Histamine and its Receptors

Histamine

• Endogenous compound found in specialized cells
• It plays an important role in allergic reactions and the regulation of gastric acid secretion
• Histamine use is limited to diagnostic procedures

Histamine Distribution

• It is present in practically all tissues
• Higher concentrations in skin, lungs, and the gastrointestinal tract (GI)
• Has a low content in plasma

Histamine Receptors

• H1 stimulation causes vasodilation
• It increases capillary permeability
• Can cause Bronchoconstriction
• Can cause central nervous system (CNS) effects and other responses

H1 Receptors

• Vasodilation
• Commonly found the skin of the face and upper body, causing flushing and warmth
• Extensive vasodilation can cause hypotension and increased capillary permeability, leading to edema

H2 Receptors

• Increase capillary permeability and edema
• Cause bronchoconstriction but are not the cause of asthma attacks
• It impacts the CNS and plays a role in cognition, memory, and sleep-waking cycles
• Plays other roles including itching, pain, and secretion of mucus

Role of Histamine in Allergic Response

• Mild allergy
• Rhinitis, itching, and localized edema result largely from histamine acting at H1 receptors
• Causes severe anaphylactic reactions
• Anaphylactic shock involves bronchoconstriction, hypotension, and edema
• Histamine plays a minor role in the glottis
• Leukotrienes: are the principal mediators
• Antihistamines are of little help as treatment
• Epinephrine serves as the drug of choice

Two Types of Antihistamines

• H1 Antagonists

H1 Antagonists Pharmacologic Effects

• Peripheral effects involve reduced localized flushing and decreased itching and pain
• Effects on the CNS: Therapeutic doses can cause CNS depression
• Second-generation options have negligible CNS depression in overdose
• Can cause CNS stimulation and convulsions
• Young children are especially sensitive to CNS stimulation

H1 Antagonists Therapeutic Uses

• Treats Mild and Severe allergy as an adjunct only, benefits may be limited
• Treats motion sickness
• Promethazine and dimenhydrinate are used for insomnia
• Treats the common cold
• May decrease rhinorrhea through anticholinergic properties, not H1 blockade

H1 Antagonists Adverse Effects

• Causes sedation, and is less common with second and third-generation drugs
• Causes Nonsedative CNS effects such as dizziness, fatigue, coordination problems, and confusion
• GI effects: Can cause nausea, vomiting, loss of appetite, and constipation
• Exhibits Anticholinergic effects: Weak atropine-like effects, with antimuscarinic actions drying mucous membranes

H1 Antagonists Drug Interactions

• Drug interactions: CNS depressants
• Use during pregnancy and lactation can cause acute toxicity
• Large margin of safety, with widespread availability of drugs
• Causes CNS and anticholinergic reactions leading to, dilated pupils and flushed face
• In children causes CNS excitation, hyperpyrexia, tachycardia, dry mouth, and urinary retention
• In extreme cases, can cause coma, cardiovascular collapse, and death

H1 Antagonists Treatment

• Directed at drug removal and managing symptoms
• No specific antidote to antihistamine poisoning exists
• It involves activated charcoal and cathartics
• For seizures, uses IV benzodiazepines (lorazepam, midazolam)
• Hyperthermia requires ice packs or sponge baths

H1 Antagonists: Second Generation

• Second generation
• Produce much less sedation than first-generation agents
• Cross the blood-brain barrier poorly
• Have a low affinity for H1 receptors of the CNS
• Largely devoid of anticholinergic actions

H1 Antagonists: Second Generation

• Available over the counter (OTC)
• Cetirizine
• Fexofenadine
• Loratadine

Drugs for Asthma & COPD

• Asthma

Pathophysiology

• Symptoms result from a combination of inflammation and bronchoconstriction
• Treatment must address both components

COPD

• Chronic, progressive, largely irreversible disorder
• Characterized by airflow restrictions and inflammation
• Characteristic signs and symptoms include: chronic cough, excessive sputum production, wheezing, dyspnea, and poor exercise tolerance
• Caused by smoking cigarettes

Overview of Drugs for Asthma & COPD

• Two main pharmacologic classes: anti-inflammatory agents and bronchodilators
• Glucocorticoids (prednisone)
• Beta2 agonists (albuterol)

Inhalation Drug Therapy

Anti-Inflammatory Drugs

• Mechanism of action
• Considered the most effective antiasthma drugs available
• It decreases the synthesis and release of inflammatory mediators
• Reduces infiltration and activity of inflammatory cells
• Decreases edema of the airway mucosa caused by beta2 agonists
• Usually administered by inhalation, but IV and oral routes are also options

Anti-Inflammatory Drugs: Glucocorticoids

• Mechanism of action to suppress inflammation
• Reduces bronchial hyperreactivity and decreases airway mucous production
• May increase the number of bronchial beta2 receptors and their responsiveness to beta2 agonists

Anti-Inflammatory Drugs: Glucocorticoids Use

• Prophylaxis of chronic asthma
• Dosing must be on a fixed schedule, not as needed (PRN)
• Glucocorticoids are not used to abort an ongoing attack
• Beneficial effects develop slowly

Anti-Inflammatory Drugs: Glucocorticoids Inhaled Use

• First-line therapy for managing the inflammatory component of asthma
• Most patients with persistent asthma should use these drugs daily
• Inhaled glucocorticoids are very effective and much safer than systemic glucocorticoids

Anti-Inflammatory Drugs: Glucocorticoids Oral Use

• Used For patients with moderate to severe persistent asthma or for the management of acute exacerbations of asthma or COPD
• Potential for toxicity; should be used only when symptoms cannot be controlled with safer medications (inhaled glucocorticoids, inhaled beta2 agonists)
• Treatment should be as brief as possible

Anti-Inflammatory Drugs: Glucocorticoids Adverse Effects of Inhaled Forms

• Includes adrenal suppression, oropharyngeal candidiasis and dysphonia

Anti-Inflammatory Drugs: Glucocorticoids Adverse Effects of Oral Forms

• Includes short-term, long-term therapy with adrenal suppression
• Has a high risk of osteoporosis and hyperglycemia
• It can cause peptic ulcer disease
• In young patients: it can cause Growth suppression initially, but does not impact a final adult height

Anti-Inflammatory Drugs: Glucocorticoids Adrenal Suppression

• Prolonged glucocorticoid use can decrease the ability of the adrenal cortex to produce glucocorticoids of its own
• Can be life-threatening at times of severe physiologic stress (eg, surgery, trauma, or systemic infection)
• Is required at high levels of glucocorticoids
• Adrenal suppression prevents production of endogenous glucocorticoids
• Patients must be given increasing doses of oral or IV glucocorticoids at times of stress
• Failure to do so can prove fatal

Anti-Inflammatory Drugs: Glucocorticoids Discontinuing treatment

• Must be done slowly
• Recovery of adrenocortical function takes several months
• Dosage of exogenous sources must be reduced gradually
• During this time, patients—including those switched to inhaled glucocorticoids—must be given supplemental oral or IV glucocorticoids at times of severe stress

Anti-Inflammatory Drugs: Leukotriene Receptor Antagonists

• Suppress effects of leukotrienes
• Leukotrienes promote smooth muscle constriction and blood vessel permeability
• They also promote inflammatory responses through direct action and recruitment of eosinophils and other inflammatory cells
• In patients with asthma, leukotriene modifiers can reduce bronchoconstriction and inflammatory responses such as edema and mucous secretion

Anti-Inflammatory Drugs: Leukotriene Receptors Antagonists

Second-line agents

• Generally, well tolerated but can cause adverse neuropsychiatric effects, including depression, suicidal thinking, and suicidal behavior
• Available agents include Zileuton [Zyflo], Zafirlukast [Accolate], and Montelukast [Singulair]

COPD: Other Drugs

COPD: Bronchodilators

Bronchodilators: Beta2-Adrenergic Agonists

• Mechanism of action involves the activation of beta2 receptors in the smooth muscle of the lung
• These drugs promote bronchodilation, relieving bronchospasm
• Limited role in suppressing histamine release in the lung
• Increases ciliary motility

Bronchodilators: Beta2-Adrenergic Agonists Use

• Used in asthma and COPD
• Inhaled short-acting beta2 agonists (SABAs) are taken PRN to abort an ongoing attack
• EIB involves taking PRN before exercise to prevent an attack
• Nebulized SABA is the traditional treatment of choice for hospitalized patients undergoing a severe acute attack
• Delivery with an MDI in the outpatient setting may be equally effective

Bronchodilators: Beta2-Adrenergic Agonists

• Inhaled long-acting beta2 agonists (LABAs) help with long-term control in patients who experience frequent attacks
• Dosing is on a fixed schedule, not PRN
• Effective in treating stable COPD
• When used to treat asthma, beta2-Adrenergic Agonists must always be combined with a glucocorticoid
• Use alone in asthma is contraindicated

Bronchodilators: Beta2-Adrenergic Agonists Adverse effects

• Includes Inhaled preparations
• Systemic effects include tachycardia, angina, and tremor
• Includes Oral preparations that can cause excessive dosage, angina pectoris, tachydysrhythmias, and tremor

Bronchodilators: Methylxanthines

• Other methylxanthines include aminophylline and dyphylline
• Theophylline produces bronchodilation by relaxing the smooth muscle of the bronchi
• Has a narrow therapeutic index
• Its plasma level is 10 to 20 mcg/mL
• Toxicity is related to theophylline levels
• This drug is usually administered by mouth but may also be administered intravenously

Bronchodilators: Methylxanthines Use

• Used in asthma and COPD
• Oral theophylline: Used for maintenance therapy of chronic stable asthma
• Theophylline is no longer recommended for the treatment of COPD due to toxicity
• Plasma levels below 20 mcg/mL: Adverse effects uncommon
• Plasma levels of 20 to 25 mcg/mL: Nausea, vomiting, and diarrhea, insomnia, and restlessness
• Plasma levels above 30 mcg/mL: Severe dysrhythmias (eg, ventricular fibrillation) and convulsions
• Death may result from cardiorespiratory collapse

Anticholinergic Drugs: Tiotropium

• Long-acting, inhaled anticholinergic agent approved for maintenance therapy of bronchospasm associated with COPD
• Not approved for asthma
• Relieves bronchospasm: by blocking muscarinic receptors in the lung
• Therapeutic effects: begin about 30 minutes after inhalation, peak in 3 hours, and persist about 24 hours
• With subsequent doses: Bronchodilation continues to improve, reaching a plateau after eight consecutive doses (8 days)
• Adverse effects includes dry mouth and minimal anticholinergic effects

Anticholinergic Drugs: Aclidinium

• Newest long-acting anticholinergic for management of bronchospasm associated with COPD
• The goal is to Relieve bronchospasm by blocking muscarinic receptors in the lung
• Peak levels have occurred within 10 minutes of drug delivery
• Only intended for maintenance therapy, not for acute symptom relief

Anticholinergic Drugs: Aclidinium

• Shows adverse effects, including headache, nasopharyngitis and cough

Glucocorticoid/LABA Combination

• Available combinations
• Fluticasone/salmeterol [Advair]
• Budesonide/formoterol [Symbicort]
• Mometasone/formoterol [Dulera]
• Is Indicated for long-term maintenance in adults and children, not recommended for initial therapy

Tests for Lung Function

• Forced expiratory volume in 1 second (FEV1)
• Forced vital capacity (FVC)
• Peak expiratory flow (PEF)

Management of Asthma

• It varies with four classes of asthma severity
• Includes intermittent, mild persistent, moderate persistent, and severe persistent

Management of Chronic Asthma

• Follows treatment goals through reducing impairment, and reducing risk

Management of Chronic Asthma

• Uses agents for long-term control (eg, inhaled glucocorticoids)
• It uses agents for quick relief of ongoing attack (eg, inhaled SABAs)

Management of Chronic Asthma

• Stepwise therapy; step for initial therapy based on pretreatment classification of asthma severity
• It is moved up or down a step is based on ongoing assessment of asthma control

Reducing Exposure to Allergens and Triggers

• Can reduce and help control or avoid dust mites through measures like encasing the patient's pillow, mattress, and box spring in covers impermeable to allergens
• It’s important to wash all bedding and stuffed animals weekly in a hot-water wash cycle (130°F)
• Reducing exposure to allergens and triggers involves removing carpeting or rugs from bedroom, avoiding sleeping or lying on upholstered furniture, and keeping indoor humidity below 50%

Management of COPD

• Seeks treatment goals to reduce symptoms to improve patient's health status and exercise tolerance
• Reduces risks and mortality by preventing progression of COPD and by preventing and managing exacerbations

Management of COPD

• Can be done through patient classification
• Group A: Few symptoms; low risk
• Group B: Increased symptoms; low risk
• Group C: Few symptoms; high risk
• Group D: Increased symptoms; high risk

Management of Stable COPD

• Through pharmacologic management through bronchodilators
• Glucocorticoids and phosphodiesterase-4 inhibitors

Management of COPD Exacerbations

• Through pharmacologic management with inhaled SABAs alone or with anticholinergics
• Can use systemic glucocorticoids, antibiotics, and supplemental oxygen to maintain an oxygen saturation of 88% to 92%

Drugs for Allergic Rhinitis & Colds

Classes of Drugs Used for Allergic Rhinitis

• Intranasal Glucocorticoids, Oral Antihistamine, Intranasal Antihistamines

Drugs for Cough

• Antitussives; suppress cough through. Opioid antitussives include codeine and hydrocodone
• Nonopioid Antitussives include Dextromethorphan, Diphenhydramine and Benzonatate

Expectorants

• Guaifenesin [Mucinex, Humibid] renders cough more productive by stimulating the flow of respiratory tract secretions, and may be effective in higher doses

Common Cold

• Acute upper respiratory viral infection. Symptoms include: rhinorrhea, nasal congestion, cough, sneezing and sore throat
• May produce a headache, hoarseness, malaise, myalgia, and fever is common in kids, rare in adults
• The common cold is self-limited and is usually benign; it provides no cure but only treatment for the symptoms

OTC Cold Remedies

• Combination cold remedies usually contain two or more of the following: Nasal decongestant, Antitussive, Analgesic, Antihistamine (for cholinergic actions) and Caffeine (to offset the effect of antihistamine)
• These should be used with caution in young children

Pediatric OTC Cold Remedies

• Avoid OTC cold remedies in children younger than 4 to 6 years and only use products labeled for pediatric use
• Consult a healthcare professional before administering these drugs
• Read all product safety information before dosing and use the provided measuring device
• Discontinue the medicine and seek professional care if the child's condition worsens or fails to improve

Immunosuppressants Uses

• Ulnhibit immune response for intended uses like prevention of organ rejection and treatment of autoimmune diseases
• Has a high risk of toxicity and it increases the risk of infection and neoplasms

Calcineurin Inhibitors

• Serve a principal use by preventing organ rejection in transplant recipients
• Cyclosporine, tacrolimus, and pimecrolimus are the available, most effective immunosuppressants
• Calcineurin Inhibitors Differ in structure, but share the same mechanism that suppresses production of interleukin (IL-2).
• IL-2 needed for T-cell proliferation
• Cyclosporine was developed first and is used more than tacrolimus

Cyclosporine [Sandimmune]

Mechanism: Suppresses the production of IL-2, interferon gamma, and other cytokines

• Can be uses as a drug of choice for organ rejection (kidney, liver, and heart) of an allogenic transplant
• Glucocorticoid is used adjunctly in treating some autoimmune diseases

Cyclosporine Pharmacokinetics

• Adverse reactions include nephrotoxicity, infection, hypertension and tumor growth
• Can lead to hirsutism, Hepatotoxicity and lymphoma
• Leukopenia, gingival hyperplasia, gynecomastia, sinusitis, hyperkalemia
• Can cause Anaphylactic reactions

Cyclosporine [Sandimmune] Drug and Food Interactions

• Includes drugs that can decrease or increase cyclosporine levels, drugs that that and leads to Nephrotoxic effects
• Grapefruit juice and repaglinide can also influence the effect

Tacrolimus [Prograf]

• Is an alternative to cyclosporine but is somewhat more effective, but also generates more toxicity and uses a narrow therapeutic index
• Concurrent use with glucocorticoids generates a therapeutic use

mTOR Inhibitors

• Enzyme is known as mammalian target of rapamycin, which is a uProtein kinase that helps regulate cell growth, proliferation, and survival
• mTOR Inhibitors are structurally similar to tacrolimus while using Somewhat different mechanism with the same goals

Sirolimus [Rapamune]

• Used for the prevention of renal transplant rejection

Sirolimus [Rapamune]

• Is used in conjunction with cyclosporine and glucocorticoids but can generate adverse effects such as increased risk of infection
• Raises levels of cholesterol and triglycerides and increases the Risk of renal injury
• Can cause Severe complications in the liver and lung along with Rash, acne, anemia, thrombocytopenia, joint pain, diarrhea, and hypokalemia

Sirolimus [Rapamune] Drug and Food Interactions

• Uses Drugsthat inhibit or induce CYP3A4 along with High-fat foods that enhance the effectiveness
• Consuming Grapefruit juice can also increase the efficacy

Everolimus [Zortress] Uses

• Use drug and food interactions and with Drugs that inhibit or induce CYP3A4 and includes usage of High-fat foods
• Consuming Grapefruit juice can also increase the efficacy

Cytotoxic Drugs

• Suppress immune response by killing B and T lymphocytes undergoing proliferation and can be Nonspecific, or toxic to all proliferating cells
• Bone marrow suppression can cause Neutropenia and Thrombocytopenia
• Other Cytotoxic Drugs include GI disturbances, Reduced fertility and Alopecia

Azathioprine [Imuran]

• Suppresses cell-mediated and humoral immune responses and is only useful for Adjuvant treatment with transplants and Autoimmune disorders using Adjuvant actions

Other Cytotoxic Drugs

• Is Cyclophosphamide in some Anticancer medications
• Can be used for Methotrexate [Rheumatrex, Trexall] or in helping with Rheumatoid arthritis
• Provides Suppression of B with and T lymphocytes by interfering with folate metabolism

Mitoxantrone [Novantrone] Use

• Used as an Anticancer agent for the Reduction of neurologic disability and clinical relapse for multiple or sclerosis (MS) patients who are who are not responsive to safer drugs

uAppoved for prophylaxis of organ rejection uActs on B and T lymphocytes to inhibit inosine monophosphate dehydrogenase that is essential for Selective inhibition of B- and T-lymphocyte proliferation

Antibodies

• Uses Basiliximab as a Monoclonal antibody that Blocks activation of T cells by IL-2 for Prophylaxis of acute organ rejection after renal transplantation
• Adverse effects are Generally well tolerated, and does not increase the risk of opportunistic infections with no cancers that have been observed after 1 year of treatment.

Glucocorticoids

• Are also Used to suppress immune response and can aide in that
• Suppression of allograft rejection and used with treatment of asthma, rheumatoid arthritis, with large doses used to prevent rejection
• Can lead to increased or decreased Risk of infection or cause thinning of skin or bone

Classification of Antibiotics Work

• By affecting the bacterial cell wall synthesis or altering the cell membrane permeability
• By affecting protein synthesis (lethal) or Nonlethal inhibitors of protein synthesis and synthesis of nucleic acids
• By serving as Antimetabolites and working in conjunction with Viral enzyme inhibitors

Classification of Antibiotics

• Bacteriocidal: Directly lethal to bacteria at clinically achievable concentrations
• Bacteriostatic: Slow bacterial growth, but do not cause cell death

Microbial Mechanisms of Drug Resistance

• Involves the ability to Decrease the concentration of a drug at its site of action, while inactivating the drug
• A high level of resistence alter the structure of drug-target molecules and produce a drug antagonist

Common Organisms with Microbial Drug Resistance

• Includes Enterococcus, Staphylococcus aureus, Enterobacter and Klebsiella
• Pseudomonas aeruginosa and Clostridium difficile

Prophylactic Use of Antimicrobials

• Agents are given to prevent infection rather than to treat an established infection:
  • Surgery (Ancef/Cefazolin)
  • Bacterial Endocarditis (prior to dental work)
  • Neutropenia (pt's undergoing chemo)
  • Other indications

Penicillin Allergy

• This can cause different degrees of severity ○ Immediate (reaction in 2 to 30 minutes) ○ Accelerated (reaction in 1 to 72 hours) ○ Delayed (reaction takes days or weeks to develop)
• Severe cases can cause aphylaxis and may be treated with epinephrine

Penicillinase-Resistant Penicillins Available

• Nafcillin
• Oxacillin
• Dicloxacillin
• Piperacillin has a Broad-spectrum, but penicillinase sensivity

Cephalosporins

• These are some of the most widely used group of antibiotics ○ Beta-lactam antibiotics and are Similar to penicillin structured and are Beta-lactam antibiotics
  • Usually given parenterally/IV and have fairly Low toxicity with first, second, third, and fourth generation subtypes
  • Fifth Generation works by treating infections associated with resistant Staphylococcus aureus (MRSA)

Vancomycin

• Can generate Adverse Effects such as Ototoxicity that is (reversible or permanent)
• Commonly causes some cases of “Red Man" Syndrome and Thrombophlebitis

Summary of Tetracyclines Major Precautions

○ Can cause a PotentiallyLife-threatening supra-infection of the bowel and has been associated with severe liver damage ○ Eliminated primarily in urine - they accumulate in patients with Tetracycline and Kidney disease

• Cause cause discoloration of deciduous and permanent teeth and has strong Drug and Food Interaction

Clindamycin (Cleocin)

• This includes the new class Oxazolidinones that displaysUse for the following:
• Active against multidrug-resistant gram-positive pathogens and used for bactericidal

Clindamycin Functions as a

Bacteriostatic inhibitor of protein synthes ○ Cross-resistance with other agents unlikely ○ Active against aerobic and facultative gram-positive bacteria

Sulfonamides Are Effective For

○ Microbial Resistance that is very high among Gonococci, Meningococci, and Streptococci, ○ Resistance may be acquired by spontaneous mutation or by transfer of plasmids

Trimethoprim Functions

○ Inhibits dihydrofolate reductase that the enzyme that converts dihydrofolic acid to its ○ It suppresses the bacterial synthesis of deoxyribonucleic acid (DNA), proteins and ribonucleic acid but can causes Adverse Effects

Chlamydia trachomatis Infection

Symptoms from this STD involve symptoms from various organs and can result in infertility

Gonococcal Infections

Symptoms include Men: Complaints of burning sensation with urination and pus draining from penis

• Symptoms in Women may be asymptomatic

Antiseptics and Disinfectants

Germicidal vs. Germistatic drug

• Use alcohol-based handrubs or Wash with water and soap after examining patients at higher risk for spread of disease.

Most Effective Use of Antiseptics and Disinfectants"

○ Antiseptics that are applied directly to a patient contribute relatively little prophylaxis

• Important to use Antiseptics by nurses, physicians, for much greater protection

Antimalarial Drugs

• Artemisinin derivatives like Arlen, Primaquine and Quinine.
• Largely based on drug resistance of whatever type of disease there is

Tuberculosis Symptoms

• The more effective drugs use always to treat the affected area with a better standard of sterilization
• The diagnosis is definitive and occurs with the detection of the disease by Chest x-ray

Antibiotics

Classified to either directly lethal drugs such as Bacteriocidal or with the presence of Bacteriostatic drugs

Microbial Drug Resistance Develops

• With the Inability of penicillins to spread the Inactivation of penicillins by bacterial enzymes
• From Production of penicillin-binding proteins that have low affinity for penicillins

Sulfonamides Are Good For

• Silver sulfadiazine is effective for suppress bacterial colonization in patients with second- and third-degree burns
• However Local application of mafenide is frequently painful and may be a problem with systematic application

An overview of histamine, an endogenous compound involved in allergic reactions and gastric acid regulation. It discusses histamine distribution in tissues, its receptors (H1 and H2), and their effects such as vasodilation and increased capillary permeability.