Pharmacology of Drugs and Abuse: Alprazolam and Adderall

Alprazolam

General Description

Alprazolam is an anxiolytic agent, a triazolobenzodiazepine derivative that has sedative, anticonvulsant, and central muscle relaxant effect. The drug is marked by the anxiolytic activity that is expressed in the reduction of emotional stress, anxiety, and panic attacks, which is combined with a moderately pronounced hypnotic effect (Griffin Kaye, Bueno, & Kaye, 2013). Alprazolam may also increase the duration of sleep and reduce the number of night awakenings. Among other indications, there are neurosis and psychopathy, reactive depressive states, including somatic diseases, panic disorder, and withdrawal syndrome in patients with alcoholism and drug addiction.

Mechanism of Action (Neurotransmitters and Receptors Affected)

The mechanism of action is to enhance the inhibitory effect of endogenous inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the central nervous system (CNS) by increasing the sensitivity of GABA receptors to the mediator as a result of stimulation of benzodiazepine receptors (Griffin et al., 2013). The latter are situated in postsynaptic GABA receptors’ allosteric center, activating reticular construction of the brain stem and intercalated neurons of the lateral horns of the spinal cord. Alprazolam reduces the impulsiveness of the subcortical structures of the brain, namely, the limbic system, hypothalamus, and thalamus as well as inhibits polysynaptic spinal reflexes. The mechanism of hypnotic action is the inhibition of the cells of the reticular formation of the brain core.

Dosage, Administration, Absorption, and Metabolism

The dosage of Alprazolam should be identified individually for every patient, and it is recommended to use the minimum effective dose. If necessary, the increase in the dosage should be gradual to avoid serious side effects. The initial dose is 0.25 to 0.5 mg three times per day, if necessary, the maximum possible increase is up to 4 mg daily. For geriatric and debilitating patients, the initial dose is 0.25 mg 2-3 times daily. The cancellation or reduction of Alprazolam should be carried out steadily by reducing the daily dose by up to 0.5 mg once in three days.

After oral administration of immediate-release or extended release tablets, Alprazolam is rapidly and entirely imbibed from the gastrointestinal tract. Its maximum presence in blood plasma is achieved within 1-2 hours, while plasma protein binding is estimated at 80 percent. The drug is metabolized in the liver, and its metabolites are excreted mainly by the kidneys – the period of half-life is 12-15 hours. The course of treatment with Alprazolam is from several days (with an acute state of panic disorder or severe anxiety) to three months.

Side Effects and Contraindications

Primarily at the beginning of therapy with Alprazolam, patients may experience increased fatigue, impaired concentration drowsiness, dizziness, the development of drug dependence, as well as slowed psychomotor reactions. Regardless of the age and duration of treatment, it is possible to note several most common side effects. In particular, tremor of the limbs, headache, and impaired memory and coordination of movements with regard to the nervous system should be taken into account since Alprazolam escalates the inhibitory outcome of gamma-aminobutyric acid in CNS (Griffin et al., 2013). Also, the reduced visual acuity, changes in taste, weight loss, nausea, abnormal stools, dystonia, decreased libido, enuresis, dysmenorrhea, and renal dysfunction may be noted.

With a sharp decrease in dose or termination of the therapy with Alprazolam, patients may develop a withdrawal syndrome, which is accompanied by dystrophy, smooth muscle layer of internal organs, spasm of skeletal muscles, sleep disorders, vomiting, and excessive sweating. Alprazolam is not used for the treatment of patients with respiratory failure, severe impaired renal and hepatic function, acute glaucoma, psychotropic, narcotic, and in pediatric practice. Alprazolam should not be prescribed to patients with alcoholism (during the period of alprazolam therapy, the use of alcoholic beverages and preparations containing ethyl alcohol is prohibited).

Overdose

As a rule, the overdose reasons are an inadequate combination of other OTC drugs and medical errors. While taking Alprazolam in doses significantly higher than recommended (more than 0.5 mg at a time), patients may develop drowsiness, poor coordination of movements, blurred vision, nystagmus, decreased reflexes, speech disorders, hypertension, and coma (Jann, Kennedy, & Lopez, 2014). In case of an overdose, gastric lavage and administration of enterosorbent agents are indicated in order to reduce the absorption of Alprazolam.

Drug Interactions

The combined use of Alprazolam with antidepressants in patients with endogenous depressions is allowed. The mutual enhancement of action is noted with the simultaneous use of Alprazolam with antipsychotics, sleeping drugs, and anticonvulsants, narcotic analgesics, and centrally acting muscle relaxants (Coplan, Aaronson, Panthangi, & Kim, 2015). However, the combined use of the drug with inhibitors of microsomal oxidation increases the risk of toxic effects of Alprazolam, and there is a decrease in the effectiveness of the latter. Alprazolam may increase the impact of some drugs that may invoke dizziness, including sedatives, antihistamines, painkillers, and muscle relaxants.

Concluding Remarks

Thus, Alprazolam is an anxiolytic agent that is prescribed to patients diagnosed with anxiety, panic disorder, sleeping difficulties, and similar conditions. It raises the sensitivity of GABA receptors to CNS due to the stimulation of the benzodiazepine receptors of the supramolecular GABA-benzodiazepine-chlorinophore. Despite such key side effects of Alprazolam are fatigue, drowsiness, dizziness, and drug dependence, its effectiveness is proved by various research studies, yet it should be administered consciously.

Adderall

General Description

Adderall is an amphetamine-based psychostimulant and pharmaceutical drug that is utilized to treat narcolepsy and attention deficit hyperactivity disorder (ADHD). The active ingredients of the drug are salts of racemic amphetamine and dextroamphetamine. Currently, there is one product on the market that contains dextroamphetamine (dextrorotatory enantiomer) and left-amphetamine (levorotation enantiomer) in a three to one ratio (Heal, Smith, Gosden, & Nutt, 2013). Adderall is available in two versions, including immediate release and prolonged release options.

Mechanism of Action (Neurotransmitters and Receptors Affected)

After Adderall is absorbed into the bloodstream, it introduces into the central nervous system (CNS) and affects the neurons of the brain. The drug is designed to store in the areas of the brain, inhibiting such neurotransmitters as dopamine, epinephrine, and noradrenaline. These hormones are also known as catecholamines and released during periods of stress and excitement with the need for additional energy and concentration. By artificially activating adrenergic systems, Adderall increases the release of these key neurotransmitters into CNS (Heal et al., 2013). Through the neural membrane or the dopamine transporter (DAT), it achieves the presynaptic neurons.

After that, Adderall penetrates synaptic vesicles through vesicular monoamine transporter 2 (VMAT2) or connects to trace amine-associated receptor 1 (TAAR1). When the drug is bound to TAAR1, the pulsation frequency of the dopamine receptor decreases, and the signaling of protein kinase A and C is triggered, thereby ensuring DAT phosphorylation. The activation of TAAR1 increases the production of immuno‐cyclic‐AMP (cAMP) through the activation of adenylyl cyclase. The mentioned stimulation also reduces the postsynaptic pulsation frequency and, through protein kinase signaling, inhibits the function of the dopamine, norepinephrine, and serotonin transporters and also contributes to the release of these mediators.

Dosage, Administration, Absorption, and Metabolism

Adderall is available in immediate and sustained release forms to be taken orally. A commonly recommended daily dose for adults is from 5 mg to 60 mg (Allen, 2014). The extended release capsules are usually used in the morning, while generic forms are available in different dosing options. The prolonged release formulas are available under the trademark Adderall XR and intended to provide a therapeutic effect and plasma concentration that is identical to two doses taken with an interval of four hours (Allen, 2014). Adderall metabolizes in the liver, and its half-life is 9-14 hours. The absorption of the drug depends on a patient’s pH: in case it is acidic, the absorption tends to be longer due to water-soluble cationic (salt) form, while basic pH promotes absorption via lipid-rich cell membranes.

Side Effects and Contraindications

There can be various side effects, the most common of which are cardiovascular issues, including arrhythmia as well as hypertension or hypotension due to vasovagal response and Raynaud’s phenomenon. Since Adderall stimulates the average respiratory centers, it may increase the speed of breathing and contribute to the deepening of breathing (Fitzgerald & Bronstein, 2013). When taken in therapeutic doses by patients, Adderall does not cause a noticeable increase in the speed or depth of breathing, but in the presence of respiratory abnormalities, it can excessively stimulate breathing. Common psychological side effects while taking amphetamines at doses may include anxiety, alertness, low concentration, fatigue, mood alterations such as elation and euphoria followed by mild dysphoria, increased initiative, and insomnia, increased self-confidence with sociability. Among the contraindication, one may enumerate drug abuse, cardiovascular issues, atherosclerosis, neurotic diseases, glaucoma, hyperthyroidism, and hypertension (Fitzgerald & Bronstein, 2013). In case a patient has bipolar disorder, depression, liver and kidney diseases, or Raynaud’s syndrome, Adderall is prescribed under constant supervision.

Overdose

An overdose by Adderall is rarely fatal if the is necessary care, but it can lead to a number of symptoms. With a moderate overdose of Adderall, symptoms such as arrhythmia, urination disorders, confusion, hypertension or hypotension, hyperreflexia, hyperthermia, muscle pain, tachypnea, acute agitation, and urinary retention can be observed (Fitzgerald & Bronstein, 2013). As a result of serious overdose, a variety of symptoms such as a dramatic increase in levels of epinephrine and norepinephrine in the blood, amphetamine psychosis, serotonin syndrome, cardiogenic shock, renal failure, anuria, bleeding in the brain, hyperpyrexia, vascular collapse, rhabdomyolysis, and stereotypy may occur.

Drug Interactions

It is rather significant to notify a doctor about all the medicines a person takes. If one took some of the following drugs during the last two weeks, he or she should not take Adderall: Nardil, Marplan, Eldepryl, Zelapar, and Parnat. The drugs that are known to interact with Adderall and may cause problems include blood pressure drugs, including adrenergic blocker or alpha blockers such as Cardura, Uroxatral, and Minipress. In addition, blood thinners such as Warfarin and over the counter cough and cold medicines containing decongestants also eliminate the possibility of taking Adderall.

Concluding Remarks

Adderall is a psychostimulant that works by increasing the activity of norepinephrine, serotonin, and dopamine neurotransmitters in the brain. It is used in the treatment of attention deficit hyperactivity and narcolepsy, while side effects and contraindications are also present. The studies show that long-term drug treatment leads to a decrease in anomalies in the structure of the brain of patients with ADHD, improving the brain functioning and concentration of patients.

References

Allen, S. N. (2014). Adderall XR® and Vyvanse™. Mental Health Clinician, 4(1), 8-10.

Coplan, J. D., Aaronson, C. J., Panthangi, V., & Kim, Y. (2015). Treating comorbid anxiety and depression: Psychosocial and pharmacological approaches. World Journal of Psychiatry, 5(4), 366-378.

Fitzgerald, K. T., & Bronstein, A. C. (2013). Adderall®(amphetamine-dextroamphetamine) toxicity. Topics in Companion Animal Medicine, 28(1), 2-7.

Griffin III, C. E., Kaye, A. M., Bueno, F. R., & Kaye, A. D. (2013). Benzodiazepine pharmacology and central nervous system – Mediated effects. The Ochsner Journal, 13(2), 214-223.

Heal, D. J., Smith, S. L., Gosden, J., & Nutt, D. J. (2013). Amphetamine, past and present – A pharmacological and clinical perspective. Journal of Psychopharmacology, 27(6), 479-496.

Jann, M., Kennedy, W. K., & Lopez, G. (2014). Benzodiazepines: A major component in unintentional prescription drug overdoses with opioid analgesics. Journal of Pharmacy Practice, 27(1), 5-16.