Pulmonary Pharmacology - University of Hawaii€¦ · asthma attacks - Causes a prolonged narrowing of airways. 10 INFLAMMATORY MEDIATORS . Leuktotrienes (LTs) SRS-A •Binds to CysLT

1

Pulmonary Pharmacology

JACOBS Wednesday, Feb 03

3:00 – 4:50 PM

PHPP 516 (IT-II) Spring 2016

2

PULMONARY FUNCTION

TV = Tidal Volume TLC = Total Lung Capacity VC = Vital Capacity IC = Inspiratory Capacity

IRV = Inspiratory Reserve Volume ERV = Expiratory Reserve Volume FRC = Functional Residual Capacity RV = Residual Volume

Spirometer TV TLC

IRV IC

RV

ERV

FRC

VC

Spirogram

• Asthma • COPD (emphysema and chronic bronchitis)

3

OBSTRUCTIVE PULMONARY DISEASES

FVC = Forced Vital Capacity. = Volume that can be forcibly exhaled after a full inspiration (not timed)

FEV1 = Forced Expiratory Volume 1. = Volume that can be forcibly exhaled after a full inspiration IN ONE SECOND

OBSTRUCTIVE DISEASE = Difficulty Exhaling Quickly

• LOW FEV1 • LOW FEV1/FVC

4

• Pneumonitis • Fibrosis • ARDS • etc.

RESTRICTIVE PULMONARY DISEASES

RESITRICTIVE DISEASE = Difficulty Inhaling Fully • Low FVC • Near normal FEV1/FVC

• Acute inflammation of bronchi caused by various triggers, associated with airway ‘remodeling’

Acute (reversible) changes: • Leukocyte (WBC) infiltration • Mucous production • Bronchoconstriction

Chronic changes: • Persistent leukocyte (WBC)

infiltration • Less airway epithelium • More SMC, fibroblasts, goblet cells • More extracellular matrix

5

ASTHMA

- Alveolar destruction

- Poor gas exchange

- Reduced compliance (loss of elastic recoil)

- MAJOR cause = SMOKING (also air pollution)

• Permanent enlargement of gas-exchanging airways • Destruction of alveolar walls (w/no obvious fibrosis)

normal

emphysema

6

COPD: EMPHYSEMA

• Chronic inflammation of bronchi leading to mucus formation and muscle constriction

- Persistent (chronic) and productive cough (with sputum)

- Bronchial inflammation

- More mucus production

- Increased airway muscle tone (bronchoconstriction)

7

COPD: CHRONIC BRONCHITIS

Prostaglandins (PGs)

• Released by mast cells, eosinophils and Th2 cells

• Derived from arachidonic acid (AA)

• Produced in two steps from AA:

1. Cyclooxygenase-1 or -2 (COX-1 or COX-2), makes PGH2 (biologically inactive)

2. Various Prostaglandin synthases, make the active prostaglandins:

PGD2, PGE2, PGF2 PGI2 and TXA2

8

INFLAMMATORY MEDIATORS

Prostaglandin D2 (PGD2)

• Major contributor to asthma • Binds to DP1 receptor

• Actions (PGD2):

- Chemoattractant: Recruits eosinophils and Th2 cells

- Bronchoconstriction (asthmatics are typically more sensitive to PGD2)

- Vasodilation and edema (swelling) in airways

9


Leuktotrienes (LTs)

• Released by mast cells and eosinophils • Derived from arachidonic acid • Produced by 5-lipoxygenase (5-LO), then GST

• Leukocytes in the airways release a mixture of cysteineyl leukotrienes (LTC4 LTD4 and LTE4) known as SRS-A (slow reacting substance of anaphylaxis)

- Secreted during anaphylactic reactions and asthma attacks - Causes a prolonged narrowing of airways.

10


Leuktotrienes (LTs) SRS-A

• Binds to CysLT1 and CysLT2 receptor in airways • Extremely potent

• Actions (SRS-A):

- Chemoattractant: Recruits eosinophils and mast cells

- Activates mast cells: (degranulation, histamine release)

- Causes bronchoconstriction and edema (results in airway swelling)

11


Membrane Lipids Phospholipase A2 (cPLA2)

Arachidonic Acid (AA)

Prostaglandins (e.g. PGD2)

COX-1 or COX-2 + PG synthases

5-LO + GST

Cysteinyl Leukotrienes (SRS-A)

DP1 receptor • Bronchoconstriction • Swelling • Eosinophil infilitration • Th2 infiltration

CysLT1,2 receptors • Bronchoconstriction • Swelling • Eosinophil infiltration • Mast cell activation 12


Histamine

• Released by mast cells

• Binds to H1 receptor in pulmonary smooth muscle and in the vascular endothelium (blood vessel lining)

• Actions:

• Causes bronchoconstriction (and airway narrowing)

• Increases vascular permeability: - Causes mucosal edema

(increases airway swelling and narrowing) - Allows leukocyte infiltration into tissues

(enhances inflammatory response)

13


ECF-A (eosinophilic chemotatic factor of anaphylaxis)

• Peptide released by mast cells in response to antigen-stimulated activation of IgE’s on mast cell surface

• Actions:

- Released in an allergen-stimulated asthma attack

- Chemoattractant: Recruits eosinophils, worsens inflammation and prolongs the asthma ‘attack’

14


15


Antigen (allergen)

B-cells

Plasma cells

IgE Mast cells

ECF-A

Antigen (allergen)

Parasympathetic Sympathetic

ACh NE/EPI

Muscarinic M1 M2

M3 M4 M5

GPCR

Alpha 1

2

GPCR

Beta 1

2

3

GPCR

Nicotinic (α1)2β1δε (α1)2β1δγ (α3)2(β4)3

(α4)2(β2)3

(α3)2(β4)3

(α7)5

Ion Channels

16

NEUROGENIC CONTROL OF AIRWAYS

Parasympathetic (VAGUS)

ACh

M3

Sympathetic (T1-T5) NE

(Adrenals) EPI

EPI>>NE

2

• Bronchoconstriction • Increased mucous

• Bronchodilation • Decreased mucous

resistance

1

r4

17


2

Gs AC

ATP

cAMP PKA

K+

EPI

B. LOWER INTRACELLULAR CALCIUM PKA INHIBITS PLC/IP3/Ca2+

PATHWAY

AC = Adenylate cyclase PKA = Protein kinase A

A. LOWER MEMBRANE POTENTIAL (HYPEROLARIZED) DUE TO K+ EFFLUX

= SMC RELAXATION 18


BK Channel

2 = airway dilation

C. LESS SMC CONTRACTION PKA INHIBITS MYOSIN LIGHT CHAIN KINASE (MLCK)

2

Gs AC

ATP

cAMP

EPI

AMP

PDE

PHOSPHODIESTERASE (PDE) in pulmonary airways = LESS cAMP/PKA activity

= SMC CONTRACTION

19


PDE = airway constriction

M3

Gq

HIGHER INTRACELLULAR CALCIUM LEVELS

ACh

Ca++

IP3R

PLC

PIP2 DAG

Ca++ Ca++ Ca++

IP3

Ca++ Ca++ Ca++ Ca++ Ca2+

PLC = Phospholipase C

= SMC CONTRACTION

20


M3 = airway constriction

= MORE SECRETIONS

SHORT-ACTING: Albuterol (Proventil®) Epinephrine (Primatene®) Ephedrine Isoproterenol (Isuprel®) Levabuterol (Xopenex®) Metaproterinol (Alupent®) Pirbuterol (Maxair®) Terbutaline (Brethaire®)

21

BRONCHODILATORS: Drug Classes

LONG-ACTING: Arformoterol (Brovana®) Formoterol (Foradil®) Indacaterol (Arcapta®) Olodaterol (Striverdi Respimant®) Salmeterol (Serevent®)

ANTICHOLINERGICS Aclidinium Br (Tudorza™) Ipratropium Br (Atrovent®) Tiotropium Br (Spiriva®) Umeclidinium Br (Incruse Ellipta®)

METHYLXANTHINES Aminophylline (theophylline) Dyphylline (Dylix®, Lufyllin®) Theophylline

SYMPATHOMIMETICS

2

Gs

BETA2 AGONIST

AC cAMP PKA

ATP

2 agonists act as “FUNCTIONAL ANTAGONISTS”

• Antagonize bronchoconstriction by promoting the opposite effect (bronchodilation)

• They do not block the causative agent, they inhibit its actions at the “functional” level

Bronchodilation Broncho- constriction

Neurogenic Allergenic Chemical

22

BRONCHODILATORS: Sympathomimetics

DIRECT Actions (on SMC)

• Increases cAMP levels (and activates PKA) • Opens K+ channels (hyperpolarize SMCs) • Causes inhibition of Ca2+ release • Causes inhibition of MLCK

INDIRECT Actions (that also have therapeutic effect)

• Block release of inflammatory mediators from mast cells

• Prevent microvascular leak/edema during inflammation

• Activate presynaptic 2 receptors (parasympathetic nerves) which opens K+ channels and prevents depolarization (i.e. less release of ACh in the airways)

23


SHORT-ACTING BETA AGONISTS (SABA)

Albuterol* Levalbuterol* Metaproterinol Pirbuterol Terbutaline

(Non-Selective) Epinephrine Ephedrine Isoproterinol

24


*Animal studies suggested that S enantiomers of 2 agonists increased airway responsiveness (worsens symptoms over time)

Albuterol = R/S (L/D) racemic mixture Levalbuterol = R (L) albuterol

Clinical data are still not conclusive

“Chiral Switch”

SABA

USES: Commonly used as inhalation therapy for on-demand relief of Acute asthma attacks and Exercise-Induced Bronchoconstriction (EIB)

ADMIN: INHALATION (fewer side effects) but also available as ORAL (sustained release) and IV PK: Resistant to metabolizism by either catecholamine-O-methyltransferase (COMT) or monoamine oxidase (MAO) Onset: immediate Duration: 3-4 hr (lower in severe asthma)

25


26


LONG-ACTING BETA AGONISTS (LABA)

Arformoterol* (Brovana®) Formoterol* (Foradil®) Salmeterol (Serevent®)

* “chiral switch” Formoterol = R/S racemic Arformoterol = R formoterol

ULTRA LONG-ACTING BETA AGONIST (ultra-LABA)

Indacaterol (Arcapta Neohaler®) Olodaterol (Striverdi Respimat®) Vilanterol

USES: maintenance therapy of Asthma and COPD ADMIN: INHALATION

Example fixed combination w/corticosteroids: • fluticasone/salmeterol (Advair®) • budesonide/formoterol (Symbicort®) • mometasone/formoterol (Dulera®)

PK: Resistant to metabolizism by either catecholamine-O-methyltransferase (COMT) or monoamine oxidase (MAO) Onset: 3 min – 50 min (depends on drug) Duration: 12 hr

27


LABA

USES: maintenance therapy of COPD ADMIN: INHALATION

Example fixed combination w/corticosteroids: • fluticasone/vilanterol (Breo Ellipta®)

Example fixed combination w/anticholinergics: • umeclidinium/vilanterol (Anoro Ellipta®)

PK: Resistant to metabolizism by either catecholamine-O-methyltransferase (COMT) or monoamine oxidase (MAO) Onset: 5 min Duration: 24 hr

28


ultra-LABA

Adverse Effects More common/severe with ORAL or IV route

TACHYCARDIA, PALPITATIONS caused by:

a. Reflex cardiac stimulation secondary to peripheral vasodilation (drop in bp)

b. Direct stimulation of atrial 2 receptors c. Stimulation of myocardial 1 receptors

(at high drug doses)

These side effects tend to disappear with continued use of the drug reflecting the development of tolerance

29



MUSCLE TREMOR (most common side effect) caused by: Stimulation of 2 receptors in skeletal muscle More troublesome with elderly (COPD patients)

RESTLESSNESS

METABOLIC EFFECTS Increases in FFA, insulin, glucose, pyruvate, lactate Typically only after a large systemic doses.

QTc PROLONGATION (dose-related)

30


31


HYPOKALEMIA

Stimulation of K+ entry into skeletal muscle from blood.

May be insulin-mediated, because 2 receptors cause insulin secretion

If a severe acute asthma attack is treated with bolus 2 agonist, you can get hypokalemia and hypoxia together, which can be dangerous (severe cardiac arrhythmias)


32


VENTILATION/PERFUSION (V/Q) MISMATCH

2 agonists cause pulmonary vasodilation, which results in shunting of blood to poorly ventilated areas (previously constricted before being given drug)

This causes a fall in arterial oxygen tension (paO2)

Effect is more noticeable with severe COPD and is treatable with inspired O2


AC PKA cAMP

ATP

Bronchodilation

PDE

AMP

cAMP Methyl- xanthines

MECHANISM 1: Phosphodiesterase inhibition

• Inhibit breakdown of cAMP • More cAMP = more bronchodilation

33

BRONCHODILATORS: Methylxanthines

AC = adenylate cyclase PKA = protein kinase A (cAMP-activated) PDE = phosphodiesterase

MECHANISM 2: Adenosine receptor antagonism (significance unclear, probably less important)

AC

ATP

cAMP A1

Ado

Gi

Methylxanthines

• “De-repress” (i.e. activate) adenylate cyclase • More cAMP = more bronchodilation • Also inhibit A2B receptors on mast cells (i.e. block mast cell activation)

PKA

Bronchodilation

34


INFLAMMATORY CELL TYPES

AIRWAY CELL TYPES

35


USE: Overnight prophylaxis of Asthma and COPD

ADMIN: Oral (sustained release)

IV aminophylline was used for several years for treatment of acute asthma attacks, but has largely been replaced by 2 agonists

METHYLXANTHINES Aminophylline (Theophylline ethylenediamine) Dyphylline Theophylline

36


INCREASE CLEARANCE • CYP1A2 induction

(rifampin, barbiturates, ethanol, cigarettes)

• High protein diet • Children

REDUCE CLEARANCE • CYP1A2 inhibition

(cimetidine, Cipro®, fluvoxamine, erythromycin, zileuton, zafirlukast)

• CHF, Liver disease • High carbohydrate diet • Elderly

37


PK: Absorption is rapid and complete, but rates of clearance can vary significantly

Metabolism: Hepatic, CYP1A2

Duration: 12 hr (slow release formulation)

Adverse Effects NARROW Therapeutic Window! (e.g. 5-15 mg/L for theophylline)

HEADACHE, NAUSEA, VOMITING (common), caused by inhibition of PDE4 in CNS GI UPSET, DIARRHEA caused by inhibition of PDE4 DIURESIS caused by antagonism of Ado A1 receptor

38


Adverse Effects NARROW Therapeutic Window!

ARRHYTHMIAS Caused by

• Inhibition of PDE3 • Antagonism of cardiac A1 receptors

HYPERSENSITIVITY (mainly to the ethylenediamine component in aminophylline – i.e. not the active drug)

39


Roflumilast (Daliresp®) FDA approved March 2011

AMP

PDE cAMP Methylxanthines

AMP

PDE4 cAMP Roflumilast

More specific for airways = fewer side effects But some side effects remain: • Diarrhea, weight loss • Headache • CNS effects (anxiety, depression) 40

BRONCHODILATORS: PDE4 Inhibitor

Bronchoconstriction Airway secretions

M-Antagonists • Inhibit bronchoconstriction • Reduce airway secretions

41

M3

Gq PLC

ACh

Ca++

IP3R Ca++ Ca++ Ca++

IP3

Ca++ Ca++ Ca++ Ca++ Ca2+

BRONCHODILATORS: Anticholinergics

Anticholinergics

USE: Control of asthma (off-label) and COPD

ADMIN: INHALATION

ABSORPTION (lungs): POOR (has + charge)

ONSET: 30-60 min

42


ANTICHOLINERGICS

Umeclidinium Br Aclidinium Br Tiotropium Br

LONG-ACTING (24 hr)

Ipratropium Br

SHORT-ACTING (6-8 hr)

ACh

M3

M2

M2 is an autoreceptor that inhibits further ACh release


Inhibition of M2 increases ACh release and enables BRONCHOCONSTRICTION

43


nerve ending

ACh ACh

ACh ACh

Inhibition of M3 causes BRONCHODILATION

ACh

ACh M2

M3


44


ACh ACh

ACh

Iporatropium

Iporatropium

Ipratropium is NONSPECIFIC for M2 and M3 receptors. It blocks M3-mediated bronchoconstriction and airway secretions, but can also enable vagally-mediated Ach release (which can outcompete ipratropium blockade of M3 receptors)

This effect can INCREASE ACh release!

Newer agents preferentially block M3 receptors AND they have longer durations of action. Receptor specificity is due to differences in OFF RATES. Although they are not selective in binding they dissociates VERY SLOWLY from M3, so inhibit M3>M2 (because they stay bound to that receptor for a long time)

45


OFF-RATES M3 < M2

(drug dissociation from M3 are 50-200x SLOWER than ipratropium!)

M3 M2

ON RATES M3 = M2

M3 M2

46


Ipratropium – partially metabolized by esterases (half-life: 2 hr)

Aclidinium – rapidly metabolized by esterases (half-life: 5-8 hr)

Tiotropium – not metabolized (half-life: 5-6 days)

Umeclidinium – metabolized by CYP2D6 (half-life: 11 hr)

Metabolism (and circulatory half-lives)

Adverse Effects (Minor, generally well tolerated)

DRY MOUTH AND UPPER AIRWAYS (common) Systemic (PNS, not local) effect of drug – less incidence with aclidinium because of rapid metabolism

COUGH

UNPLEASANT TASTE

47


48

Drug Interactions


Tachycardia caused by cannabis

Constipation and urinary retention caused by opiates

Will enhance the side effects of other anticholinergics drugs.

Examples:

Magnesium Sulfate (MgSO4)

Used IV or inhalation in combination with 2 agonist in clinical studies in emergency setting (acute asthma attack) when FEV1 <30% normal

Mechanism: Reduces intracellular Ca2+ in SMC Side effects: Flushing and nausea Onset: IV immediate Duration: 30 min

49

BRONCHODILATORS: Other Agents

Vasoactive Intestinal Peptide (VIP) Analogs

VIP binds to two GPCRs (VPAC1 and VPAC2) that couple to Gs and lead to SMC relaxation.

Ro 25-1533 is a stable VIP analog that selectively binds to the airway receptor (VPAC2) and causes SMC relaxation.

Effect is rapid, but not lasting

50

BRONCHODILATORS: Other Agents

IkB P

NF-kB

Inflammatory Genes

INHIBIT gene expression • Less cytokine production • Less of certain WBC types

Inflammatory Stimuli

IkB

Corticosteroids

GR NF-kB

WBC 51

INHALED CORTICOSTEROIDS

Some of the genes INHIBITED by corticosteroids

Phospholipase A2 Less eicosanoids (prostaglandins and leukotrienes)

Cyclooxygenase-2 (COX-2) Less prostaglandins

Th2 Cytokines Less inflammatory signaling molecules (IL-4, IL-5, IL-9 and IL-13)

Extracellular proteases Less vascular leak and airway remodeling

Cell survival genes Causes fewer of some WBC types

52


Anti-inflammatory actions of corticosteroids in the airways

IMMUNE CELLS AIRWAY CELLS

53


Beclomethasone (QVAR®) Triamcinolone Flunisolide (Aerobid®)

Low systemic bioavailability drugs: Budesonide (Pulmicort®) Fluticasone hemihydrate (Aerospan®) Fluticasone propionate (Flovent®, Flonase®) Mometasone furoate (Asmanex®, Nasonex® - nasal spray) Ciclesonide (Alvesco®) i.e. Less side effects

if swallowed

DPI MDI DPI

54


Ciclesonide is a prodrug that is converted to an active metabolite by esterases in the lung epithelium

USES: Asthma and COPD – Inhalation Exercise-induced bronchoconstriction (EIB) – Inhalation Allergic rhinitis (Hay fever) – Nasal spray

55


Fate of inhaled corticosteroids (and other inhaled drugs)

MDI = metered dose inhaler (HFA-charged aerosol) DPI = dry powder inhaler

56


LOCAL Adverse Effects (airways) Dysphonia (hoarse voice) Oropharyngeal candidiasis (thrush) Cough

SYSTEMIC Adverse Effects Adrenal suppression and insufficiency Easy bruising, thin skin Osteoporosis Cataracts (spray in eyes) Glaucoma (spray in eyes) Metabolic abnormalities (glucose, triglycerides) Psychiatric disturbances (euphoria, depression) Immune suppression (pneumonia) 57


5-LO INHIBITORS Zileuton (Zyflo®, Zyflo CR®)

CysLT1 RECEPTOR ANTAGONISTS Montelukast (Singulair®) Zafirlukast (Accolate®)

USES: Asthma (All agents) - ORAL Exercise-induced bronchoconstriction (EIB) (Montelukast) - ORAL Allergic rhinitis (Montelukast) - ORAL

58

LEUKOTRIENE ANTAGONISTS

59


5-LO inhibitors

LT antagonists

Zileuton – PK Metabolism: Hepatic, several P450 isoforms Elimination: Renal (as metabolites) Half-life: 2.5 hr (short)

Immediate release: four times daily Extended release (ER): twice daily

Adverse Effects Sinusitis, URI (5-9%) Upset stomach, nausea (5-8%) Elevated ALT (2-5%)

Drug Interactions Theophylline – Zileuton may inhibit theophylline clearance

60


Montelukast – PK Absorption: Rapid (63-73% bioavailable) Metabolism: Hepatic, CYP2C9, CYP3A4 Elimination: Feces (as metabolites) Half-life: 2.7-5.5 hr (once daily) Adverse Effects (minor)

Increased serum AST (about 2%) Drug Interactions

CYP2C9 or CYP3A4 Inducers (rifampin, barbiturates) may montelukast levels CYP2C9 Strong Inhibitors (fluconazole) or CYP3A4 Strong Inhibitors (protease inhibitors, clarithromycin, telithromycin, chloramphenicol) may montelukast levels 61


Zafirlukast – PK Absorption: REDUCED BY FOOD (40% Lower) Metabolism: Hepatic, CYP2C9 Elimination: Feces (as metabolites) Half-life: 20 hr (twice daily) Adverse Effects (minor)

Eosinophilic conditions (Churg–Strauss syndrome) “controversial”

Drug Interactions CYP2C9 Inducers (rifampin, barbiturates) may lower levels of zafirlukast CYP2C9 Strong Inhibitors (fluconazole) may raise levels of zafirlukast

62


Cromolyn sodium

63

IMMUNE MODULATION THERAPY

Cromolyn sodium • for asthma – Inhalation • for allergic rhinitis – Nasal

Mechanism: “mast cell stabilizer”

BUT, other (more effective) “mast cell stabilizers” do not have the anti-asthmatic effects of cromolyn.

Cromolyn may also inhibit T-cells and eosinophils. Also used for mastocytosis (too many mast cells) and various other inflammatory conditions (e.g. gastrointestinal)

64


Omalizumab (Xolair®) Asthma – INJ (SQ every 2-4 weeks) -not for acute attacks

Mechanism: IgG1 monoclonal antibody that selectively binds to free human immunoglobulin E (IgE) in the blood and interstitial fluid. Blocks type I hypersensitivity reactions. Adverse Effects: BLACK BOX: anaphylaxis (0.1-0.2%)

Drug Interactions: Avoid combination with other immunosuppressants or use of live vaccines

65


66

Mepolizumab (Nucala®) – Approved Nov 2015 Asthma – INJ (SQ once every 4 weeks) -not for acute attacks


Adverse Effects: Hypersensitivity, infections (immunosuppression: herpes zoster, parasites)

Mechanism: IgG1 monoclonal antibody that selectively binds to (neutralizes) IL-5 and blocks IL-5 signaling and interferes with eosinophils.

Interleukin-5 (IL-5) Recruitment and activation

Inflammation and chronic airway changes

Alkylamines (nonselective) Brompheniramine Chlorpheniramine Dexbrompheniramine Dexchlorpheniramine Triprolidine

Ethanolamines (nonselective) Carbinoxamine Clemastine Diphenhydramine Doxylamine

Phenothiazines (nonselective) Promethazine

Piperazines (nonselective)

Chlorocyclizine Hydroxyzine

(peripherally selective) Cetrizine (Zyrtec®) Levocetrizine (Xyzal®)

Piperidines (nonselective)

Cyproheptadine (peripherally selective)

Loratidine (Claritin®) Desloratidine (Clarinex®) Fexofenadine (Allegra®)

ANTIHISTAMINES – Allergic rhinitis

67

ANTIHISTAMINES

H1: INFLAMMATON AND BRONCHOCONSTRICTION

vasodilation, vascular permeability, contraction of nonvascular smooth muscle

H2: gastric acid secretion (may be involved in cardiac stimulation)

H3: feedback inhibition in CNS, GI tract, lung, heart

3 Types of Histamine Receptors

68

ANTIHISTAMINES

PERIPHERAL USES FOR H1 BLOCKERS:

1. Allergic rhinitis: relieves rhinorrhea, sneezing, itchy eyes

2. Common cold: (palliative) dries out the nasal mucosa (Often combined with nasal decongestant and analgesics)

3. Allergic dermatoses: itching associated with insect bites ASTHMA OR COPD? No good evidence that these have efficacy

69

ANTIHISTAMINES

70

ANTIHISTAMINES

CENTRAL USES FOR H1 BLOCKERS:

4. Pre-anesthetic sedation in outpatient procedures For prevention of nausea and vomiting. Promethazine (Phenergan) is also used to inhibit salivary and bronchial secretions

5. Antiemetic: prevention or treatment of nausea and vomiting (Doxylamine with Pyridoxine)

Neurogenic/Chemical Control of DYSPNEA/VENTILATION

+ COPD

‘sensation’ of dyspnea

Blocked by opioids (morphine)

Opioids can also be used as antitussives (cough suppressants)

71

Documents

Pulmonary Pharmacology - University of Hawaii€¦ · asthma attacks - Causes a prolonged narrowing of airways. 10 INFLAMMATORY MEDIATORS . Leuktotrienes (LTs) SRS-A •Binds to CysLT