Drugs and the Brain | National Institute on Drug Abuse (NIDA)
The brain regulates your body's basic functions, enables you to interpret and Over time, a person with substance use disorder uses drugs to get powerfully reinforcing the connection between consumption of the drug, the. Themes and plugins can cause actions to be called multiple times and at Actions are called with the function do_action(), except those marked (ref array), which . edited_term_taxonomy: Runs after a term-taxonomy relationship is updated. Continuing use is typically harmful to relationships and work or school obligations. Because addiction affects the brain's executive functions, individuals who develop an Over time, pursuit of the pleasurable effects of the substance or behavior may dominate an Among the factors that contribute to risk are these.
The term affinity describes the tendency of a drug to bind to a receptor; efficacy sometimes called intrinsic activity describes the ability of the drug-receptor complex to produce a physiological response.
Together, the affinity and the efficacy of a drug determine its potency. Differences in efficacy determine whether a drug that binds to a receptor is classified as an agonist or as an antagonist.
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A drug whose efficacy and affinity are sufficient for it to be able to bind to a receptor and affect cell function is an agonist. A drug with the affinity to bind to a receptor but without the efficacy to elicit a response is an antagonist.
After binding to a receptor, an antagonist can block the effect of an agonist.
The degree of binding of a drug to a receptor can be measured directly by the use of radioactively labeled drugs or inferred indirectly from measurements of the biological effects of agonists and antagonists.
Such measurements have shown that the following reaction generally obeys the law of mass action in its simplest form: Thus, there is a relationship between the concentration of a drug and the amount of drug-receptor complex formed. The structure-activity relationship describes the connection between chemical structure and biological effect.
Such a relationship explains the efficacies of various drugs and has led to the development of newer drugs with specific mechanisms of action. The contribution of the British pharmacologist Sir James Black to this field led to the development, first, of drugs that selectively block the effects of epinephrine and norepinephrine on the heart beta blockersor beta-adrenergic blocking agents and, second, of drugs that block the effect of histamine on the stomach H2-blocking agentsboth of which are of major therapeutic importance.
Receptors for many hormones and neurotransmitters have been isolated and biochemically characterized. All these receptors are proteins, and most are incorporated into the cell membrane in such a way that the binding region faces the exterior of the cell.
This allows the endogenous chemicals freer access to the cell. Receptors for steroid hormones e. Once the drug has bound to the receptor, certain intermediate processes must take place before the drug effect is measurable.
Various mechanisms are known to be involved in the processes between receptor activation and the cellular response also called receptor-effector coupling. Among the most important ones are the following: In the first type of mechanism, the ion channel is part of the same protein complex as the receptor, and no biochemical intermediates are involved. Receptor activation briefly opens the transmembrane ion channel, and the resulting flow of ions across the membrane causes a change in the transmembrane potential of the cell that leads to the initiation or inhibition of electrical impulses.
Such mechanisms are common for neurotransmitters that act very rapidly. Examples include the receptors for acetylcholine and for other fast excitatory or inhibitory transmitter substances in the nervous systemsuch as glutamate and gamma-aminobutyric acid GABA.
In the second mechanism, chemical reactions that take place within the cell trigger a series of responses. The receptor may control calcium influx through the outer cell membrane, thereby altering the concentration of free calcium ions within the cell, or it may control the catalytic activity of one or more membrane-bound enzymes.
One of these enzymes is adenylate cyclasewhich catalyzes the conversion of adenosine triphosphate ATP within the cell to cAMPwhich in turn binds to and activates intracellular enzymes that catalyze the attachment of phosphate groups to other functional proteins; these may be involved in a wide variety of intracellular processes, such as muscle contraction, cell divisionand membrane permeability to ions. A second receptor-controlled enzyme is phosphodiesterase, which catalyzes the cleavage of a membrane phospholipid, phosphatidylinositol, releasing the intracellular messenger inositol triphosphate.
This substance in turn releases calcium from intracellular stores, thus raising the free calcium ion concentration. Regulation of the concentration of free calcium ions is important because, like cAMP, calcium ions control many cellular functions. For more information on intracellular signaling molecules, see second messenger and kinase. In cells the stimulatory effects of epinephrine are mediated through the activation of a second messenger known as cAMP cyclic adenosine monophosphate.
The activation of this molecule results in the stimulation of cell-signaling pathways that act to increase heart rate, to dilate blood vessels in skeletal muscle, and to break down glycogen to glucose in the liver.
In the third type of mechanism, which is peculiar to steroid hormones and related drugs, the steroid binds to a receptor that consists primarily of nuclear proteins. Because this interaction occurs inside the cell, agonists for this receptor must be able to cross the cell membrane. The drug-receptor complex acts on specific regions of the genetic material deoxyribonucleic acid DNA in the cell nucleus, resulting in an increased rate of synthesis for some proteins and a decreased rate for others.
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Steroids generally act much more slowly hours to days than agents that act by either of the two other mechanisms. Many receptor-mediated events show the phenomenon of desensitizationwhich means that continued or repeated administration of a drug produces a progressively smaller effect.
Among the complex mechanisms involved are conversion of the receptors to a refractory unresponsive state in the presence of an agonist, so that activation cannot occur, or the removal of receptors from the cell membrane down-regulation after prolonged exposure to an agonist.
Desensitization is a reversible processalthough it can take hours or days for receptors to recover after down-regulation. The converse process up-regulation occurs in some instances when receptor antagonists are administered.
These adaptive responses are undoubtedly important when drugs are given over a period of time, and they may account partly for the phenomenon of tolerance an increase in the dose needed to produce a given effect that occurs in the therapeutic use of some drugs.
Functional macromolecules Many drugs work not by combining with specific receptors but by binding to other proteins, particularly enzymes and transport proteins. For example, physostigmine inhibits the enzyme acetylcholinesterase, which inactivates the neurotransmitter acetylcholine, thereby prolonging and enhancing its actions; allopurinol inhibits an enzyme that forms uric acid and is used therefore in treating gout.
Transport proteins are important in many processes, and they may be targets for drug action. For example, some antidepressant drugs work by blocking the uptake of norepinephrine or serotonin by nerve terminals.
Gleevec; imatinibDocking of the anticancer drug Gleevec imatinib in the abl domain of the bcr-abl tyrosine kinase. Abnormalities in bcr-abl stimulate the continuous proliferation of bone marrow stem cells, causing an increase in myelogenous cells granulocytes and macrophages in the body and leading to chronic myelogenous leukemia CML. Courtesy of ArgusLab Membrane lipids Some drugs produce their effects by interaction with membrane lipids. A drug of this type is the antifungal agent amphotericin Bwhich binds to a specific molecule ergosterol found in fungal cells.
This binding results in the formation of pores in the membrane and leakage of intracellular components, leading to death of the cell.
Other types of drug action Certain drugs act without engaging in any direct interaction with the components of the cell. An example is mannitolan inert polysaccharide that acts purely by its osmotic effect. This drug increases urine production markedly because it interferes with water reabsorption by the kidney tubule. Another example is magnesium sulfate, which works similarly in the intestine and has a cathartic effect. Fate of drugs in the body Dose-response relationship The effect produced by a drug varies with the concentration that is present at its site of action and usually approaches a maximum value beyond which a further increase in concentration is no more effective.
A useful measure is the median effective doseED50, which is defined as the dose producing a response that is 50 percent of the maximum obtainable. ED50 values provide a useful way of comparing the potencies of drugs that produce physiologically similar effects at different concentrations. Sometimes the response is measured in terms of the proportion of individuals in a sample population that show a given all-or-nothing response e.
Similar measurements can be used as a rough estimate of drug toxicitythe result being expressed as the median lethal dose LD50which is defined as the dose causing mortality in 50 percent of a group of animals. When a drug is used therapeutically, it is important to understand the margin of safety that exists between the dose needed for the desired effect and the dose that produces unwanted and possibly dangerous side effects.
This relationship, known as the therapeutic indexis defined as the ratio LD In general, the narrower this margin, the more likely it is that the drug will produce unwanted effects. The therapeutic index has many limitations, notably the fact that LD50 cannot be measured in humans and, when measured in animals, is a poor guide to the likelihood of unwanted effects in humans.
Mean IELT with daily placebo was Coital frequency increased to 4. Coital frequency increased to 2.
Drugs, Brains, and Behavior: The Science of Addiction
The results of PME treatment with tramadol are similar with both continued and sporadic administration. The sex life of patients improved and they reported greater satisfaction with the sporadic treatment. Short time interval between penetration and ejaculation; little or no voluntary control of ejaculation; and negative consequences, like distress. Operation criteria provided by the American Psychiatric Association is the accepted guide.
Diagnosis of this condition is made when: It is possible that one or a combination of these effects leads to a delay in ejaculation. Patients who fit the following criteria were included in the study: Male years of age Healthy not presenting with major physical illness such as type 2 diabetes mellitus, high blood pressure, sexually transmitted diseases, or psychiatric illnesses Not taking medication such as benzodiazepines, drugs to relieve anxiety, sleep-inducing drugs In an emotionally stable relationship Not using barrier contraception methods Strict stopwatch use during coitus patients were taught how to use stopwatch in their mobile phone.
All participants were informed and written consents were taken. All men were heterosexual; sexually active; in an ongoing, stable, sexual relationship for at least 3 months; and had no other sexual disorders, including erectile dysfunction ED as determined by the international index of erectile function questionnaire.
Patients with chronic psychiatric or systemic diseases, such as diabetes mellitus; with hypertension; with alcohol or substance abuse; or who used any medications were excluded. Urinalysis and urine cultures were performed routinely to exclude urinary infections.
IELTs before and after treatment were calculated by using a partner-held stopwatch. Patients who did not abide to strict stopwatch use during coitus, who changed their sexual partner or whose partner did not agree to participate in the study and patients who did not tolerate the side-effects of tramadol were excluded from the study. All patients signed letters of informed consent. A total of 60 patients were randomly distributed into two groups 30 each.
Group A patients were given mg daily of tramadol for 4 weeks and then on request every 2 or 8 h before sexual contact for next 4 weeks. Group B patients were given a placebo tablet for 4 weeks then a placebo on request 2 or 8 h prior to sexual contact for next 4 weeks.
Subjects were instructed to take study medication h before engaging in vaginal intercourse, with an interval between sexual intercourse events of at least 20 h to ensure wash-out of the drug and its effect. Female partners were instructed to time the IELT for each event by using the stopwatch mobile phone stopwatch application and recording the time in a study diary.
Data were analyzed with descriptive tests and data inference analysis was obtained using the Student t-test. The frequency of sexual intercourse and the characteristics of PE are shown in Table 1. The majority of the subjects Table 1 Open in a separate window The frequency of sexual intercourse and the characteristics of IELT after treatment are shown in Table 2. The mean IELT has increased to Coital frequency has also increased from 2.
In the placebo group, mean IELT has increased Coital frequency has increased from 2.
It has been seen that sporadic treatment has produced slightly higher effects, although, it was not statistically significant in compare to daily treatment. Table 2 Open in a separate window The overall AE rate was 9. Vertigo was observed in 3. There were no serious AEs. Tramadol was well tolerated; the overall AE rate was 6. Chronic use of serotonergic and selective serotonin reuptake inhibitor SSRI agents has shown effectiveness in delaying ejaculation.
Today, they are the main treatment option available for the treatment of PME. Dapoxetine has shown efficacy in PME when used as on-demand basis. Tramadol has shown significant improvement in IELT in both doses over placebo. Although, abuse potential of tramadol is less but with continued treatment it has been reported. Besides this, considering the economical aspects, tramadol has greater advantage over other drugs used in the treatment of PME.
It is worth noting that in relation to degree of satisfaction patients stated that they felt better with the on request administration. This is perhaps due to the fact that the results are the same with both types of administration but with the on request regimen there was a reduction in undesirable side-effects and there was also a lower monetary cost.