A female patient, 32 year old is admitted in emergency department, she was dehydrated, hyperventilating and have impaired consciousness. After investigations relevant findings are- known diabetic type-1 patient, using insulin subcutaneously and presently suffering from fever for 5 days, recently having episode of nausea, vomiting along with pain abdomen. blood investigations are suggestive of hyperglycemia, hyperketonemia and acidosis. Urine examination demonstrate ketones in urine.

Discussion-

It is a case of Diabetic Ketoacidosis. It can be life threatening and considered as medical emergency. More common in Type-I Diabetics, it is precipitated by Infection, stress, trauma, inadequate dose of insulin. Patient has severe hyperglycemia and excessive ketone bodies along with vomiting, abdominal pain, impaired consciousness, metabolic acidosis, dehydration etc.

Management-

As it is a life threatening condition, regular monitoring of vital signs, plasma glucose, blood pH, electrolytes, plasma acetone is needed. As management plan we have to take care of Dehydration, hyperglycemia ( 600-800 mg/dl) and acidosis along with infection (if present) .

(1) Fluid and electrolyte replacement – Normal saline is infused i.v., initially at the rate of 1 liter in first hour (If shock is present then rapid infusion of normal saline until blood pressure rises to normal), then Continue IV normal saline 500 ml/hour for next four hours

(2) Hyperglycaemia management– Intravenous Regular insulin (0.1 U/kg i.v. is followed by 0.1 U/kg/hour till blood glucose reaches 300 mg/dl, usually takes 4-6 hours). Then stepwise approach to shift from IV to SC insulin when patient has fully recovered.

(3) Acidosis Management- If severe acidosis is present (arterial blood pH <7.00) then sodium bicarbonate is used.

(4) KCl – As we know that there is loss of potassium in urine during ketoacidosis and IV insulin causes dose dependent decline in serum potassium and ultimately both conditions can lead to serious hypokalemia. So, after 2–3 hours, KCl 10–20 mEq/hr is added to the i.v. fluid.

(5) Antibiotics- If the precipitating cause is infection, then find and treat the infection with appropriate antibiotic simultaneously.

I hope that this case based study will help you to understand the basic principles in management of this medical emergency……..have a great day

Lets start SERM in brief…………

Tamoxifen, Raloxifene and Toremifene are the example of SERMs

Tamoxifen – Estrogen receptor antagonistic activity in Breast, used in the treatment and prevention of breast carcinoma.

Toremifene– Newer congener of tamoxifen

Raloxifene– Used in Prevention and treatment of osteoporosis in postmenopausal women.

Now after short briefing, lets dive deeper…………………

Well, as we know that female hormone Estrogen plays a variety of roles.

It decreases the bone resorption

It improves the lipid profile

But it increases the risk of Brest and endometrium carcinoma also

So, while giving the estrogen due to any cause (eg. in postmenopausal women as Hormone replacement therapy or to prevent osteoporosis in menopausal women) we are having some good and wanted effects and some unwanted/deleterious effects like increased incidences of breast and uterus carcinoma.

And after lots of experiments especially on the ovariectomized rats, SERMs were introduced which have agonistic action on estrogen receptors in some tissues and antagonistic action on other tissue in a selective manner. In another words they have estrogenic or antiestrogenic effects depending on tissues.

Tamoxifen-

Estrogen antagonistic activity  – In Breast

Estrogen agonistic activity – Bone and uterus

It is used in the treatment of breast carcinoma in postmenopausal women with more prominent effect on estrogen receptor positive tumors.

Also used in Prevention of breast carcinoma in high risk women

Increased bone density due to reduced bone resorption (estrogen agonistic activity)

Tamoxifen is a orally effective drug with long duration of action.

Due to its agonistic/ estrogenic activity on uterus, it increases the chances of endometrial carcinoma.

It increases the chances of thromboembolism due to increased blood coagulability (induction of synthesis of clotting factors II, VII, IX & X).

Nausea, vomiting , anorexia, hot flushes, vaginal dryness skin rashes can also occur.

Toremifene

It is a newer congener of Tamoxifen with similar effects and side effects, indicated in treatment of metastatic breast cancer in postmenopausal women.

Raloxifene

Estrogen receptor Agonist at bones

Used in Prevention and treatment of osteoporosis in postmenopausal women.

And it has antagonistic activity at endometrium and breast

Hence no increased chances of endometrial and breast carcinoma.

And it is also approved for prevention of breast cancer in high risk women

Side effect profile includes – hot flushes, vaginal bleeding

However increased chances of thromboembolism is also a serious concern which also increases the chances of deep vein thrombosis and pulmonary embolism.

So, this is SERM in a brief manner….

Hope this article helps you to understand the concept better………Happy learning

Now, I have taken this challenge to simplify Bisphosphonates,  let me try to complete this task in three sentences…..

1. Bisphosphonates are the drugs commonly used for treatment of Osteoporosis.
2. Example are Alendronate, Zoledronate (zoledronate is most potent, given by infusion in dose of 4 mg yearly, i repeat, once every 12 month, for t/t of osteoporosis)
3. Esophageal irritation, erosion and ulcers with oral drugs are common and renal toxicity, osteonecrosis of jaw are seen with use of zoledronate

Now if i get your attention………..lets dive deeper

Bisphosphonates are the drugs which act by decreasing the activity of osteoclasts,  they get entry in osteoclasts by endocytosis and they –

1. Increased apoptosis of osteoclasts
2. Inhibit differentiation of osteoclast precursors (this is method by which osteoclasts are formed) by suppressing IL-6

If we talk about pharmacokinetics, Bisphosphonates are poorly absorbed from GIT and produce esophageal irritation, erosion and ulcers as major side effects.

To prevent these side effects of oral bisphosphonates, it is advised to take these drugs empty stomach with full glass of water, and instruction is given to patient “not to lie down for at least thirty minutes after taking these drugs” , these measures prevent the contact of drug from esophageal mucosa.

These drugs are divided into three generations

First generation –  Etidronate

Least potent, rarely used now a days

Second generation – Alendronate, Pamidronate

Third Generation– Risedronate, Zoledronate

More potent, Higher efficacy

These drugs are widely used for-

1. Osteoporosis – Idiopathic osteoporosis, age related osteoporosis, steroid induced osteoporosis, postmenopausal osteoporosis etc.  
2. Hypercalcemia of malignancy– common complication in malignancy, this is a condition of medical emergency. oral bisphosphonates are not useful. Pamidronate or zoledronate are used.
3. Bone metastasis (Osteolytic)– Due to osteolytic suppression action, they are useful in stopping osteolytic lesions and reduce bone pain
4. Paget’s disease– this is a disease caused due to abnormal osteoclast activity, thus  bisphosphonates are useful

Now a days, Bisphosphonates are the First choice drugs for osteoporosis

Zoledronate has also antitumor effect (it additionally interfere with mevalonate pathway)

Case based Learning of Pharmacology –

Q.     A 30 years old female came to the OPD with complaints of weakness, feeling tired all the time, sudden weight gain, puffiness on the face and eyelids and headache.

On further examination she gives history of irregular scanty menses and intolerance to the cold, also dry skin and dry, brittle hair along with brittle nails, she has heart rate of 52/ min (bradycardia) with ECG showing long PR interval and flat T wave.

The diagnosis is confirmed by the blood reports which shows raised serum TSH and low serum free thyroxine (FT3 and FT4).

• What is the diagnosis and
• How will you manage this patient ?

Answer-

• It is a case of Hypothyroidism, which is one of the commonest endocrine disorders.
• To mange this patient we give Levothyroxine (synthetic salt of Thyroxine i.e. T4 )

Here now, the treatment strategy is to provide thyroxine (T4 ) by oral route and goal is to achieve normal TSH level.

Levothyroxine 50-100 mcg/day empty stomach is usually prescribed, and dose is adjusted by adding 12.5 or 25 mcg Levothyroxine gradually, if TSH is still high or decrease the dose by  12.5 or 25 mcg if TSH is suppressed.

If T4 and TSH both are low or both are high, then refer this case to the endocrinologist as it indicates the pathology at Hypothalamus or Pituitary level.

• Clinical Gems-
• Levothyroxine should always be given empty stomach to avoid interaction with food as it can impair the absorption of levothyroxine.
• Always explain to the patient that treatment is lifelong and the decision to modify dose or stop treatment should be done with proper consultation always.
• In pregnant hypothyroid patient, it is really important to take daily dose of Levothyroxine and maintain normal thyroid level, as it can affect the foetal brain development.
• Hypothyroidism can cause infertility in females due to frequent anovulatory cycles and it can be managed by restoring normal thyroid level.
• Myxoedema coma is a condition of medical emergency, arises as an end state untreated hypothyroidism, although rare, it has high mortality.
• Treatment of choice in Myxoedema coma is LevoThyroxine 500 mcg given as IV bolus and then 100 -300 mcg daily, along with warming the patient, iv corticosteroids, correction of metabolic disturbances and other symptomatic measures like mechanical ventilation for respiratory failure.

Hope this post will help you to understand concept more clearly……….Happy learning……..