INTRODUCTION:

Respiratory performance of human being is affected by many factors. The potential and indiscriminate use of narcotics, high exposure to sedative-hypnotic drugs and overdose of general anaesthetics can lead to serious and life-threatening conditions that range from censorious physiological crisis to severe respiratory failure. In order to thrash the maladies of respiratory failure and obstructive pulmonary disease, analeptics came into existence. Analeptic drugs in general are referred as respiratory stimulants¹. The most relevant and primary use of analeptics is in recovery of respiratory depression due to overdose of anesthesia or sleep inducing pills. They can also be used in conditions such as attention deficit hyperactivity disorder and respiratory despondencies². They include a wide array of medicines used for the restoration of respiration when the natural reflex has been lost due to overdose of central nervous system depressants or in case of critical apnoea or suffocation on drowning.

They act on the respiratory centre present in the brain and also on peripheral carotid chemo receptors in order to increase the rate and depth of respiration by improving sensitivity to carbon dioxide. The most widely used respiratory stimulant for mitigation of respiratory depression is doxapram and almitrine. Some common side effects include palpitations, tachycardia, anxiety, restlessness, and hypertension³.

With the growing thrust of pollution on environment, there is severe crash in the performance of respiratory organs of human beings. Suspended particulate matters and toxic pollutants are imposing many adverse effects such as obstructive lung disease and depressed respiratory function⁴. Despite these maladies, excessive or over dose of sleep/stupor inducing drugs can also lead depression in respiration. Acute respiratory depression can only be treated by analeptics. The term ‘analeptic’ is a Greek word meaning ‘restorative’ which refers to agents that stimulates autonomic centre especially to that part of nervous system which is involved in regulation of respiration. In 20^th century, many naturally occurring drugs having respiratory stimulant property came into existence; hence that period was also known as the age of naturally occurring analeptics⁵. The drugs were caffeine (central nervous system and respiratory stimulant), strychnine (respiratory and circulatory stimulant) and camphor (respiratory stimulant). Few synthetic analeptics such as nikethamide, pentylenetetrazole and picrotoxin also evolved for the same purpose. Nikethamide was used to overcome the respiratory depression caused by morphine, also found useful in managing respiratory insufficiency in chronic obstructive pulmonary disease. In the latter half of 20^th century, second generation analeptics came into existence such as amiphenazole, bemegride, methylphenidate, modafinil and doxapram which are more selective respiratory stimulant⁶. Modafinil is rather used to control the symptoms related to narcolepsy. This drug is used by militaries as “go pill” for fatigue management⁷. Modafinil is a well known medication that promotes wakefulness. Previously dextroamphetamine was used as an analeptic and anti-narcoleptic substance, but the use of dextroamphetamine is no longer approved⁸.

VARIOUS ROLES OF ANALEPTICS IN THERAPEUTICS:

The drugs under the umbrella of analeptics are generally given for their resuscitative value in coma and fainting⁹. These drugs stimulate the centre of respiration in sub convulsive dose, while the margin of safety is quite narrow. There is a chance that patient may get convusion even in the state of coma. Analeptics have various roles in therapeutics despite of having some serious adverse effects. Most of the analeptics are used as in the treatments of overdose of CNS depressant medications. Doxapram is the most widely used analeptic is generally given to counteract post-anaesthetic respiratory depression¹⁰. Analeptics are also given as an aid in the treatment of chronic obstructive pulmonary disease¹¹. Patients in terminal coma or with severe respiratory failure are also managed with analeptics. In cases of acute exacerbation of chronic lung disease with hypercapnia and inability to cough or patient with low concentrations of inspired oxygen, respiratory stimulant can arouse the patient sufficiently to permit effective lung activity. Apnoea in premature infants can also be overcome by the use of analeptics in appropriate dose¹².

USE AND ABUSE OF ANALEPTICS:

The illicit use of analeptics continues to be a major issue internationally. Many earlier analeptics which could not get approval because of their addictive and pschycoactive nature are still being used by cad people for the purpose of euphoria and excitement. Amphetamine, methamphetamine and dextroamphetamine are the potential analeptics as well as psycho stimulants that are acutely abused by freshmen due to the lack of knowledge and awareness. Addicts utilize these substances through intravenous, nasal and oral routes along with alcohol or other drugs¹³. Amphetamine and methamphetamine have great tendency to let out cytoplasmic dopamine from the vesicles of concerned nerve terminals. They have noradrenergic and serotonergic effects also. Therefore, adverse upshots like tachycardia, elevated respiratory rate, hypertension and appetite depressant effects are also observed with the users of amphetamine. Acute consequences of amphetamine include very high respiration rate, tachycardia, hypertension, hyperpyrexia, vascular collapse, coma and death also¹⁴. Another infamous drug is cocaine. Cocaine brings out cholinergic ally linked analeptic property. It is also a well-known psycho stimulant and addictive substance. It can have very serious adverse effect on health and well-being¹⁵.

Favourable outcome and toxicological characteristics of contemporary analeptics:

Analeptics overdose can produce convulsions even in the state of coma. It may be fatal if given in exceeds beyond the therapeutic level. The analeptics are used to enhance the momentum of recovery from various classes of drugs like sedative and anaesthetic. They were also used in limited dose to minimize the negative effects of various opiods and respiratory depressant drugs. Administration of analeptics can also lead to stimulation of central nervous system and at higher dose can cause convulsion also¹⁶.

A variety of analeptics such as picrotoxin, pentylenetetrazole nikethamide, bemegride etc have been in the uses, but with the passage of time safer drugs (Doxapram and Almitrine) have come into existence as they are more specific and have better therapeutic window with respect to the older ones. The oldest analeptics caffeine and camphor are still being used for their multifarious values.

Caffeine:

Caffeine has mild analeptic action. It acts on central nervous system as stimulant and works via adenosine-receptor blocking property. It is most widely used as psychostimulant. The specific neuron on which caffeine acts to trigger arousal has not been identified. The FDA recommends a limit for caffeine intake in a healthy adult which is 400mg/day (about 4 to 5 cups of coffee per day). Caffeine is the most widely used drug worldwide, but it has little clinical significance because of its mild analeptic action¹⁷.

Camphor:

Camphor is the oldest analeptic drug which is derived from the sap of evergreen trees of pine family. A piece of camphor gives strong smell due to its sublime nature. It has tendency to stimulate respiratory centre and spinal reflexes. Camphor has many other properties also. It is used to relieve pain, irritation, itching, inflammation and chest congestion. It has strong odor and taste, and can easily be absorbed through cutaneous layers¹⁸.

Ephedrine:

Ephedrine is a short acting adrenergic agonist. It crosses blood brain barrier and has a mild analeptic effect. It can prevent drowsiness while it is banned now. It was commonly used as energy enhancer, because of its sympathomimetic and central nervous system stimulant action¹⁹. It has severe withdrawal syndromes and dose dependent morbidities, hence it faced ban by Food and Drug Administration (FDA) as supplements in 2004.

Methylphenidate:

Methylphenidate is a stimulant drug used for the treatment in the severe case of attention deficit hyperactive disorder (ADHD) and narcolepsy. Initially it was used for the treatment of drug overdose, but now it has been abandoned because of its addictive and dependence liabilities similar to amphetamine²⁰. It has some benefit in replacement therapy in those individuals who are addicted to methamphetamine or cocaine.

Other drugs:

There are many drugs under the same umbrella which are now not being preferred either because of their narrow therapeutic window or higher extent of toxicity such as picrotoxin, nikethamide, pentylenetetrazol and bemegride²¹. Picrotoxin, bimgegride and pentylenetetrazol are used in experimental animals to induce convulsion. Nikethamide is also a stimulant drug which was used in the mid-twentieth century as a countermeasure against overdoses of tranquilizers, before the advent of positive-pressure lung expansion and endotracheal intubation. Now it is not being preferred. Clinical preference of doxapram and almitrine is significantly high because of their specific mechanism of action and minuscule adverse effects³ (figure 1).

Figure 1: Common adverse effects of contemporary analeptics at therapeutic dose level

DOXAPRAM AND ALMITRINE:

Doxapram was synthesized for the first time in 1962 and achieved clinical recognition after 20 years of investigations. It has strong and dose dependent action in mammals. During its preliminary studies, it was found that anaesthetized animals with Phenobarbital were awakened by intravenous doxapram (5mg/kg) while animals of control group got convulsion at the elevated dose level. The oral LD₅₀ of doxapram in rats is 211 mg/kg with a greater margin of safety with respect to other analeptics⁵. During clinical studies, it was observed that doxapram produces elevation in the rate of respiration and tidal volume in patients anaesthetized with inhalation anaesthetics like halothane, cyclopropane and ether. Arterial blood gas analysis indicates that doxapram has significant tendency to induce respiratory alkalosis with lower pCO2 and higher pH compared to individuals of control group. This drug is also known as pharmacologic ventilator. When doxapram was compared with other respiratory stimulants such as nikethamise, pentylenetetrazol, bemegride, methylphenidate, benzquinamide and ethamivan, it was observed that doxapram produces a significant increase in the degree of ventilation as well as safety compared to other agents. In another study doxapram has been proven as an antagonist to general anaesthetics with a greater margin of safety and efficacy²². Doxapram shows superior pharmacokinetics when given intravenously. It goes on rapid metabolism with a short duration of action in human (8-10 minutes). Approximately 40 to 50% of doxapram is metabolized and excreted through urine. Its effective concentration in circulating blood is approximately 2μg/mL.

Figure 2: Doxapram - mechanism of action

Doxapram is generally used in intensive care of patients in order to stimulate the rate of respiration in patients with respiratory failure. In case of drug induced respiratory depression, it is used to treat the patient who have consumed opioids such as fentanyl or its analogues where naloxone is failed to respond adequately. The principal site of action of doxapram is peripheral carotid chemoreceptors. It also stimulates central respiratory centres in the medulla and other parts of brain and spinal cord. It is a short acting respiratory stimulant that acts by promoting excitation of central neurones (figure 2). At low dose it is more selective for respiratory centre and rapidly excreted through body. It has been found to abolish episodes of apnea even in premature infant not responding to methylxanthines. Doxapram is also used in post anaesthetic conditions when the possibility of air way obstruction or hypoxia has been removed. It is given to stimulate respiration in patients with drug induced respiratory depression and apnoea.

The prime objective of respiration is to maintain appropriate concentrations of oxygen, carbon dioxide and hydrogen ion inside the body. The peripheral chemoreceptors are located in the larger arteries of neck and thorax while medulla oblongata of brain has central chemoreceptors in respiratory centre. The primary function of central chemoreceptors is to increase ventilation in response to elevation in pCO2. The peripheral chemoreceptors (carotid and aortic) are principal oxygen sensors that stimulate ventilation when the level of oxygen (oxygen tension) of the arterial blood goes down in hypoxemia and other respiratory maladies.

Figure 3: Almitrine - mechanism of action

Almitrine bismesylate is another pharmacologically distinctive respiratory stimulant that enhances suppressed respiratory activity by agonising the peripheral chemoreceptors present on the carotid bodies (figure 3). Unlike other centrally active respiratory stimulants, almitrine has advantage of oral dosage forms having prolonged duration of action and has no central adverse effects like other analeptics. Almitrine has been seen to increase arterial oxygen tension while reducing the tension of carbon dioxide in patients with chronic obstructive pulmonary disease²³. Almitrine shows rapid absorption through oral route. Its bioavailability is approximately 70-80%. Food appears to enhance the degree of absorption through oral route. The volume of distribution of almitrine is 14L/kg in healthy human volunteers. This drug shows 99% plasma protein binding tendency having 45 to 50 hours of biological half life (following single dose) and extensively metabolized by hepatic enzymes²⁴. Contemporary analeptics may have sufficient recognition in the management of critical maladies such as medullary depression and obstructive pulmonary disease, but in lenient cases of respiratory depression, reflex stimulation should be executed. Smelling ammonia or a drop of alcohol in the nostril may be enough for managing hysterical fainting.

CONCLUSION:

A number of critical and life-threatening conditions can be managed with the drugs that can encourage respiratory drive. These include post-anaesthetic depression of respiratory system, acute respiratory failure due to overdose of tranquilizers and chronic obstructive pulmonary disease. Analeptics are the class of drugs used to stimulate respiration in various conditions of acute respiratory failure. They are also capable to antagonize the medullary depression of general anaesthetics; drug induced respiratory failure as well as depressed respiration in barbiturate poisoning. In the mid of twentieth century, a number of analeptics came into existence, but most of them are withdrawn from the clinical use because of their narrow therapeutic window and severe adverse effects. The drugs like picrotoxin, pentylenetetrazole, methylphenidate, benzquinamide, ephedrine, methylphenidate and bemegride are no longer in clinical use. Most of them have addictive and psychoactive adverse effects. At present, the most preferred analeptics are doxapram and almitrine. Doxapram enhances respiration through central as well as peripheral mechanism where as almitrine enhances respiration through peripheral mechanism only. Although these drugs have also adverse effects like insomnia, headache and gastrointestinal distress, but their clinical preferences are fair because of their specific action and less convulsive nature.

ETHICAL CLEARANCE:

This article has been routed through the anti-plagiarism cell of Institutional Review Board.

CONFLICT OF INTEREST:

None.

REFERENCES:

1. Dekhuijzen PNR, Machiels HA, Heunks LMA, Van Der Heijden HFM, Van Balkom RHH. Athletes and doping: Effects of drugs on the respiratory system. Thorax. 1999;54(11):1041–1046.

2. Wax PM. Analeptic use in clinical toxicology: A historical appraisal. Journal of Toxicology - Clinical Toxicology. 1997; 35(2): 203–209.

3. Cotton JF. The latest pharmacologic ventilator. Anesthesiology. 2014;121(3):442–444.

4. Gupta JK, Shah K, Mishra P. Environmental pollutants and aggressive climatic conditions: combination scaffolds of brain stroke. Current Science. 2018; 114 (10): 2034-38.

5. Yost CS. A new look at the respiratory stimulant doxapram. CNS Drug Reviews. 2006;12(3–4):236–249.

6. Docherty JR. Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA). British Journal of Pharmacology. 2008; 154(3): 606–622.

7. Caldwell JA, Caldwell JL, Smith JK, Brown DL. Modafinil’s effects on simulator performance and mood in pilots during 37 h without sleep. Aviation Space and Environmental Medicine. 2004;75(9):777–784.

8. Leong GB, Shaner AL, Silva JA. Narcolepsy, paranoid psychosis, and analeptic abuse. Psychiatric Journal of the University of Ottawa: Revue de psychiatrie de l’Universite d’Ottawa. 1989;14(3):481–3.

9. Richards JR, Davis MT, Curry MR, Tsushima JH, McKinney HE. Doxapram reversal of suspected gamma-hydroxybutyrate–induced coma. American Journal of Emergency Medicine. 2017;35(3): 517.e1-517.e3.

10. Kruszynski S, Stanaitis K, Brandes J, Poets CF, Koch H. Doxapram stimulates respiratory activity through distinct activation of neurons in the nucleus hypoglossus and the pre-bötzinger complex. Journal of Neurophysiology. 2019; 121(4): 1102–1110.

11. Bales MJ, Timpe EM. Respiratory stimulant use in chronic obstructive pulmonary disease. Annals of Pharmacotherapy. 2004;38(10):1722–1725.

12. Zhao J, Gonzalez F, Mu D. Apnea of prematurity: From cause to treatment. European Journal of Pediatrics. 2011;170(9):1097–1105.

13. Coper H, Herrmann WM. Psycho stimulants, analeptics, nootropics: An attempt to differentiate and assess drugs designed for the treatment of impaired brain functions. Pharmacopsychiatry. 1988; 21(5):211–217.

14. Steinkellner T, Freissmuth M, Sitte HH, Montgomery T. The ugly side of amphetamines: Short-and long-term toxicity of 3,4-methylenedioxymethamphetamine (MDMA, ’Ecstasy’), methamphetamine and d-amphetamine. Biological Chemistry. 2011; 392(1–2):103–115.

15. Tseng W, Sutter ME, Albertson TE. Stimulants and the lung: Review of literature. Clinical Reviews in Allergy and Immunology. 2014;46(1):82–100.

16. Nehlig A. Effects of respiratory stimulants on cerebral metabolism and blood flow. Neonatology. 1994;65(3–4):258–264.

17. Whitsett TL. The cardiovascular effects of caffeine. Primary Cardiology. 1986;12(2):36–44.

18. Taylor R. Chemical stimulants to respiration. Applied therapeutics. 1963;5: 1019–21 PASSIM.

19. Hutas I. Respiratoty analeptics in the treatment of chronic respiratory failure. Therapia Hungarica (English edition). 1964;12: 109–14.

20. Dodson ME, Fryer JM. Postoperative effects of methylphenidate. British Journal of Anaesthesia. 1980;52(12):1265–1270.

21. Zetler G. Drug-induced catalepsy as influenced by convulsant and anticonvulsant drugs. Neuropharmacology. 1973;12(8):741–749.

22. De Waal CG, Hutten GJ, Kraaijenga J V., De Jongh FH, Van Kaam AH. Doxapram treatment and diaphragmatic activity in preterm infants. Neonatology. 2019;115(1):85–88.

23. Chiumello D, Coppola S, Ferrari E. A Simple Effective Pharmacological Treatment of Hypoxemia During One-Lung Ventilation. Journal of Clinical Medicine. 2019;8(8):1139.

24. Gillart T, Bazin JE, Cosserant B, Guelon D, Aigouy L, Mansoor O, Schoeffler P. Combined: nitric oxide inhalation, prone positioning and almitrine infusion improve oxygenation in severe ARDS. Canadian Journal of Anaesthesia. 1998;45(5 I):402–409.

Received on 06.02.2020 Modified on 09.04.2020

Research J. Pharm. and Tech. 2021; 14(2):1104-1108.

DOI: 10.5958/0974-360X.2021.00199.2