Parkinson’s Disease Medications

Medications for the management of Parkinson’s disease improve the symptoms of tremor, rigidity, and postural instability by increasing dopamine levels in the brain. While levodopa is the drug of choice in individuals of any age with moderate or severe symptoms, other agents can be used as monotherapy for milder symptoms or in conjunction with levodopa–carbidopa for symptom control. Other classes of medications work by preventing central and peripheral dopamine metabolism (monoamine oxidase (MAO) type B inhibitors, catechol O-methyltransferase (COMT) inhibitors, and carbidopa), or by exerting an antidyskinetic effect (amantadine). Serious side effects include arrhythmias and psychiatric symptoms ranging from mood disorders to hallucinations and psychosis. Abrupt withdrawal can result in neuroleptic malignant syndrome Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening reaction to antipsychotic drugs. Neuroleptic malignant syndrome presents with ≥ 2 of the following cardinal symptoms: fever, altered mental status, muscle rigidity, and autonomic dysfunction. Neuroleptic Malignant Syndrome–like symptoms, which can be life-threatening. Drug interactions may occur with other agents that are metabolized by the hepatic cytochrome P450 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, and caution must be used to avoid serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Parkinson’s disease (PD) is a degenerative disease of the basal ganglia Basal Ganglia Basal ganglia are a group of subcortical nuclear agglomerations involved in movement, and are located deep to the cerebral hemispheres. Basal ganglia include the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. Basal Ganglia characterized by a clinical syndrome manifesting with diminished facial expression, bradykinesia, festinating gait (progressively shortened and accelerated steps), cogwheel rigidity, and a “pill-rolling” tremor at rest.

Pathophysiology

  • Cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death in basal ganglia Basal Ganglia Basal ganglia are a group of subcortical nuclear agglomerations involved in movement, and are located deep to the cerebral hemispheres. Basal ganglia include the striatum (caudate nucleus and putamen), globus pallidus, substantia nigra, and subthalamic nucleus. Basal Ganglia
  • Degeneration of dopaminergic neurons of the substantia nigra → loss of central dopamine supply → symptoms begin
  • Alpha-synuclein clumps together → Lewy bodies
  • PD has no cure; decreased dopamine levels → motor symptoms

Pharmacotherapy for Parkinson’s disease

  • Medications restore dopaminergic activity → reduce symptoms, improve quality of life
  • Therapeutic options:
    • Levodopa (increases dopamine supply)
    • Dopamine agonists (increase activation of D2 and D3 receptors)
    • N-methyl-D-aspartate (NMDA) receptor antagonists
    • Monoamine oxidase (MAO) type B inhibitors 
    • Catechol O-methyltransferase (COMT) inhibitors
Pharmacologic strategies for the management of parkinson’s disease

Pharmacologic strategies for the management of Parkinson’s disease
COMT: catechol O-methyltransferase
3-MT: 3-Methoxytyramine
3-OMD: 3-O-methyldopa
DOPAC: 3,4-dihydroxy-phenylacetic acid
L-DOPA: levodopa
MAO-B: monoamine oxidase type B

Image by Lecturio.

Levodopa

Chemistry and pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is "what the body does to the drug," whereas pharmacodynamics is "what the drug does to the body." Pharmacokinetics and Pharmacodynamics

  • Structure:
    • Amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids precursor of dopamine
    • Levorotatory stereoisomer of dopa (L-dopa)
  • Mechanism of action: 
    • Levodopa crosses the blood–brain barrier (BBB); dopamine itself cannot cross the BBB.
    • Converted to dopamine in the brain, even if the dopaminergic neurons are dying.
    • Protected in the plasma from decarboxylation by concomitant administration of carbidopa (pills come as levodopa–carbidopa combination, previously known as brand name Sinemet)
    • In the brain parenchyma, levodopa is decarboxylated to dopamine.
    • Dopamine supply is restored → stimulates dopaminergic receptors

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption:
    • Absorbed in 30–60 minutes, increased with high-fat/high-protein meals
    • Oral preparations include carbidopa to prevent decarboxylation in the plasma.
  • Distribution: 
    • Crosses the BBB
    • Peak plasma concentration: 20–30 minutes 
  • Half-life: 30 minutes to 4 hours, depending on form (immediate-release or extended-release) 
  • Metabolism: in the brain parenchyma → metabolized into dopamine
  • Excretion: urine

Indications

Recommended as 1st-line therapy for moderate to severe symptoms of PD

Adverse effects

  • Nausea 
  • Dizziness
  • Headache
  • Somnolence
  • Arrhythmias: 
    • Ventricular extrasystole
    • Atrial fibrillation Atrial fibrillation Atrial fibrillation (AF or Afib) is a supraventricular tachyarrhythmia and the most common kind of arrhythmia. It is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. Atrial Fibrillation
  • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Neuroleptic malignant syndrome (NMS)–like symptoms can be seen with the sudden withdrawal of levodopa:
    • Hyperthermia/very high fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Other symptoms:
      • Confusion
      • Muscle rigidity
      • Diaphoresis
      • Tachycardia

Drug–drug interactions

  • Dopamine antagonists may reduce therapeutic effects.
  • Pyridoxine (vitamin B6) increases extracerebral metabolism → decreased bioavailability 

Contraindications

  • Preexisting neuropathy
  • Combination with monoamine oxidase inhibitors Monoamine oxidase inhibitors Monoamine oxidase inhibitors are a class of antidepressants that inhibit the activity of monoamine oxidase (MAO), thereby increasing the amount of monoamine neurotransmitters (particularly serotonin, norepinephrine, and dopamine). The increase of these neurotransmitters can help in alleviating the symptoms of depression. Monoamine Oxidase Inhibitors (MAOIs) → hypertensive crisis
  • Requires 14 day washout period between either drug (MAOI or levodopa–carbidopa)

Dopamine Agonists

Chemistry and pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is "what the body does to the drug," whereas pharmacodynamics is "what the drug does to the body." Pharmacokinetics and Pharmacodynamics

  • Dopamine agonists:
    • Greater affinity for D2 and D3 receptors
    • Inhibit anterior pituitary prolactin secretion 
    • Medications for PD-associated neurologic symptoms:
      • Bromocriptine (generic)
      • Pramipexole (Mirapex)
      • Ropinirole (Requip)
      • Rotigotine (Neupro transdermal patch)
    • For PD-associated acute intermittent hypomobility: apomorphine
  • Mechanism of action: 
    • Bind to dopamine receptors directly on the postsynaptic terminal
    • The D2, D3, and D4 receptors couple to the Gi/o family of G proteins, and dopamine agonists inhibit adenylyl cyclase and thus cAMP synthesis.

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption:
    • Oral medications except for rotigotine transdermal patch
    • Absorbed quickly, with peak plasma concentration in 30 minutes to 6 hours
    • Available in immediate-acting or extended-release forms
  • Distribution: 
    • Crosses the BBB
    • Half-life: 5–12 hours, depending on the agent and age of individual
  • Metabolism: hepatic cytochrome P450 system (CYP1A2 and CYP3A4)
  • Excretion: renal and fecal, in different proportions depending on the agent

Indications

  • Mild to moderate symptoms of PD that impact daily living.
  • Other non-Parkinson indications for dopamine agonists:
    • Pramipexole, ropinirole, and rotigotine: restless legs syndrome Restless legs syndrome Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is marked by a severe urge to move the legs, and an unpleasant sensation only relieved by movement. Restless legs syndrome occurs after inactivity, especially during the evening and night, and is associated with sleep disturbance. Restless Legs Syndrome
    • Bromocriptine:
      • Hyperprolactinemia Hyperprolactinemia Hyperprolactinemia is defined as a condition of elevated levels of prolactin (PRL) hormone in the blood. The PRL hormone is secreted by the anterior pituitary gland and is responsible for breast development and lactation. The most common cause is PRL-secreting pituitary adenomas (prolactinomas). Hyperprolactinemia due to prolactin-secreting pituitary adenoma Pituitary adenoma Pituitary adenomas are tumors that develop within the anterior lobe of the pituitary gland. Non-functioning or non-secretory adenomas do not secrete hormones but can compress surrounding pituitary tissue, leading to hypopituitarism. Secretory adenomas secrete various hormones depending on the cell type from which they evolved, leading to hyperpituitarism. Pituitary Adenomas
      • Acromegaly Acromegaly Acromegaly and gigantism are caused by an excessive production of growth hormone (GH) by the pituitary gland. Acromegaly is usually produced by pituitary tumors secreting GH or, less commonly, by extrapituitary disorders. Acromegaly and Gigantism
      • New indication (as of 2020) for uncontrolled type 2 diabetes mellitus Diabetes mellitus Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus ( DM DM Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus; brand name, Cycloset); guidelines do not consider bromocriptine a common treatment for type 2 DM DM Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus except with specific considerations.

Adverse effects

  • Sleep attacks, particularly with pramipexole and ropinirole
  • Nausea/vomiting
  • Dizziness
  • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Headache
  • Cardiac arrhythmia
  • Dyskinesias
  • Long-term use may cause:
    • Choreiform and dystonic movements
    • Psychiatric symptoms: 
      • Mania or depression (different reactions in different individuals)
      • Hallucinations/psychosis
      • Delusions

Drug–drug interactions

  • MAOIs
  • Dopamine antagonists (1st- and 2nd-generation antipsychotics)
  • Other drugs that are metabolized by cytochrome P450 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes

Contraindications

  • History of psychotic illness
  • Severe cardiovascular disease
  • Postpartum or breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding
  • Type 1 diabetes
  • Sleep disorder
  • Alcohol use

Amantadine (N-methyl-D-aspartate Antagonist)

Chemistry and pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is "what the body does to the drug," whereas pharmacodynamics is "what the drug does to the body." Pharmacokinetics and Pharmacodynamics

  • Structure: synthetic tricyclic amine
  • Mechanism of action: 
    • Antagonist of the NMDA-type glutamate receptor → antidyskinetic effect
    • May influence synthesis, release, or reuptake of dopamine 
    • Antagonizes the effects of adenosine at adenosine alpha-2-adrenergic (A2A) receptors (may inhibit D2 receptors)

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: oral
  • Distribution: 
    • Cross the BBB
    • Onset of action: within 48 hours
    • Peak plasma concentration: 2–12 hours, depending on the dosage form
    • Half-life: 9–31 hours
  • Metabolism: conjugation, other unknown mechanisms
  • Excretion: urine (up to 90% unchanged)

Indications

  • Originally used as a treatment for influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza A
  • Recommended for mild Parkinsonian symptoms, specifically dyskinesia and rigidity:
    • May be used in combination with other agents
    • Only for individuals with symptoms that have a minimal impact on daily living
    • Therapeutic effect lasts only 1st few weeks.

Adverse effects

While generally a well-tolerated medication, there are some side effects to be aware of: 

  • Restlessness
  • Depression
  • Suicidal ideation
  • Somnolence
  • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
  • Agitation
  • Hallucinations/psychosis

Drug–drug interactions

  • Clozapine: may cause severe constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation or ileus
  • Trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim: may increase amantadine levels and risk of psychosis
  • Bupropion: may increase risk of adverse CNS effects
  • Influenza nasal vaccine Vaccine A vaccine is usually an antigenic, non-virulent form of a normally virulent microorganism. Vaccinations are a form of primary prevention and are the most effective form due to their safety, efficacy, low cost, and easy access. Vaccination (amantadine is an antiinfluenza agent)

Contraindications

  • Pregnancy (likely teratogenic effect) and breastfeeding Breastfeeding Breastfeeding is often the primary source of nutrition for the newborn. During pregnancy, hormonal stimulation causes the number and size of mammary glands in the breast to significantly increase. After delivery, prolactin stimulates milk production, while oxytocin stimulates milk expulsion through the lactiferous ducts, where it is sucked out through the nipple by the infant. Breastfeeding
  • End-stage renal disease because amantadine is metabolized by the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys
  • Potassium chloride or citrate: may increase risk of GI ulceration

Monoamine Oxidase (MAO) Inhibitors

Chemistry and pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is "what the body does to the drug," whereas pharmacodynamics is "what the drug does to the body." Pharmacokinetics and Pharmacodynamics

  • Classified as:
    • Irreversible inhibitors: selegiline (generic) and rasagiline (Azilect)
    • Reversible inhibitors: safinamide (Xadago)
  • Mechanism of action: 
    • Types of MAO:
      • Type A metabolizes norepinephrine, serotonin, and dopamine (used for depression but largely replaced by newer, safer agents).
      • Type B metabolizes dopamine selectively (used for PD).
    • In the brain parenchyma, MAO type B (MAO-B) is selectively inhibited → increased intracerebral concentration of dopamine

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: oral or transdermal
  • Distribution: 
    • Crosses the BBB
    • Peak plasma concentration: 1–3 hours, depending on the agent
    • Onset of action: 2–3 weeks
    • Half-life: 3–26 hours, depending on the agent
    • Metabolism: hepatic (substrate of CYP1A2, CYP2D6, and other CYP450 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes)
    • Excretion: renal and fecal, in different proportions, depending on the agent

Indications

  • Recommended as an adjunct therapy for individuals with PD taking levodopa–carbidopa who exhibit a deterioration in response to it.
  • Transdermal form has also been used in individuals with major depressive disorder Major depressive disorder Major depressive disorder (MDD), commonly called depression, is a unipolar mood disorder characterized by persistent low mood and loss of interest in association with somatic symptoms for a duration of ≥ 2 weeks. Major depressive disorder has the highest lifetime prevalence among all psychiatric disorders. Major Depressive Disorder.

Adverse effects

  • Drug–food interactions can lead to a hypertensive crisis:
    • Avoid foods with high tyramine levels: aged cheese, cured meats (sausage, salami), fava beans, and fermented foods (marmite, soy sauce, sauerkraut)
    • Avoid fermented beverages: red wine, beer
  • Xerostomia (dry mouth)
  • Nausea
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea or constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation (different reactions in different individuals)
  • Drowsiness or insomnia
  • Dizziness

Drug–drug interactions and contraindications

  • Other drugs that use the cytochrome P450 enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes for metabolism interact with MAO-B inhibitors: CYP1A2, CYP2A6, and CYP2B6 substrates
    • Some NSAIDs: naproxen, nabumetone
    • Some beta-blockers (e.g., bisoprolol) → additive hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
    • Antidepressant Antidepressant Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications bupropion → increased risk of hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
    • Opioid pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain medications:
      • Tramadol
      • Methadone
      • Codeine
    • Risk of serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome with:
      • Selective serotonin reuptake inhibitors Serotonin Reuptake Inhibitors Antidepressants encompass several drug classes and are used to treat individuals with depression, anxiety, and psychiatric conditions, as well as those with chronic pain and symptoms of menopause. Antidepressants include selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and many other drugs in a class of their own. Serotonin Reuptake Inhibitors and Similar Antidepressant Medications (SSRIs) (e.g., fluoxetine, paroxetine)
      • Serotonin–norepinephrine reuptake inhibitors (SNRIs) (e.g., duloxetine)
      • Tricyclic antidepressants Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications used in the management of mood disorders, primarily depression. These agents, named after their 3-ring chemical structure, act via reuptake inhibition of neurotransmitters (particularly norepinephrine and serotonin) in the brain. Tricyclic Antidepressants (TCAs) (e.g., amitriptyline)
      • Migraine Migraine Migraine headache is a primary headache disorder and is among the most prevalent disorders in the world. Migraine is characterized by episodic, moderate to severe headaches that may be associated with increased sensitivity to light and sound, as well as nausea and/or vomiting. Migraine Headache medications (e.g., sumatriptan, rizatriptan)
      • Symptoms include altered mental status, autonomic instability, tremors, myoclonus, and seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures.
  • Other drugs that cause CNS depression (any sedative medications):
    • Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines
    • 1st-generation antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines
    • Sedative/hypnotics
  • Other MAOIrs used for psychosis:
    • 1st-generation antipsychotics (e.g., thioridazine, haloperidol): 
      • Increased risk of extrapyramidal side effects ( dystonia Dystonia Dystonia is a hyperkinetic movement disorder characterized by the involuntary contraction of muscles, resulting in abnormal postures or twisting and repetitive movements. Dystonia can present in various ways as may affect many different skeletal muscle groups. Dystonia, bradykinesia)
      • Increased risk of CNS depression, hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
      • Decreased efficacy of selegiline
    • 2nd-generation antipsychotics (e.g., aripiprazole, clozapine): 
      • Increased risk of CNS depression, psychomotor impairment, hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, and syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope
      • Decreased selegiline efficacy
    • Avoid for 14 days, as the combination may increase the risk of serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome:
      • Dextromethorphan cough syrup 
      • Muscle relaxant: cyclobenzaprine
      • Supplement: St. John’s wort 
      • ADHD medication: atomoxetine (Strattera) 
Clinical characteristics of serotonin syndrome

Clinical characteristics of serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome:
Serotonin syndrome occurs from any combination of drugs that have the net effect of increasing serotonergic neurotransmission Neurotransmission The junction between 2 neurons is called a synapse. The synapse allows a neuron to pass an electrical or chemical signal to another neuron or target effector cell. The plasma membranes of the 2 neurons are placed very close together, and the space between the 2 neurons is called the synaptic cleft. The molecules that mediate the interaction are called neurotransmitters. Synapses and Neurotransmission, causing altered mental status, autonomic instability, and neuromuscular abnormalities.

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Catechol O-methyltransferase (COMT) Inhibitors

Chemistry and pharmacodynamics Pharmacodynamics Pharmacodynamics is the science that studies the biochemical and physiologic effects of a drug and its organ-specific mechanism of action, including effects on the cellular level. Pharmacokinetics is "what the body does to the drug," whereas pharmacodynamics is "what the drug does to the body." Pharmacokinetics and Pharmacodynamics

  • Structure: parent compound is 3-nitrobenzene-1,2-diol, also called nitrocatechol.
  • Drug names:
    • Entacapone (Comtan)
    • Tolcapone (Tasmar)
    • Opicapone (Ongentys)
  • Mechanism of action: 
    • COMT peripherally metabolizes levodopa into 3-O-methyldopa.
    • COMT is selectively inhibited → increased bioavailability of levodopa → prolonged action of levodopa
    • Clearance of levodopa is also decreased → greater bioavailability

Pharmacokinetics Pharmacokinetics Pharmacokinetics is the science that analyzes how the human body interacts with a drug. Pharmacokinetics examines how the drug is absorbed, distributed, metabolized, and excreted by the body. Pharmacokinetics and Pharmacodynamics

  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption: oral
  • Distribution: 
    • Act peripherally
    • Peak plasma concentration: 1–2 hours, depending on the agent
    • Half-life: 1–3 hours, depending on the agent
  • Metabolism: hepatic
  • Excretion: renal and fecal

Indication

For mild PD symptoms that have a minimal impact on daily living

Adverse effects

  • Dyskinesia
  • Hallucinations/psychosis
  • Orthostatic hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension
  • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Sleep disturbances
  • Orange discoloration of the urine
  • Hepatotoxicity
  • Abrupt discontinuation can cause NMS-like symptoms

Drug–drug interactions

  • Codeine
  • Metoclopramide
  • Selegiline
  • Promethazine
  • Calcium channel blockers Calcium Channel Blockers Calcium channel blockers (CCBs) are a class of medications that inhibit voltage-dependent L-type calcium channels of cardiac and vascular smooth muscle cells. The inhibition of these channels produces vasodilation and myocardial depression. There are 2 major classes of CCBs: dihydropyridines and non-dihydropyridines. Class 4 Antiarrhythmic Drugs (Calcium Channel Blockers)
  • Benzodiazepines Benzodiazepines Benzodiazepines work on the gamma-aminobutyric acid type A (GABAA) receptor to produce inhibitory effects on the CNS. Benzodiazepines do not mimic GABA, the main inhibitory neurotransmitter in humans, but instead potentiate GABA activity. Benzodiazepines
  • TCAs

Contraindications

  • History of neuroleptic malignant syndrome Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening reaction to antipsychotic drugs. Neuroleptic malignant syndrome presents with ≥ 2 of the following cardinal symptoms: fever, altered mental status, muscle rigidity, and autonomic dysfunction. Neuroleptic Malignant Syndrome 
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease: Agents should be withdrawn as soon as liver toxicity is detected as indicated by elevated liver enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes.

Comparison of Drug Classes

Table: Comparison of Parkinson’s disease (PD) medications
Agent Mechanism of action Indications Side effects Contraindications
Levodopa Decarboxylated into dopamine Moderate to severe PD symptoms
  • Arrhythmias
  • NMS-like symptoms if abrupt withdrawal
Combination with MAOIs
Dopamine agonists Increase dopaminergic activity by binding to postsynaptic dopamine receptors Current 1st-line therapy for mild to moderate PD symptoms that impact daily living
  • Choreiform and dystonic movements
  • Mania
  • Depression
  • Hallucinations
  • Confusion
  • Pregnancy
  • History of psychotic illness
  • Severe cardiovascular disease
  • Combination with monoamine oxidase inhibitors Monoamine oxidase inhibitors Monoamine oxidase inhibitors are a class of antidepressants that inhibit the activity of monoamine oxidase (MAO), thereby increasing the amount of monoamine neurotransmitters (particularly serotonin, norepinephrine, and dopamine). The increase of these neurotransmitters can help in alleviating the symptoms of depression. Monoamine Oxidase Inhibitors (MAOIs)
Amantadine (NMDA antagonist) Antagonist of the NMDA-type glutamate receptor → antidyskinetic effect Recommended for mild PD symptoms that have minimal impact on daily living
  • Restlessness
  • Depression/ suicide Suicide Suicide is one of the leading causes of death worldwide. Patients with chronic medical conditions or psychiatric disorders are at increased risk of suicidal ideation, attempt, and/or completion. The patient assessment of suicide risk is very important as it may help to prevent a serious suicide attempt, which may result in death. Suicide
  • Somnolence
  • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
  • Agitation
  • Hallucinations
  • Confusion
  • Pregnancy
  • End-stage renal disease
MAO-B inhibitors MAO-B is selectively inhibited → increased intracerebral concentration of dopamine Recommended for mild PD symptoms that have minimal impact on daily living
  • Xerostomia
  • Nausea
  • Constipation
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Drowsiness
  • Dizziness
  • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
Individuals receiving meperidine, tramadol, methadone, propoxyphene, cyclobenzaprine, or St. John’s wort → increased risk of serotonin syndrome Serotonin syndrome Serotonin syndrome is a life-threatening condition caused by large increases in serotonergic activity. This condition can be triggered by taking excessive doses of certain serotonergic medications or taking these medications in combination with other drugs that increase their activity. Serotonin Syndrome
Catechol O-methyltransferase (COMT) inhibitors Selective inhibition of COMT → increased bioavailability of levodopa → prolonged action of levodopa Recommended for mild PD symptoms that have minimal impact on daily living
  • Dyskinesia
  • Nausea
  • Confusion
  • Abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
  • Orthostatic
  • Hypotension
  • Sleep disturbances
  • History of neuroleptic malignant syndrome Neuroleptic malignant syndrome Neuroleptic malignant syndrome (NMS) is a rare, idiosyncratic, and potentially life-threatening reaction to antipsychotic drugs. Neuroleptic malignant syndrome presents with ≥ 2 of the following cardinal symptoms: fever, altered mental status, muscle rigidity, and autonomic dysfunction. Neuroleptic Malignant Syndrome
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver disease

References

  1. Aminoff, M.J. (2021). Pharmacologic management of parkinsonism & other movement disorders. In Katzung B.G., & Vanderah T.W. (Eds.), Basic & Clinical Pharmacology, 15th ed. McGraw-Hill. https://accessmedicine-mhmedical-com.ezproxy.unbosque.edu.co/content.aspx?bookid=2988&sectionid=250598520 
  2. National Center for Biotechnology Information. (2021). PubChem compound summary for CID 6047, Levodopa. Retrieved July 7, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Levodopa
  3. Lexicomp. (2021). Carbidopa and levodopa: drug information. UpToDate. Retrieved August 17, 2021, from https://www.uptodate.com/contents/carbidopa-and-levodopa-drug-information
  4. Deik, A., Tarsy, D. (2021) Essential tremor: treatment and prognosis. UpToDate. Retrieved August 17, 2021, from https://www.uptodate.com/contents/essential-tremor-treatment-and-prognosis
  5. Gandhi, K.R., Saadabadi, A. (2021). Levodopa (L-dopa). StatPearls. Retrieved July 8, 2021, from http://www.ncbi.nlm.nih.gov/books/NBK482140/ 
  6. Spindler, M.A., Tarsy, D. (2021). Initial pharmacologic treatment of Parkinson disease. UpToDate. Retrieved July 8, 2021, from https://www.uptodate.com/contents/initial-pharmacologic-treatment-of-parkinson-disease
  7. National Center for Biotechnology Information (2021). PubChem Compound Summary for CID 8223, Ergotamine. Retrieved July 8, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Ergotamine
  8. Garcia, E., Santos, C. (2021). Monoamine oxidase inhibitor toxicity. StatPearls. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK459386/ 
  9. Sub Laban, T., Saadabadi, A. (2021). Monoamine oxidase inhibitors (MAOI). StatPearls. Retrieved July 8, 2021, from http://www.ncbi.nlm.nih.gov/books/NBK539848/ 
  10. Hirsch, M., Birnbaum, R.J. (2021). Monoamine oxidase inhibitors (MAOIs): pharmacology, administration, safety, and side effects. UpToDate. Retrieved July 8, 2021, from https://www.uptodate.com/contents/monoamine-oxidase-inhibitors-maois-pharmacology-administration-safety-and-side-effects
  11. National Center for Biotechnology Information (2021). PubChem Compound Summary for CID 4675622, 3-Nitrobenzene-1,2-diol. Retrieved July 8, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/3-Nitrobenzene-1_2-diol 
  12. Willman, C., Tadi, P. (2021). Tolcapone. StatPearls. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK560593/ 
  13. National Center for Biotechnology Information (2021). PubChem Compound Summary for CID 2130, Amantadine. Retrieved July 8, 2021, from https://pubchem.ncbi.nlm.nih.gov/compound/Amantadine 
  14. Chang, C., Ramphul, K. (2021). Amantadine. StatPearls. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK499953/ 

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