Category: Topics/Drug Classes (page 5 of 6)

Why is succinylcholine considered an “indirect” anticholinergic?

February 25, 2017 / / 0 Comments

Succinylcholine is a direct nicotinic receptor agonist but is used clinically as an indirect anticholinergic. 

Succinylcholine (suxamethonium) is a highly potent agonist at the neuromuscular junction (NMJ) nicotinic acetylcholine receptors.  It is a direct cholinergic agonist in that it binds to the same binding site as the endogenous transmitter acetylcholine and activates the receptor in the same manner as acetylcholine. In contrast, non-depolarising neuromuscular blocking agents (NMBAs), such as pancuronium, are direct antagonists at NMJ nicotinic acetylcholine receptors. NMBAs are direct anticholinergics and can be used to produce paralysis when required under surgical anaesthesia.

In the context of autonomic pharmacology, indirect agonist effects are any effects mimicking the effect of the endogenous transmitter and other direct agonists not caused by direct agonism at the receptor. Conversely, indirect antagonist effects are any effects mimicking the effect of direct antagonists not caused by direct antagonism at the receptor.

Although it is a direct agonist of nicotinic acetylcholine receptors, clinically succinylcholine is used as an indirect anticholinergic to block the action of nicotinic acetylcholine receptors at the NMJ causing paralysis when required under surgical anaesthesia. The paralysis is caused because succinylcholine activates the nicotinic acetylcholine receptors so intensely that depolarising block occurs (Phase I) followed by desensitising block (Phase II).  The clinically desired paralysis mimics the direct anticholinergic effect of the NMBAs but is produced indirectly via the depolarising block and desensitising block secondary to direct agonism at the receptor. Therefore, succinylcholine is an indirect anticholinergic.

What does “nonselective” muscarinic receptor antagonist mean?

February 25, 2017 / / 0 Comments

In the context of autonomic system pharmacology, you will often come across drugs described as “nonselective muscarinic antagonists” or “nonselective alpha-adrenoceptor antagonists”. What does “nonselective” mean in this context?

The potential confusion here is that you might think that a “nonselective muscarinic antagonist” is a drug that is not selective for muscarinic receptors and so also acts on other types of receptors (for example, adrenoceptors) at therapeutic doses.  This is not what is meant when these phrases are used in the context of autonomic nervous system pharmacology.

There are many subtypes of muscarinic acetylcholine receptors: M1, M2, M3, M4 and M5 receptors. However, most of the muscarinic cholinergic and anticholinergic drugs in current clinical use are nonselective between the muscarinic receptors subtypes. These drugs are selective for muscarinic receptors over other types of receptor, such as nicotinic acetylcholine receptors or adrenoceptors, but are nonselective between the muscarinic receptor subtypes (M1, M2, M3, M4 and M5 receptors). For example, atropine is a nonselective muscarinic acetylcholine receptor antagonist because it blocks all muscarinic receptor subtypes: M1, M2, M3, M4 and M5 receptors.  But atropine is selective for muscarinic acetylcholine receptors over other classes of receptor, such as nicotinic acetylcholine receptors.

Likewise, there are many subtypes of adrenoceptors: α1A-, α1B-, α1D-, α2A-, α2B-, α2C-, β1-, β2– and β3-adrenoceptors. Many of the adrenergic and antiadrenergic drugs in current clinical use target alpha- or beta-adrenoceptors but are nonselective between the subtypes of alpha or beta receptors. For example, oxymetazoline is selective for alpha-adrenoceptors over beta-adrenoceptors but may be described as a nonselective alpha-adrenoceptor agonist because it is largely nonselective between α1A-, α1B-, α1D-, α2A-, α2B– and α2C-adrenoceptors.

How does atropine cause flushing?

February 25, 2017 / / 0 Comments

Atropine can cause patients to become “as red as a beet” due to superficial vasodilation. How does atropine cause this flushing response? 

At toxic doses, and even occasionally therapeutic doses, atropine can cause dilation of cutaneous blood vessels resulting in an atropine flush. This reaction, making the patient “as red as a beet”, is well recognised as a classical sign of atropine overdose.

Atropine is a muscarinic receptor antagonist. Muscarinic receptors are involved in controlling the dilation of some blood vessels (see Sympathetic cholinergic innervation of blood vessels? Not in humans) but they are not known to be important for control of superficial cutaneous blood vessels.  It has therefore been something of a mystery why atropine should cause flushing. The mechanisms by which atropine causes this “anomalous vascular response” have therefore long been debated.

One hypothesis is that the response is due to the fact that atropine has alpha-adrenoceptor antagonist effects at very high doses (1). Antagonism of alpha adrenoceptors could block alpha-adrenoceptor-mediated vasoconstriction resulting in vasodilation and flushing. However, the more widely accepted explanation in recent years has been that the flushing is secondary to overheating due to block of sweating. Antagonism of M3 receptors on sweat glands will block the sweating response. This will cause overheating and compensatory superficial cutaneous vasodilation to increase heat loss.

Reference:
(1) Chang KC, Hahn KH. (1995) Is alpha-adrenoceptor blockade responsible for atropine flush? Eur J Pharmacol. 1995 Sep 25;284(3):331-4.

Can parasympatholytics cause nausea and vomiting?

February 25, 2017 / / 0 Comments

Why are nausea and vomiting reported as adverse effects of some parasympatholytics, such as oxybutynin, when nausea and vomiting are known to be parasympathomimetic adverse effects, and muscarinic antagonists can be used to treat nausea and vomiting? 

Parasympathomimetics often cause nausea and vomiting. Increased stimulation of muscarinic receptors in the gastrointestinal tract leads to increased secretion and motility, which can trigger nausea and vomiting.  Perhaps more importantly, activation of muscarinic cholinergic receptors, in particular, M1 receptors, in the vestibular nuclei, the nucleus of the solitary tract and the vomiting centre can directly activate the CNS pathways triggering nausea and vomiting. Hence, muscarinic receptor antagonists, such as scopolamine (hyoscine), can be used to prevent nausea and vomiting.

As muscarinic antagonists can be used to treat nausea and vomiting, it can be confusing that some parasympatholytics, such as oxybutynin, are reported to cause nausea and vomiting.  Oxybutynin is a muscarinic antagonist. It can be used to treat urinary incontinence. Historically it was also important for treatment of peptic ulcers although now it is rarely used for this indication as we have better drugs such as H2 receptor antagonists (for example, cimetidine) and proton pump inhibitors (PPIs)  (for example, omeprazole).  However, the fact that oxybutynin can be used to treat peptic ulcers reminds us that this drug blocks M1 receptors on the enterochromaffin-like cells in the stomach and prevents gastric acid secretion. The nonselective muscarinic antagonism of oxybutynin also blocks secretions and motility all along the gastrointestinal tract. These effects can lead to delayed gastric emptying.  The delayed gastric emptying leads to nausea and vomiting.

Alpha adrenoceptor agonists and reflex bradycardia

February 25, 2017 / / 0 Comments

Phenylephrine and oxymetazoline can increase blood pressure and at the same time cause bradycardia.

Phenylephrine is a selective alpha-1 adrenoceptor agonist while oxymetazoline is a non-selective alpha adrenoceptor agonist. You are likely to most commonly come across phenylephrine and oxymetazoline in their us as nasal decongestants. Acting as agonists at the alpha adrenoceptors on blood vessels, they can vasoconstrict the blood vessels of the nasal mucosa. Phenylephrine can also be administered as eye drops to produce mydriasis (dilation of the pupil) without cycloplegia (paralysis of the ciliary muscle of the eye resulting in loss of accommodation and blurred near vision).  In contrast, muscarinic receptor antagonists, such as cyclopentolate, produce both mydriasis and cycloplegia.

The vasoconstriction caused by the alpha adrenoceptor agonists increases blood pressure. In fact, phenylephrine is also used as a vasopressor to treat hypotension. Our baroreceptors constantly monitor blood pressure and trigger reflex bradycardia as a compensatory measure when they detect increases in blood pressure. Thus phenylephrine and oxymetazoline are associated with increases in blood pressure and reflex bradycardia.

When treating hypotension, phenylephrine is most useful as a choice of drug for hypotensive patients who are tachycardic. Other vasopressors that increase the heart rate and force via beta-1 adrenoceptor activation, such as dopamine, adrenaline and noradrenaline, would be more likely used for hypotensive patients with normal heart rates or bradycardia.

VX Nerve Agent

February 24, 2017 / / 0 Comments

VX nerve agent,  which has been in the news lately with the killing of Kim Jong-nam, is another example of an organophosphate anticholinesterase.

The newspapers and other media have recently reported that it was the VX nerve agent that was used to kill Kim Jong-nam, the half-brother of North Korea’s leader, in Malaysia. VX nerve agent is an example of an organophosphate anticholinesterase. Other examples of organophosphate anticholinesterases include the chemical weapon sarin and the organophosphate insecticides such as a malathion.

VX (S-2 Diisoprophylaminoethyl methylphosphonothiolate) is one of the most toxic nerve agent known. It is especially insidious as it is a highly viscous, tasteless and odourless liquid that can easily be transferred via clothing to be absorbed into the body by inhalation, ingestion, skin contact, or eye contact.

Although more potent and fast-acting, the effects of VX poisoning would be the same as for any organophosphate anticholinesterase. Inhibition of acetylcholinesterase will result in increased levels of acetylcholine at all cholinergic synapses in the body.

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Why does increasing adenosine levels with methotrexate help rheumatoid arthritis?

February 11, 2017 / / 0 Comments

Methotrexate can be used to control the autoimmune attack and auto-inflammatory response in rheumatoid arthritis.  It has a number of mechanisms of action, including increasing adenosine levels. How does increasing adenosine levels help to combat autoimmune and auto-inflammatory attack on the joints? 

Let’s first dispel a potential misunderstanding. Adenosine is not the same thing as adenine.  If we confuse adenosine with adenine, then it may appear contradictory that the mechanisms of action of methotrexate include both increasing adenosine levels and reducing pyrimidine levels. There is no contradiction here. Adenine and guanine are purines. Purines and pyrimidines are nitrogenous bases required for the nucleotide building blocks of DNA. Thus depletion of pyrimidines with drugs such as methotrexate and leflunomide or depletion of purines, including adenine, with drugs such as azathioprine and mycophenolate can interfere with DNA synthesis and proliferation of immune system and inflammatory cells.

Adenosine is a purine nucleoside composed of a molecule of adenine attached to a ribose sugar molecule.  It is a ribonucleoside necessary for the synthesis of RNA but has many other cellular functions as well. Adenosine triphosphate (ATP) is, of course, well-known as the cellular energy currency.  Adenosine itself is also a transmitter acting at adenosine receptors. Adenosine signalling suppresses recruitment and functions of inflammatory and immune cells. Thus increasing adenosine levels has an anti-inflammatory and immunosuppressant effect.

 

Sympathetic cholinergic innervation of blood vessels? Not in humans.

February 7, 2017 / / 0 Comments

Exceptions to the general rule that the sympathetic nervous system is adrenergic include cholinergic innervation of sweat glands expressing M3 receptors and dopaminergic innervation of the renal blood vessels expressing D1 receptors. But what about the arteries of skeletal muscle? 

Parasympathetic cholinergic fibres innervate some blood vessels. In arterial blood vessels, the release of acetylcholine activates M3 receptors on the vascular endothelium, which are coupled to formation of nitric oxide (NO) that produces vasodilation (1). However, if the synthesis of NO is inhibited, the activation of M3 and M2 receptors can produce vasoconstriction. In contrast, cerebral arteries express M5 receptors, which produce vasodilation in response to acetylcholine (1).

In cats and dogs, some of the arterial blood vessels in skeletal muscle are innervated by sympathetic cholinergic nerves that release acetylcholine, which acts at M3 receptors to produce vasodilation (1). In these species, the sympathetic nervous system innervation of the arterial blood vessel in skeletal muscle appears to play a role in active hyperaemia, increasing blood flow to the muscle at the start of exercise (1).

In contrast to cats and dogs, humans do not have sympathetic cholinergic innervation of arterial blood vessels in skeletal muscle (1).

Reference:
(1) Richard E Klabunde Cardiovascular Physiology Concepts: Adrenergic and Cholinergic Receptors in Blood Vessels http://www.cvphysiology.com/Blood%20Pressure/BP010b [Accessed 7 Feb 2017]

Why is guaifenesin so difficult to spell?

February 6, 2017 / / 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.

 

Adverse effects of guaifenesin and acetylcysteine

February 6, 2017 / / 0 Comments

When the expectorant, guaifenesin, and the mucolytic, acetylcysteine, are prescribed together patients are monitored for bronchospasm and anaphylactoid reactions. Which of these two drugs is responsible for these serious adverse effects?

 Guaifenesin is an expectorant. It increases the production of respiratory tract fluids. This helps to liquefy and reduce the viscosity of mucus in the respiratory tract.  Generally, guaifenesin is a relatively safe drug, but it has been associated with dizziness, headache, vomiting, nausea, rash and urticaria. 

Acetylcysteine can be used as a mucolytic. It possesses a free sulfhydryl group that splits disulphide bonds between mucoproteins. This reduces the viscosity of pulmonary secretions.  Acetylcysteine can also be used to treat paracetamol overdose as it restores liver glutathione levels. However, acetylcysteine can trigger bronchospasm and severe anaphylactoid reactions, including rash, hypotension, dyspnoea, and wheezing. If they occur, these responses are usually observed within 30 to 60 minutes of starting intravenous infusion for the treatment of paracetamol poisoning.  Anaphylactoid reactions are less likely in use as a mucolytic. Nevertheless, caution must be exercised when using acetylcysteine. Due to the risk of bronchospasm, the acetylcysteine must also be used with caution in elderly or debilitated patients with severe respiratory insufficiency and in patients with asthma.

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