Attention Deficit Hyperactivity Disorder
Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, usually diagnosed first in childhood but often lasts into adulthood (National Center on Birth Defects and Developmental Disabilities, 2022). Persons with ADHD present with symptoms of inattention and hyperactivity-impulsivity. Inattentive patients have problems organizing tasks, are often forgetful, find it hard to pay attention to details, often lose things necessary for tasks and activities, and are reluctant to perform tasks requiring mental activity for a long period. Hyperactivity-impulsivity manifests with fidgets, squirms in seats, talking excessively, trouble waiting for their turns, intruding on others in conversations, blurting out answers before questions are finished, and being unable to participate in leisure activities quietly (Posner et al., 2020).
While there is no cure for ADHD, the currently available treatments improve functioning and reduce symptoms. Therapies include medications, psychotherapy, training, education, and a combination of various approaches. Medications used for ADHD, the primary interest of this first part of the paper, are broadly categorized into stimulants and non-stimulants. Magnus et al. (2022) note that stimulants are further classified into amphetamines and methylphenidates, and they are the mainstay of treatment for ADHD, being effective in more than 70% of the cases. Stimulants come in various formulations, such as immediate-release, extended-release, long-acting, and sustained-release. On the other hand, non-stimulant options include antidepressants and alpha agonists.
Stimulants
They work to enhance arousal in the prefrontal cortex by boosting norepinephrine and dopamine neurotransmission in that region. Methylphenidate inhibits the presynaptic dopamine transporters of central adrenergic neurons and norepinephrine neurotransporters (to a much less degree). Consequently, the synaptic cleft concentration of dopamine increases, amplifying the dopaminergic neurotransmission (Brown et al., 2018). Amphetamine is a competitive inhibitor of dopamine, acting as a pseudo-substrate that binds to the norepinephrine and dopamine neurotransmitter transporter binding sites. Both methylphenidate and amphetamines increase the dopamine levels that enhance one’s response to environmental stimuli. Therefore, stimulants achieve the therapeutic effect of increased attention in patients with ADHD.
Pharmacokinetics
Absorption of methylphenidate is slow and incomplete after oral administration; absorption of sustained or extended-release (ER) tablets is delayed and provides continuous release, well absorbed from the skin. Distribution is unknown. Metabolism and excretion are 80% by the liver. The half-life is about 2-4 hours. The time taken for the onset of actions following oral or transdermal route administration is unknown. The peak action is approximately 4-7 hours after the PO-ER tablets (Verghese & Abdijadid, 2022).
Dextroamphetamine (Dexedrine) is the primary amphetamine. It is well-absorbed after administration. It is widely distributed with high concentrations in the brain and CSF. It crosses the placenta, enters breast milk, and is potentially embryotoxic. Metabolism and excretion: some metabolism by the liver, urinary excretion is pH-dependent. Alkaline urine promotes reabsorption and prolongs its action. Half-time is about 10-12 hours (6.8 hours in children) (National Center for Biotechnology Information [NCBI], 2022).
Adverse Effects
Methylphenidate causes insomnia, nervousness, growth retardation, dizziness, headache, tics, akathisia, nausea/vomiting, weight loss, abdominal pain, reduced appetite, excessive sweating, blurry vision, decreased libido, stroke, and myocardial infarction are commonly reported in adults (Verghese & Abdijadid, 2022).
Dextroamphetamine causes headache, insomnia, mood swings, nervousness, cardiomyopathy, seizure, toxic epidermal necrolysis, Stevens-Johnson syndrome, weight loss, abdominal pain, nausea, diarrhea, reduced appetite, dry mouth, hypersensitivity reactions, and emotional lability (Shoar et al., 2022).
Non-Stimulant Medications
Antidepressants
Within this class, Atomoxetine is the best known. It is a selective (presynaptic) norepinephrine reuptake inhibitor. It inhibits the presynaptic NET, preventing the reuptake of NE throughout the brain and inhibiting dopamine reuptake in specific brain regions such as the prefrontal cortex (Fedder et al., 2022). Its therapeutic effect is that it increases the attention span in ADHD.
Pharmacokinetics
Well-absorbed after oral administration and is minimally affected by food. Well-distributed, 98% of the drug is bound to albumin at therapeutic plasma concentrations and penetrates the BBB. It is metabolized predominantly through the CYP2D6 enzymatic pathway. Half-life is about 6-8 hours and can reach 40 hours in poor metabolizers. Lastly, it is excreted primarily through urine (83%) and feces (17%) (Fedder et al., 2022).
Adverse Effects
Headache, insomnia, hyperhidrosis, decreased appetite, vomiting, abdominal pain, xerostomia, nausea, palpitations, excoriation, flushing, increased thirst, emotional lability, paresthesia, restlessness, seizure, dyspepsia, anorexia, pollakiuria, delayed ejaculation, priapism, muscle spasms, weakness, and dysgeusia, among others (Fedder et al., 2022).
Alpha-2-Agonists
Clonidine and guanfacine are specifically used for the treatment of ADHD as monotherapy or as adjunctive therapy (extended-release tablets) (Taylor & Cassagnol, 2022). Clonidine is an antihypertensive drug that lowers blood pressure by relaxing the arteries and increasing the blood supply to the heart, and it is FDA-approved for the treatment of ADHD. It acts centrally on alpha-2-adrenergic as an agonist. It results in reduced sympathetic outflow inhibiting cardio-acceleration and vasoconstriction centers. Its therapeutic effects are reduced blood pressure, decreased pain, and an improvement of ADHD symptoms.
Pharmacokinetics
Well-absorbed from the GIT and skin. Enters systemic circulation following epidural use. There is some absorption after sublingual use. It is well-distributed, enters the CNS, readily crosses the placenta, and enters breast milk in high concentrations. Metabolized by the liver, and 40-50% is excreted/eliminated unchanged in the urine. Its half-life is 44-72 hours (neonates), 8-12 hours (children), and 12-22 hours (adults).
Adverse Effects
Abdominal pain, headache, hypotension, constipation, fatigue, nausea, xerostomia, diarrhea, sexual dysfunction, dizziness, emotional instability, angioedema, bradycardia, fever, atrioventricular block, syncope, agitation, and sedation, among others (Yasaei & Saadabadi, 2022).
Treatment of Dementia
Dementia describes the overall decline in memory and thinking skills severe enough to reduce a person’s ability to perform daily tasks. A persistent and progressive deterioration of cognitive functions characterizes it. There is a cognitive decline in memory, personality, praxis, abstract thinking, language, complex attention, executive functioning, visuospatial skills, and social skills (Emmady & Tadi, 2022). Occurring sporadically or demonstrating a familial pattern, Alzheimer’s disease (AD) is the commonest cause of dementia, accounting for 70 to 80% of all cases. AD is characterized by widespread atrophy of the cortex and neuronal degeneration. The nature and severity of the symptoms and any safety concerns guide management. Cunningham et al. (2015) assert that acetylcholinesterase inhibitors and memantine (an NMDA receptor antagonist) are the only FDA-approved medications for the treatment of dementia.
Acetylcholinesterase Inhibitors
The cholinesterase inhibitors are donepezil, galantamine, and rivastigmine (Emmady & Tadi, 2022). These drugs work by inhibiting the cholinesterase enzyme, thus preventing its hydrolyzing action of acetylcholine into acetate and choline, consequently increasing the availability and duration of action of acetylcholine (associated with memory formation and learning) in neuromuscular junctions (Singh & Sadiq, 2022). While these drugs lessen some of the dementia associated with AD and enhance cognition, they do not cure the disease.
Donepezil is absorbed well with a relative oral bioavailability of 100%, bound to plasma proteins (primarily albumin), easily crosses the BBB, metabolized by the liver, has a half-life of 70 hours, and is mainly excreted by the kidneys and in feces. The most common adverse effects include nausea, diarrhea, vomiting, fatigue, anorexia, muscle cramps, bradycardia, edema, hypertension, nightmares, and syncopal episodes (Kumar & Sharma, 2022).
Galantamine has an absolute oral bioavailability of approximately 90% and is not affected by food. It is distributed in red blood cells, bound to plasma proteins, and crosses the BBB. It is metabolized by the hepatic cytochrome P450 enzymatic pathways and excreted in the urine in the unchanged form. Adverse effects include bradycardia, syncope, delirium, loss of appetite, nausea, vomiting, diarrhea, weight loss, erythema multiforme, exanthematous pustulosis, Stevens-Johnson syndrome, dizziness, bladder outflow obstruction, bronchospasms, somnolence, syncope, nightmares, rhinorrhea, dysgeusia, asthenia, and hyperhidrosis, among others (Kalola & Nguyen, 2022).
Rivastigmine is well-absorbed after oral administration, widely distributed, rapidly, and extensively metabolized by the liver, and the kidneys excrete its metabolites. It has a half-life of 1.5 hours (PO) and 24 hours after administration via the transdermal route. The common adverse effects include nausea, vomiting, sleep disturbances, muscle cramps, weakness, and allergic reactions (Patel & Gupta, 2022).
Memantine
It is an antagonist of the N-Methyl-D-Aspartate (NMDA) receptor subtype of the glutamate receptors. Its blockade of the NMDA-receptor subtype is thought to antagonize the overactive glutaminergic system in the CNS, thought to be involved in the neurotoxicity seen in AD. AD is believed to arise from glutamate overstimulation, leading to excitotoxicity and neuronal degeneration. Therefore, memantine is proposed to be neuroprotective through its counteraction of excessive glutamate stimulation (Kuns et al., 2022).
It is well-absorbed with 100% oral bioavailability, not affected by food, well-distributed while protein-bound, crosses the BBB, partially metabolized by the liver, and excreted via the renal route. Its terminal elimination half-life is 60 to 80 hours. The common adverse side effects include dizziness, headache, confusion, diarrhea, abnormal gait, seizures, tardive dyskinesia, syncope, tachycardia, loss of appetite, nausea, anemia, rash, Stevens-Johnson syndrome, arthralgia, somnolence, among others (Kuns et al., 2022).
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