A GENERAL OVERVIEW ON: STRESS AND ADAPTOGENS

About Author:
Sachin Kaushik
P.G. Department of Pharmacology,
B.L.D.E.A.’s college of Pharmacy,
Bijapur- 586103, Karnataka,India.
sachin_2004_kaushik@yahoo.com

ABSTRACT
In this general overview, we discussed about stress, types of stress, mechanism and its management. According to the report of WHO, approximately 450 million people suffer from mental or behavioral disorders like stress. This amounts to 12.3% of the global burden of disease and predicted to rise up to 15% by 2020. Therefore there is a need of an effective management to control stress and stress induced disorders.

Reference Id: PHARMATUTOR-ART-1389

INTRODUCTION
Stress
WHO has defined stressas "the pattern of physiological reaction that prepares an organism for action". It is a common problem and a major health hazard of life, prevalent in all age groups. Any factor that threatens the body or has adverse effects on its functioning is called stress. It varies from person to person with rapid advancement in the civilization, industrialization and over-population; there has been a proportional rise in the stressors of diverse nature. Atmospheric pollution, food adulteration, highly ambitious and competitive life style, hostility and synthetic drugs are some of the example of stressors to which modern man is constantly being exposed. The existence of any form of stresstends to diminish resistance.

Stress is a particular response of the body to threatening external events. In order to cope with the stressful situation, the body responds by releasing certain hormones like cortisol and adrenaline. This leads to an increased heart rate, blood pressure and metabolic rate, all intended to heighten the overall performance and ability of body to overcome the challenge. They may lead to disorders like anxiety, depression, indigestion, gastritis, bowel disturbances, muscular aches and worsening conditions like angina, hypertension and asthma.

Stressors
Hypothalamus is also known as body's watch dog which has the sensors to detect changes in the chemistry, temperature and pressure of the blood. It is the transformation of emotions through tracts that connect it with the emotional centers of the cerebral cortex. When the hypothalamus senses stress, it initiates a chain of reactions that produces GAS (General Adaptation Syndrome). The stimuli that produce the syndrome are called stressors.

Classification
Stressors can be broadly classified into two groups -
1.      External Stressors
2.      Internal Stressors

External Stressors
External stressors include adverse physical conditions (such as pain, hot or cold temperatures) or stressful psychological environments (such as poor working conditions or abusive relationships). 

Internal Stressors
Internal stressors can also be physical (infections, inflammation) or psychological. An example of an internal psychological stressor is intense worry about a harmful event that may or may not occur. Internal psychological stressors are rare or absent in most animals except humans.

Further, internal stressors can be -
Acute or Chronic Stress
Stressors may be of short-term (acute) or long-term (chronic).

Acute Stress
Acute stress is the reaction to an immediate threat, commonly known as the fight or flightresponse. The threat can be any situation that is experienced, even subconsciously or falsely, as a danger.

Common acute stressors include

• Noise
• Crowding
• Isolation
• Hunger
• Danger
• Infection
• Imagining a threat or thinking of dangerous events.

Once the acute threat is over the response becomes inactivated and the elevated levels of stress hormones return to normal. This condition is called as relaxation response.

Chronic Stress
Frequently, however, modern life possesses on-going stressful situations that are not short-lived and the urge to act (to fight or to flee) is suppressed, then it will be chronic.  Common chronic stressors include

• On-going highly pressured work
• Long-term  personal  problems
• Loneliness
• Persistent financial worries.

The effect of acute stress
The best way to envision the effect of acute stress is to imagine oneself in a primitive situation, such as being chased by a bear.

Every organ of our body responds in a different way for stress, such as:
Brain
Hypothalamic-Pituitary-Adrenal (HPA) system is activated, which leads to release of steroid hormones. The HPA system triggers the production and release of steroidal hormones (glucocorticoids), including the primary stress hormone cortisol.  Cortisol is very important in monitoring the systems throughout the body (including the heart, lungs, blood circulation, metabolism, immune systems and skin) to deal quickly with the situation.

Catecholamines
The HPA system also releases certain neurotransmitters (chemical messengers) called catecholamines, particularly dopamine, norepinephrine and epinephrine (adrenaline). 

• Catecholamines activate the amygdala, part of brain, which apparently triggers an emotional response to a stressful event (most likely fear).
• Neurotransmitters then signal the hippocampus of the brain to store the emotionally loaded experience in long-term memory. In primitive times, this combination of responses would have been essential for survival when long-lasting memories of danger (i.e. fear) would be critical for avoiding such threats in the future.
• During stress catecholamines suppress short-term memory, concentration, inhibition and rational thought of the brain.  Such sequence of mental events allows a person to react quickly, either to fight or to flee. 

Heart, lungs and blood circulation

• Heart rate and blood pressure increase instantaneously.
• Breathing becomes rapid and in turn affects the lungs.
• Multifold increase in blood flow leads to priming of muscles, lungs and brain for added demands.
• RBC&WBC count will be increased allowing the blood to transport more oxygen.

Immune system
A stress or a threat makes the immune system to be alert; they extend their defensive line to potentiate the critical areas.

• The steroid hormones help the immune molecules to be redistributed.
• These immune-boosting troops are sent to the body's front lines where injury or infection is most likely, occurs to the skin, to the bone marrow and to the lymph nodes.

The acute response in the mouth and throat
During the threat or stress fluids are diverted from non-essential locations, including the mouth. This causes dryness and difficulty in talking. In addition, stress can cause spasms of the throat muscles, making it difficult to swallow.

Skin
The stress diverts blood flow away from the skin to support the heart and muscle tissues. The physical effect is a cool, clammy, sweaty skin. The scalp tightens so that the hair seems to stand up.

Response of a stress by different systems
Metabolism
Stress shuts down digestive activity, a non-essential body function during short-term periods of physical exertion or crisis. Repeated stress induction disturbances the digestive capacity.

The Relaxation Response
If the threat was not that serious and it was acute and of short duration, after the stress, hormones retain to normal and is known as the relaxation response.

General Adaptation Syndrome (GAS)
Hans Selye (1976) termed body's response to stressor as General Adaptation Syndrome (GAS) the effector of stress syndrome is stress system.

The main components of stress systems are corticotrophin releasing hormone (CRH), and the locus ceruleus-norepinephrine (LC-NE)/autonomic (sympathetic) nervous system and their peripheral effectors, the pituitary-adrenaline axis and the limbs of autonomic system. The activation of stress system leads to behavioral and peripheral changes that improve the ability of organism to adjust homeostasis.
GAS consist of three stages

1. The alarm reaction

2. The stage of resistance

3. Stage of exhaustion

The alarm reaction: This is essentially the emergency response of the body to the stressor mediated by the sympathetic nervous system.

The stage of resistance: It begins, wherein the body resists the effects of continuous stressor.  During this stage, certain hormones respond to the stressors.

Stage of exhaustion:
In this final stage, the body capacity to respond continuously and new stressors become seriously compromised. Due to actions of cortisol described above, a person may no longer be able to resist infection and may become sick and perhaps die.   Because of the other stresses there may be imbalance of induced hormonal effects, stomach ulcers, diabetes, skin diseases, asthma, increased susceptibility to cancer or a host of other diseases may occur.

The central key to this control is the excitation of the hypothalamus by different types of stress. These activate the entire system to cause enhanced secretion of ACTH and consequently the cortisol.  And this cortisol initiates a series of metabolic effects such as gluconeogenesis, protein mobilization, fat mobilization and stabilises lysosomes directed towards relieving the damaging nature of the stressful state. In addition, there is also direct feedback of the cortisol to the hypothalamus and anterior pituitary gland to stabilize the concentration of cortisol in the plasma at the times when the body is not experiencing stress. However the stress stimuli are pre-potent ones. Prolonged elevation of cortisol level can also have other harmful effects, such as rise in B.P.

Stress physiology
Stress physiology is the state of disharmony or threatened homeostasis. The steady state required for successful adaptation is maintained by physical and mental reactions that counteract the effect of stressor to re-establish homeostasis. The adaptive responses can be specific to stress or can be generalized and non-specific. A stress may be almost any disturbance like heat or cold, environmental poisons, poisons given off by bacteria during a raging infection, heavy bleeding from wound or surgery or a strong emotional reaction.

Psychologic effects of stress
Studies suggest that the inability to adapt to stress is associated with the onset of depression or anxiety. In one study, two-thirds of subjects who experienced a stressful situation had nearly six times the risk of developing depression within that month. Some evidences suggest that repeated release of stress hormone produces hyperactivity in the hypothalamus-pituitary-adrenal axis (HPA) and disrupts normal levels of serotonin, the nerve chemical that is critical for feelings of well-being. Certainly, on a more obvious level, stress diminishes the quality of life by reducing feelings of pleasure and accomplishment and relationships are often threatened.

Heart disease
Mental stress is as major a trigger for angina as physical stress. Incidents of acute stress have been associated with a higher risk for serious cardiac events, such as heart rhythm abnormalities and heart attacks and even death from such events in people with heart diseases.

Stress activates the sympathetic nervous system. Such actions and others may negatively affect the heart in several ways

• Sudden stress increases the pumping action and heart rate and causes the arteries to constrict, thereby posing a risk for blocking blood flow to the heart.
• Emotional effects of stress alter the heart rhythms and pose a risk for serious arrhythmias in people with existing heart rhythm disturbances.
• Stress causes blood to become stickier (possibly in preparation of potential injury), increasing the likelihood of an artery-clogging blood clot.
• Stress may signal the body to release fat into the bloodstream, raising blood-cholesterol levels, at least temporarily.
• Stress cause inflammation and damage to cells.

Chronic stress appears to blunt the immune response and increase the risk for infections and may even impair a person's response to immunizations. A number of studies have shown that subjects under chronic stress have low white blood cell counts and are vulnerable to colds. And once any person catches a cold or flu, stress can exacerbate symptoms. People who harbor Herpes or HIV viruses may be more susceptible to viral activation following exposure to stress. Even more serious, some research has revealed that HIV-infected men with high stress levels progress more rapidly to AIDS when compared to those with lower stress levels. (In some studies, stressful events most linked with a higher incidence of infections were interpersonal conflicts, such as those at work or in a marriage.)

Immune disorders
The contradictory effects of stress on the immune system can have mixed effects on autoimmune diseases (which are caused by inflammation and damage from immune attacks on the body), eczema, lupus and rheumatoid arthritis may demonstrate changes ranging from improvement to deterioration in response to stress.  A report says that short-term stress appears to have no negative effect on multiple sclerosis, but chronic stress is a major risk factor for flare-ups.

Gastrointestinal disorders
The brain and the intestine are strongly related and mediated by many of the same hormones and nervous system. It is not surprising that prolonged stress can disrupt the digestive system, irritating the large intestine and causing diarrhoea, constipation, cramping and bloating. Excessive production of digestive acids in the stomach may cause a painful burning.

Weight loss:
In rare cases, stress may trigger hyperactivity of the thyroid gland, stimulating appetite but causing the body to burn up calories at a faster than normal rate.

Muscular and joint pain:
Chronic pain caused by arthritis and other conditions may be intensified by stress. Psychological distress also plays a significant role in the severity of back pain. Some have clearly associated job dissatisfaction and this depression leads to back problems.

Headache:
Headache due to tension is highly associated with stress and stressful events, predisposition for translating stress into muscle contraction. Among the wide range of possible migraine triggers is emotional stress

Sleep disturbance
The tensions of unresolved stress frequently cause insomnia, generally keeping the stressed person awake or causing awakening in the middle of the night or early morning.

Memory, concentration and learning
Stress has significant effects on the brain, particularly on memory. The typical victim of severe stress suffers loss of concentration at work and at home and may become inefficient and accident-prone.

Other disorders
Skin disorders: Stress plays a role in exacerbating a number of skin conditions, including hives, psoriasis, acne and eczema. Unexplained itching may also be caused by stress.

Unexplained hair loss (alopecia areata): Alopecia areata is hair loss that occurs in localized (or discrete) patches. The cause is unknown.  Hair loss often occurs during periods of intense stress, such as mourning.

Fertility:Stress may even affect fertility. Stress hormones have an impact on the hypothalamus gland, which produces reproductive hormones. Severely elevated cortisol levels can even shut down menstruation.

MECHANISM OF STRESS
Almost any type of physical or even mental stress can lead within minutes to greatly enhanced secretion ACTH and consequently of cortisol as well, often increasing cortisol secretion as much as 20-fold. It is believed that pain stimuli caused by the stress are first transmitted upward through the brain stem to the perifornical area of the hypothalamus and from here into the medial basal hypothalamus and eventually to the median eminence where CRF is secreted into the hypophysial portal system.  Within minutes the entire control sequence leads to large quantities of the glucocorticoids in the blood.

Mental stress can also cause an almost instantaneous increase in ACTH secretion.  This is lieved to result from increase activity.

Inhibitory effect of cortisol on the hypothalamus and on the anterior pituitary to cause decreased ACTH secretion.

Cortisol has direct negative feedback effects on the hypothalamus to decrease the formation of CRF and the anterior pituitary gland to decrease the formation of ACTH.  These feedbacks help regulate the plasma concentration of cortisol.  That is, whenever automatically reduce the ACTH toward a normal control level.  Or, if the level of cortisol falls too low, lack of the negative feedback will increase the cortisol again toward normal

ADAPTOGENS
The actual word adaptogen was first used by a Soviet scientist, Dr. Nikolai Lazarev, who under grants from the military was researching substances which produced a “state of nonspecific resistance (SNIR)”. The idea was to find ways to enhance the productivity and performance of soldier, athletes and workers without using dangerous stimulants. Much of the early research into adaptogens was done by Dr. I.I. Brekhman who, in the late 1950’s studied Panax ginseng. Looking for a less expensive and more available substitute, he changed his focus to a native Russian shurb, Eleutherococcus senticosis. His first monograph of this now popular herb (Siberian Ginseng, Eleuthero) was published in 1960.

In 1969 Brekhman and Dardymov defined the general pharmacological properties of adaptogenic substances. These include
* The substance is relatively non-toxic to the recipient.

* An adaptogen has “non-specific” activity and acts by increasing resistance of the organism to a broad spectrum of adverse biological, chemical and physical factors.

* These substances tend to help regulate or normalise organ and system function within the organism.

Several theories have been suggested to explain the effects of adaptogenic substances. One theory proposed by Dardymov and Kirkorian argues that adaptogens function primarily due to their antioxidant and free radical scavenging effects. While their theory is partially accurate, it is inadequate to explain the full effects of these medicinals. More recent research postulate that adaptogens work primarily by affecting the hypothalamic/ pituitary/adrenal (HPA) axis and the sympathoadrenal system (SAS). Thus, adaptogens modulate our response to stress (physical, environmental, or emotional) and help to regulate the interconnected endocrine, immune and nervous systems. This re-regulation of a disordered or highly stressed system is achieved by metabolic regulators such as cytokines, catecholamines, glucocorticoids, cortisol, serotonin, nitric oxide (NO), cholecystokinin, corticotrophin-releasing factor (CRF), and sex hormones. This broad array of biochemical activators helps to explain why adaptogens also have anti-inflammatory, antioxidant, anxiolytic, antidepressant, nervine, and amphoteric effects as well. Brekhman and Dardymov’s list of physiological actions of adaptogens states that adaptogens help modulate system function and maintain homeostasis. So all adaptogens act as broad spectrum amphoterics to living organisms, but they rarely have a pronounced effect on only one specific organ or system.

In the indigenous system there are number of herbal formulations and plant extracts recommended to enable one to withstand stress and strain of the life without altering physiological function of the body.  These anti-stress agents induce resistance against aversive stimuli and impart immunity to give protection against disease, postpone aging, improve vigour, vitality and longevity, which is known as adaptogenic activity and the drugs are adaptogens. Adaptogens are biologically active substances, which improve physical endurance for leading a better life.

Management of stress:
There are a number of allopathic and alternative/complementary treatments that are effective in relieving the symptoms of stress-related disorders. Some of these are enlisted below.
* Medications may include drugs to control anxiety and depression as well as drugs that treat such physical symptoms of stress as indigestion or high blood pressure.
* Psychotherapy, including insight-oriented and cognitive/behavior approaches, is effective in helping people understand how they learned to overact to stressors.
* Anger management techniques are recommended for people who have stress related symptoms due to chronic anger.
* Relaxation techniques, anxiety reduction techniques, breathing exercises, yoga, and other physical exercise programmes that improve the body’s relaxation response.
* Therapeutic massage, hydrotherapy and body work are forms of treatment that are particularly helpful for people who tend to carry stress in their muscles and joints.
* Aromatherapy, pet therapy, humor therapy, music therapy and other approaches that emphasize sensory pleasure are suggested for severely stressed people who lose their capacity to enjoy life; sensory-based therapies can counteract this tendency.
* Naturopathic recommendations regarding diet, exercise and adequate sleep and the holistic approach of naturotherapic medicine can help persons with stress-related disorders to recognize and activate the body’s own capacities for self-healing.

List of medicinal plants reported to be having antistress activity

Sl. No.	Name of plant	Part of plant	Family
01. 02. 03. 04. 05. 06. 07. 08. 09. 10.    11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29.	Alchornea cordifolia Aframomum melegueta Allium sativum(Garlic) Annona muricata Boerhaavia diffusa Butea monosperma Bacopa moniera Cytisus scoparius Cnestisferruginea Clerodendron colebrrokianum Cmellia sinensis Caesalpinia bonduc Diospyros peregrine Evolvulus alsinoides Ginkgo biloba Hypericun perforatum Neulumbo nucifera Oscimum santum Panax ginseng Polyalthia cerasoids Rubia cordifolia Rhodiola rosea Sida cordifolia Tribulus terrestris Trichopus Zeylanicus Tinospora malabarica Vitis venifera Withania somnifera Withania somnifera	Root Seed Dried bulbs Stem bark Root powder Flower Aerial part Whole plant Root Leaf Leaves Seed Bark Whole plant Leaf Leaves, flower Leaves Leaf Root Stem bark Root Roots Root Whole plant Whole plant Stem Grape seed Whole plant Root	Euphorbiaceae Zingiberaceae Alliaceae Annonaceae Nytiginacea Fabaceae Scrophulariaceae Leguminosae Connaraceae Vermanaceae Theceae Caesalpiniaceae Ebenaceae Convolvulaceae Ginkgoacae Clusiceae Nymphaceae Lamiceae Aralaceae Allonaceae Rubiaceae Crassulaceae Malvaceae Zygophyllacee Trichopodacee Menispermace Vitaceae Solanaceae Solanaceae

Adaptogenic polyherbal formulations
01.    Siotone
02.    Geriforte
03.    Trasina
04.    AVM
05.    OB-200G
06.    Zeetress

DISCUSSION
Stress  basically is a reaction of mind and body against change in homeostasis.The term stress in the classical sense defined by Hans Selye as a state of threatened homoestasi. Exposure to stressful situation is among the most common human experinces. Stress disturbs the normal physiological condition and result in a state of threatened homeostasis. Stress has been postulated to be involved in the etiopathogenesis of a diverse variety of diseases ranging from psychiatric disorders such as anxiety and depression, immunosuppression, endocrine disorders including diabetes mellitus, male sexual dysfunction, cognitive dysfunctions, peptic ulcers, hypertension and ulcerative colitis. Benzodiazepines and anxiolytics despite having significant antistress activity, have not proved effective against chronic stress induced adverse effects on immunity, behavior cognition, male sexual dysfunction, during pregnancy and lactation. Additionally, the problems of tolerance and physical dependence on their prolonged use, limits the clinical utility of these drugs.

Therefore,Rasayanas of ayurveda may be moreeffective anti-stress agents, because they appear to prolong Selye’s propounded second phase of the “General Adaptation syndrome” the stage of resistance to stress and prevent the final and third phase of exhaustion.

BIBLIOGRAPHY
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