Blood/Endocrine Flashcards
An 85-year-old woman is admitted to the acute medical unit with a urinary tract infection. Her past medical history includes a left-leg deep vein thrombosis 5 years ago, for which she was treated with warfarin for 3 months. She has no risk factors for bleeding and her renal function is normal.
What is the most appropriate antithrombotic therapy while in hospital?
A. Aspirin 75 mg orally daily
B.Dalteparin 5000 units SC daily
C.Dalteparin 5000 units SC daily and warfarin orally to target INR 2–3
D. Unfractionated heparin 5000 units SC 12-hourly
E. Warfarin orally to target INR 2–3
B. Dalteparin 5000 units SC daily. All patients admitted to hospital should be assessed for the risk of developing venous thromboembolism (VTE). Pharmacological prophylaxis should be prescribed if there are any thrombotic risk factors, provided the patient is not at risk of bleeding. This patient’s thrombotic risk factors include her age, history of deep venous thrombosis, and likely immobility during her acute illness. The usual choice is a low molecular weight heparin (LMWH) prescribed at a ‘prophylactic dose’, such as dalteparin 5000 units SC daily or enoxaparin 40 mg SC daily.
LMWH is preferred over unfractionated heparin (UFH) because its effect is more predictable. However, it is eliminated by the kidneys so is less appropriate in patients with renal impairment. In these cases, UFH may be used. Aspirin is usually employed to prevent arterial thromboembolism, for example after a stroke. Its role in the prophylaxis of venous thrombosis is limited. Warfarin is used in the treatment of established VTE to prevent clot extension and recurrence. In this context, it is often initially combined with a LMWH. However, it is not employed routinely in inpatients to prevent VTE.
A 77-year-old woman attends the anticoagulation clinic. She has a past medical history of atrial fibrillation and stroke. She takes warfarin and has been on a stable dosage for about 2 years. Last month, she was briefly admitted to hospital following a seizure. This was ascribed to cerebrovascular disease and she was put on an ‘antiepileptic medicine’. She does not know its name and has not brought a list of her medications.
Her INR today is 1.6 (target 2–3).
What drug is most likely to interact with warfarin to lower the INR?
A. Carbamazepine
B. Diazepam
C. Gabapentin
D. Pregabalin
E. Valproate
A. Carbamazepine. Warfarin is metabolised by cytochrome P450 enzymes. Carbamazepine is an ‘inducer’ of certain cytochrome P450 enzymes; that is, it interacts with the regulatory regions of the genes to increase their transcription. The resulting increase in the amount of enzyme allows warfarin to be metabolised more rapidly. This means that less warfarin is available to inhibit clotting factor production, so its anticoagulant effect is diminished and the INR falls. This puts the patient at risk of thromboembolic complications.
Valproate is a cytochrome P450 inhibitor, so its effect would be to increase the INR. Gabapentin and pregabalin are notable among antiepileptic drugs in having few drug interactions. Diazepam is a benzodiazepine which is used to treat acute seizures, but not for chronic seizure prophylaxis. It does not interact with warfarin.
The term ‘cytochrome P450’ refers to a family of enzymes. At undergraduate level you would not be expected to know about the individual members of this family, so it is reasonable to consider them collectively. Moreover, there is some cross-talk between the family members. For example, carbamazepine is a major inducer of CYP3A4 (the cytochrome P450 enzyme that, in general, makes the greatest contribution to drug metabolism), but like most other CYP3A4 inducers, it also induces CYP2C9 (the most important contributor to warfarin metabolism).
p450 inducers:
Carbamezepine
Rifampicin
Alcohol
Phenytoin
Griseofulvin
Phenobarbitone
Sulfonyureas
What are the different types of insulin?
Types (rapid acting, short acting, intermediate acting, long acting, biphasic insulin)
Clinical indications
Mechanisms of action
Important adverse effects
Warnings
Types
- rapid acting-> insulin aspart (novorapid)
- short acting-> soluble insulin (actrapid)
- intermediate acting-> isophane insulin (humulin)
- Long acting-> insulin determir-preferred in biphasic regime (levemir)/insulin glargine (lantus)
- Biphasic insulin-> mixture of rapid acting/intermediate acting (novomix)
Clinical indications
- Diabetes mellitus T1/2
- Diabetic emergencies (DKA/HHS-given IV actrapid)
- Treatment of hyperkalaemia with 5% dextrose solution (actrapid)
Mechanisms of action
- Stimulates glucose uptake into skeletal muscles and other cells, stimulates glycogenesis, lipogenesis, protein synthesis. Prevents ketogenesis and gluconeogenesis
- Stimulate Na+/K+ pump
Important adverse effects
- Can cause hypoglycaemia
Warnings
- For those with renal impairment, can cause hypoglycaemia
Metformin
Clinical indications
Mechanisms of action
Important adverse effects
Warnings
Clinical indications
- T2DM (biguanide)
Mechanisms of action
- Increases insulin sensitivity therefore increasing glucose uptake into skeletal cells; Suppresses gluconeogenesis by liver and suppresses glucose reabsorption by intestine
Important adverse effects
- GI symptoms like nausea and vomiting
- Lactic acidosis-especially with renal impairment (reduced excretion), hepatic impairment (reduced metabolism), or sepsis/hypotension/cardiac failure
Warnings
- Avoid in renal impairment (reduced excretion), hepatic impairment (reduced metabolism), or sepsis/hypotension/cardiac failure
Thiazolidinediones (pioglitazone)
Clinical indications
Mechanisms of action
Important adverse effects
Warnings
Thiazolidinediones (pioglitazone)
Clinical indications
- T2DM
Mechanisms of action
- Insulin sensitizers that cause glucose uptake into cells by activating PPAR receptor (nuclear peroxisome proliferator activated receptor)
Important adverse effects
- GI upset
- Anaemia
- Neurological signs like headaches, dizziness, visual disturbances
- Oedema and cardiac failure
- Bladder cancer and Bone fractures
- Liver toxicity
Warnings
- Avoid in those with cardiac problems, bladder cancer or hepatic impairment
Sulfonyureas (glicazide)
Clinical indications
Mechanisms of action
Important adverse effects
Warnings
Sulfonyureas
Clinical indications
- T2DM
Mechanisms of action
- Promote insulin secretion by pancreas by blocking K+ ATPase channel and stimulating depolarisation
Important adverse effects
- Hypoglycaemia because of insulin stimulation (especially in hepatic/renal impairment)
- weight gain
Warnings
- Hepatic/renal impairment
GLP-1 agonists (glucagon-like peptide) ~glutide
DPP-4 agonists (~gliptin)
SGLT2 inhibitors (~glifozin)
Mode of action
GLP-1 agonists (glucagon-like peptide) ~glutide
DPP-4 agonists (~gliptin)
SGLT2 inhibitors (~glifozin)
Mode of action
- GLP-1 agonists (glucagon-like peptide-1)
GLP-1 agonists work on receptor in B cells of pancreas and enhances insulin secretion.
Example: dulaglutide, exenatide liraglutide (~tide)
- exenatide is used in combination with metformin + sulfonyurea + GLP-1 agonists if BMI>35
- can also be used if BMI<35 and insulin is not tolerated
- DPP-4 inhibitors
Works in synergy with GLP-1 agonists. They prevent DPP-4 enzyme from deactivating GLP-1, thus increasing GLP-1 levels in the blood stream.
Example: alogliptin, linagliptin, sitagliptin (~gliptin)
Medication that works in the intestine:
- Alpha glucosidase inhibitor
Example is acarbose, a sugar that competitively inhibits alpha glucosidase, brush border enzyme that breaks down carbohydrate into glucose, thus preventing glucose reabsorption.
Medication that work in the kidneys:
- SGLT-2 inhibitors
Inhibit sodium-glucose transport protein 2, thus preventing reabsorption of glucose in the kidney.
Example: canaglifozin, dapaglifozin, empaglifozin (~glifozin)
