NUR1121 – Page 2 – PharmaNUS

Category: NUR1121 (page 2 of 3)

Do levocetirizine and cetirizine really cause drowsiness?

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).

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

Side effects, adverse effects and contraindications

February 25, 2017 / phcdgs / 0 Comments

What is the difference between side effects, adverse effects and contraindications?

The terms “side effects” and “adverse effects” are often used interchangeably. This may be correct in many contexts, but the two terms do not mean exactly the same thing.

Side effects are effects seen on the side in clinical use. These effects occur at clinical therapeutic doses. Side effects encompass any effects that are not the intended clinical effect of the drug, whether or not these effects are harmful or adverse.

Why is aspirin not used in gout?

February 11, 2017 / phcdgs / 0 Comments

Non-steroidal anti-inflammatory drugs (NSAIDs) are used to control pain and inflammation in gout. Aspirin is the prototypical NSAID and is available over-the-counter (i.e. without a doctor’s prescription or consultation with a pharmacist or prescribing nurse). So why are patients with gout told not to take aspirin?

Gout is caused by elevated uric acid levels. At high levels, uric acid is deposited as monosodium urate crystals in the tissues of the joints. When the body’s immune system attacks the monosodium urate crystals, it triggers severe bouts of pain and inflammation. During these acute gouty attacks, the priority in the treatment of gout is to reduce the pain and inflammation. NSAIDs can help to achieve this. Between gouty attacks, a key aim in the treatment of gout is to reduce the plasma levels of uric acid to prevent recurrence of acute gouty attacks. This can be achieved by dietary modifications together with drugs such as allopurinol, which inhibits uric acid synthesis, and uricosuric drugs, which increase uric acid excretion through the kidney.

Aspirin is both an NSAID and uricosuric at high doses. Therefore, it might at first seem reasonable to use aspirin for the treatment of gout. However, the story is more complicated. At lower doses, aspirin and other salicylates are in fact anti-uricosuric. Taking aspirin or other salicylates can increase plasma uric acid levels and increase the risk of gout. Aspirin and other salicylates can also interfere with the action of uricosuric drugs prescribed for the treatment of gout.

So, what about taking high doses of aspirin? No, that is not helpful either.

Firstly, the uricosuric effect of apsirin only manifests at or above the higher end of the normal analgesic and anti-inflammatory therapeutic dosage range. Meanwhile, aspirin has a very short half-life of only about 20 min. This is the reason why for analgesic and anti-inflammatory use you have to take aspirin once every 4 to 6 hours. This means that it is hard, likely impossible, to maintain aspirin levels continuously within the uricosuric range without risking overdose and other adverse effects. Meanwhile, any time the plasma concentration of aspirin drops, the anti-uricosuric effects can kick in.

Secondly, the analgesic and anti-inflammatory actions of NSAIDs are more useful in combating acute gouty attacks. However, during acute gouty attacks, uricosuric agents are contraindicated. During gout attacks, uric acid is already mobilising out of the joints, and plasma levels are elevated. Forcing more uric acid out through the kidneys with uricosuric agents can increase the risk of kidney stones and kidney damage. Moreover, rapidly reducing plasma concentrations of uric acid creates a concentration gradient from the joints to the plasma causing more uric acid to mobilise from the joints. During mobilisation of the monosodium urate crystals, there is a greater chance of attack on the crystals by the body’s immune system. This increases the risk of making the gouty attack worse and triggering further gout attacks at other joints.

Neuropsychiatric adverse events with leukotriene inhibitors

February 7, 2017 / phcdgs / 1 Comment

Neuropsychiatric adverse events are reported in some patients taking leukotriene inhibitors (e.g. montelukast and zileuton)

In 2009, the USA Food and Drug Administration (FDA) reported on an investigation of neuropsychiatric adverse events associated with the leukotriene pathway inhibitors, both the leukotriene receptor antagonists (e.g. montelukast) and the 5-lipoxygenase inhibitor (zileuton) (1). It was concluded that “reported neuropsychiatric events include postmarket cases of agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, insomnia, irritability, restlessness, suicidal thinking and behavior (including suicide), and tremor”. The FDA, therefore, issued the following advice to patients and healthcare professionals:

“Advice to patients and healthcare professionals

Patients and healthcare professionals should be aware of the potential for neuropsychiatric events with these medications.
Patients should talk with their healthcare providers if these events occur.
Healthcare professionals should consider discontinuing these medications if patients develop neuropsychiatric symptoms.”

Reference:
(1) Updated Information on Leukotriene Inhibitors: Montelukast (marketed as Singulair), Zafirlukast (marketed as Accolate), and Zileuton (marketed as Zyflo and Zyflo CR)

Why is zileuton not a bronchodilator?

February 7, 2017 / phcdgs / 0 Comments

If cysteinyl-leukotriene receptor antagonists such as montelukast can relax the airways, why is it that the 5-lipoxygenase inhibitor, zileuton, does not produce any clinically significant bronchodilation?

Montelukast and other cysteinyl leukotriene (CysLT) receptor antagonists are unique among the anti-asthma drugs in that they are used clinically both for their anti-inflammatory and their bronchodilator effects. They are weak bronchodilators compared to the beta-2 agonists. They can not be used for relief of acute asthma attack because their effect is too weak and their onset of action is too slow. Nevertheless, they do have some bronchodilator effect because they block CysLT receptor-mediated bronchoconstriction. But CysLT receptor antagonists are weak bronchodilators because the CysLTs are just one of many signals triggering bronchoconstriction.

Zileuton is an inhibitor of the 5-lipoxygenase (5-LOX) enzyme necessary for the synthesis of the leukotrienes, including the CysLTs. So, if zileuton prevents the production of CysLTs, why does it not produce clinically significant bronchodilation? In fact, zileuton does produce some bronchodilation but not enough for it to be clinically useful as a bronchodilator. In theory, if zileuton was given at a sufficiently high dose to block all production of the CysLTs, one would expect that zileuton could achieve the same degree of bronchodilation as the CysLT receptor antagonists. In practice, however, this is not possible as side effects become the limiting factor in giving high doses of zileuton since it inhibits 5-LOX, and so blocks production of all the leukotrienes. Thus, within the clinical dose range, zileuton has anti-inflammatory effects but does not have a sufficient bronchodilator effect to be considered as a bronchodilator clinically. Zileuton does not inhibit either the early reaction acute bronchoconstrictor response or the late reaction to inhaled antigen and irritants. It is therefore not useful clinically as a bronchodilator.

What about the bronchodilators that have anti-inflammatory effects? Why are they not also considered to be dual-use bronchodilator and anti-inflammatory drugs?

Some of the bronchodilators do produce some beneficial anti-inflammatory effects. But these anti-inflammatory effects are nowhere near strong enough for these drugs to be used alone as preventers in the treatment of asthma. For example, both beta-2 agonists and theophylline stabilise mast cells, reducing mast cell degranulation, and reduce microvascular leakiness, thus reducing airway oedema. These are anti-inflammatory effects, but they are not sufficiently strong anti-inflammatory effects for these bronchodilators alone to prevent the ongoing inflammatory disease and airway remodelling. Hence, these bronchodilators are not considered to be anti-inflammatory drugs in the treatment of asthma.

Why is guaifenesin so difficult to spell?

February 6, 2017 / phcdgs / 2 Comments

Even among drugs names that are often difficult to pronounce or spell, guaifenesin stands out for tripping up more students on spelling in exams than other drug names. Why is “guaifenesin” spelt this way?

Breaking “guaifenesin” up into “guai” and “fenesin” may help us to remember how to spell the word. It is the “guai” that in particular seems unnatural in English and is difficult to spell. Perhaps understanding the origins of the “guai” in “guaifenesin” can help us to remember how to spell the word.

The “guai” in “guaifenesin” comes from the word “guaiac”. Guaiac has been an English word since at least 1558, some say 1533. It is the common name for trees of the genus Guaiacum. The word originates from the Maipurean language spoken by the native Taínos people of the Bahamas. “Guaiac” has the honour of being the first American language word adopted into the English language. The guaiac is famous for being the source of the hardest wood known. The resin and bark of the guaiac were also used in traditional medicine for coughs and various other conditions. Guaifenesin is the active compound in the treatment of coughs isolated from guaiac resin and bark.

Guaifenesin was also formerly spelt “guaiphenesin”. It is one of the few drugs for which the American contraction of “ph” to “f” is now adopted for the official international nonproprietary name of the drug. The chemical name for guaifenesin is glyceryl guaiacolate.

Interestingly, guaiac resin also made another significant contribution to medicine. A phenolic compound derived from guaiac tree resin has also been used in the faecal occult blood test (FOBT). The presence of haeme from blood causes this compound to form a coloured product when exposed to hydrogen peroxide.