Pharm Exam 4 Factoids Flashcards
Catalyzes production of leukotrienes, HETES and HPETES
Lipoxygenase
Enzyme required for release of arachundonic acid from membrane phospholipids
Phospholipase A2
Catalyzes production of prostaglandins and thromboxane
Prostaglandin H synthase
Enzyme
Arachidonic acid to 5-HPETE
5-LOX
Enzyme
5-HPETE to LTA4
LTA synthase
Enzyme
LTA4 to LTB4
LTA4 hydroxylase
Enzyme
LTA4 to LTC4
LTC synthase
GSH
Function of 5-HETE
Chemotaxis for leukocytes
Function of LTB4
Chemotaxis
Aggregation
Adhesion
All for leukocytes
Function of LTC4, LTD4, LTE4
Vasoconstriction
Bronchospasm
Increase vascular permeability
Function of PGI2
Vasodilation
Decrease platelet aggregation
Distribution: endothelium, kidney, platelets, brain
Function of theomboxane TxA2
Vasoconstriction
Increase platelet aggregation
Distribution: platelets, vascular smooth muscle, macrophages, kidney
Function of PGD2, PGE2, PGF2a
Vasodilation
Potentiation of edema, pain and fever
Distribution PGD: mast cells, brain, airways, lymphocytes, eosinophils
PGE: brain, kidney, vascular smooth muscle cells, platelets
PGF: uterus, airways, vascular smooth muscles, eye
Features of COX-1
Arachidonic acid to PGG2
Constitutive expression
Functions: housekeeping, cytoprotective, maintains gastric mucosal integrity, mediates normal platelet function
Not inducible, regulated developmentally
Features of COX2
Arachidonic acid to PGG 2
Inducible
Constitutive in areas of the brain, kidney, vas deferens, GI tract
Not in platelets
Functions: inflammation, memory, salt/ water balance, uterine contractions, colon and breast cancer
Inducers: bacteria, tissue damage, growth factors, inflammatory cytokines
Metabolizes of Arachidonic acid on smooth muscle
PGE2 and PGI2 relax TxA2 contracts PGD2 either constricts or dilates Ductus arteriousus sensitive to vasodilators effects of PGE and PGI2 Uterine contraction is PGE2 or PGF2alpha
Cytoprotective metabolites
PGE2 and PGI2 inhibit gastric acid secretion
PGE2 increase mucus secretion
PGI2 regulate mucosal blood flow
Platelet regulation metabolites
TxA2 promote platelet aggregation
Prostacyclin PGI2 inhibits aggregation
Fever and pain metabolites
PGE2 increased concentration in hypothalamus
Therapeutic uses of NSAIDS
Reduce pain Reduce fever associated with inflammation, tissue damage or disease Close ductus arteriousus Prophylactic of thromboembolic disorders Decrease risk of colon cancer
Side effects of NSAIDS and reason why
Gastric or intestinal irritation NSAID induced gastric or duodenal ulcer Due to decreases synthesis of cytoprotective PGs (COX-1) Increased bleeding Prolonged gestation Renal injury/ failure
Overcoming gastric irritation
Co administration of a proton pump inhibitor
Selective blockade of COX2
Salicylate poisoning
Uncoupling of oxidative phosphorylation in mitochondria-hyperventilation and respiratory alkalosis, compensatory bicarbonate secretion
Large doses and small children medullary response depressed-hypoventilation and respiratory acidosis
Both have metabolic acidosis-toxic plasma concentrations of salicylates, decreased renal excretion of acids, impaired metabolism of carbs leading to increased lactic & pyruvic acid
High incidence of severe headaches
Indomethacin-acetic acid derivative
Causes peri operative pain
Etodolac and ketorolac
TNF facts
Pro inflammatory cytokines
Activates NFkB leading to production of pro inflammatory mediators
Activates MAP kinase pathways especially JNK leading to transcription factor activation, changes in signaling, proliferation, differentiation, and apoptosis of cells
Stimulates acute phase response, attracts neutrophils, stimulates phagocytosis by macrophages
Receptors: TNFR1 expressed widely, TNFR2 expressed on immune cells
TNF Ab causing TB
Certolizumab pegol
Define gout
Hyperurecemia caused by overproduction of uric acid and/or decreased ability to excrete it
Deposition of monosodium urate in tissues, particularly joints and kidneys
Cause inflammation
Contraindications examples ( reasons to withhold treatment)
Coma Convulsions Strong acids or bases Petroleum distillates Heart disease Pregnancy CNS stimulants
Causes emesis (vomiting)
Ipecac, mustard powder, apomorphine
Steps to treat poisonings before arrival
Obtain useful information Emesis Adsorbents: activated charcoal Decontaminate skin and eyes Get to treatment center
Steps to treat poisoning at treatment center
- Emergency management
- Initial exam-consistent symptoms
- Remove unabsorbed toxicant:emesis, gastric lavage, whole bowel irritation (sorbitol, Na2SO4, MgSO4), adsorbents
- Supportive treatment
- Hasten elimination of absorbed toxicant-diuresis, urinary ph adjustment, dialysis, hemodialysis-slowly eliminated toxicants and small MW
Receptor ligand interactions toxicity examples
Nicotine, organophosphates, TCDD (dioxin)
Interference with excitable membranes examples
Saxitoxin, tetrodotoxin-block Na channels
Organic solvents-alter membrane fluidity
DDT: interferes with Na channel closing
Organophosphates, carbamates: inhibit AChe
Examples of interference with energy production
Carbon monoxide Nitrite Cyanide, hydrogen sulfide, azide Nitrophenols Fluoroacetate ATP depletion affects membrane integrity, ion pumps, protein synthesis Heart and Brain most sensitive
Examples of calcium homeostasis disrupters
Nitro phenols, quinones, peroxides, aldehydes, dioxins, heavy metal ions
Periods of teratogenic susceptibility
Early: lethal effects
Late: no major structural malformations instead growth retardation, functional disorders, Carcinogenesis
Organogenesis: period of high susceptibility
Malignant hyperthermia pharmacogenomics
Idiosyncratic response to general anesthetics such as halothane in combo w/ succinylcholine
Rigidity of skeletal muscles, tachycardia, and hyperthermia
MOA: increased release of Ca from sarcoplasmic reticulum leads to increased muscle contractions and heat production
Change from lys to arg in ryanodine receptor
Treat with dantrolene
GP6D deficiency pharmacogenomics
Erythrocyte Glucose 6 phosphate dehydrogenase deficiency occurs in 1 in 10 Africans
X-linked recessive
Resistance to plasmodium falciparum Malaria
Lowers NADPH and GSH
Drugs produce H2O2 which oxidizes glutathione
G6PD deficiency leads to premature rupture or red blood cells
Drugs: primaquine, quinine, quinidine, sulfonamides, dapsone, methylene blue
Isoniazid and N-Acetyltransferase-2 SNPs (NAT-2) pharmacogenetics
Rapid metabolizers (more NAT-2) have an inadequate response for TB to isoniazid Poor metabolizers (less NAT-2) may exhibit toxicity Egyptians, Africans and Caucasians most likely slow acetylators
Aldehyde dehydrogenase pharmacogenetics
10 human ALDH and 13 alleles result in autosomal dominant trait that lacks catalytic activity if one subunit is inactive
ALDH-2 deficiency leads to accumulation of acetylaldehyde leading to facial flushing, palpitations, and tachycardia
Absent in 45% of Chinese but not in Caucasians or Africans
Involved in alcohol metabolism
CYP450 2C19 pharmacogenetics
Cure rate for helicobacter pylori infection is greater in patients who are poor metabolizers of omeprazole
CYP2C19 poor metabolizers: Filipinos, Japanese, Chinese Taiwanese
100% vs 25% cure rate
Cytochrome P450 CYP2D6 pharmacogenomics
Low to absent in 7% of Caucasians and 2% of Asians and Africans
Causes poor analgesia with acetaminophen plus codeine
Ultra rapid metabolizers carry multiple copies of CYP2D6 gene-10% of Spanish, 1-2% of Swedish and 30% of Ethiopian
Inhibited by fluoxetine, paroxetine, haloperidol, quinidine, ritonavir
Thioopurine methyl transferase pharmacogenomics
TPMT Catalyzes S-methylation of Azathioprine and 6-mercaptopurine
Very low or no activity occurs in <.5% of populations
Can have fatal consequences for children treated with 6-mercaptopurine for acute lymphocytic leukemia and cause inability to tolerate Azathioprine
Autosomal co dominant
Deficiency leads to accumulation of XC thioguanine nucleotides leading to bone marrow toxicity
Polymorphic beta 2 receptor pharmacogenomics
SNPs have been associated with abnormal receptor expression, signaling and down regulation
Have clinical importance in asthma and hear failure
Drugs that cause type I hypersensitivities
Chimeric monoclonal Abs Immunoglobulin preparations NMJ blockers Quinolone antibiotics Beta lactam antibiotics-penicillins, cephalosporins Toluene diisocyanate-symptoms persist Apamin-bees
Examples of type II hypersensitivities
Beta lactam antibiotics
Penicillins-hemolysis, less likely thrombocytopenia
Cephalosporins-hemolysis less likely thrombocytopenia
Aspirin, quinidine or phenytoin cause thrombocytopenic purpura
Drugs that cause type III hypersensitivity reactions
Beta lactam antibiotics Sulfonamides Nonsteroidal antiinflammatory drugs Hydralazine-lupus like Procainamide
Drugs that cause Type IV hypersensitivity
Beta lactams-penicillins, cephalosporins
Sulfonamides-May be severe, Steven Johnson syndrome or toxic epidermal
Anaphylactoid reaction
Non IgE mediated histamine release
Dose dependent
Rechallenge can be done-premedicate with antihistamine
No cross reactivity within same class/chemical
Type I hypersensitivity
Allergic reaction
Rechallenge OK
Immediate after non Reactive first exposure
B and T cells-> T cells activist ate B cells -> histamine, heparin, platelet activating factor
Type II hypersensitivity
Desensitization and rechallenge not recommended
Targets blood cells or platelets
Immediate if previous exposure, 5-8 days first time
Type III hypersensitivity
Rechallenge not recommended
Targets Vascular endothelium, skin, joints, kidney
Immune complex deposition
Joints-arthalgia, skin-purpura, kidneys-glomeruli nephritis, systemic-serum sickness, vasculitis
Immediate if previous exposure, 10-14 days if first time
Type IV hypersensitivity
Delayed
T cells exposed then rexposure activates memory T cells releasing cytokine and Chemokines attracting macrophages
Skin reactions-hives, morbilliform Rash, eczema
Rechallenge after desensitization
7-20 days onset on average
Drugs that cause anaphylactoid reactions
Codeine or morphine-high doses or epidural
Vancomycin-red neck syndrome
Radio contrast media
Caspofungin-decreased histamine
Drugs frequently causing allergic reactions
Antimicrobials, anticonvulsants, cardiovascular drugs, macromolecules, antiinflammatory, antineoplastic
Type A adverse reactions
Account for 2/3 of ADRs Predictable and dose dependent Include anaphylactoid Extension of pharmacological effect Preventable
Type B adverse reactions
Idiosyncratic or immunologic reaction
Rare and not predictable
Type C adverse reactions
Long term use
Drug accumulation
Type D adverse reactions
Delayed effects-dose independent
Carcinogenicity
Terarogenecicity
P-glycoproteins
Efflux pump in epithelial cells with an excretory function in gut wall
Induced by rifampin
Inhibited by quinidine, verapamil, itraconazole, erythromycin
Inducers of cyp450 metabolism
Phrnoarbital Carbamazepine Phenytoin Rifampin Cigarette smoking Tobacco Chronic ethanol use
Inhibitors of cyp450 metabolism
Cimetidine Omeprazole Fluoxetine Ciprofloxacin Clarithromycin Erythromycin Grapefruit juice Itraconazole Ciprofloxacin Ritonavir
Competition for secretion in proximal tubule
Probenecid and ampicillin
Ibuprofen and hydrochlorothiazide
Slows hepatic blood flow
Propranolol
Food that binds to drug and prevent absorption
Milk and tetracycline
Drug that is increased in absorption with food
Fatty meal and griseofulvin
Protective food
All foods and ibuprofen on gastric mucosa
Food and inhibition of p450 metabolism
Grapefruit and lovastatin
Grapefruit effects
Inhibits intestinal p450 responsible for first pass metabolism
May Inhibit P glycoproteins In intestinal brush border
Interaction causing increased BP
MAO inhibitors and tyrannies containing foods
Interaction that causes decreased anti coagulation effects
High vitamin K foods (green leafy veggies)
And warfarin
