AIRWAY PHARMACOLOGY 2006 ?, Updated by Mark Tuttle

ASTHMA DRUGS

Group/Mechanism

/ Drug examples / Clinical uses /

Adverse Effects

Pharmacokinetics

Beta-adrenergic agonists
Relax bronchial SM by ↑ cAMP=↓ Ca2+
Adverse effects:
- Tremor/Anxiety
- Nausea/Vomiting
- Sinus tachycardia
o Even β2-selective since β2 are 10-50% of heart adrenerg Rs
à Contraindicated w/heart disease
- Hyopkalemia
- Hyperglycemia
o ↑ liver glycogen breakdown / Short-Acting:

Epinephrine

/ · Emergencies
· Severe attacks
· OTC low doses inhaled for mild / All= tachyphylaxis =
↓ effective w/ ↑ use
Via βARK and PKA phosphorylating adrenergic Rs, downregulation of adrenergic Rs
Epinephrine
Agonist @ all adrenergic Rs
à bad adverse effects
Albuterol
- N/V, sinus tachycardia / · Can’t take orally
· Rapidly metabolized by COMT
Isoproterenol
Metaproterenol / · No longer used for rescue because of excess cardiac stimulation / · β-selective
· Slow inactivation by COMT

Albuterolinhaled/oral

/ · Acute attack
· Prevention of exercise-induced asthma
· Don’t use regularly! / · ↑ selectivity for β2 Rs
· ↑ half-life: Slow inactivation (COMT), ↑ DOA
· Rapid onset
Terbutaline
Inhaled/oral/IV
Levalbuterol / · Like albuterol, but is a racemic mixture / · R-enantiomer of albuterol= 100X higher affinity than S (inert!) LOL
Long-acting:

Salmeterol

Formoterol

/ · Long-term tx of mod-severe asthma (w/corticosteroids)
· NOT for acute attacks! (b/c slow)
· Prophylaxis of exercise-induced
· COPD bronchoconstric / Salmeterol
↑ risk of respiratory-related death w/monotherapy (especially in African-Americans) / · Longer DOA (>12hrs)
Lipophillic, sits in membrane
· 2x/day dosing
· Slower onset
· β2-selective

Anticholinergics

Parasympathetic ACh normally bronchoconstricts and ↑ mucus by:
↑ Ca2+à BLOCKED
/

Ipratropium

Quaternary atropine analog / · Treatment of COPD
· TOC for β-blocker bronchoconst.
· Asthma w/excess mucus
· Rescue tx if intol to b-agonists
· Nasal spray for rhinorrhea / **Only works when the agonist is present (unlike β-agonists) / · Minimal absorption/distribution
· Inhaled, slow onset
· No GI/CNS (Quaternary)
Tiotropium
Quat. scopolamine an. / · M3 and M1-selective
· Longer DOA
· No GI/CNS (Quaternary)
Glucocorticoids↓ Inflammatory cell proliferation
↑ β2 Receptors: Bronchodilation
↓ WBC entry into tissue
- ↓Endothelium adhesion LTB4+TNFα
- ↓ Chemotaxis: LTB4, PGD2
- ↓ Vascular perm.: LTC4, LTD4
- ↑ Vasodilation:PGE2, PGD2
Short-term= mod-severe attacks resort to dilators
Long-term (inhaled) =1st line Tx for mild-mod asthma
· w/β2 agonists for mod-severe persistent asthma
Long-term (systemic) for very severe persistent asthma / Prednisone (prodrug)
Methylprednisolone / · Mod-severe acute attacks and used w/β-agonists since don’t take effect for hours / >2 wks of systemic treatment:
1) Iatrogenic Cushing’s Syndrome
- Moon facies, Buffalo hymp
- Osteoporosis
- Hyperglycemia à diabetes
- ↓ collagen synthesis
- Glaucoma
- Mineralcorticoid effects
o Edema, hypokalemia, alkalosis, BP↑
2) Hypothalamic-pituitary-adrenal suppression (pseudo Addison’s Disease)
- B/c of negative feedback loop
3) Inhaled glucocorticoid side effects
- Oral candida infections (thrush)
- Dysphonia, cough
- High doses= systemic effects (↓ growth in kids, osteoporosis, glaucoma, cataracts) / · Oral
Triamcinolone acetonide / · / · Topical use (inhalation)
· Triamcinolone-systemically (oral)
Beclomethasone
Fluticasone
Budesonide / · Only prophylaxis
· NOT severe acute attacks
· Used w/long-acting β-agonist
· Also nasal sprays-allergic rhinitis / · Topical use (inhalation)
· Slow onset of action (3 weeks)
· Low oral bioavailability helps
but still 20-30% enter systemic
· Rapidly inactivated in liver
à Double bond in quinoline group increases specificity for glucocorticoid R over mineralcorticoid R

ASTHMA DRUGS continued

Group/Mechanism

/ Drug examples / Clinical uses /

Adverse Effects

Pharmacokinetics

Anti-Leukotrienes

Prophylaxis, NOT acute
Block Leukotrienes which:
1) Bronchoconstrict
2) ↑ mucus secretion
3) Inhibit cilia
4) ↑ Vascular permeability / LT receptor antagonist / Zafirlukast
Kids > 5yo / · Alternative to GCs for mild persistent asthma
· Used w/GCs for moderate persistent asthma
· Allergic rhinitis
Cause (or reveal) Churg-Strauss
(↑ asthma, eosinophilia, vasculitis) / · Liver toxicity

· Inhibit CytP450 2C9 and 3A4

· Oral admin

· Slow onset of action
Montelukast

Once per day

Kids 2yo (better) / · Metabolized by CytP450 but does not inhibit
5-LO inhibitor / Zileuton / · Prophylaxis, NOT acute
· Used w/β-agonists /

· Inhibits synthesis of all LTs, not just the asthma-related ones

· Oral

· High first-pass metabolism

· Short half-life
· Inhibits metabolism of:
Theophylline, warfarin and propranolol
Mast Cell Stabilizers
Inhibit histamine release from Mast cells in lung
- Block entry of Ca2+ into Mast
-does NOT bronchodilate / Cromolyn Sodium
Nedocromil
Pemirolast / · Prophylaxis, NOT acute
· and exercise bronchoconstric
· Only mild persistent asthma as alternative to GCs /

· Few AEs, but low efficacy since partition coefficient is low

· Inhaled dry powder

· Little GI absorption
· Low partition coefficient
Methylxanthines
Ex. caffeine
- Induces bronchodilation
-↓ PDE = ↑cAMP
-↓adenosine receps =↑cAMP
-↓activation of inflamm. Cells via Ca2+ ↓ / Theophylline / · Prophylaxis, NOT acute
· Alt to low dose GCs for mild persistent asthma
· Alternative to long-acting β-agonists w/GCs for moderate asthma, but GCs are preferred / · CNS= nervous, insomnia, headache
· GI= ↑ acid secreted
Heartburn, N/V, anorexia
Heartburn can exacerbate asthma
· Toxicities at high levels
o Arrhythmias (SV tachycardia)
o Seizures, tremor
o Hypotension (peripheral vasodilat.)
o Treat:
§ Whole-bowel irrigat, NOT Ipecac
§ β-blocker, diazepam, dialysis
· NARROW THERAPEUTIC WINDOW /

· Oral or IV

· Slow release preparations reduce dosing frequency

Ab’s against IgE

Prevent IgE binding to mast cell receptor / Omalizumab / · Moderate-severe allergic asthma
· Allergic rhinitis (possibly) /

· $100k/year price tag

· SC injection

PULMONARY HYPERTENSION DRUGS

Group/Mechanism

/ Drugs / Clinical Uses / Adverse effects /

Pharmacokinetics

Prostaglandins
Abrupt discontinuation: rebound hypertension / Epoprostenol / Pulmonary HTN (1° + scleroderma)
↑ Exercise capacity + ↓Mortality / · Flushing
· Hypotension
· GI: Nausea, vomiting, diarrhea /

· Very short t½

· Continuous IV

Treprostinil / · Pulmonary arterial HTN / · Infusion site pain & rxn /

· t½: 2-4 hrs

· Continuous SC
Iloprost /

· t½: 20-30 min

· Inhaled

Endothelin Antagonists
-Antags at ET receps (ETA +ETB)
-In endothelium & vascular sm.
à Vasodilation
à Bronchodilation / Bosentan
Abrisentan / · SEVERE pulmonary hypertension / · Hepatotoxicity: ↑serum ALT
Potentiated by cyrosporine & ketokonazole
· Major birth defects

Drug interactions:

- Hormonal birth control pills fail
- Satins less effective /

· t½: 5 hrs

· Oral admin
· Induces own metabolism by CYP3A4/2C9
Shared w/ grapefruit juice & cyclosporin
à takes longer than 4-5 t½’s to reach steady state
ANTITUSSIVES (COUGH SUPPRESSANTS)
Opioid AgonistsAct in CNS to ↑ cough threshold
Contraindicated w/asthma, emphysema, smoking b/c in that case it is good to cough up shit /

Codeine

(agonist at opioid receptors) /

· Antitussive

· Effects on GI motility

· Antagonized by naloxone

· Interacts w/fluoexetine, paroxetine

· Antitussive effect at < analgesic doses

· Metabolized by CytP450 2D6 to form morphine

Dextromorphan

(antag at NMDA receptors) /

· Antitussive

· Blocks Serotonin uptake /

· Overdose= excitation, hallucinationsà abuse

· NOT antagonized by naloxone

· Interacts w/fluoexetine, paroxetine

· Do NOT use w/MAO inhibitors

· Metab by CYP 2D6 = dextrophan

· Oral admin
· T1/2= 11hrs, DOA- 5-6
Expectorants
↑ respiratory secretions
↓ phlegm viscosity
↑ ciliary action /

Guaifenesin

· Tx of dry, unproductive coughs due to colds and URTIs

· In many OTC drugs

· Makes cough more productive

DRUGS FOR ALLERGIC RHINITIS

Glucocorticoids /

Beclomethasone

Fluticasone

Triamcinolone

· >effective than anti-histamines

· used prophylactically / /

· admin as nasal spray

/
Cromolyn Sodium / /

· GCs>CS>antihists

· Used prophylactically /

· admin as nasal spray

/
Sympathomimetics(decongestants)
-act at a1 receps or release NEP from nerve terminals
=vasoconstric /

Phenylephrine

Pseudoephrine

· Decongestion

· Topical= rebound congestion

· Systemic= vasocontric and ↑ HR= ↑BP/CNS effects /

· Topical or systemic

Group/Mech

/ Drugs / Clinical Uses / Adverse effects /

Metab/P-kinetics

Other

Anticholinergics-inhibit mucus secretion /

Ipatropium

Older antihists

· Decongestion

· Ipatropium= nasal spray

-older antihists have antimusc effects, but newer ones don’t

Antileukotrienes /

Montelukast

· Seasonal allergic rhinitis

/ / /
Antihistamines / /

· relieve itching, sneezing, rhinorrhea (but not congestion)

· sedation and antimuscarinic effects (older generation)

· most= oral admin

· azelastine= nasal spray /

-drugs most frequently used to treat allergic rhinitis