Case Study (Foye’s) “LV, a 65-year-old male, ingested what was described as a large quantity of d-CON Mouse Prufe II rodenticide (0.005% brodifacoum) in a suicidal gesture. He told his wife of the ingestion 6 hr later, and she immediately called 911. Police and paramedics arrived and the man was transported by ambulance to the local emergency department (ED). On arrival in the ED, the patient was alert, oriented, and tearful. His vital signs on presentation were heart rate (HR) = 100, blood pressure (BP) = 140/86 mm Hg, respiration rate (RR) = 16 and nonlabored. His past medical history is significant only for an appendectomy at age 35 and a myocardial infarction (MI) at age 59. LV has been on daily aspirin therapy since his MI, and he has no known medical allergies. The attending ED physician asks you, the pharmacist at the local poison control center, to review the toxicity of brodifacoum and to suggest a course for initial management for this case.” 1. Please fill out the blank areas with appropriate key words
Work #1 by LG-M9-Beaulac, Dominique, Huynh, Mitsopoulos, and Skidmore
Compound 1: Bromadiolone
MOA: a rodenticide; inhibits vitamin K epoxide reductase like warfarin
SAR: substitution at C3 confers great lipophilicity which allows bromadiolone to accumulate in hepatocytes Compound 2: ASA
MOA: inhibits production of prostaglandins and thromboxanes due to inhibition of COX-1 and COX-2
SAR: acetyl group must be donated to COX in order to inactivate the enzyme Compound 3: Warfarin
MOA: blocks the recycling of vitamin K thus inhibiting coagulation
SAR: chiral carbon of the substituent at C3 confers differential activity (S is more potent than R) Compound 4: Vitamin KH2
MOA: involved in the post-translational carboxylation of the glutamic acid residues on the N-terminal portions of factors II, VII, IX, and X necessary for coagulation
SAR: two hydroxyl groups are needed to be oxidized in order for the carboxylation of glutamic acid to occur Compound 5: Menadione
MOA: a precursor to vitamin K
SAR: elimination of long hydrophobic substituent from vitamin K allows for high water-solubility Compound 6: Heparin
MOA: binds to antithrombin thus forming an active complex which inactivates thrombin and other proteases in the clotting cascade
SAR: comprised of a heterogeneous mixture of straight chain, sulfated, and negatively charged mucopolysaccharides; binds to antithrombin via interactions between the sulfate and carboxylate anions in a pentasaccharide sequence of heparin and arginine and lysine cations in antithrombin
Work #2 by LG-W9-Almetwazi, Chen, Ho, McNeill, Patel, and Syoufjy
#1 Brodifacoum : interfering with the cyclic interconversion of vitamin K and vitamin K 2,3-epoxide. SAR: Substitution of the lactone ring, specifically in position 3 and 4. The acidity of the proton on the 4-hydroxy group allows dormation of water soluble.
#2 Aspirin: MOA: works by its ability to acetylate and irreversibly deactivate platelet COX (COX-1).
SAR: The active moiety appears to be the salicylate anion. The side effects of aspirin, especially GI, are associated with the carboxylic acid function. Substitution on the carboxyl or phenolic hydroxyl groups may affect potency and toxicity.
#3 Warfarin: MOA: produce their effect on blood coagulation by interfering with the cyclic interconversion of vitamin K and vitamin K 2,3-epoxide. SAR: Warfarin is a water-insoluble lactone. It's weakly acidic because of the presence of a 4-hydroxy substitution.
2. You are aware that the hospital from which the physician is calling has its formulary compounds 1–4. Which should be considered immediately?
Work #1 by LG-M10-Belfiore, Dufresne, Johnson, Ndungi, and Smith
Compound #2, Vit. K1 should be administered. Brodifacoum inhibits Vit. K1. Vit. K1 should be administered immediately via slow IV injections of 10-25mg every 3-6 hours until the prothrombin time is normalized. Then the patient will need to take vitamin K1 10mg po QID for several months.
Wok #2 by LG-W10: Alsaedi, Colton, Ibrahem, Moore, Patel, and Tai
Compound # 2 - Vitamin K1. It will induce coagulation. It has faster onset of action that vitamin K3 and vitamin K4.
It also requires smaller dose (by mouth).
3. Could any medication the patient has already taken interact with the compound(s) you plan to give to the patient?
Work #1 by LG-W11-Ameyaw, Condon, Ikonomu, Morgan, Patel, and Tashakor
Yes. The following medications may interact with Vit K1:
Cholestyramine
Anisindione
Colesevelam
Warfarin
Dicumarol
Work #2 by LG-W12-Anderson, Conti, Iromuanya, Morin, Patel, Tchani
Vitamin K doesn't interact with ASA or brodifacoum.
4. Based on your structure/function studies, please provide your counseling tips.
Work #1 by LG-W13-Asal, Danella, Islam, Myzyri, Pereira, and Thomas
If you notice excessive bruising or black/tarry stool contact your doctor as this may be a sign of bleeding due to the aspirin.
Monitor intake of Vitamin K because this will interact with warfarin.
Do not take any new over the counter medications or herbals without first speaking to your doctor or pharmacist.
Work #2 by LG-W14-Asante-Somuah, Dang, Jackson, Nammour, Peters, and Tolpa Do not take any new medication during therapy unless approved by prescriber
Follow diet and activity as recommended by prescriber; check with prescriber before changing diet.
Do not make major changes in your dietary intake of vitamin K (green vegetables).
You will have a tendency to bleed easily while taking this drug (use soft toothbrush, waxed dental floss, electric razor, and avoid scissors or sharp knives #2 Aspirin: Irreversibly and permanently inactivating cyclooxygenase through covalent acetylation of a serine residue in close proximity to the active site of enzyme.
SAR:reducing the acidity of carboxylic group will maintain the analgestic actions but eliminate the anti- inflammatory properties. Placing in meta or para to carboxyl group abolishes.
#3 Warfarin: interfering with the cyclic interconversion of vitamin K and vitamin K 2,3-epoxide. SAR: Substitution of the lactone ring, specificallu in position 3 and 4. The acidity of the proton on the 4-hydroxy group allows dormation of water soluble.
#4 Vitamin K1: is essential cofactor necessary for the post-translational carboxylation of the glutamic acid residues on the N-terminal portion of the specific clotting factor.
SAR: the two carbonyl group
5 Vitamin K3: synthetic form of vitamin K the two carbonyl group imprtant for activity
Case Study (Foye’s) “LV, a 65-year-old male, ingested what was described as a large quantity of d-CON Mouse Prufe II rodenticide (0.005% brodifacoum) in a suicidal gesture. He told his wife of the ingestion 6 hr later, and she immediately called 911. Police and paramedics arrived and the man was transported by ambulance to the local emergency department (ED). On arrival in the ED, the patient was alert, oriented, and tearful. His vital signs on presentation were heart rate (HR) = 100, blood pressure (BP) = 140/86 mm Hg, respiration rate (RR) = 16 and nonlabored. His past medical history is significant only for an appendectomy at age 35 and a myocardial infarction (MI) at age 59. LV has been on daily aspirin therapy since his MI, and he has no known medical allergies. The attending ED physician asks you, the pharmacist at the local poison control center, to review the toxicity of brodifacoum and to suggest a course for initial management for this case.”
1. Please fill out the blank areas with appropriate key words
Work #1 by LG-M9-Beaulac, Dominique, Huynh, Mitsopoulos, and Skidmore
Compound 1: Bromadiolone
MOA: a rodenticide; inhibits vitamin K epoxide reductase like warfarin
SAR: substitution at C3 confers great lipophilicity which allows bromadiolone to accumulate in hepatocytes
Compound 2: ASA
MOA: inhibits production of prostaglandins and thromboxanes due to inhibition of COX-1 and COX-2
SAR: acetyl group must be donated to COX in order to inactivate the enzyme
Compound 3: Warfarin
MOA: blocks the recycling of vitamin K thus inhibiting coagulation
SAR: chiral carbon of the substituent at C3 confers differential activity (S is more potent than R)
Compound 4: Vitamin KH2
MOA: involved in the post-translational carboxylation of the glutamic acid residues on the N-terminal portions of factors II, VII, IX, and X necessary for coagulation
SAR: two hydroxyl groups are needed to be oxidized in order for the carboxylation of glutamic acid to occur
Compound 5: Menadione
MOA: a precursor to vitamin K
SAR: elimination of long hydrophobic substituent from vitamin K allows for high water-solubility
Compound 6: Heparin
MOA: binds to antithrombin thus forming an active complex which inactivates thrombin and other proteases in the clotting cascade
SAR: comprised of a heterogeneous mixture of straight chain, sulfated, and negatively charged mucopolysaccharides; binds to antithrombin via interactions between the sulfate and carboxylate anions in a pentasaccharide sequence of heparin and arginine and lysine cations in antithrombin
Work #2 by LG-W9-Almetwazi, Chen, Ho, McNeill, Patel, and Syoufjy
#1 Brodifacoum : interfering with the cyclic interconversion of vitamin K and vitamin K 2,3-epoxide.
SAR: Substitution of the lactone ring, specifically in position 3 and 4. The acidity of the proton on the 4-hydroxy group allows dormation of water soluble.
#2 Aspirin: MOA: works by its ability to acetylate and irreversibly deactivate platelet COX (COX-1).
SAR: The active moiety appears to be the salicylate anion. The side effects of aspirin, especially GI, are associated with the carboxylic acid function. Substitution on the carboxyl or phenolic hydroxyl groups may affect potency and toxicity.
#3 Warfarin: MOA: produce their effect on blood coagulation by interfering with the cyclic interconversion of vitamin K and vitamin K 2,3-epoxide. SAR: Warfarin is a water-insoluble lactone. It's weakly acidic because of the presence of a 4-hydroxy substitution.
2. You are aware that the hospital from which the physician is calling has its formulary compounds 1–4. Which should be considered immediately?
Work #1 by LG-M10-Belfiore, Dufresne, Johnson, Ndungi, and Smith
Compound #2, Vit. K1 should be administered. Brodifacoum inhibits Vit. K1. Vit. K1 should be administered immediately via slow IV injections of 10-25mg every 3-6 hours until the prothrombin time is normalized. Then the patient will need to take vitamin K1 10mg po QID for several months.
Wok #2 by LG-W10: Alsaedi, Colton, Ibrahem, Moore, Patel, and Tai
Compound # 2 - Vitamin K1. It will induce coagulation. It has faster onset of action that vitamin K3 and vitamin K4.
It also requires smaller dose (by mouth).
3. Could any medication the patient has already taken interact with the compound(s) you plan to give to the patient?
Work #1 by LG-W11-Ameyaw, Condon, Ikonomu, Morgan, Patel, and Tashakor
Yes. The following medications may interact with Vit K1:
Cholestyramine
Anisindione
Colesevelam
Warfarin
Dicumarol
Work #2 by LG-W12-Anderson, Conti, Iromuanya, Morin, Patel, Tchani
Vitamin K doesn't interact with ASA or brodifacoum.
4. Based on your structure/function studies, please provide your counseling tips.
Work #1 by LG-W13-Asal, Danella, Islam, Myzyri, Pereira, and Thomas
If you notice excessive bruising or black/tarry stool contact your doctor as this may be a sign of bleeding due to the aspirin.
Monitor intake of Vitamin K because this will interact with warfarin.
Do not take any new over the counter medications or herbals without first speaking to your doctor or pharmacist.
Work #2 by LG-W14-Asante-Somuah, Dang, Jackson, Nammour, Peters, and Tolpa
Do not take any new medication during therapy unless approved by prescriber
Follow diet and activity as recommended by prescriber; check with prescriber before changing diet.
Do not make major changes in your dietary intake of vitamin K (green vegetables).
You will have a tendency to bleed easily while taking this drug (use soft toothbrush, waxed dental floss, electric razor, and avoid scissors or sharp knives
#2 Aspirin: Irreversibly and permanently inactivating cyclooxygenase through covalent acetylation of a serine residue in close proximity to the active site of enzyme.
SAR:reducing the acidity of carboxylic group will maintain the analgestic actions but eliminate the anti- inflammatory properties. Placing in meta or para to carboxyl group abolishes.
#3 Warfarin: interfering with the cyclic interconversion of vitamin K and vitamin K 2,3-epoxide. SAR: Substitution of the lactone ring, specificallu in position 3 and 4. The acidity of the proton on the 4-hydroxy group allows dormation of water soluble.
#4 Vitamin K1: is essential cofactor necessary for the post-translational carboxylation of the glutamic acid residues on the N-terminal portion of the specific clotting factor.
SAR: the two carbonyl group