4.3.4 Adverse actions of major psychotropic/psychoactive drug classes

‘Non-Target’ (Off-Target/Adverse) Actions of Major Psychotropic/Psychoactive Classes and their Management

The non-target or off-target actions of psychotropic or psychoactive substances refer to the unintended or unwanted effects they may produce, in addition to their therapeutic actions. These adverse effects can be classified into different categories such as cardiovascular, neurological, gastrointestinal, endocrine and sexual side effects, among others. Management of these effects involves identifying the cause, modifying the dose or switching to a different medication, and treating the symptoms. It is important to weigh the benefits and risks of medication and to continuously monitor and manage adverse effects in order to optimize treatment outcomes.

General Pharmacology

Off-target/adverse effect:	Examples:
Postural hypotension	Medications that cause postural hypotension work by blocking the actions of the sympathetic nervous system, which is responsible for increasing heart rate and blood pressure in response to stress or changes in position. This disruption of sympathetic tone leads to a drop in blood pressure and the onset of postural hypotension. For example, medications that block alpha-1 receptors, such as alpha-blockers, can cause postural hypotension by reducing the tone of blood vessels and decreasing the resistance to blood flow. Similarly, diuretics can cause postural hypotension by reducing blood volume and cardiac output. Antidepressants, such as tricyclic antidepressants, can also cause postural hypotension by blocking the reuptake of norepinephrine, which is a key neurotransmitter involved in regulating blood pressure.
Sedation	Benzodiazepines, for example, bind to the GABA (gamma-aminobutyric acid) receptor, increasing the affinity of GABA for the receptor and enhancing its inhibitory effect on the central nervous system. This leads to sedation, anxiolysis, and muscle relaxation. Antidepressants, such as tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs), can also cause sedation by increasing the levels of neurotransmitters, such as serotonin and norepinephrine, that regulate sleep-wake cycles and modulate arousal and alertness. Opioids bind to specific opioid receptors in the brain and spinal cord, causing sedation, pain relief, and a decrease in the perception of pain. Anti-histamines, such as diphenhydramine, bind to the histamine H1 receptor, causing sedation and reducing the symptoms of allergies.
Sexual dysfunction	Selective serotonin reuptake inhibitors (SSRIs) can cause sexual dysfunction by altering the levels of serotonin, a neurotransmitter involved in regulating sexual function, or by blocking the reuptake of serotonin and altering the balance of other neurotransmitters. Beta-blockers can cause sexual dysfunction by reducing the heart rate and blood flow to the sexual organs, which is important for maintaining an erection. Anti-androgens can cause sexual dysfunction by reducing testosterone levels and impairing sexual function. Testosterone is a hormone that is important for sexual function in both men and women.
Weight gain	Antipsychotics can cause weight gain by affecting the levels of hormones such as leptin, which regulate appetite and body weight, or by altering the activity of neurotransmitters such as dopamine, which play a role in regulating food intake and metabolism. Steroids can cause weight gain by altering the balance of hormones such as cortisol, which regulate metabolism and body weight, and by increasing fluid retention. Insulin and other anti-diabetic medications can cause weight gain by increasing insulin sensitivity, which can result in increased appetite and increased storage of fat.
Metabolic dysfunction	Clinical examples of medications that can cause metabolic dysfunction include: antipsychotics (e.g. olanzapine, quetiapine, clozapine), corticosteroids (e.g. prednisone, dexamethasone), antidepressants (e.g. tricyclic antidepressants, mirtazapine, paroxetine), mood stabilizers (e.g. valproic acid). These medications can cause metabolic dysfunction by altering insulin sensitivity, altering the levels of hormones that regulate glucose and lipid metabolism, and by affecting the activity of neurotransmitters that play a role in regulating metabolism. For example, antipsychotics can cause weight gain by increasing insulin resistance and altering the levels of hormones such as leptin, which regulate appetite and body weight. Corticosteroids can cause weight gain by altering the balance of hormones such as cortisol, which regulate glucose and lipid metabolism.
QTc prolongation	Clinical examples of medications that can cause QTc prolongation include: antiarrhythmics can cause QTc prolongation by blocking specific ion channels involved in the electrical conduction of the heart, such as potassium channels, antidepressants can cause QTc prolongation by inhibiting the activity of enzymes involved in the regulation of the heart rate, such as CYP3A4, which is involved in the metabolism of certain medications, antipsychotics can cause QTc prolongation by blocking specific ion channels involved in the electrical conduction of the heart and by affecting the levels of hormones such as dopamine, which play a role in regulating heart rate, antimalarials can cause QTc prolongation by affecting the levels of ions such as magnesium, which are involved in the electrical conduction of the heart. It is important to note that the effects of medications on the heart and the receptors involved can be complex and may involve multiple mechanisms.

(Katrak, 2018)

Specific Pharmacology

Extrapyramidal symptomatology:

Extrapyramidal symptoms (EPS) refer to a group of adverse effects that can occur as a result of treatment with certain medications, especially antipsychotics. EPS include movement disorders such as akathisia (an inner restlessness and agitation), dystonia (muscle spasms), parkinsonism (symptoms similar to those of Parkinson’s disease), and tardive dyskinesia (involuntary movements of the face, tongue, and extremities).

The exact mechanisms that underlie EPS are not completely understood, but it is thought to involve alterations in the balance of neurotransmitters in the brain, such as dopamine and acetylcholine, that play a role in regulating movement. Antipsychotics, particularly typical or first-generation antipsychotics, can cause EPS by blocking dopamine receptors in the brain, which can lead to an imbalance in the neurotransmitter system.

Antipsychotics, particularly typical or first-generation antipsychotics, can cause EPS by blocking dopamine receptors in the brain, leading to an imbalance in the neurotransmitter system and a reduction in dopamine in the nigrostriatal pathway. This reduction in dopamine can result in alterations in the regulation of movement and the development of EPS (Rang, 2015).

Neuromalignant syndrome:

Neuromalignant syndrome (NMS) is a rare but life-threatening condition that can occur as a result of treatment with antipsychotic medications. NMS is characterized by a range of symptoms, including high fever, rigidity, muscle breakdown (rhabdomyolysis), and changes in mental status. The exact cause of NMS is not well understood, but it is thought to result from an overactivity of dopamine in the brain, leading to an increase in muscle tone and a reduction in the availability of dopamine.

The exact pharmacology behind NMS is not well understood, but it is believed to involve changes in neurotransmitter levels and receptor sensitivity. One of the main theories behind the development of NMS is that the dopamine blockade caused by antipsychotic medications can lead to increased levels of the neurotransmitter acetylcholine. This increase in acetylcholine can result in increased muscle tone and rigidity, as well as a range of other symptoms associated with NMS.

In addition, it is thought that antipsychotic medications may disrupt the balance of other neurotransmitters, including norepinephrine and serotonin, leading to further changes in neurotransmitter levels and receptor sensitivity.

In the case of NMS, the main goal of treatment is to discontinue the antipsychotic medication that is causing the condition, if possible. In addition, supportive care measures, such as hydration and cooling, may be used to address specific symptoms. Antipyretics, such as acetaminophen, may be used to manage fever, while intravenous fluids may be used to prevent dehydration and rhabdomyolysis. In severe cases, dantrolene or bromocriptine may be used to reduce muscle rigidity.

Serotonin syndrome:

Serotonin syndrome, on the other hand, is a condition that occurs as a result of excessive stimulation of serotonin receptors in the brain. Serotonin syndrome can be caused by an overdose of a serotonergic medication, such as an antidepressant, or by the use of multiple serotonergic medications at the same time. Symptoms of serotonin syndrome can range from mild, such as agitation and restlessness, to more severe symptoms such as seizures, high fever, and changes in mental status.

For serotonin syndrome, treatment primarily focuses on discontinuing the serotonergic medication that is causing the condition and providing supportive care. If the patient is symptomatic, benzodiazepines may be used to manage symptoms such as agitation and seizures, while cyproheptadine, a serotonin antagonist, may be used to reduce excessive serotonin activity. In severe cases, intravenous fluids, electrolyte replacement, and cooling measures may be used to address symptoms such as hyperthermia and changes in mental status.

Idiosyncratic – Toxic/Allergic Reactions

Blood dyscrasias:

Blood dyscrasias, also known as blood disorders, can occur as a result of toxic or allergic reactions to certain medications. These reactions can affect the production, function, and quality of blood cells and can lead to a range of symptoms, including anaemia, bleeding, and an increased risk of infection.

Some common medications that can cause blood dyscrasias to include chemotherapy agents, nonsteroidal anti-inflammatory drugs (NSAIDs), and antibiotics. For example, methotrexate, a chemotherapy drug, can cause a reduction in red blood cells and platelets, leading to anaemia and an increased risk of bleeding. Similarly, sulfonamide antibiotics can cause a reduction in white blood cells, increasing the risk of infection.

Hepatotoxicity/allergic hepatitis:

Hepatotoxicity is a term used to describe the toxic effect of a drug or other chemical substance on the liver. Allergic hepatitis is a type of liver injury caused by an immune response to a medication or other substance. Both conditions can result in damage to the hepatocytes, leading to a range of symptoms, including fatigue, abdominal pain, jaundice, and elevated liver enzymes.

Some medications have a known risk of causing hepatotoxicity, including NSAIDs, antibiotics, anti-tuberculosis drugs, and anticonvulsants. Certain herbal supplements and over-the-counter remedies may also increase the risk of liver injury. In some cases, liver injury can occur shortly after starting a medication, while in others, it may occur after several months of use (Stricker, 2017).

Skin reactions – including outline knowledge of Stevens-Johnson syndrome/toxic epidermal necrolysis myocarditis/cardiomyopathy:

Skin reactions refer to adverse events that affect the skin and can range from mild rashes to life-threatening conditions. Some drugs and chemicals can cause skin reactions as an adverse effect, and it is important for healthcare providers to be aware of the signs and symptoms of these conditions.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are severe forms of skin reactions that can result from drug exposure. These conditions are characterized by the blistering and peeling of the skin, and they can also affect the mucous membranes of the eyes, mouth, and genitalia. SJS and TEN are considered medical emergencies and can lead to serious complications, including infections and sepsis. Examples of drugs that can cause SJS and TEN include sulfonamides, penicillins, nonsteroidal anti-inflammatory drugs (NSAIDs), allopurinol, lamotrigine, and anticonvulsants such as phenytoin and carbamazepine (Gruchalla, 2017).

Myocarditis is an inflammation of the heart muscle that can result from a variety of causes, including viral infections, autoimmune diseases, and exposure to certain drugs or chemicals. Myocarditis can cause a wide range of symptoms, including chest pain, shortness of breath, and irregular heartbeat. In severe cases, myocarditis can progress to heart failure. Cardiomyopathy is a condition that affects the heart muscle and can lead to heart failure. There are several different types of cardiomyopathy, and the cause can vary from one person to another. Some drugs and chemicals can cause cardiomyopathy as an adverse effect, and it is important for healthcare providers to be aware of the risk factors and to monitor patients closely for the development of this condition. Drugs that have been associated with myocarditis and cardiomyopathy include antituberculosis drugs (such as isoniazid), antiretroviral drugs (such as zidovudine), and certain chemotherapeutic agents. Additionally, drugs that cause an electrolyte imbalance, such as potassium-wasting diuretics, can also lead to myocarditis and cardiomyopathy (Nelson, 2018).

References:
(1) Gruchalla, R. S., & Pirmohamed, M. (Eds.). (2017). Adverse drug reactions and drug interactions in dermatology. Springer.

(2) Katrak, P. (2018). Adverse drug reactions: an update. Journal of pharmacology and pharmacotherapeutics, 9(1), 1-7.

(3) Nelson, L. S., & Lewin, N. J. (Eds.). (2017). Goldfrank’s toxicologic emergencies (10th ed.). McGraw-Hill Education.

(4) Stricker, B. H., & Navarro, V. J. (2017). Handbook of liver disease. Elsevier Health Sciences.

(5) Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2015). Rang and Dale’s pharmacology. Churchill Livingstone.