Slides are prepared as per INC Syllabus Unit IX Drugs used in nervous system and it is most benefited for B sc Nursing students and faculty of the subject
Pharmacology of commonly used antisep, disinfect, insecticideMr. Dipti sorte
Slides are prepared as per INC Syllabus Unit III Antiseptics & Disinfectants and it is most benefited for B sc Nursing students and faculty of the subject
Slides are prepared as per INC Syllabus Unit IX Drugs used in nervous system and it is most benefited for B sc Nursing students and faculty of the subject
Pharmacology of commonly used antisep, disinfect, insecticideMr. Dipti sorte
Slides are prepared as per INC Syllabus Unit III Antiseptics & Disinfectants and it is most benefited for B sc Nursing students and faculty of the subject
This is a precise description regarding anti-coagulants and a short outlook into INR (International Normalized Ratio)............
Hope the points are worthwhile...
For further details, u can communicate me at 8086948729 or in my email address ar rxvichu623@gmail.com or in my fb inbox at "Rx Vichhu"
Thank u!!!
Keep studying well!!
@rxvichu
:)
Anticoagulants have been thoroughly covered in this SlideShare, including an overview with typical examples, their function in the human body and how they operate (MOA), side effects, contraindications, and uses.
Since they are known to regulate blood clotting, it is crucial to keep an eye on their blood levels lest they have a fatal impact on a patient on anticoagulant treatment.
also we have added novel anticoagulants which got approval in just few years.
Katzung
Anticoagulants
Hemostasis refers to the finely regulated dynamic process of maintaining the fluidity of the blood, repairing vascular injury, and limiting blood loss while avoiding vessel occlusion (thrombosis) and inadequate perfusion of vital organs. Either extreme excessive bleeding or thrombosis—represents a breakdown of the hemostatic mechanism. Common causes of dysregulated hemostasis include hereditary or acquired defects in the clotting mechanism and secondary effects of infection or cancer. The drugs used to inhibit thrombosis and to limit abnormal bleeding are the subjects of this chapter.
Best Ayurvedic medicine for Gas and IndigestionSwastikAyurveda
Here is the updated list of Top Best Ayurvedic medicine for Gas and Indigestion and those are Gas-O-Go Syp for Dyspepsia | Lavizyme Syrup for Acidity | Yumzyme Hepatoprotective Capsules etc
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
2. Physiologist Johannes Müller described fibrin, the
substance forming thrombus serving as the first
milestone for anti coagulants.
Arthus discovered in 1890 that calcium was essential
in coagulation.
First anti coagulant preservative was used by Rous &
Turner in 1916 contained of citrate-glucose solution
and was used to store human blood during first world
war in 1987.
3. Heparin is one of the oldest drugs currently in
widespread clinical use. It was originally isolated
from canine liver cells, hence its name Heparin.
Heparin's discovery can be attributed to the
research activities of two men: Jay McLean and
William Henry Howell.
1950’s Mark Rubin at Georgetown University
demonstrated that EDTA would chelate plasma
calcium.
4. A substance that prevents coagulation or clotting
of blood but doesn’t dissolve an already formed
clot.
Uses
• Storage of blood for blood transfusion or
hematological testing
• Therapeutic
5. Used in vivo
Parenteral
Heparin, Low molecular weight heparins,
heparinoids
Oral
Coumarin derivatives
Indandione derivatives
Used in vitro
Heparin
Calcium complexing agents
Sodium citrate, sodium oxalate, sodium edetate
6. Discovered by McLean
Howell and Holt coined the word “HEPARIN” in
1918
Mainly occurs in mast cells
Richest source of mast cells:
a. Lungs
b. Liver
c. Intestinal mucosa
. Commercial heparin is synthesized from :
- Porcine intestinal mucosa
- Bovine lungs
.
7. Heparin : A mixture of straight chain (anionic)
glycosaminoglycan, with a wide range of molecular
weights
Contains polymers of two sulfated disaccharides: D-
glucosamine-L-iduronic acid and D-glucosamine-D-
glucoronic acid
Strongest organic acid in our body – strong
electronegative charge
8. - Heparin highly charged poorly crosses cell
membranes thus given parenterally
- Low dose : given s.c
- High dose : given s.c and i.v
- Metabolism : by liver
- Half life depends on dose given
- 30-60 min
9. Treatment and prophylaxis
deep venous thrombosis
pulmonary embolism
peripheral arterial embolism
Atrial fibrillation with embolization
ACS
DIC
Prevention of clotting
arterial and cardiac surgery
blood transfusions
extracorporeal circulation
dialysis procedures
blood samples for laboratory purposes.
10. Monitoring the Anticoagulant Effect
activated partial thromboplastin time (aPTT) -
1.5 to 2 times normal.
Total Clotting time (2 times the normal)
Dosing
For prophylaxis - 5000 units SC BD/TDS
ACS
IV heparin bolus of 5000 units or 70 units/kg
followed by a heparin infusion rate of 12–15
units/kg per hour
13. +
Heparin accelerates
Antithrombin III
activity by 1000 fold
Especially against IIa
& Xa
Fast
Heparin
AT-III
complex
AT-III
Heparin
•Heparin
provides
scaffolding for
clotting factors
& AT-III
•Induces
confirmational
changes in AT-III
to expose its
interactive site
14. 1. AT LOW DOSES:
- Drug inactivates factor Xa and inhibits conversion
of prothrombin to thrombin
2. AT HIGH DOSES:
- Drug inactivates factors IX, X, XI, and XII,
thrombin
- Drug inhibits conversion of fibrinogen to fibrin
3. Drug inhibits activation of Factor VIII
4. Overall:
Drug binds to Antithrombin (AT)- III Forms
heparin-AT III complex inactivates clotting factors
Xa, II a, Ix a, XIII a, and XII a.
15. ANTIPLATELET
At high doses inhibits platelet aggregration, &
prolongs bleeding time.
LIPAEMIA CLEARANCE:
Inj. of low dose of heparin , releases a lipoprotein
lipase from the vessel wall or tissue , which
hydrolyzes the triglycerides of VLDL to free fatty
acids. Clears the turbid post-prandial lipaemic
plasma. Facilitates the transport of fatty acid.
16. HEPARIN – ADVERSE
EFFECTS
1. Bleeding due to overdose
2. Long term osteoporosis spontaneous fractures
3. Hypersensitivity (Anaphylaxis)
4. Transient alopecia
5. Thrombocytopenia
-Once thrombocytopenia is detected stop
heparin given direct thrombin inhibitor
-Do not give platelets platelets react with antibody
already being produced by them increased chance
of thrombosis
18. - Drug does not cross placenta should be
used instead of warfarin in pregnancy
- Warfarin crosses placenta causes changes
in fetus to cause fetal warfarin syndrome not
good……………….
19. Strongly basic LMW protein
Obtained from sperm of certain fish
1 mg IV neutralizes 100 U of heparin
Needed infrequently to antagonize heparin action
rapidly
Rapid IV injection causes flushing and breathing
difficulty
20. Barbiturate derivative:
Decrease the effect of heparin by incresing the
metabolism – use alternatives
Antithrombin iii
Increases the effect of heparin
Azithromycin:
Increases effects of heparin by decreasing
metabolism.
21. Low Molecular Weight Heparins
• M.Wt : 3000-7000
• Selectively inhibit factor Xa ,No effect on IIa
• Used for prophylaxis of Deep Vein Thrombosis
Pulmonary Embolism, Unstable angina
• ENOXAPARIN: 20-40 mg S.C , O.D
• REVIPARIN:13.8mg(0.25ml) S.C/OD for 5-10
days
• NADROPORIN :0.3ml(3075 units)
• TINZAPARIN :3500 units S.C every 24hr)
24. Dose
Side Effects
Bleeding
Thrombocytopenia
fivefold lower with LMWH than with heparin
Osteoporosis
Dalteparin Enoxaparin
Prophylaxis 2500-5000 units daily 20-40mg daily
DVT treatment 100 Units/kg BD 1mg/kg BD or
1.5mg/kg daily
25. CRITERIA HIGH MOL.WT HEPARINS LOW MOL. WT HEPARINS
Molecular weight High (30, 000 Daltons) Low (5,000 Daltons)
Biotransformation low High (90%)
Half life Short (Dose dependent) Longer (Dose independent)
MOA Inactivates both factor II a
and X a
Inactivates X a
Anticoagulant effect More effective Less effective
Monitoring By aPTT Doesn’t usually need
monitoring
Excretion Cleared by reticulo
endothelial system
Cleared unchanged by kidne
Expense Not expensive Expensive
Reversal By protamine Not fully reversed by
protamine
26. 1. Drugs bind to thrombin without additional
binding proteins such as anti- thrombin
HIRUDIN and BIVARUDIN:
ARGATROBAN
LEPIRUDIN :
- Monitored by Aptt
- Action independent of anti-thrombin
- Used in thrombosis related to heparin induced
thrombocytopenia
- No antidote
- ADR: Antibody formation against thrombin- Lepirudin
complex
27. WARFARIN
Inhibits the action of vit. K and interferes with the
synthesis of the vitamin K–dependent clotting
proteins, which include prothrombin (factor II) and
factors VII, IX, and X.
Antithrombotic effect of warfarin - depends on a
reduction in the functional levels of factor X and
prothrombin
28. - Rapidly and completely absorbed after oral
administration
- 100 % bioavailability
- High plasma protein binding capacity : 99%
- Crosses placenta- teratogenic
- Drug appears in milk thus infants are given Vit. K
- Slow hepatic clearance
- Metabolism : by liver, via OXIDATION and
GLUCURONIDATION
- Take 12-16 hours before effect is observed……
29. Indications
Atrial fibrillation
Mechanical heart valves
Deep venous thrombosis
Pulmonary embolism
Monitoring
Frequent monitoring
Prothrombin time
INR – International Normalized Ratio
produce a target INR of 2.0–3.0
Mechanical heart valves - 2.5–3.5
30. usually started at a dose of ≥5 mg
titrated to achieve the desired target INR
concomitant treatment with a rapidly acting
parenteral anticoagulant - 5-day course
Side Effects
Bleeding
Skin Necrosis
2–5 days after initiation of therapy
erythematous lesions form on the thighs,
buttocks, breasts, or toes
31. DRUG INTERACTIONS
Oral anticoagulant effect
ed by
• Broad spectrum
antibiotics
• Phenylbutazone
• Aspirin
• Sulfonamides
• Phenytoin
ed by
• Barbiturates
• Rifampin
• Oral
contraceptives
32. HEPARIN
Mucopolysaccharide
Parenteral
Immediate onset
Duration of action 4-6 hrs
Activity invitro & in vivo
Blocks action of factor X &
II
Antagonist - protamine
Monitor aPTT
WARFARIN
Coumarin derivative
Oral
Delayed onset of action
3-6 days
Only invivo
X synthesis of clotting
factors
Antagonist is Vit K
Monitor PT/INR
33. - Stop warfarin
- Administer Vitamin K (antidote)
- The following can also be given:
a. Fresh frozen plasma
b. Prothrombin complex concentrates
c. Recombinant factor VII a
34. Prior to administration:
Obtain a complete health history including recent
surgeries or trauma,
allergies, drug history, and possible drug
interactions.
Obtain vital signs and assess in context of client’s
baseline values.
Observe for skin necrosis
Monitor for signs of bleeding: excessive bruising,
pallor, epistaxis,, hematemesis, menorrhagia,
hematuria, melena
Monitor laboratory values: aPTT , PT/INR for
therapeutic values.
35. Administer :
At the same time each day to maintain steady blood
levels
Do not aspirate/massage the area when giving S/C
ADMINISTER antidotes for excessive bleeding
Instruct client to:
report sudden dyspnea, chest pain, temperature or
color change in the hands, arms, legs, or feet.
Report blood coming from a cough, the nose,
mouth, or rectum; menstrual “flooding”; “coffee
grounds” vomit; tarry stools; excessive bruising
report palpitations, fatigue, or feeling faint
Use a soft toothbrush and an electric shaver.
keep a “pad count” during menstrual periods to
estimate blood losses.
36. Avoid wearing constrictive clothing
Avoid sitting and standing in one position for long
periods of time
Avoid crossing legs and lying or sitting with pillows under
knees
Elevate legs periodically, especially when sitting
Maintain recommended weight for age, height, and body
frame.
Inform client that smoking and the use of estrogen or
oral contraceptives can increase the risk for recurrent
thrombus formation.
Provide information regarding exercise programs and
support groups that can assist the client to stop smoking
and/or lose weight.
The extrinsic pathway is initiated upon vascular injury which leads to exposure of tissue factor, TF
The contact activation pathway begins with formation of the primary complex on collagen
Antithrombin 3 plays a crucial role as natural endogenous anticoagulant by blocking the activity of activated factors 2,9,10,11,12. under physiological setting these interactions are slow and work on demand and supply basis
Heparin is a powerful and instantaneous acting anticoagulant, effective both inVivo & invitro , it acts indirectly by activating plasma antithrombin III, this complex binds to clotting factors of intrinsic as well as common pathways and inactivates them but not factor VIIa operative in extrinsic pathway. At low concentration selectively effects Xa.
Main Mech of action: The anticoagulant action is mediated by inhibition of factor Xa as well as Thrombin (IIa) mediated conversion of fibrinogen to fibrin. Low concentration of heparin prolong aPTT without significantly prolonging PT. high conc prolong both aPTT and PT, thus low conc interfere selectively with intrinsic pathway. While high conc affect the common pathway as well.
Bleeding due to overdosage is most serious adverse effect of heparin therapy, hematuria is the first clinical sign generally, with proper monitoring serious bleeding is reported in 1-3% of the patients
Thrombocytopenia (Platelet count less than 1.5 lac or reduction by 50 % of pretreatmrnt value) is another common problem. Occurs in about 0.5 % of the patients 5 to 10 days after initiation of therapy. Incidence of thrombocytopenia is low with LMWH.IgG antibodies against complexes of heparin with platelet factor 4.or other chemokines. These complexes activate platelets by binding to Fc/Iia receptors which results in platelet aggregation, release of more platelet factor and thrombin generation, heparin should be discontinued immediately if unexplained thrombocytopenia occurs
an alternative anticoagulant such as lepirudin, argatroban, or danaparoid (see below) should be administered to patients with heparin-induced thrombocytopenia. Low-molecular-weight heparins should be avoided, because these drugs often cross-react with standard heparin in heparin-dependent antibody assays. Warfarin may precipitate venous limb gangrene or multicentric skin necrosis in patients with heparin-induced thrombocytopenia and should not be used until the thrombocytopenia has resolved and the patient is adequately anticoagulated with another agent. Osteoporosis can occur on long term use of relatively high doses
Heparin can inhibit the synthesis of aldosterone by the adrenal glands and occasionally causes hyperkalemia, even when low doses are given.
Transient and reversible alopecia is infrequent . Serum transaminase levels may rise
Hypersensitivity reactions are rare- urticaria, rigor, fever, and anaphylaxis
For treatment of heparin induced bleeding due consideration should be given to amount of heparin that may have been degraded by patients body in mean time. However it is needed infrequently because the action of heparin disappears by itself in few hour, and whole blood transfusion is indicated to replinishthe loss when bleeding occurs.
Protamine is more commonly used when heparin action needs to be terminated rapidly. E.g agter cardiac or vascular surgery.
Being basic in nature it can release histamine in body . Hypersensitivity reactions have occurred .