Topics/Drug Classes – Page 4

Category: Topics/Drug Classes (page 4 of 6)

Does levothyroxine overdose cause exophthalmos and lid lag?

Graves’ disease, an autoimmune disorder resulting in hyperthyroidism, can be associated with bulging eyes (exophthalmos) and a staring gaze (lid lag). Does overdose of levothyroxine cause the same signs?

Graves’ disease is an autoimmune disease involving production of antibodies against the thyroid-stimulating hormone (TSH) receptor (TSHR), also known as the thyrotropin receptor (Davies, 2017). The autoantibodies to the thyrotropin receptor (TRAb) activate TSHRs. In most patients this results in stimulation of thyroid hormone synthesis and secretion resulting in hyperthyroidism.

Hypothyroidism, for example caused by Hashimoto’s thyroiditis, is often treated with levothryoxine to replace the deficiency in endogenous thyroxine. Overdose of levothyroxine can cause hyperthyroidism.

But Graves’ disease is not synonymous with hyperthyroidism (Davies, 2017). Some patients produce TRAb but do not have hyperthyroidism and, by mechanisms independent of thyroid hormone secretion, TRAb can cause orbitopathy resulting in exophthalmos, and dermopathy due to pretibial myxoedema.

Do levocetirizine and cetirizine really cause drowsiness?

February 12, 2018 / phcdgs / 0 Comments

I have looked at the package insert for XyzalⓇ (levocetirizine) and see no mention of drowsiness. Isn’t it that second and third generation antihistamines do not cause drowsiness or only cause drowsiness on overdose?

Levocetirizine is the levorotatory (“left-handed”) enantiomer of the second generation antihistamine cetirizine, which is a racemic mixture. Levocetirizine is sometimes referred to as a third generation antihistamine because it is a derivative of a second generation agent.

First generation antihistamines enter the brain and cause drowsiness by antihistamine actions at H₁ receptors. Second generation antihistamines enter the brain less than first generation antihistamines and so cause less drowsiness. However, among the second generation antihistamines, not all are equal. Some, including cetirizine, still cause some degree of drowsiness.

Even for levocetirizine, the drowsiness is significant enough at normal clinical doses that a special precaution when driving, having high-risk work, or operating machinery is included in the product insert (see image below). The term used for drowsiness in the package insert is somnolence.

Is dextromethorphan an opioid or not?

February 12, 2018 / phcdgs / 0 Comments

The Monthly Index of Medical Specialities (MIMS) states under Anatomical Therapeutic Chemical (ATC) Classification: “R05DA09 – dextromethorphan; Belongs to the class of opium alkaloids and derivatives. Used as cough suppressant”. But your lecture and the textbooks say that dextromethorphan is a non-opioid antitussive. Why is there this discrepancy?

An opium alkaloid is an alkaloid found in opium. An opioid is a drug which acts at opioid receptors. The major active alkaloids in opium, such as morphine and codeine, act at opioid receptors. They are both opium alkaloids and opioids. But not all opium alkaloids act at opioid receptors. Dextromethorphan is chemically an opium alkaloid derivative but it does not act at opioid receptors so pharmacologically it is not an opioid. It is a non-opioid opium alkaloid derivative.

Just as codeine is metabolised to morphine, dextromethorphan is converted to the more potent active metabolite dextrorphan. Dextrorphan is a dextro- (right-handed) enantiomer (dextrorotatory-stereoisomer) of which the corresponding levo- (left-handed) enantiomer is levorphanol, a potent opioid analgesic. Dextromethorphan and dextrorphan are right-handed enantiomers that do not act at the opioid receptor. They are therefore not opioids despite being opium alkaloid derivatives closely related to the potent opioid levorphanol.

The importance of dextromethorphan being a non-opioid is that does not share the same mechanisms of opioid dependence and addiction as codeine and so has a lower potential for abuse than codeine. However, dextromethorphan is not utterly devoid of risk of abuse. Dextromethorphan is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and at high doses has dissociative anaesthetic-like effects similar to ketamine and phencyclidine (PCP).

Myxoedema in hypothyroidism versus pretibial myxoedema in Graves’ disease

January 8, 2018 / phcdgs / 0 Comments

Intravenous (IV) liothyronine is used to treat severe hypothyroidism resulting in myxoedema and myxoedematous coma. But Graves’ disease, which causes hyperthyroidism, is also associated with myxoedema in the form of infiltrative dermopathy or pretibial myxoedema. Can liothyronine be used to treat pretibial myxoedema? But, if we give IV liothyronine to someone with Graves’ disease suffering from pretibial myxedema, wouldn’t this cause thyroid storm instead?

Myxoedema refers to a relatively hard oedema (as opposed to a soft, fluid oedema) caused by the accumulation of mucopolysaccharides in the interstitial fluids.

The term “myxoedema” alone refers to generalised myxoedema and is used to describe severe hypothyroidism characterised by myxoedema of cutaneous tissue together with other symptoms including somnolence, slow mentation, dryness and loss of hair, ascites, hypothermia etc. This is a severe condition that can result in coma and death. The accumulation of mucopolysaccharides is a direct result of the hypothyroidism as thyroxines are required for their turnover.

When IV liothyronine is used for the treatment of myxoedema or myxoedematous coma, it is the treatment of this form of severe hypothyroidism that is being referred to.

“Pretibial myxoedema” refers explicitly to infiltrative dermopathy localised in the pretibial area (the shin). In this case, the infiltration and accumulation of mucopolysaccharides (especially the glycosaminoglycan hyaluronic acid) is due to secretion from fibroblasts. The pathogenesis is not caused by thyroid hormone levels. The exact pathogenic mechanism is not known, but it is generally thought that it is due to the autoimmune response. Fibroblasts express TSH receptor protein and are likely targeted by the TSH receptor antibodies produces in Graves disease. Cytokines secreted by Th1 type T cells activated by TSH receptor antigen may also stimulate fibroblasts to secrete glycosaminoglycans.

Pretibial myxoedema is not treated with IV liothyronine as thyroid hormone levels are not responsible for this localised inflammatory myxoedema.

Reference:

Davies, TF. Pretibial myxedema (thyroid dermopathy) in autoimmune thyroid disease. Ross, DS, Mudler, JE ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on January 8, 2018).

Carbimazole, thiamazole, methimazole – what is the difference?

November 29, 2017 / phcdgs / 0 Comments

Carbimazole is a pro-drug converted to the active metabolite thiamazole. Thiamazole and methimazole are the same chemical. Thiamazole is the international nonproprietary name (INN) while methimazole is the United States adopted name (USAN).

Thiamazole is a thioamide used to treat hyperthyroidism such as in Graves’ disease. In the USA, thiamazole (known there as methimazole) is the most widely used thioamide. However, in many other parts of the world carbimazole is the preferred thioamide. The half-life of carbimazole is 3 to 6 hours, while the half-life of thiamazole is 6 to 15 hours. As thiamazole is the active compound, when a patient takes carbimazole, the half-life of the drug effect is 9 to 21 hours. Thus carbimazole can be taken once per day while thiamazole usually has to be taken three times per day or twice per day.

Why does vagotomy cause diarrhoea?

November 29, 2017 / phcdgs / 0 Comments

Discussing the use of bile salt-binding resins, such as colestyramine (cholestyramine USAN), and somatostatin peptide drugs, such as octreotide, for the treatment of diarrhoea we saw that these drugs are only used for specific types of diarrhoea, such as secretory diarrhoeas. One example given was diarrhoea following vagotomy.

But why does vagotomy cause diarrhoea? Vagotomy is a surgical technique indicated for patients who develop acute complications from peptic ulcer disease or chronic symptoms despite being on maximally tolerated medical therapies. Damage to the vagus nerve can also occur following bariatric surgery, fundoplication, and oesophagal resection. Postvagotomy diarrhoea has been described in up to 30 percent of patients. Many patients have transient watery diarrhoea for three to six months postvagotomy but in some the diarrhoea can be severe and chronic.

Does nicotine cause sweating?

October 25, 2017 / phcdgs / 0 Comments

The eccrine sweat glands express muscarinic M3 cholinergic receptors. In an exception to the usual rule that the postganglionic neurotransmitter for the sympathetic nervous system is noradrenaline or adrenaline, the sympathetic nervous system innervates the eccrine sweat glands with cholinergic nerve fibres. Thus, sweating associated with the fight-or-flight response is a sympathetic nervous system response mediated by cholinergic activation of M3 receptors.

But does nicotine not also cause sweating? Nicotine can contribute to sweating in a number of ways. The preganglionic nerve fibres of both the sympathetic and parasympathetic nervous system are cholinergic release acetylcholine to activate nicotinic cholinergic receptors on the ganglionic neurones. Thus nicotine can directly activate the ganglionic neurones triggering activation of the cholinergic postganglionic sympathetic nervous system innervation of the eccrine sweat glands.

The nerve terminals innervating the sweat glands also have presynaptic nicotinic receptors. Application of acetylcholine or nicotine to the skin will activate these nerve terminals triggering action potentials to branches of the nerve innervating adjacent sweat glands to release acetylcholine and activate postsynaptic M3 receptors on these sweat glands. This is referred to as the sudomotor axon reflex.

Image credit: http://www.medicavisie.eu/de/technologien/#sudomotor

Note that to acheive activation of nicotinic receptors exposure to nicotine has to be at a low dose and for a short duration. High doses of nicotine or prolonged exposure to nicotine can lead to depolarising and desensitising block of nicotinic receptor neurotransmission.

How long is the window before ageing of acetylcholinesterase after organophosphate poisoning?

October 25, 2017 / phcdgs / 0 Comments

Organophosphates essentially irreversibly inhibit acetylcholinesterase by leaving a phosphate group bound to the enzyme. Oximes, such as pralidoxime, reversibly bind to acetylcholinesterase and have high affinity for binding to phosphate groups. They can, therefore, bind to acetylcholinesterase, pick up the phosphate group inhibiting the acetylcholinesterase, and take the phosphate group with them when they leave the acetylcholinesterase. Thus pralidoxime can be used to regenerate acetylcholinesterase after organophosphate poisoning.

A limitation of pralidoxime is that it is only effective in a limited time window before ageing of the organophosphate inhibition of acetylcholinesterase occurs. Pralidoxime itself binds to and competitively inhibits acetylcholinesterase. Therefore, if pralidoxime is administered after all the organophosphate-inhibited acetylcholinesterase has already aged, pralidoxime will just make the anticholinesterase poisoning worse. It is therefore important to administer pralidoxime in the appropriate time window.

How can I remember the adverse effects of over-activation of the parasympathetic nervous system?

October 25, 2017 / phcdgs / 5 Comments

The adverse effects of over-activation of the parasympathetic nervous system, for example by poisoning with an acetylcholinesterase inhibitor, can be remembered by the following mnemonic, SLUDGE/BBB:

Salivation
Lacrimation
Urination or urinary incontinence
Defecation or diarrhoea
Gastrointestinal distress
Emesis
/
Bradycardia
Bronchoconstriction
Bronchorrhoea

Alternatively, you can use the mnemonic, DUMBELS:

Defecation or diarrhoea
Urination or urinary incontinence
Miosis
Bradycardia / Bronchoconstriction / Bronchorrhoea
Emesis
Lacrimation
Salivation

Why does it matter that neostigmine is resistant to hydration or hydrolysis?

March 2, 2017 / phcdgs / 0 Comments

Why do we say that neostigmine inhibition of acetylcholinesterase is resistant to hydration or hydrolysis? Why do some textbooks say resistant to hydration, while others say resistant to hydrolysis? Are hydration and hydrolysis the same thing?

Neostigmine is an example of a carbamate anticholinesterase. It inhibits the breakdown of acetylcholine by acetylcholinesterase and so increases the availability of synaptic acetylcholine wherever it is release. Clinically it is used to reverse non-depolarizing neuromuscular blockade (e.g. coming out of surgical anaesthesia) and in the treatment of myasthenia gravis. It is also sometimes used to increase gastrointestinal motility on postoperative or neurogenic ileus and in the treatment of urinary retention secondary to bladder atony.

Acetylcholinesterase works by rapidly hydrolyzing acetylcholine (which is an ester of acetic acid and choline) to acetic acid and choline. Carbamate esters competitively inhibit acetylcholinesterase by occupying the active site on the enzyme and taking much longer to be hydrolyzed. They work by forming a carbamoylated acetylcholinesterase-drug complex that is resistant to hydration and hence is resistant to hydrolysis.

Hydration and hydrolysis are not the same thing. Hydration is the addition of water (H₂O) whereas hydrolysis is the breaking of a bond by reaction with water. However, in the case of the carbamoyl group attached to acetylcholinesterase the hydrolysis is a two-step process: first requiring hydration (addition of the water) before hydrolysis (breaking of the bond between the carbamoyl group and the acetylcholinesterase). Hence, for the carbamate anticholinesterase inhibition of acetylcholinesterase, the resistance to hydrolysis is a consequence of resistance to hydration.