Category: Topics/Drug Classes (page 3 of 6)

Ganglionic blockers versus depolarising NMBAs

May 5, 2021 / / 0 Comments

High-dose nicotine induces depolarising blockade and subsequent secondary non-depolarising blockade at autonomic ganglia. Meanwhile, depolarising NMBAs induce depolarising block consisting of Phase I and Phase II. Is it the same thing?

Yes, they are essentially the same mechanisms as far as the nicotinic receptors go. It is primarily a difference in terminology. Although secondary non-depolarising block is a more scientifically descriptive term than Phase II, the depolarising NMBAs are already called “depolarising” to contrast with the non-depolarising NMBAs (direct nicotinic receptor antagonists). It would therefore be confusing to say that depolarising NMBAs have a secondary non-depolarising block. Hence, the common usage of the Phase I and Phase II terminology.

Depolarising versus non-depolarising NMBAs

May 5, 2021 / / 0 Comments

What is the difference between a depolarising and a non-depolarising NMBA? Do both result in flaccid paralysis?

Depolarising neuromuscular blocking agents (NMBAs) are potent agonists at nicotinic receptors that cause depolarising block (and necessarily also the secondary desensitising/non-depolarising block). In contrast, non-depolarising NMBAs are direct competitive nicotinic receptor antagonists.

An important difference is that non-depolarising NMBAs can be reversed by increasing acetylcholine (ACh) levels by using an acetylcholinesterase inhibitor such as neostigmine. Depolarising NMBAs cannot be reversed in the same way since increasing ACh availability just causes more depolarizing block (and inevitably secondary desensitising/non-depolarising block).

As depolarising NMBAs initially cause activation, they will cause twitching/fasciculation followed by rigid paralysis on onset (although this phase is over quickly) before switching to flaccid paralysis. In contrast, non-depolarising NMBAs will go straight to progressive flaccid paralysis.

Allopurinol versus febuxostat

May 5, 2021 / / 0 Comments

When would a patient diagnosed with hyperuricaemia who had been successfully managed with allopurinol be switched to febuxostat?

Allopurinol is a purine analogue and competitive inhibitor of xanthine oxidase, a key enzyme in the production of uric acid by purine metabolism. Thus, allopurinol can effectively reduce plasma urate levels in the management of hyperuricaemia and chronic gout. Febuxostat is a non-purine competitive inhibitor of xanthine oxidase recommended for people who cannot tolerate allopurinol.

Allopurinol is associated with increased risk of rare but potentially fatal serious cutaneous adverse reactions (SCAR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS). Risk factors for allopurinol-induced SCAR include HLA-B5801 allele, starting dose of allopurinol, and renal impairment. The HLA-B5801 allele is more common among people of Asian ancestry, particularly the Han Chinese and Koreans. For example, in Singapore, the frequency of HLA-B*5801 prevalence is estimated at 18.5% (approximately 1 in 5 Singaporeans or 1 in 5 Chinese, 1 in 15 Malays, and 1 in 25 Indians).

Suppose a patient’s urate levels have responded well to allopurinol, but the patient has developed allopurinol-induced adverse effects, such as SCAR. In that case, switching to the other available xanthine oxidase inhibitor, febuxostat is a reasonable option.

https://www.hsa.gov.sg/announcements/safety-alert/allopurinol-induced-serious-cutaneous-adverse-reactions-and-the-role-of-genotyping

Neostigmine versus pyridostigmine

February 22, 2020 / / 0 Comments

What is the preferred oral acetylcholinesterase inhibitor for myasthenia gravis?

Pyridostigmine is often preferred to neostigmine for myasthenia gravis for three reasons:

(1) The onset of the effect of oral pyridostigmine (approximately 45 minutes) is faster than that for neostigmine (approximately 4 hours). The speedier onset allows for more precise adjustment of the dosing schedule around daily living activities to ensure as much muscle function as possible when required.

(2) The half-life of pyridostigmine (approximately 90 to 110 minutes) is longer than that for neostigmine (approximately 50 to 90 minutes). The difference is not great, but when the patient has to take the drug multiple times in a day, it is an advantage that 3 or 4 times per day is often sufficient with pyridostigmine.

(2) Pyridostigmine is about four times less potent than neostigmine. That is right, being less potent is an advantage because it is easier to titrate the dose to a level that controls the motor symptoms without causing too many adverse effects. This is especially important in the early stages of the disease when the motor symptoms are less pronounced.

Beta-adrenoceptors and intraocular pressure

July 25, 2019 / / 0 Comments

Non-selective beta-blockers (e.g. timolol) and beta1-adrenoceptor selective beta-blockers (e.g. betaxolol) can reduce intraocular pressure in glaucoma. But I read online that the adrenoceptors in the ciliary body of the eye, which regulates aqueous humour production, are beta2-adrenoceptors. So why are beta2-adrenoceptor selective beta-blockers not used to treat glaucoma?

Glaucoma is a group of eye diseases associated with optic neuropathy and progressive loss of retinal ganglion cells resulting in visual field loss, and irreversible blindness if left untreated (Jacobs, 2019; Weinreb and Khaw, 2004). In some forms of glaucoma, intraocular pressure (IOP) is elevated and likely contributes to damage to the retinal ganglion cells and their axons exiting the eye via the optic nerve. Drugs that reduce IOP have helped to slow the progression of visual field loss in glaucoma.

We can use topical application of beta-blockers to reduce IOP (although topical prostaglandin F2alpha analogues are now usually the first-line choice for pharmacological reduction of IOP). Both non-selective beta-blockers (e.g. timolol) and beta1-adrenoceptor selective beta-blockers (e.g. betaxolol) can reduce IOP when applied topically to the eyes. They are thought to work by blocking beta-adrenoceptors in the ciliary body to reduce the production of aqueous humour and so reduce IOP.

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Why is monotherapy with LABAs contraindicated in asthma?

October 5, 2018 / / 0 Comments

Why is the chronic use of long-acting beta agonists (LABAs) alone without the concomitant use of an inhaled corticosteroid contraindicated in asthma? What about short-acting beta agonists (SABAs), can they be used without taking an inhaled corticosteroid at the same time?

Activation of β2-adrenoceptor promotes bronchodilation. β2-adrenoceptor agonists are the most potent bronchodilators in current clinical use. Inhaled short-acting beta agonists (SABAs), for example salbutamol (known as albuterol in the USA) have a bronchodilator effect that lasts for 4 to 6 hours, while long-acting beta agonists (LABAs), for example salmeterol, have a  bronchodilator effect that lasts for 12 to 24 hours (depending upon the drug). SABAs are used to relieve acute bronchoconstriction. Use of a SABA can be a life-saving intervention during an asthma attack. In contrast, LABAs are used chronically to mainain bronchodilation improving airway function and controlling occurance of symptoms.

Chronic use of LABAs causes tolerance due to downregulation of β2-adrenoceptors. This is associated with an increased risk of mortality in patients with asthma. Therefore the use of LABAs alone is contraindicated. The downregulation of β2-adrenoceptors by chronic use of LABAs can impair the response to SABAs when they are need for acutre relief of symptoms during an asthma attack.

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Practical guide to good prescribing?

August 8, 2018 / / 0 Comments

I have completed my pre-clinical pharmacology studies. The lecturers helped me to build a framework of understanding of the pharmacological mechanisms of the major drug classes. This has given me a solid foundation of understanding of the pharmacology of the various drug classes on which I can continue to build as I learn more. But now going into my clinical years I feel lost about how to apply this knowledge in practice for clinical pharmacology. Where can I find a clear and practical guide on how to go about good prescribing in clinical practice?

The WHO has an excellent Guide to Good Prescribing – A Practical Manual.

You are likely not alone in feeling a little lost as you progress from pre-clinical theoretical understanding of pharmacology to practical application of clinical pharmacology. As the WHO Guide to Good Prescribing describes in its introduction on “Why you need this book”: “At the start of clinical training most medical students find that they don’t have a very clear idea of how to prescribe a drug for their patients or what information they need to provide. This is usually because their earlier pharmacology training has concentrated more on theory than on practice. The material was probably ‘drug-centred’, and focused on indications and side effects of different drugs. But in clinical practice the reverse approach has to be taken, from the diagnosis to the drug.”

This does not mean that your pre-clinical pharmacology training was wrong. It is just that finishing your pre-clinical years does not mean that you have finished learning pharmacology. Now in your clinical years, you need to learn clinical pharmacological applications and good prescribing. Your pharmacological learning should never end.  Throughout the rest of your career, you will have to continue to update your pharmacological knowledge as new drugs are approved or evidence-based best medical practice changes with new information. That is why your pre-clinical pharmacological training focused on helping you to build a solid foundation of a knowledge framework into which you can continue to integrate new pharmacological understanding as you come across new drugs in clinical practice.

 

Clonidine as an analgesic?

April 3, 2018 / / 0 Comments

Administration of clonidine can reduce the doses of opioid analgesics required for pain control. Clonidine is also used to counteract symptoms of opioid withdrawal. How does this work? 

Clonidine is an alpha-2-adrenoceptor agonist. Clonidine activates presynaptic alpha-2-adrenoceptors serving as autoreceptors on both central and peripheral nervous system noradrenergic nerve terminals. Activation of these autoreceptors reduces release of nordrenaline. Clonidine also activates alpha-2-adrenoceptors on the neurones of the locus coeruleus,  the major source of noradrenergic innervation in the brain, to inhibit locus coeruleus neurone firing and further reduce central nervous system noradrenergic neurotransmission. By these mechanisms, clonidine is an indirect sympatholytic agent and has been used as an antihypertensive drug.

Clonidine is also a direct adrenoceptor agonist at presynaptic alpha-2-adrenoceptors serving as heteroreceptors on the primary afferent neurone nerve terminals bringing nociceptive signals into the spinal cord and at postsynaptic alpha-2-adrenoceptors on secondary spinal cord neurones relaying pain information up to the brain. The descending systems gating pain transmission through the spinal cord include noradrenergic neurones releasing noradrenaline to activate the presynaptic alpha-2-adrenoceptor heteroreceptors on the primary afferent neurone nerve terminals preventing them from releasing their neurotransmitters and transmitting their nociceptive signals. Meanwhile, the noradrenergic descending projections also active postsynaptic alpha-2-adrenoceptors on secondary spinal cord neurones, inhibiting these neurones, and preventing them from relaying the nociceptive signals up to the brain. Therefore, clonidine, which activates these alpha-2-adrenoceptors, has analgesic properties.

The descending pain gating systems also activate local engodenous opioid peptide releasing interneurones within the spinal cord. These interneurones inhibit the secondary spinal cord neurones relaying the nociceptive information up to the brain and so further block transmission of nociceptive signals through the spine. There is therefore a good additive effect between clonidine and the opioid analgesics, which produce spinal analgesia by mimicking the action of the endogenous opioid peptides. Administering clonidine can reduce the doses of opioid analgesics required to control pain.

Another use for clonidine is in controlling symptoms of opioid withdrawal. Part of the reason why clonidine helps is that by its non-opioid analgesic mechanisms it controls the pain associated with opioid withdrawal. Opioid receptors also normally inhibit the neurones of the locus coeruleus and opioid withdrawal is also associated with over activation of the locus coeruleus and the brain noradrenergic system. This results in symptoms such as anxiety, agitation, irritability, and mood swings.  Clonidine activates  alpha-2-adrenoceptors inhibiting the cells of the locus coeruleus and presynaptic alpha-2-adrenoceptor autoreceptors reducing noradrenaline release.

Why does overdose of salbutamol cause tachycardia?

March 14, 2018 / / 0 Comments

Salbutamol is beta-2 adrenoceptor agonist used to treat the respiratory symptoms of asthma. We learned that it is beta-2 adrenoceptors in the lungs and beta-1 adrenoceptors in the heart. So why does overdose of salbutamol cause a rapid heart rate? 

Activation of beta-2 adrenoceptors in the airways promotes bronchodilation, reduction of airway secretions, and stimulation of mucociliary clearance.  Thus beta-2 adrenoceptor agonists are used in treating the symptoms of asthma. Meanwhile, in the heart, beta-1 adrenoceptor activation has inotropic and chronotropic effects, increasing contractile force and heart rate, respectively.

For the treatment of the symptoms of asthma without causing cardiovascular adverse effects, selective beta-2 adrenoceptor agonists would be the preferred.  Salbutamol is an example of a selective beta-2 adrenoceptor agonist. However, the beta-2 and beta-1 adrenoceptors are very similar, so salbutamol is not entirely selective. Salbutamol shows dose-dependent selectivity for beta-2 adrenoceptors but does still act as a weak beta-1 agonist.  Thus, on overdose, the beta-1 agonist activity of salbutamol can start to cause cardiovascular adverse effects by activating beta-1 adrenoceptors in the heart to increase the force and rate of heart contractions.

Does hyperthyroidism cause constipation or diarrhoea?

March 14, 2018 / / 0 Comments

Hyperthyroidism causes sympathetic overactivation such that many of the symptoms of thyroid storm can be alleviated by beta-blockers. The sympathetic nervous system “fright, flight or fight” response opposes the parasympathetic nervous system “rest and digest” response and shuts down gastrointestinal function. So hyperthyroidism causes constipation, correct? 

Sorry, not correct. Yes, hyperthyroidism can stimulate overactivation of the sympathetic nervous system. Yes, symptoms of thyroid storm can be treated with sympatholytic beta-blockers. But no, hyperthyroidism does not cause constipation. Hyperthyroidism causes diarrhoea.  Conversely, hypothyroidism causes constipation.

So, next, you will ask “What is the mechanism?”. Unfortunately, the mechanism is not known. Recent reviews have speculated that it might be due to beta-2 adrenoceptor-mediated effects on gastrointestinal motility and secretions (Daher et al., 2015; Kyriacou et al., 2015) but the evidence for this is very limited.  For example, a case report on one patient has suggested that propranolol can control intractable diarrhoea in hyperthyroidism (Bricker et al., 2001) but another study on ten hyperthyroid patients found no effect of propranolol on the gastrointestinal transit time (Bozzani et al., 1985).

For the moment, as we do not know the underlying mechanism, it is just one of those exceptions that you have to remember. In nearly every other respect, hyperthyroidism has a sympathomimetic effect and hypothyroidism has a sympatholytic effect. But for the gastrointestinal system, it is the opposite.

References:

Bozzani A, Camboni MG, Tidone L, Cesari P, Della Mussia F, Quatrini M, Ghilardi G, Ferrar L, Bianchi PA (1985) Gastrointestinal transit in hyperthyroid patients before and after propranolol treatment. Am J Gastroenterol. 1985 Jul;80(7):550-2.

Bricker LA, Such F, Loehrke ME, Kavanaugh K (2001) Intractable diarrhea in hyperthyroidism: management with beta-adrenergic blockade. Endocr Pract. 2001 Jan-Feb;7(1):28-31.

Daher R, Yazbeck T, Jaoude JB, Abboud B (2009) Consequences of dysthyroidism on the digestive tract and viscera. World J Gastroenterol. 15(23):2834-8.

Kyriacou A, McLaughlin J, Syed AA (2015) Thyroid disorders and gastrointestinal and liver dysfunction: A state of the art review. Eur J Intern Med. 26(8):563-71.

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