflammatory events activate a series of proteolytic reactions that generate bradykinin and kallidin in tissues.
What do kinins cause?
Kinins are peptide autocoids that act locally to produce pain, vasodilation, increased vascular permeability, and the synthesis of vasoactive substances, including prostaglandins.
Constitute a subset of the large number of mediators that contribute to the inflammatory response.
How are kinins synthesized?
Kinins are cleaved from α2 globulins termed kininogens
Bradykinin and kallidin are cleaved by plasma or tissue kallikrein; plasma kallikrein activated by Factor XII
What inactivates kinins?
Cascade is restrained by protease inhibitors in plasma
Inactivated by ACE (Kininase I) or converted to active Des-Arg metabolites by other peptidases
What happens when bradykinin and kallidin act on B2 receptors?
Pain, vasodilation, Na excretion
What happens when (des-arg) bradykinin and kallidin act on B1 receptors?
Vasodilation, pain, leukocyte recruitment,
Describe B2 kinin receptors and their function
B2 receptors are constitutively present and mediate the effects of bradykinin in the absence of inflammation.
B2 receptors activate proinflammatory transcription factors, NO synthesis, and prostaglandin synthesis
Describe the funciton of B1 kinin receptors
B1 receptors bind des-Arg metabolites; present in normal vascular smooth muscle.
B1 receptors are upregulated during inflammation and by cytokines, growth factors, and endotoxins.
How do kinins effect the kidneys?
Na and H20 excretion
What do kinins cause in respiratory disease?
bronchoconstiction
What do ACE inhibitors do to kinins
Prolong their action
Name a Kallikrein inhibitor that's been pulled off the market
aprotonin, used to inhibit bleeding. Pulled of market because of increased clot formation- increased MI, stroke, etc. postop
What are Eicosanoids
Prostaglandins, leukotrienes, and related compounds are called eicosanoids because they are derived from 20-C essential fatty acids that contain 3, 4, or 5 double bonds
Name examples of Eicosanoids
Dihomo-γ-linolenic acid, archidonic acid, fish oil
What causes eicosanoid production?
Eicosanoids are found in almost every tissue and body fluid, especially semen
Production increases in response to diverse stimuli, and they produce a broad spectrum of biological effects.
What is the lipoxygenase pathway of archidonic acid?
Lipoxygenase pathways leads to HPETEs, HETEs, and the leukotrienes.
What is the cyclooxygenase pathway of archidonic acid?
Cyclooxygenase pathway leads to cyclic endoperoxides (PGG and PGH) and subsequent metabolic products depending on other enzymes present.
Cyclooxygenase-1 (COX-1) is constitutively expressed.
Cyclooxygenase-2 (COX-2) constitutive in endothelial cells, kidney, and brain
Induced by cytokines, growth factors, and endotoxin at other sites, an effect that is blocked by glucocorticoids; further induced in endothelial cells by laminar shear forces.
What are things to know about PGE, PGF, and PGD synthase?
PGE- most common
PGF- respiratory
PGD- reproductive
What is important about the free radical limited chain reaction?
How tylenol inhibits cyclooxygenase
What do eicosanoids cause?
inflammation --smooth muscle tone --hemostasis/thrombosis --parturition --gastrointestinal secretion.
Name leukotreine receptor antagonists
Zafirlukast
Montelukast
What drug class is Zileuton?
5-Lipoxygenase inhibitor
Name principal pharmacologic properties of eicosanoids
Vasodilate (PGI2-endothelium; PGE2, PGD2)
Hypotension (LTC4; LTD4)
Vasoconstrict (TXA2- platelets, PGF2; endoperoxides)
↑ C.O. (PGE2, PGF2)
↑ capillary permeability (LTC4, LTD4)
What part of the arachidonic cycle affects platelets?
(PGI2 inhibits; TXA2 promotes)
What does LBT4 and PGE2 do to the immune system?
Chemotaxis (LTB4)
Inhibit lymphocyte function (PGE2)
What chemical contracts most smooth muscle?
leukotreines
Which leukotreines are heavily implicated in bronchoconstriction?
LTC4, LTD4
Which prostaglandins are implicated in uterine contraction?
PGE2, PGF2)
Which chemicals cause contraction of GI smooth muscle?
LTC4, LTD4, PGE2, PGF2
What is the effect of prostaglandins on the GI tract?
Gastrointestinal ( gastric secretion;  mucus; local blood flow; epithelial growth (PGE2, PGI2)
What is the effect of prostaglandins on the kidneys?
Kidney and urine formation (renal blood flow;  chloride reabsorption renin secretion.
What are the effects of prostaglandins on afferent nerves?
Afferent nerves (direct pain producer; hyperalgesia)
What are the effects of prostaglandins on the CNS and eye?
CNS (elevate body temperature; modulate NT)
Eye (decreases intraocular pressure)
Name therapeutic uses of prostaglandins
Cervical ripening (PGE2)
Therapeutic abortion
Gastric cytoprotection (Misoprostol; PGE1 analog)
Impotence- once IV, replaced by viagra
Maintenance of patent ductus arteriosus
Primary pulmonary hypertension- replaced by NO
What is the most common mechanism for a rxn between two drugs
One inhibiting the metabolism of the other
Name drugs that inhibit IgE mediated mast cell release of histamine
Cromolyn sodium; Nedocromil
Beta-2 receptor agonists (epinephrine)
Describe triple response
Triple response: If histamine is released intradermally, it elicits a characteristic
phenomenon known as the “triple response” consisting of (1) a localized red spot;
(2) a brighter red flush or “flare”; and (3) a wheal that is discernible in 1 to 2
minutes that occupies the original red spot.
What does the Kallikrein-kinin system do for the heart?
Cardiovascular system: Kallikrein-kinin system appears to be
cardioprotective
What does COX (1 and 2) do to PGG?
Cyclooxygenase-2 (COX-2) is
constitutively expressed in endothelial cells, and is induced at other sites by cytokines,
growth factors, and endotoxin, an effect that is blocked by glucocorticoids. The
cyclooxygenases have 2 distinct activities: an endoperoxide synthase activity that forms PGG
and a peroxidase activity that converts PGG to PGH.
What do eicosanoids do locally?
Eicosanoids activate membrane receptors locally near their sites of formation; all are Gprotein
coupled receptors that modulate the activities of adenylyl cyclase and phospholipase
C.
What do eicosanoids do to bone and what is their role in fever?
Central nervous system
1. Raise hypothalamic set point (fever)
2. Modulate neurotransmission and several endocrine systems
I. Bone (PGE2) stimulates bone formation and resorption
What is the relationship between COX1 and COX2?
COX-1 is the primary constitutive form found in
most normal cells and tissues, while cytokines and inflammatory mediators that accompany
inflammation induce COX-2 production.
Name effects of COX1 and COX2 inhibition
The inhibition of COX-2 is thought to
mediate, at least in part, the antipyretic, analgesic, and anti-inflammatory action of NSAIDs, but the
simultaneous inhibition of COX-1 results in unwanted side effects, particularly those that lead to gastric ulcers, that result from decreased prostaglandin production.
Name a selective COX 2 inhibitor and its effects
Adverse cardiovascular effects of
selective COX-2 inhibitors related to increased risk of thrombosis have been identified, resulting in
withdrawal from the market of all of these agents except for celecoxib (Celebrex®).
By which chemical method does ASA inhibit COX1 and COX2?
NSAIDs include aspirin, which irreversibly acetylates COX 1 & 2
Name anti-inflammatory effects of NSAIDS
1. PGE2 and PGI2 cause erythema, increase in local blood flow; effects of PGE2 on
cutaneous vessels and superficial veins are long lasting.
2. Potentiate increased vascular permeability associated with other inflammatory
mediators (eg, bradykinin; leukotrienes; histamine).
3. Some NSAIDs may inhibit expression of cell adhesion molecules or directly
impair leukocyte function.
Name analgesic effects of NSAIDS
1. Particularly effective in settings where inflammation has caused sensitization
of pain receptors.
2. PG’s cause hyperalgesia (sensitize nerve endings to other chemical mediators).
Name anti-pyretic effects of NSAIDS
Antipyretic - Pyrogens/cytokines increase endogenous hypothalamic formation of
PGE2, which elevates the body temperature set point thereby promoting increases in
heat generation and decreases in heat loss.
Name GI side effects of NSAIDS
1. Gastric effects range from mild dyspepsia ad heartburn to ulceration of the
stomach or duodenum, sometimes with fatal results, especially in older patients.
2. May be accompanied by anemia from resultant blood loss.
3. Local irritation from drug (organic acids) plus removal of PGE2 and PGI2
cytoprotective effects.
4. Administration of the PGE1 analog, misoprostol, can be beneficial.
Name effects of NSAIDS on platelet function
1. NSAIDs prevent platelet formation of TXA2 which promotes “stickiness” and
clumping (aggregation).
2. COX-2 appears to be major source of PGI2 from endothelial cell; which is
antithrombotic.
3. Small doses of aspirin primarily (and irreversibly) inhibit TXA2 synthesis,
preserving PGI2; larger doses of COX-2 inhibitors suppress PGI2 without much
effect on TXA2
4. ↑ TXA2/PGI2 = prothrombotic; ↑PGI2/TXA2 = antithrombotic
By what mechanism do NSAIDS cause renal toxicity?
1. NSAIDs decrease renal blood flow and GFR in patients with congestive
heart failure, liver disease (ascites); chronic renal disease; or those who are
hypovolemic; PG’s oppose vasoconstrictor influences within kidney.
2. NSAIDs promote salt and water retention by reducing PG-induced inhibition
of both the reabsorption of chloride and the action of ADH; may cause edema in
some patients; reduce the effectiveness of antihypertensive regimens; or promote
hyperkalemia.
3. Analgesic nephropathy from chronic use in some patients.
By which mechanisms do NSAIDS cross react with ASA?
1. Certain individuals display intolerance to aspirin and most NSAIDs manifesting
as symptoms ranging from vasomotor rhinitis, generalized urticaria, and
bronchospasm to laryngeal edema and bronchoconstriction, flushing, hypotension
and shock.
2. Occurs most often in patients with “nasal polyps, asthma, and chronic urticaria.”
3. Nonimmunologic mechanism; defect in mast cell histamine storage and/or
shunting of arachidonic acid to lipoxygenase pathways.
Name effects of NSAIDS in utero
Prolongation of gestation – PG’s are potent uterotropic agents, and their biosynthesis
by the uterus increases dramatically in the hours before parturition.
 NSAIDs may provoke premature closure of the ductus arteriosus
Name drug interactions of NSAIDS
1. Prolong bleeding time (warfarin; heparin)
2. Increase the ulcerogenic effects of glucocorticoids
3. Reduce effects of diuretics and other antihypertensive agents
4. Reduce lithium clearance
Name non obvious clinical uses of NSAIDS
With antihistamines, in patients with systemic mastocytosis
F. Adjunct in cancer-related hypercalcemia
G. Bartter’s syndrome
H. To moderate cutaneous reactions in patients receiving niacin
I. Prevention of colon cancer?
Name pharmacokinetics of ASA
Pharmacokinetics – rapid absorption; metabolism in plasma to yield salicylic acid
which undergoes further biotransformation in the liver and mitochondria. Dosedependent
elimination of salicylic acid.
What is the mechanism of action of ASA?
Mechanism – aspirin acetylates cyclooxygenase, permanently inactivating. Salicylic
acid is a competitive inhibitor
Name therapeutic uses of ASA
Therapeutic uses – Aspirin exerts dose-dependent therapeutic effects. Lowest doses
inhibit platelet function; moderate doses provide analgesia and antipyresis; larger
doses are needed for full anti-inflammatory/antirheumatoid effects.
Name side effects of ASA
1. Gastric irritation, ulceration, erosion, hemorrhage
2. Increased bleeding time (doubling for 4 to 7 days)
3. Uric acid excretion: Low doses inhibit; large doses promote
4. Decreased renal function in patients at risk
5. Hepatic injury (large doses associated with treatment of RA) or idiosyncratic at
lower doses.
Name neuro and respiratory symptoms of ASA overdose
Confusion; tinnitus, dizziness
Respiration (contributes to acid-base disturbances)
-stimulation via uncoupling of oxidative phosphorylation
-direct stimulation of respiratory center
-toxic doses suppress respiration
Name metabolic effects of ASA overdose
Uncoupling of oxidative phosphorylation (↑ O2 consumption and CO2
production↑).
Toxic doses may inhibit aerobic respiration leading to accumulation of
pyruvic, lactic, and acetoacetic acids.
Epinephrine release which promotes hyperglycemia and depletes muscle
and hepatic glycogen.
Reduce lipogenesis with ↑ oxidation of fatty acids
Large doses stimulate glucocorticoid secretion
Name metabolic disparagement seen with ASA overdose
Full therapeutic doses produce respiratory alkalosis; compensation is
achieved by increased renal excretion of bicarbonate, accompanied by
increased Na+ and K+ exertion
o In extreme cases, this is followed by metabolic acidosis from salicylate
accumulation; renal dysfunction; and derangement of carbohydrate
metabolism
At approximately which serum level does ASA intoxication begin?
around 60 mg/dl. Severe intoxication >160 mg/dl
What is the mechanism of action (MOA) of tylenol?
The mechanism of action of acetaminophen is not
established. It inhibits cyclooxygenase in vitro, perhaps by interrupting free
radical based peroxidase activity of the cyclooxygenase enzyme. The ability of acetaminophen to inhibit cyclooxygenase is impaired in the presence of peroxides (ie, inflammation) and enhanced in the presence of high concentration of antioxidants (ie, brain).
What are effects of tylenol?
Effective antipyretic and analgesic. Lacks significant anti-inflammatory effects, and
does not affect the GI tract or platelets. Main toxicity is directed toward the liver.
How is tylenol eliminated?
Acetaminophen is primarily metabolized in the liver by first-order
kinetics and involves three principal separate pathways:
 conjugation with glucuronide
 conjugation with sulfate
 oxidation via the cytochrome, P450
How does P450 metabolize tylenol?
forms a reactive intermediate metabolite, which conjugates
with glutathione and is then further metabolized to form cysteine and
mercapturic acid conjugates. The principal cytochrome P450 isoenzyme
involved appears to be CYP2E1, with CYP1A2 and CYP3A4 as additional
pathways.
Describe the mechanism of tylenol toxicity
large doses (~10 g may cause hepatoxicity). Mediated by
metabolite formed by P450, which is normally inactivated by glutathione. .
Hepatotoxic dose may be much smaller in individuals with preexisting liver
disease or who consume alcohol regularly.
When can mucomyst be used in tylenol overdose?
acute ingestions of
the drug who presented to medical centers with 24 hours of the overdose. Not
applicable in patients presenting with late stage toxicity, patients with chronic
ingestion of acetaminophen, alcoholics, or patients who take drugs that may
substantially alter the pharmacokinetics of acetaminophen.
Name the nonimmunologic mechanism in ASA intolerance
Nonimmunologic mechanism; defect in mast cell histamine storage and/or shunting of arachidonic acid to lipoxygenase pathways.
What pharmokinetic modes describes ASA metabolism
zero order/ saturation kinetics
75% of salicyate is metabolized by which enzyme?
glycine
What pharmokinetic model describes tylenol elimination?
First order kinetics