Your mouth becomes watered when you listen or think about your favorite food. But have you seen someone with water in their mouths every time? So much water that it overflows and comes out of the mouth. Have you seen someone with excess salivation and drooling? That is called sialorrhea or hypersalivation. Children with cerebral palsy or adults who have Parkinson’s disease present with this symptom. It is a very debilitating symptom. The person is unable to speak properly, have wet clothes and is very uncomfortable.
Glycopyrrolate or Glycopyrronium bromide is a medicine used for the management of this condition. In this article, we will discuss what is sialorrhea and how glycopyrrolate can help someone suffering from this condition. We will also review various other conditions in which this drug can be used along with its side effects, toxicity, and rationale of its use in pregnancy and lactation. Stay with us!
Sialorrhea or Hypersalivation
As discussed earlier, sialorrhea is a condition in which there is excessive production and drooling of saliva. It may be due to excess production of saliva or failure to remove normally produced saliva. Although drooling is common in newborn babies, it is considered abnormal if occurs in babies who are 4 years or older in age. It may occur alone but is often associated with other neurological conditions.
In children, the most common cause of sialorrhea is cerebral palsy (CP). However, in adults, the most common cause is Parkinson’s disease (PD).
Excessive salivation occurs due to hyperactivity of salivary glands. Humans have 3 pairs of salivary glands; parotid glands in front of the ears, submandibular glands under the chin and sublingual glands under the tongue. They produce saliva when signals come from the brain via nerves.
Excess salivation can be idiopathic, or drug-induced. It can also be due to some neurological illness, leading to excessive excitation and activation of glands.
Sialorrhea can also occur due to some neurological illness in which there is neuromuscular incoordination. Incoordination of the muscles involved in swallowing inhibit swallowing of saliva. As a result, saliva pools up in the mouth and hence drooling occurs. This is seen in conditions like cerebral palsy and Parkinson’s disease.
Sialorrhea is difficult to treat. Its management can be simple and conservative or more invasive. Conservative treatments include changes in diet or habits, oral-motor exercises to improve swallowing, intra-oral devices such as palatal training devices to prevent pooling of saliva, and medical treatments such as medication or botulinum toxin injections that can either prevent saliva secretion or its pooling in the mouth. Behavior modification has been considered as a treatment for years, but the results are inconsistent and time-consuming.
Invasive treatments include surgery or radiation. Surgical cases seem to offer more permanent results, but they are invasive and are not without side effects. Radiation therapy is now rarely applied. It is typically reserved for elderly patients who are not fit for surgery and cannot tolerate medical therapies.
Glycopyrrolate is the available medical treatment for sialorrhea. The rest of the article now will be on this drug.
This drug belongs to the anti-cholinergic or anti-muscarinic category of drugs that act on the autonomic nervous system (ANS). Anti-cholinergic means the drugs that antagonize or oppose the action of acetylcholine on various cells. Acetylcholine is a neurotransmitter, released by the nerve cells at the nerve endings. It is through this neurotransmitter that most of the signals are passed on from the nervous system to other cells for the automatic control of body functions.
Mechanism of action
As evident from the classification, glycopyrrolate is a drug that blocks the action of acetylcholine. It is a muscarinic receptor blocker that binds to the receptors and blocks the action of acetylcholine. All the receptors are occupied by glycopyrrolate, they do not yield to acetylcholine either endogenous or exogenous.
Salivary glands also have muscarinic receptors. When signals come from the brain, acetylcholine is released and activates the glandular cells to produce and secrete saliva. However, when the patient is on glycopyrrolate, the activation of salivary glands is inhibited and thus no saliva is produced. Hence, this drug is a very good choice for patients suffering from sialorrhea and drooling.
Muscarinic receptors are also present in the lungs. When activated, these receptors cause narrowing of the airways due to bronchiolar muscle contraction. Patients of COPD (chronic obstructive pulmonary disease) have obstructed and narrow airways. Muscarinic stimulation can cause further narrowing of bronchi and worsen the symptoms. When glycopyrrolate is used in such patients, it prevents activation of the receptors and thus provides relieved breathing.
Glycopyrrolate can be absorbed from the intestines into the blood when taken orally and from lungs into the blood when inhaled. The bioavailability of this drug, like any other drug is highest when via inhalation.
It is not yet studied how this drug is metabolized in the body to various metabolites. The drug is excreted from the body by kidneys. Kidneys remove the drug from the blood and add it to the urine. It leaves the body along with the urine.
Glycopyrrolate comes in four formulations
- Oral tablets come in various doses such as 1 mg, 1.5 mg and 2 mg tablets.
- Oral solutions with 1mg per 5ml dose.
- Injectable form in doses of 0.2mg per 1ml.
- Glycopyrrolate capsules with inhalation machine are also available in the market for patients of COPD.
Glycopyrrolate is classically used for the treatment of sialorrhea or drooling. It is also used for the long term management of COPD patients. Surgeons use this drug to prevent pre-operative saliva production and to reduce intraoperative cholinergic effects. It is approved to be used along with physostigmine for neuromuscular blockade reversal.
Use in Patients of Bradycardia
Glycopyrrolate is also beneficial for use in patients with bradycardia. Bradycardia may be due to vagal response or other conditions. In normal people, acetylcholine acts oh M2 cholinergic receptors present in the heart. The effect of m2 receptor activation is to decrease the heart rate and cause bradycardia. This response is normally initiated in patients with high blood pressure.
Glycopyrrolate can be used to inhibit this response. Glycopyrrolate inhibits the action of acetylcholine on M2 receptors in the heart. As a result, myocardial cells (cells of the heart tissue) do not respond to acetylcholine release. The heart rate is not affected and is not decreased. This is the rationale of the use of glycopyrrolate in bradycardia patients
Use in anesthesia
As stated earlier, glycopyrrolate is also used in anesthesia. It is used in injectable form for anesthesia. The rationale of the use of glycopyrrolate is to prevent the accumulation of secretions in pharynx, mouth and tracheobronchial tree. If the secretions accumulate, they would hinder the normal respiratory mechanism and can cause the death of the patients.
The other reason why it is used in anesthesia is to prevent vagal inhibition of the heart. Vagal responses to the heart during a surgical procedure may stop the heart leading to the death of the patient. This is prevented by the anti-muscarinic effects of glycopyrrolate as stated in the above section.
CNS effects of glycopyrrolate
It is believed that glycopyrrolate usually does not cross the blood-brain barrier and thus does not have significant central nervous system effect. This is the reason why this drug has been ineffective in causing the reversal of CNS symptoms of patients who are treated for cholinesterase inhibitor overdose.
However, in some cases, glycopyrrolate is associated with some CNS side effect. These include excitement, restlessness, insomnia, convulsions, high neuronal activity, etc. All these effects are due to the absence of the inhibitory effects of acetylcholine. Research studies have shown that CNS involvement is seen only in case of overdose with glycopyrrolate and only in a few patients.
Muscarinic receptors are present in almost every tissue of the body. Using a muscarinic receptor blocker can result in a number of symptoms. Use of glycopyrrolate can cause the following side effects.
- Dry mouth, due to decreased or no saliva production
- Dry/sore throat, due to decreased secretions produced by glands in the pharynx
- Gastrointestinal (GI) disturbances such as vomiting, constipation, and stomach bloating.
Some serious side effects can also occur such as:
- Painful or difficult urination due to contraction of smooth muscles in the urethra (the urine tube)
- Fast and irregular heartbeat, due to the absence of inhibitory cholinergic signals to the heart.
- Eye pain, swelling or redness of eyes can also occur due to decreased production of aqueous humor in the eye leading to vision changes (such as seeing rainbows around lights at night) and blurred vision.
- Rarely, it may cause worsening of breathing problems (paradoxical bronchospasm) that may be severe.
Allergic reactions to this drug are rare and are not yet identified.
Glycopyrrolate has renal clearance and thus is contraindicated in patients with renal failure or any other renal impairment.
It is contraindicated in patients who are hypersensitive to glycopyrrolate and other muscarinic blockers of this category.
It is also contraindicated in patients with other conditions like glaucoma; obstructive uropathy (for example, bladder neck obstruction due to prostatic hypertrophy or hyperplasia); obstructive disease of the gastrointestinal tract ( such as achalasia, pyloroduodenal stenosis etc.); paralytic ileus, intestinal atony of the elderly or debilitated patient; unstable cardiovascular status in acute hemorrhage; severe ulcerative colitis; toxic megacolon complicating ulcerative colitis; myasthenia gravis.
Glycopyrrolate is not an over the counter drug. The abuse liability and suicidal overdose is not very common. Accidental overdose can occur in patients who are already on this drug.
Overdose can cause worsening of the symptoms mentioned in the section of side effects.
Patient presents to emergency with fast and irregular heart rate due to decreased action of acetylcholine which usually decreases heart rate, dyspnea and difficult breathing due to severe obstruction of the airways and constipation due to decreased contraction of smooth muscles in the GI system.
Closely monitor patients for therapeutic response and side effects of glycopyrrolate. It should not be used in high doses because may produce mental depression and mental disturbances. It should be used with caution in patients over 40yrs.
Because it may increase the risk of glaucoma. It should be used with caution in patients with asthma, heart or kidney diseases. It should be used with caution in infants and small children. Glycopyrrolate Should be used with caution in coronary artery disease and uremia.
The drug should not be given to Pregnant Mothers, Cardiac / Hypertensive Patients, and Geriatrics. If the prescribing authority such as your doctor justifies the benefits of the drug against the possible damages, he/she should reevaluate them and consult the reference material and previous studies.
Glycopyrrolate and Atropine
Both these drugs are anti-cholinergic and block muscarinic receptors. They have a similar mechanism of action and indications. The side effects of both these drugs are also similar. However, there is a difference between these drugs in relation to potency. Studies have shown that glycopyrrolate is twice as effective as atropine when used for the management of neuromuscular blockade. However, both these drugs are equally effective when used in patients with sialorrhea or drooling.
When used in a mixture along with neostigmine, atropine causes more potent bradycardia as compared to glycopyrrolate. Studies show that use of glycopyrrolate results in a more stable cardiovascular system with fewer risk of arrhythmias as compared to atropine use.
Glycopyrrolate in Pregnancy and Lactation
Drugs who can easily cross the placenta and cause harm to the fetus are prohibited in pregnancy. No sufficient data is available to prove that glycopyrrolate can cross the placenta and is teratogenic to the developing embryo or fetus. However, it is assigned to category B drug for pregnancy by the FDA. It should be only used in pregnancy if the benefits outweigh the risks.
If a drug is excreted in milk, it can cause harm to the baby who feeds on breast milk. Such a drug is prohibited for use in lactating mothers. There is no data to confirm the excretion of glycopyrrolate in human milk.
However, manufacturers are of the opinion that it is the choice of doctor to choose whether he should continue lady on glycopyrrolate or not.
Glycopyrrolate is a very effective drug for use in patients of sialorrhea or drooling. It is also a proven drug to be used in patients of COPD on a long term basis. However, the drug has some serious side effects. It can prove fatal if taken in overdose and can cause severe toxicity.
Whether you are a patient of sialorrhea or COPD, you should not start this drug on your own. Always visit your doctor to get better advice. He will evaluate your condition on medical criteria and prescribe you the best suitable medicine for your condition.
A doctor has a better understanding of how a drug works and interacts with the patient’s body. He knows the past medical history of the patient, is aware of the drugs he is already taking, his allergies, any drug addiction, and other personal histories. Based on this information, a doctor can decide which anti-diabetes drug will be best for you.