Category: PA1113 (page 1 of 3)

NSAIDs increase risk of gastritis and gastric ulcers

May 7, 2021 / / 0 Comments

What is the mechanism for NSAIDs leading to gastric ulcer formation? Can it also cause gastritis?

With high levels of acidity and digestive enzymes, and food movement, the stomach is an aggressive environment for the tissues lining the stomach wall. Prostaglandins mediate endogenous protective mechanisms, including (1) increased mucosal blood flow; (2) increased mucus secretion; (3) increased bicarbonate secretion; and, at high concentrations, (4) reduced acid secretion.

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the cyclo-oxygenase (COX) enzyme. COX is involved in the production of prostanoids, including classical prostaglandins. In the stomach, COX-1 is essential for the production of the protective prostaglandins. Therefore, inhibition of COX by NSAIDs increases the risk of gastritis (the general term for conditions involving inflammation of the lining of the stomach), including gastric ulcers.

Brimonidine for glaucoma

May 5, 2021 / / 0 Comments

If brimonidine is an adrenergic agonist, how and why does it reduce glaucoma?

Brimonidine acts at postsynaptic alpha-2 adrenoreceptors on blood vessels to cause vasoconstriction, reducing aqueous humour production. Long-term, there are also effects on uveoscleral drainage, perhaps secondary to reduced blood flow to the ciliary muscle.

Brimonidine alone is not as potent at reducing intraocular pressure (IOP) as beta-blockers or prostaglandin F2alpha analogues (e.g., latanoprost). The primary reason that brimonidine has come back into use is that it also has a neuroprotective action, reducing the death of retinal ganglion cells through mechanisms that remain poorly understood.

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.

How does ageing impact on drug dosing

May 5, 2021 / / 0 Comments

Physiological changes associated with ageing can impact the appropriate dosing for many drugs. General principles to keep in mind include:

Absorption:

  • Absorption usually does not change with normal ageing.

Distribution:

  • Concentrations of water-soluble drugs are usually higher as there is less water and so a lower volume of distribution.
  • Concentrations of free or active (unbound) drug are usually higher due to lower serum proteins.

Metabolism:

  • The half-life of lipophilic drugs is usually higher due to more fat resulting in an increased volume of distribution and prolonged duration of action.
  • There is slower Phase I metabolism (e.g., oxidation, reduction and dealkylation) due to cytochrome P450 pathways resulting in higher levels of drugs dependent on these pathways for metabolism (e.g., warfarin).
  • However, Phase II reactions (e.g., conjugation, acetylation, and methylation) are usually unchanged in normal ageing.
  • There is a greater risk of drug-drug interactions in metabolism due to increased numbers of drugs for multiple medical problems.

Excretion:

  • Hepatic excretion may be impaired.
  • Renal clearance may be impaired, and serum creatinine may not be an accurate reflection of renal clearance in elderly patients due to decreased lean body mass (muscle mass).
  • Active drug metabolites can accumulate, resulting in prolonged therapeutic actions and a greater risk of adverse effects.

There is also increased susceptibility to adverse effects. Older adults are also more likely to have multiple chronic medical problems, and disease states can result in physiological changes:

  • Cardiac disease can result in impaired cardiac output resulting in impaired ADME and greater susceptibility to cardiac adverse effects.
  • Liver or kidney disease can decrease metabolism and excretion, reducing drug clearance.
  • Neurological diseases result in greater sensitivity to neurological adverse effects due to diminished neurotransmitter levels and/or impaired cerebral blood flow.

 

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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What is the difference between pharmacology and pharmacy?

May 8, 2019 / / 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.

 

Bioequivalence

March 9, 2019 / / 0 Comments

How do the regulatory authorities evaluate the bioequivalence of generic drugs?

Dr. Kimberly W. Raines, a reviewer for the United States Food and Drug Administration (FDA) Division of  Bioequivalence 2, has provided a good primer on generic drugs and bioequivalence at https://www.fda.gov/downloads/forpatients/about/ucm410215.pdf. The details of the evaluation process for bioequivalence can vary between the national regulatory authorities of different countries but most countries adopt the same principles as used by the FDA. 

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.

 

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