Phosphodiesterase Inhibitors

Phosphodiesterase (PDE) inhibitors are a group of drugs that act by inhibiting PDE 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. Phosphodiesterase inhibitors have various mechanisms of action depending on the subtype of PDE targeted, but their main action is increasing the amount of intracellular cAMP or cGMP, which in turn results in physiologic effects such as reducing inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation, promoting smooth muscle relaxation, and vasodilation. Phosphodiesterase inhibitors are indicated in a wide variety of medical conditions, such as intermittent claudication, decompensated heart failure, chronic obstructive pulmonary disease Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD), psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis, atopic dermatitis Atopic Dermatitis Atopic dermatitis, also known as eczema, is a chronic, relapsing, pruritic, inflammatory skin disease that occurs more frequently in children, although adults can also be affected. The condition is often associated with elevated serum levels of IgE and a personal or family history of atopy. Skin dryness, erythema, oozing, crusting, and lichenification are present. Atopic Dermatitis (Eczema), erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction, pulmonary artery 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, and benign prostatic hypertrophy. Contraindications, adverse effects, and warnings are category- and drug-dependent.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Phosphodiesterase 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

  • Phosphodiesterase: 
    • Breaks phosphodiester bonds
    • Degrades secondary messengers, cAMP, and cGMP 
    • Regulates signal transduction pathways
  • Common functions:
    • Vasoconstriction
    • Contraction of smooth muscle 
    • Inflammatory effects

General mechanism of action

The common mechanisms of phosphodiesterase (PDE) inhibitors are:

  • Inhibition of phosphodiesterase → ↑ levels of cAMP and cGMP 
  • Effect: vasodilation and relaxation of smooth muscle in:
    • Heart
    • Vasculature
    • Lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs
    • Genitals 

Classification

The PDE inhibitors are classified based on the subtype(s) affected:

  • PDE3 selective inhibitors
    • Cilostazol
    • Dipyridamole 
    • Milrinone
  • PDE4 selective inhibitors
    • Roflumilast
    • Apremilast
    • Crisaborole
  • PDE5 selective inhibitors
    • Sildenafil
    • Tadalafil
    • Avanafil
    • Vardenafil
  • Nonselective phosphodiesterase inhibitors
    • Theophylline 
    • Pentoxifylline

Phosphodiesterase-3 Inhibitors

Medications in this class

  • Cilostazol
  • Dipyridamole 
  • Milrinone

Mechanism of action

  • Inhibition of PDE3 enzyme can cause the following effects:
    • Heart: ↑ cAMP → Ca influx → ↑ cardiac chronotropy, isotropy, and dromotropy
    • Vasculature: 
      • ↑ cAMP → myosin light-chain kinase (MLCK) inhibition → vasodilation
      • Also ↓ vascular smooth muscle cell proliferation
    • Platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets: ↑ cAMP → ↓ platelet aggregation
  • Drug targets:
    • Cilostazol and dipyridamole: vessels and platelets
    • Milrinone: vascular and cardiac cells
The mechanism of action of milrinone, a phosphodiesterase-3 (pde3) inhibitor

Mechanism of action of milrinone, a phosphodiesterase-3 (PDE3) inhibitor:
By blocking the effect of PDE3, milrinone increases the concentration of cAMP in cardiac cells. This results in increased strength of contraction (inotropy).

Image by Lecturio.

Pharmacokinetics

The following table summarizes the pharmacokinetics of the PDE3 inhibitors:

Table: Pharmacokinetics of the PDE3 inhibitors
Medication Formulation Distribution Metabolism Excretion
Cilostazol Oral Highly protein-bound
  • Hepatic
  • Cytochrome P450
Mostly in urine
Dipyridamole
  • Oral
  • IV
  • Hepatic
  • Glucuronidation
Feces
Milrinone IV (continuous infusion) Majority not metabolized Urine

Indications

  • Cilostazol:
    • Intermittent claudication (reduces symptoms)
    • Secondary prevention of stroke:
      • Transient ischemic attack Transient ischemic attack Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA) ( TIA TIA Transient ischemic attack (TIA) is a temporary episode of neurologic dysfunction caused by ischemia without infarction that resolves completely when blood supply is restored. Transient ischemic attack is a neurologic emergency that warrants urgent medical attention. Transient Ischemic Attack (TIA))
      • Noncardioembolic ischemic stroke Ischemic Stroke An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke
    • Alternative agent in percutaneous coronary intervention (if allergy to either aspirin or clopidogrel)
  • Dipyridamole:
    • Adjunct to warfarin in individuals with heart valve replacements
    • Adjunct to aspirin in individuals for secondary prevention of stroke. If someone has a stroke while taking aspirin, they can add dipyridamole.
    • Pharmacologic stress testing (diagnostic agent)
  • Milrinone: cardiac support for heart failure with reduced ejection fraction and ↓ cardiac output
    • ↓ Incidence of dysrhythmia as compared with dobutamine
    • Use may be limited by 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 (due to vasodilation effect)

Adverse effects

Cilostazol:

  • CNS: 
    • Headache
    • Dizziness
  • GI: 
    • 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 and abnormal stools
  • Cardiovascular:
    • Palpitations
    • Tachycardia
    • Peripheral edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema
    • Hypotension

Dipyridamole:

  • Bleeding risk
  • Angina
  • Dizziness
  • Headache
  • Hepatic insufficiency

Milrinone:

  • Ventricular arrhythmias
  • Supraventricular arrhythmia
  • Hypotension
  • Headache

Contraindications

  • Cilostazol: heart failure
  • Milrinone:
    • Severe pulmonary hypertension Pulmonary Hypertension Pulmonary hypertension (PH) or pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure, which can lead to chronic progressive right heart failure. Pulmonary hypertension is grouped into 5 categories based on etiology, which include primary PAH, and PH due to cardiac disease, lung or hypoxic disease, chronic thromboembolic disease, and multifactorial or unclear etiologies. Pulmonary Hypertension → can worsen ventilation/perfusion mismatch
    • Severe renal impairment

Drug interactions

Cilostazol and dipyridamole are associated with ↑ bleeding risk when used with:

  • Antiplatelet agents Antiplatelet agents Antiplatelet agents are medications that inhibit platelet aggregation, a critical step in the formation of the initial platelet plug. Abnormal, or inappropriate, platelet aggregation is a key step in the pathophysiology of arterial ischemic events. The primary categories of antiplatelet agents include aspirin, ADP inhibitors, phosphodiesterase/adenosine uptake inhibitors, and glycoprotein IIb/IIIa inhibitors. Antiplatelet Agents
  • Anticoagulants Anticoagulants Anticoagulants are drugs that retard or interrupt the coagulation cascade. The primary classes of available anticoagulants include heparins, vitamin K-dependent antagonists (e.g., warfarin), direct thrombin inhibitors, and factor Xa inhibitors. Anticoagulants
  • Thrombolytic agents

Phosphodiesterase-4 Inhibitors

Medications in this class

  • Roflumilast
  • Apremilast
  • Crisaborole

Mechanism of action

Inhibition of PDE4 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 leads to ↑ intracellular cAMP in immune and/or lung cells:

  • Antiinflammatory effect:
    • Suppression of cytokine release
    • Regulates inflammatory mediators (e.g., nitric oxide, interleukins Interleukins Interleukins are a type of cytokines (signaling proteins) that communicate messages between different parts of the immune system. The majority of interleukins are synthesized by helper CD4 T lymphocytes along with other cells such as monocytes, macrophages, and endothelial cells. Interleukins, tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) alpha)
  • ↓ Smooth muscle cell proliferation and pulmonary remodeling

Pharmacokinetics

The following table summarizes the pharmacokinetics for the PDE4 inhibitors:

Table: Pharmacokinetics of the PDE4 inhibitors
Medication Formulation Distribution Metabolism Excretion
Roflumilast Oral Highly protein-bound
  • Hepatic
  • Cytochrome P450 system
Urine
Apremilast Oral 68% protein-bound
  • Hepatic
  • Cytochrome P450 system
Urine and feces
Crisaborole Topical Highly protein-bound Hepatic Urine

Indications

  • Roflumilast: 
    • Prevention of chronic obstructive pulmonary disease Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD) ( COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD)) exacerbation
    • Not used for acute bronchospasm
  • Apremilast:
    • Oral ulcers from Behçet disease
    • Moderate to severe psoriasis Psoriasis Psoriasis is a common T-cell-mediated inflammatory skin condition. The etiology is unknown, but is thought to be due to genetic inheritance and environmental triggers. There are 4 major subtypes, with the most common form being chronic plaque psoriasis. Psoriasis
    • Psoriatic arthritis
  • Crisaborole: topical treatment for atopic dermatitis Atopic Dermatitis Atopic dermatitis, also known as eczema, is a chronic, relapsing, pruritic, inflammatory skin disease that occurs more frequently in children, although adults can also be affected. The condition is often associated with elevated serum levels of IgE and a personal or family history of atopy. Skin dryness, erythema, oozing, crusting, and lichenification are present. Atopic Dermatitis (Eczema)

Adverse effects

Roflumilast and apremilast:

  • Neuropsychiatric:
    • Depression
    • Headache
    • 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
    • Suicidal ideation
  • Metabolic: weight loss
  • GI: 
    • 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
    • Nausea
  • Respiratory: upper respiratory tract infection

Crisaborole:

  • Urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives)
  • Allergic contact dermatitis

Contraindications

Roflumilast:

  • Acute bronchospasm 
  • Hepatic impairment (moderate to severe)
  • Use with caution in individuals with depression

Apremilast:

  • Lack of data on use in pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care 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
  • Use with caution in individuals with depression

Phosphodiesterase-5 Inhibitors

Medications in this class

  • Sildenafil
  • Tadalafil
  • Avanafil
  • Vardenafil

Mechanism of action

Erectile dysfunction:

  • Erection in men:
    • Initiated by NO release in the corpus cavernosum during sexual stimulation
    • NO activates guanylate cyclase → ↑ cGMP → relaxes smooth muscle 
    • ↑  Blood flow into the corpus cavernosum → erection
  • PDE5 inhibitors:
    • ↑ NO effect: inhibits PDE5
    • Prevents degradation of cGMP in the corpus cavernosum → ↑ cGMP

Pulmonary arterial 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 (PAH):

  • PDE5 degrades cGMP in the smooth muscle of the pulmonary vasculature.
  • PDE5 inhibitors prevent the degradation of cGMP → ↑ cGMP → ↑ relaxation and vasodilation in the pulmonary vasculature

Benign prostatic hyperplasia Benign prostatic hyperplasia Benign prostatic hyperplasia (BPH) is a condition indicating an increase in the number of stromal and epithelial cells within the prostate gland (transition zone). Benign prostatic hyperplasia is common in men > 50 years of age and may greatly affect their quality of life. Benign Prostatic Hyperplasia (BPH): 

  • PDE5 inhibition → ↓ endothelial and smooth muscle cell proliferation
  • Additional effects:
    • ↑ NO effect → ↑ smooth muscle relaxation
    • ↓ Afferent nerve activity

Pharmacokinetics

  • Formulation:
    • Oral: 
      • Should be taken on an empty stomach Stomach The stomach is a muscular sac in the upper left portion of the abdomen that plays a critical role in digestion. The stomach develops from the foregut and connects the esophagus with the duodenum. Structurally, the stomach is C-shaped and forms a greater and lesser curvature and is divided grossly into regions: the cardia, fundus, body, and pylorus. Stomach
      • Fatty meals can delay absorption.
    • Sildenafil can be given IV.
  • Distribution: highly protein-bound
  • Metabolism:
    • Hepatic
    • Cytochrome P450 system (CYP3A4, CYP2C9)
    • Most have active metabolites.
  • Excretion: primarily fecal

Indications

  • Erectile dysfunction:
    • Can be used as initial therapy
    • ↑ Number and duration of erections
    • PDE5 inhibitors function only in the presence of sexual stimulation.
  • PAH:
    • May be indicated for:
      • Nonvasoreactive PAH
      • Vasoreactive PAH and failed calcium channel blocker therapy
    • Often used in combination with another drug class, such as an endothelin receptor antagonist
  • BPH:
    • Good choice for men with concurrent erectile dysfunction Erectile Dysfunction Erectile dysfunction (ED) is defined as the inability to achieve or maintain a penile erection, resulting in difficulty to perform penetrative sexual intercourse. Local penile factors and systemic diseases, including diabetes, cardiac disease, and neurological disorders, can cause ED. Erectile Dysfunction
    • Can improve symptoms
  • Other indications:
    • High-altitude pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema
    • Raynaud’s phenomenon

Adverse effects

  • CNS:
    • Headache
    • Paresthesia
    • 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
    • Visual disturbances (sildenafil: blue-tinted vision)
  • Respiratory:
    • Nasal congestion
    • Rhinitis Rhinitis Rhinitis refers to inflammation of the nasal mucosa. The condition is classified into allergic, nonallergic, and infectious rhinitis. Allergic rhinitis is due to a type I hypersensitivity reaction. Non-allergic rhinitis is due to increased blood flow to the nasal mucosa. Infectious rhinitis is caused by an upper respiratory tract infection. Rhinitis
  • Cardiovascular: 
    • Flushing
    • Hypotension
    • 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
    • Tachycardia
  • GI: 
    • Nausea
    • Dyspepsia
  • Musculoskeletal: 
    • Myalgia
    • Back pain Back pain Back pain is a common complaint among the general population and is mostly self-limiting. Back pain can be classified as acute, subacute, or chronic depending on the duration of symptoms. The wide variety of potential etiologies include degenerative, mechanical, malignant, infectious, rheumatologic, and extraspinal causes. Back Pain
  • Genitourinary: priapism

Precautions

Be cautious with individuals who may be predisposed to priapism:

  • Sickle cell anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
  • Multiple myeloma Multiple myeloma Multiple myeloma (MM) is a malignant condition of plasma cells (activated B lymphocytes) primarily seen in the elderly. Monoclonal proliferation of plasma cells results in cytokine-driven osteoclastic activity and excessive secretion of IgG antibodies. Multiple Myeloma
  • Leukemia

Drug interactions

Increased risk of 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 associated with:

  • Ethyl alcohol
  • Alpha-1 blockers
  • Nitrates Nitrates Nitrates are a class of medications that cause systemic vasodilation (veins > arteries) by smooth muscle relaxation. Nitrates are primarily indicated for the treatment of angina, where preferential venodilation causes pooling of blood, decreased preload, and ultimately decreased myocardial O2 demand. Nitrates (contraindication)
  • Nitroprusside

Nonselective Phosphodiesterase Inhibitors

Medications in this class

  • Theophylline 
  • Pentoxifylline

Mechanism of action

Theophylline:

  • PDE3 and PDE4 inhibition: ↑ cAMP → pulmonary smooth muscle relaxation → bronchodilation
  • Additionally: 
    • Suppresses airway response to stimuli
    • ↑ Calcium uptake through adenosine-mediated channels → ↑ diaphragmatic muscle contraction

Pentoxifylline:

  • ↑ cAMP → vasodilation
  • ↑ RBC ATP and cAMP → ↑ RBC flexibility
  • ↑ Fibrinolysis
  • ↓ Thromboxane synthesis
  • Effect:
    • ↓ RBC aggregation 
    • ↓ Blood viscosity
    • ↑ Blood flow

Pharmacokinetics

The following table summarizes the pharmacokinetics for the nonselective PDE inhibitors:

Table: Pharmacokinetics of the nonselective PDE inhibitors
Medication Formulation Metabolism Excretion
Theophylline
  • Oral
  • IV
  • Hepatic
  • Cytochrome P450 system
  • Active metabolites
Urine
Pentoxifylline Oral
  • Hepatic
  • Extensive 1st-pass
  • Active metabolites
Primarily in urine

Indications

Theophylline:

  • COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD) and asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma
  • Has been used for acute and chronic therapy
  • Use is now controversial; not a preferred medication
  • Reversal of dipyridamole-induced reactions (e.g., during cardiac stress testing) 

Pentoxifylline:

  • Intermittent claudication
  • Improves symptoms
  • Not definitive therapy
  • Severe alcoholic hepatitis (when corticosteroids are contraindicated)

Adverse effects

Theophylline:

  • Cardiac: arrhythmia
  • CNS:
    • Headache 
    • Hyperactivity in children
    • Restlessness and insomnia
    • 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 and status epilepticus 
    • Tremors
  • GI:
    • Gastroesophageal reflux
    • Nausea and vomiting

Pentoxifylline:

  • Nausea 
  • Vomiting

Contraindications and precautions

The following are contraindications and precautions for theophylline.

  • Contraindication: allergy to corn-related products (IV route)
  • Use with caution:
    • Coronary artery disease 
    • Renal impairment 
    • Hepatic impairment
    • Hyperthyroidism Hyperthyroidism Thyrotoxicosis refers to the classic physiologic manifestations of excess thyroid hormones and is not synonymous with hyperthyroidism, which is caused by sustained overproduction and release of T3 and/or T4. Graves' disease is the most common cause of primary hyperthyroidism, followed by toxic multinodular goiter and toxic adenoma. Thyrotoxicosis and Hyperthyroidism
    • Epilepsy Epilepsy Epilepsy is a chronic brain disorder marked by recurrent and unprovoked seizures. These seizures can be classified as focal or generalized and idiopathic or secondary to another condition. Clinical presentation correlates to the classification of the epileptic disorder. Epilepsy 
    • Elderly

Drug interactions

  • Theophylline:
    • ↓ Serum concentration of theophylline derivatives:
      • Carbamazepine
      • Macrolides Macrolides Macrolides and ketolides are antibiotics that inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and blocking transpeptidation. These antibiotics have a broad spectrum of antimicrobial activity but are best known for their coverage of atypical microorganisms. Macrolides and Ketolides
    • ↑ Serum concentration of theophylline derivatives:
      • Fluconazole
      • Isoniazid
      • Quinolones 
      • Verapamil
      • Allopurinol
      • Antithyroid agents Antithyroid agents Antithyroid agents are used in the management of hyperthyroidism, particularly that due to Graves' disease. This group of medications includes the thionamides (methimazole and propylthiouracil), potassium iodide, and radioactive iodine. Thionamides are currently the preferred choice for hyperthyroid management. Antithyroid Agents
    • ↓ Bronchodilation effect: beta blockers
  • Pentoxifylline: ↑ risk of bleeding:
    • Anticoagulants Anticoagulants Anticoagulants are drugs that retard or interrupt the coagulation cascade. The primary classes of available anticoagulants include heparins, vitamin K-dependent antagonists (e.g., warfarin), direct thrombin inhibitors, and factor Xa inhibitors. Anticoagulants
    • NSAIDs
    • Antiplatelet agents Antiplatelet agents Antiplatelet agents are medications that inhibit platelet aggregation, a critical step in the formation of the initial platelet plug. Abnormal, or inappropriate, platelet aggregation is a key step in the pathophysiology of arterial ischemic events. The primary categories of antiplatelet agents include aspirin, ADP inhibitors, phosphodiesterase/adenosine uptake inhibitors, and glycoprotein IIb/IIIa inhibitors. Antiplatelet Agents

References

  1. Khera, M. (2021). Treatment of male sexual dysfunction. UpToDate. Retrieved October 4, 2021, from Treatment of male sexual dysfunction – UpToDate
  2. Hopkins, W., Rubin, L. (2021). Treatment of pulmonary arterial hypertension (group 1) in adults: pulmonary hypertension-specific therapy. UpToDate. Retrieved October 10, 2021, from https://www.uptodate.com/contents/treatment-of-pulmonary-arterial-hypertension-group-1-in-adults-pulmonary-hypertension-specific-therapy
  3. Cilostazol: drug information. UpToDate. Retrieved September 22, 2021, from Cilostazol: Drug information – UpToDate
  4. Milrinone: drug information. UpToDate. Retrieved September 22, 2021, from Milrinone: Drug information – UpToDate
  5. Manaker, A. (2021). Use of vasopressors and inotropes. UpToDate. Retrieved September 22, 2021, from Use of vasopressors and inotropes – UpToDate
  6. Roflumilast: drug information. UpToDate. Retrieved September 23, 2021, from Roflumilast: Drug information – UpToDate
  7. Apremilast: drug information. UpToDate. Retrieved September 23, 2021, from Apremilast: Drug information – UpToDate
  8. Crisaborole: drug information. UpToDate. Retrieved September 23, 2021, from Crisaborole: Drug information – UpToDate
  9. Sildenafil: drug information. UpToDate. Retrieved September 24, 2021, from Sildenafil: Drug information – UpToDate
  10. Tadalafil: drug information. UpToDate. Retrieved September 25, 2021, from Tadalafil: Drug information – UpToDate
  11. Vardenafil: Drug information. UpToDate. Retrieved September 25, 2021, from Vardenafil: Drug information – UpToDate
  12. Avanafil: drug information. UpToDate. Retrieved September 25, 2021, from Avanafil: Drug information – UpToDate
  13. Theophylline: drug information. UpToDate. Retrieved September 30, 2021, from Theophylline: Drug information – UpToDate
  14. Aminophylline: drug information. UpToDate. Retrieved September 30, 2021, from Aminophylline: Drug information – UpToDate
  15. Padda, I. S., Tripp, J. (2020). Phosphodiesterase inhibitors. StatPearls. Retrieved September 30, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK559276/
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