MDG5238 – Page 2 – PharmaNUS

Category: MDG5238 (page 2 of 4)

Neostigmine versus pyridostigmine

February 22, 2020 / phcdgs / 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

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 F_2alpha 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.

What is the difference between pharmacology and pharmacy?

May 8, 2019 / phcdgs / 1 Comment

What is the difference between pharmacology and pharmacy?

Pharmacology is the study of the sources, uses, and mechanisms of action of drugs. That is what the body does to drugs (pharmacokinetics) and what drugs do to the body (pharmacodynamics).

Pharmacy is the science or practice of the preparation, formulation, and dispensing of medicinal drugs.

Aspirin for prevention of preeclampsia

February 19, 2019 / phcdgs / 0 Comments

Non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated in the third trimester of pregnancy because of the risk of premature closure of the ductus arteriosus. So why is aspirin used to prevent preeclampsia?

Low-dose aspirin is used to prevent preeclampsia in women at high risk of developing preeclampsia. However, NSAIDs are known to promote closure of the ductus arteriosus (see Cyclooxygenase inhibitors for closure of the ductus arteriosus) and so are contraindicated in the third trimester of pregnancy. So why is aspirin used to prevent preeclampsia?

Preeclampsia is associated with increased platelet turnover and increases in platelet-derived thromboxane levels. Low doses of aspirin once per day are sufficient to be antiplatelet and reduce thromboxane production by the platelets. Such low doses are unlikely likely to trigger closure of the ductus arteriousus and so are relatively safe even in the third trimester of pregnancy. Thus, for the women at high risk of preeclampsia the risk-to-benefit ratio is in favour of prescribing low-dose aspirin.

Additionally, it has been reported that preeclampsia is associated with exaggerated inflammatory responses. The anti-inflammatory actions of aspirin may therefore also be beneficial in preventing preeclampsia, although the low doses used would not produce a strong anti-inflammatory effect.

There remains debate over the optimal dose and the best time to start aspirin treatment. Typically, doses between 75 mg and 162 mg/day have been used started typically before 12 weeks of gestation and certainly before 16 weeks.

Reference:

August, P & Jeyabalan, A (2019) Preeclampsia: Prevention. Lockwood, CJ & Barss, VA ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on February 19, 2019).

Why is monotherapy with LABAs contraindicated in asthma?

October 5, 2018 / phcdgs / 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.

Cyclooxygenase inhibitors for closure of the ductus arteriosus

September 25, 2018 / phcdgs / 0 Comments

Why is it that older non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen or indomethacin, not newer NSAIDs, such as etoricoxib, are used to promote closure of patent ductus arteriosus in preterm infants?

In the fetus, the ductus arteriosus acts as a lung bypass diverting blood from the pulmonary artery into the aorta. After birth, the ductus arteriosus constricts and is eventually obliterated. In preterm births, the ductus arteriosus may remain patent resulting in insufficient blood flow through the pulmonary circulation and increased risk of mortality.

Prostaglandin E₂ (PGE₂) is a vasodilator promoting patency of the ductus arteriosus. NSAIDs inhibit the cyclooxygenase (COX) enzyme responsible for producing PGE₂. NSAIDs are therefore contraindicated in the third trimester of pregnancy as they can cause premature closure of the ductus arteriosus in utero. However, in preterm infants, NSAIDs can be valuable in enabling closure of patent ductus arteriosus (PDA).

The NSAIDs used are typically ibuprofen or indomethacin. These are older NSAIDs for which there is a longer history of experience with use in infants. Ibuprofen is generally the preferred agent as it has a lower risk of reducing gastrointestinal and renal blood flow resulting in necrotizing enterocolitis and transient renal insufficiency. The newer coxibs, such as etorixocib, are not used because there is less knowledge of their safety in infants.

Reference:

Philips III, JB (2018) Management of patent ductus ateriosus in preterm infants. Garcia-Prats JA, Fulton DR, Kim MS ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com (Accessed on October 5, 2018).

Practical guide to good prescribing?

August 8, 2018 / phcdgs / 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 / phcdgs / 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 / phcdgs / 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.

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.