PA2131 – Page 2 – PharmaNUS

Category: PA2131 (page 2 of 4)

NSAIDs increase risk of gastritis and gastric ulcers

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 / phcdgs / 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.

How does ageing impact on drug dosing

May 5, 2021 / phcdgs / 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.

Beta-adrenoceptors and intraocular pressure

July 25, 2019 / phcdgs / 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 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.

Bioequivalence

March 9, 2019 / phcdgs / 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.

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).

Important drugs for dental pharmacology?

July 9, 2018 / phcdgs / 0 Comments

I want to be a dentist, not a doctor. Do I really need to know about all the drugs covered in the pharmacology lectures? Where can I find a simple guide to the drugs I will commonly prescribe as a dentist?

It is true that as a dentist you will likely never prescribe many of the drugs discussed in the pharmacology lectures. But it is crucial that you know about these drugs and their mechanisms of action. When you take your patient’s history before performing dental procedures or prescribing drugs in your dental practice, you will need to ask about what medications they are using. You will need to understand whether any of the medications that your patient is using could have effects on their dental health (for example, causing dry mouth) or could impact on the dental procedures that you perform (for example, anticoagulant effects causing an increased risk of severe bleeding). If you are going to prescribe drugs for your patient, you will need to evaluate the risk of drug-drug interactions with the other medications that the patient is already taking.

There are certain drugs that you will be more likely to prescribe in your dental practice. It is imperative that you are familiar with the mechanisms of action and potential adverse effects and interactions of these drugs. An excellent guide to drugs commonly prescribed for dentistry can be found at http://www.sdcep.org.uk/published-guidance/drug-prescribing/.