Pharmacology Lecture Notes

Bronchopulmonary Diseases

• Asthma bronchiale
• Chronic bronchitis
• Emphysema
• COPD = Chronic bronchitis + Emphysema

Asthma

• 23 million patients/year
• 12.4 million attacks
• 1.8 million ER visits
• 21 billion health care costs & meds
• >5000 deaths
• Asthmatic Lung:
  • Inflammation in bronchial wall
  • Airways bronchoconstriction
  • Airway hyperresponsiveness
  • Increasing of mucous secretion
• Consequences if untreated:
  • Reversible airways obstruction with possible chronicism and progressive inflammation

Pathomechanism of Asthma

• Immune response to allergen
  • Genes predisposing to allergies & lack of TH1 stimulation → Increase of TH2 expression→ Secretion of IL4-13 → Activation of B cells→ Releasing of IgE & some of them link to high-affinity IgE receptor
• Acute allergic inflammation of the airways
  • Early stage: Allergen + IgE (attached on mast cells)→ mast degradation with the releasing of: Eosinophils chemotactic factor (ECF) & Histamine→ incr. mucous secretion, airways edema and bronchoconstriction
    • Other important factors in bronchoconstriction and mucous secretion are LTB4, LTC4, LTD4, TXA2, PGD2 and PGF2
  • Late stage response: Due to the cellular infiltrate (eosinophils, mast cells, dentritic cells, basophils and neutrophils) that maintains the response
• Chronic inflammation of the airways
  • Main cellular unit in this phase is the eosinophil
  • Eosinophils → secrete ROS (reactive oxygen species)→ cytotoxic effects on bronchial epithelium
  • Eosinophils → secrete LT => stimulates: remodelling, edema and mucus production & bronchocostriction

Airway Remodeling

• Muscular hypertrophy and hyperplasia
• Mucus gland hypertrophy & Goblet cells hyperplasia
• Vasodilation of lamina propria

Medications Used for Asthma

• Quick Relief (RESCUE)
  • Provide relief of acute asthma episodes & Bronchodilators
• Long-term Control
  • Control and prevent asthma symptoms
  • Make airways less sensitive to triggers and prevent inflammation that leads to an acute asthma episode (Immunomodulatory)
  • Taken on a daily basis
• Pharmacotherapy
  • Bronchodilators
    • Adrenergic agonist
    • Selective beta2-R stimulants
    • Methylxanthines
    • Anticholinergics - Muscarinic antagonists
  • Anti-inflammatory
    • Glucocorticoids
    • Cromolyn, nedocromil
    • Leukotriene-antagonists
    • H1 -R antagonists
  • Inhalatory therapy = First line

Bronchodilators

1. Adrenergic Agonists

• Older non-selective drugs
  • Ephedrine, Epinephrine (still used for status asthmaticus) & Isoproterenol
• Newer selective Beta-2 adrenergic Agonist
  • Fewer systemic side effects
  • Promote bronchodilation
  • Suppress lung histamine
  • Increase ciliary motility
    Clinical use
• Relievers: Short-acting (SABAs)
  • Adrenaline (epinephrine), ephedrine: α, β1,β2 (Stimulates cAMP production)
  • Terbutaline, albuterol, pirbuterol, bitolterol, levalbuterol (R-albuterol): β2 > β1 (220-400 x)
• Controllers: Long-acting (LABAs); selective β2 agonists
  • Formoterol, Salmeterol, Indacaterol & Olodaerol
  • Warning: increased chance of serious or fatal asthma
• MoA
  • beta-2 agonists act as ligands to adrenergic receptors with increased selectivity towards beta-2 adrenergic receptors
  • the activation of the beta-2 adrenergic receptor initiates a transmembrane signal cascade => Gs and the effector, adenylyl cyclase (AC).
  • adenylyl cyclase then increases intracellular cAMP
  • cAMP concentration serves to activate cAMP-dependent protein kinase A (PKA)
  • PKA phosphorylates Gq-coupled receptors => reduces intracellular Ca^{2+} or decrease the sensitivity of Ca^{2+}
  • The change in Ca^{2+} => inhibition of myosin light chain phosphorylation => subsequently preventing airway smooth muscle contraction.
    Side effects
• Tachycardia, Nervousness, Irritability, Tremor & Angina
• Inhaled preparations: Less common
• Oral preparations: More common
• Tachydysrhythmias
  • Usually dose related & May also be related to additives
• Pharmacokinetics
  • Duration
    • Short acting (begin immediately, 3-5 hour dur) = SABA
    • Long acting (begin 2-30 min, 10-12 hour dur) = LABA
  • Routes
    • Inhaled & Oral
  • Use
    • Short acting: PRN for symptoms
    • Long acting: Fixed schedule (NOT PRN EVER)
      List of Drugs
• Short acting
  • Albuterol (Proventil, Ventolin): Metered Dose Inhaler(MDI), nebulization
  • Levalbuterol (Xopenex): neb only
  • Bitolterol (Tornalate): neb only
  • Pirbuterol (Maxair): neb only
• Long Acting
  • Salmeterol (available only in combination)
  • Formoterol (Foradil Aerolizer): DPI
• Oral
  • Albuterol: Tablets, Extended tabs, syrup
  • Terbutaline: Tablets
    Dosing for Albuterol
• MDI: usually 1-2 puffs Q 4-6 hrs
  • Deep exhale, Inhale and puff, Hold breath for slow ten count, Exhale slowly & Wait one minute before second puff
  • Use spacer
• Dry Powder
  • Usually one inhalation, not a puff & One smooth continuous inhalation

2. Methylxanthines

• MoA
  • Inhibits PDE (phosphodiesterase)
  • High levels cAMP => Smooth muscle relaxation
  • Inhibits IgE release of mast cell mediators
  • Competitive antagonist at adenosine (A2) receptors
  • Adenosine (Bronchoconstriction & Potentiate inflammatory mediator release)
• Forms
  • THEOPHYLLINE, Caffeine (>)
  • Synthetic: AMINOPHYLINE (>theophylline) , DYPHILLINE, OXTRIPHYLINE
• Use: Very limited (CNS stimulants)
• Administration: Oral, Inhaled, (rectal, IV)
• Pharmacokinetics:
  • Onset: Unknown, Effect: 1-2 h & Duration: Varies
• Side Effects: Nausea, vomiting, anorexia
  • Cardiac effects: sinus tachycardia, extrasystole, palpitations, arrhythmia
  • Kidney: weak diuretic
  • Skeletal Muscle: increase contractions
• Primary actions
  • CNS excitation & Bronchodilation
• Other actions
  • Cardiac stimulation, Vasodilation & Diuresis
• Usually considered third line
  • High side effect profile & Narrow therapeutic range
• Theophylline and Aminophylline
  • Oral
  • IV (dangerous, usually aminophylline)
  • Longer duration
  • Metabolized in liver, variable half-life
  • Requires periodic blood level monitoring
  • Toxicity: NVD, restlessness, dysrhythmias, seizures
  • Interactions: caffeine, cimetidine, fluoroquinolones, other CNS drugs

3. Anticholinergics

• MoA: Competitive antagonists of muscarinic Ach receptors
• Clinical indications:
  • Asthma (Not responsive to inhaled β2 -adrenergic agonists & Inhaled β agonists are contraindicated)
  • Chronic bronchitis
  • Emphysema
  • COPD & Excercise-induced bronchospasm
• Administration: A: IV, I, T: inhalation, T: oral
• Pharmacokinetics:
  • Onset: 5-15 m, Effect: 1-2 h & Duration: 4-5 h
• Side Effects: Dryness of mouth and airway, headache
  • Rarely: tachycardia, dry eyes/blurred vision, urinary retention
    Effects
• Anticholinergic (atropine derivative)
  • Approved only for COPD bronchospasm but used in asthma too
  • Decrease secretions from nose, mouth, pharynx and bronchi
  • Provoke a relaxing state in bronchi and bronchioles muscles
  • Decrease airways resistance & Provoke bronchodilation
  • Few systemic side effects
• Ipratropium (Atrovent)
  • Onset 30 minutes; lasts 6 hours, MDI, Neb
  • Combivent MDI: combo with Albuterol
  • Also available intranasally for allergic rhinitis
• Tiotropium (Spiriva)
  • Newer, lasts longer &
  • Dry Powder Inhaler (Handi-haler)

Antiinflammators

1. GCS - Glucocorticosteroids

• MoA: Gene regulation (Anti-inflammatory & Immunosuppression)
• Administration
  • Inhaled: beclomethasone, triamcinolone, fluticasone, budesonide, flunisolide, mometasone
    • Side Effects: Oropharyngeal candidiasis, dysphonia
  • Oral (most potent): dexamethasone, prednisone
    • Side Effects: mood disturbances, increased appetite, impaired glucose control in diabetics, and candidiasis
    • Long -term use: bone resorption
  • Inhaled Prednisone
• Pharmacokinetics (inhaled):
  • Onset: unknown, Effect: unknown, Duration: 24 h
  • Warning: Poor compliance!
• PK
  • Rapidly absorbed from the GI tract and reversibly bound to plasma proteins
    • At normal or low plasma concentration binding is largely to globulins - corticosteroid binding globuline
    • At higher concentrations there is an increase in albumin-bound and free Cs
    • In hypoalbumineamic patients' highs dosages leads to high levels of free-CS and increases side-effects
  • Rapidly metabolized in the liver and conjugated and excreted in the urine.
  • It disappears from the blood within 1.5-3 hours, having a half-life of 1 hour
• PD
  • Inhibition PhLA2, Release of lytic enzymes & Synthesis of IL1, IL6, TNF, IF
• Classification
  • GC and MC: Hydrocortisone, Prednisone
  • GC and no MC: Dexamethasone, Betamethasone
• Inflammatory pathways
  • The main anti-inflammatory effect is achieved by controlling the rate of synthesis of mRNA and proteins
  • Increased of lipocortin synthesis and subsequent inhibition of phospholipase A2
  • Reduced production of cytokines
  • Reduced activation, proliferation differentiation and migration of inflammatory cells
  • Reduced inflammatory enzymes
  • Alteration in T and B cell function
  • Reduction of Fc and C3 receptor expression
  • Changes in white cell traffic (in 4-6 hours and return to normal by 24 hours)
  • Stabilization of neutrophil lysosomal membranes
  • Reduced NO synthesis in macrophages
    *Effects On different organs and systems
  • MUSCULOSKELETAL – cortisone myopathy, osteoporosis
  • GASTROINTESTINAL – peptic ulceration
  • CENTRAL NERVOUS SYSTEM – psychiatric disorders
  • OPHTALMOLOGICAL – Glaucoma, posterior subcapsular cataracts
  • CARDIOVASCULAR AND RENAL – hypertension, sodium and water retention-edema, hypokalemic alkalosis
  • ENDOCRINE – growth failure, secondary amenorrhea, suppression of hypothalamic-pituitary adrenal system
  • INHIBITION OF FIBROPLASIA – impaired wound healing
  • BLOOD – lymphopenia
  • METABOLISM
    • Glucose => hyperglycemia
    • Lipids => adipose tissue redistribution
    • Proteins => negative azote balance (Stimulation of protein catabolism, Myopathy, osteoporosis)
    • Electrolytes => negative Ca-balance
  • SUPRESSION OF THE IMMUNE RESPONSE
• effects in asthma
  • Decrease release of inflammatory mediator, infiltration and action of WBCs & complement components
  • Decrease the Histamine-mediated reaction, airway edema & mucus production
  • Increase number of beta-2 receptors & sensitivity of beta-2 receptors
    Doses
• RA patients – 7. - SLE, PAN and PM/DM patients – 1-2 mg/per kg/daily oral or pulses therapy
• Clinind
  • Substitution (Addison's & Diagnose (Cushing's - Dexa stimulation))
  • Anti-inflammatory
    • Rheumatoid and autoimmune diseases
    • Dermatological disorders: psoriasis, dermatitis
    • Acute cerebral edema & antiallergic
    • Asthma, Anaphylactic reactions, Quincke edema, Larynx edema, Herxheimer reaction, Allergic rhinitis, skin reactions, Insect bites & Drug induced allergy
  • Immunosuppresive
    • Autoimmune diseases (Chronic autoimmune hepatitis, Organ transplant & Nephrotic syndrome)
  • Lympholytic
    • Lymphomas (Hodgkin & Non-Hodgkin) & Acute lymphoblastic leukemia
• indications – extra-adrenal summary:
  • Allergic reactions, Collagen-vascular disorders, Eye diseases, GiT diseases, Systemic inflammation, Infections, Inflammatory conditions of joints and bones, Nausea and vomiting, Organ transplantation, Pulmonary diseases, Renal diseases, Skin disorders & Thyroid disorders
• short half-life - Hydrocortisone PK, PD, ClinInd
• medium half-life - t1/2 tissue 12-36h GC and MC effect except Triamcinolone, anti-inflammatory effect, Prednisone – locally inactive, Prednisolone, Methylprednisolone (Medrol) – very potent & Triamcinolone – very potent
• long half-life
  • Very potent anti-inflammatory effect, No MC effect – no salt-water retention & Strong inhibition of the Hypoth-hypoph-corticosuprarenal axis
  • High risk of cortico-dependency, Dose high then tapered down
  • Dexamethasone & Betamethasone
• Systemic & Inhaled
• Inhaled Corticosteroids
  • Fluticasone (Flovent) MDI & Drugs for allergic rhinitis
• SE
  • Hypercorticism: exogenic, endogenic, Steroid diabetes, Osteoporosis, Cortisone myopathy, .Disseminated infections, .Delayed growth, & Skin atrophy, GiT ulcer, Psychosis, Glaucoma & cataract, Teratogenity
• Side effects for Inhaled GCS & General
  *Contralnd GiT ulcer Heert fallure

2. Cromolyns: Mast Cell Stabilizers

• Cromolyn & nedocromil
• MoA
  • Alter activity of delayed Cl- channels (inhibiting their activation)
  • Blocks release of inflammatory mediators
• Use
  • Prophylactic therapy for mild- moderate allergic asthma
  • Allergic rhinitis (C)
• Administration: Inhalation
• Pharmacokinetics:
  • Effect: Weeks (takes weeks to see whether it is efficient or not)
• Side Effects:
  • C: safest of all
  • Increased coughing, wheezing
  • Cromolyn: Children, adolescents & Nedocromil: ≥12 years
• Used for prophylaxis, not acute treatment
  • Seasonal allergy, Exercise induced asthma & Can be used intranasally for allergic rhinitis
• Stabilizes mast cells
  • Prevents release of histamine, inflammatory mediators
  • Inhibits eosinophils, macrophages

3. Leukotriene Modifiers

Leukotriene-Synthesis Inhibitors, Zileuton & Leukotriene Receptor Antagonists, Montelukast, zafirlukast

• Two approaches
  • 1) Inhibit leukotriene synthesis – Zileuton
  • 2) Inhibit leukotriene receptors – Zafirkulast (Accolate) & Monteleukast (Singulair)
• Decrease of Inflammation, bronchoconstriction, edema, mucus, recruitment of eosinophils
• Use
  • “Responder” mild chronic asthma & allergic rhinitis
• Administration: Inhalation (oral M,Z)
• Pharmacokinetics:
  • Onset: 3-6 h, Effect: 4 h & Duration: 24h
• Side Effects: Churg-Strauss syndrome
• Drug interactions for Montelukast, Zafirlukast & Zileuton

4. Antagonism of IgE

• Anti-IgE: Omalizumab
  • 95% humanized
  • High cost >10K/yr
• Use: moderate-to-severe persistent asthma
• Administration: SC
• Pharmacokinetics:
  • Pk Plasma: 7-8d, Duration: 26 d
• Side Effects: injection-site reaction, infections, anaphylaxis & cancer

Step-wise Approach to Asthma Therapy

• Intermittent Asthma – SABA
• Persistent asthma (daily medication)
  • Low dose ICS (Alternatively: Cromolyn, LTRA, Nedocromil Theophylline or Zileuton)
  • Or Medium dose ICS (Alternative: Low-dose ICS + LTRA, Theophylline or Zileuton)
  • Low dose ICS + LABA (Alternative: Medium-dose ICS + LTRA, Theophylline or Zileuton)
  • Medium-dose ICS + LABA + Omalizumab for patients with allergies(?)
  • High-dose ICS + LABA + Oral corticosteroid & Omalizumab for patients with allergies(?)
  • If a SABA is used > 2 days a week that means the treatment is not controlled properly! → Treatment escalation

COPD

• 12 million, 4th leading cause of death

• Year, 26 billion / year & >127,000 deaths

• DEFINITION: Chronic inflammatory lung disease that leads to an irreversible obstructive respiratory dysfunction

• ASTHMA vs COPD

  • ASTHMA symptoms before adulthood, Reversible obstructive respiratory dysfunction, Normal DLCO & Atopic disorders in family
  • COPD Symptoms at 40-50 y.o, Smoker, Irreversible obstructive respiratory dysfunction & Decrease of DLCO

• Staging COPD – GOLD (made by spirometry)
  Treatment

• Similar to asthma, difference is the damage that here is progressive and irreversible

• Ipratropium & O_2 in advanced disease

Cough Therapy

• Cough: Complex reflex mechanism
• Cough: Cleans airways from mucous and external agents
• Afferent nerve/fibre: N.Vagus, N.Laryngeus sup., N.Glossopharyngeus, N.Trigeminus
• Cough center: truncus cerebri (brain stem)
• Efferent nerve/fiber: larynx, diaphragm, intercostal muscles
• Appears after a short, deep inhalation
• = Forced expiration with closed glottis
• Result: increased pressure in the airways, forced dilation of the glottis
• The air drifts mucus out
• The negative thoracic pressure ceases & The filling of the right heart is inhibited

1. Cough Suppressants (Antitussives)

• Opioid – centrally acting, Codeine and Hydrocodone
• Non-opioid
  • Dextromethorphan (DM) (Codeine derivative & Reduces cough reflex centrally)
  • Butamirate & Pentoxyverine
  • Benzonatate - Local anesthetic Decreases stomach receptor sensitivity; do not chew
  • Can deprive respiratory center (except DXM, BTM)
• Dependence & Tolerance

2. Expectorants

Help clean bronchi, clinical efficacy: pros and cons & Use: Lot of liquid

• Secretolytics
  • Reflex MoA: through the N.Vagus from the stomach through the stomach (Sapoines, Ipeca, Guajacol)
  • Volatiles orally: increase bronchosecretion
    *MoA to decrease the viscosity of the secretum. - Bromhexin - Ambroxol: active metabolite of BH
• Mucolytics
  Ambroxol: active metabolite of BH, Acetylcystein (Dissociates mucus & Decreases viscosity), Carbocystein (+ Decreases amount of secretum), Erdostein & Dornase alfa: gene technology
  **Cystic fibrosis!
  *Secretomotorics - Beta-sympatomimetics
  *Surfactants to Stop the alveolus from collapsing during exhalation

Active Peptides - Histamine

• mediator of immediate allergic reaction & inflammatory reactions

• important role in gastric acid secretion

• functions as a neurotransmitter and neuromodulator

• plays a role in immune functions and chemotaxis of white blood cells.

• AntiHistamine
  * Blocks action of histamine at receptor & Competes with histamine for binding
  * Displaces histamine from receptor
  * Most beneficial when given early

• Pharmacological Effects of Histamine
  * Exocrine glands contraction: Vasodilation
  - Therapeutic Uses of H1 Blockers Allergic rhinitis etc

• Classification

  • First generation Short antiallergic effect anticholinergic effect:
    Side Effects Sedating

• Generally, do not cause the sedation Second generation: and drying - Azelastine

*For allegic rhiniti