Download Document

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project

Document related concepts

Prescription costs wikipedia , lookup

Medication wikipedia , lookup

Nicotinic agonist wikipedia , lookup

Psychedelic therapy wikipedia , lookup

Toxicodynamics wikipedia , lookup

Drug interaction wikipedia , lookup

Pharmacogenomics wikipedia , lookup

Hormesis wikipedia , lookup

Adherence (medicine) wikipedia , lookup

Neuropharmacology wikipedia , lookup

Ofloxacin wikipedia , lookup

Stimulant wikipedia , lookup

Theralizumab wikipedia , lookup

Neuropsychopharmacology wikipedia , lookup

Dydrogesterone wikipedia , lookup

Psychopharmacology wikipedia , lookup

Bilastine wikipedia , lookup

Transcript
Drug therapy of bronchial asthma
By Dr Attia Jabr, 2009
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
What is asthma?
Physiology (Symp., parasymp., CAMP, sensory
nerves)
Predisposing factors
Drugs & asthma
Pathogenesis (bronchoconstriction + chronic
inflammation + hyperreactivity)
Many cytokines + chemokines
Immediate phase & late phase
Types of asthma
Pattern of asthma
Goals of treatment of asthma
General lines of treatment of asthma
Pharmacological therapy of BA
1.
Bronchodilators
1.
2.
3.
2.
B2 agonists (▲C.AMP)
Methylxanthines (▲CAMP #Adenosine)
Anticholinergic (# M3)
Anti-inflammatory
1.
2.
3.
4.
Corticosteroids
Mast cell stabilizers: Na cromoglycate
Antileukotriens: Zeuloton, zafirlukast, montelukast
PAF antagonist: Ketotifen
3. Anti IgE Antibody: Omalizumab
B2-agonists
Types: B2 phenotypes
1. Short acting: Salbutamol (acute attack)/4-6h
2. Long acting: Salmeterol (Used for prophylaxis)/12h
Administration:
1.
2.
3.
4.
Inhalation: (MDI, Nebulizer); Is the best. Why?
Oral: children < 5 years-prophylaxis
Parenteral: rarely used e.g. in SA
Compare between oral and inhalation B2 agonists? Dosesystemic effect-distribution in lung-Compliance-ease of
administration-effectiveness
Mechanism of action:
↑B2- receptors → ↑AC → ↑CAMP → ↓ Ca→ relax airway
smooth muscle →
1.
2.
3.
Bronchodilatation (physiological antagonist)
▼Mediators release from mast cells & others
▲Muco-ciliary clearance & ▼Microvascular leakage in the
Side effects of B2 agonists:
(Systemic + large dose inhalation only)

1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Why side effects are more in poorly controlled
asthma? Inhalation safe in pregnancy
Tremors Why?
Tachycardia & arrhythmias? Why?
Throbbing headache
Tolerance Why?
Nervousness? Why?
Hyperglycemia. Why? (with IV)
Hypokalemia? Why? (With IV)
Weakness? Why?
Hypoxemia: ▼PaO2 tension if lung ventilation/perfusion
ratio worsens
Constipation (with oral treatment) 11. Death????
Dosages of B2-agonists:
A. Short acting: Salbutamol (4444) for acute attacks
1.
2.
3.
4.
5.
6.
7.
Onset: 4 min by inhalation
Duration: 4 hours
Oral : 4mg/4h (children < 5 years, severe asthma)
IM & SC: 0.4mg/4h
IV: 4 micrg/kg (life threatening cases) (5-10 micr/min
MDI: 1-2 puffs (100micr) up to 4-8 puffs/20 min for 1 h
then/1-4 h
Nebulizer: 2.5-5 (4) mg/20 min for 1 h then /4h
B. Long acting;
1.
2.
3.
Used as a prophylaxis of nocturnal and exercise induced
asthma.
Can you use salmeterol alone in prophylaxis of asthma?
Why?
Dose 50 ug/12 h by inhalation only
Anticholinergic drugs (Ipratropium)


Generally are less effective than B2-agonists. Why?
Useful in patients who are unable to tolerate B2 e.g.
Thyrotoxic patients, cardiac patients
Drugs: Ipratropium & tiotropium
Mechanism : competitiely block muscarinic receptors
(M1, M2, M3). Which one is important?
Quaternary amines: given by inhalation only
Kinetics: Delayed onset of action (20-90 min) duration
4h, tiotropium 24 h. Why?
 Could be combined with B2 agonists in severe asthma
Indications of anticholinergic drugs:
1.
2.
3.


Acute, status, prophylaxis (added to B2 agonists in
severe asthma)
Old age + COPD. Why?
Increased parasympathetic tone (Psychogenic)
Why some patients respond good while others not?
Why increasing the doses above therapeutic is not more effective?
Disadvantages & side effects: Rare
1.
2.
Local: Dry mouth, Cough
Systemic: Atropine; Nausea, constipation urinary
retention, glaucoma
Kinetics: Delayed onset (30-60 min)
1.
2.
MDI: 4-8 puffs (20 ug /Puff ) as needed
Nebulizer: 0.5 mg /30 min for 3 doses, then/ 2-4 h as
needed
Methylxanthines
Theophylline, caffeine, theobromine
Mechanism of action:
1.
2.
Inhibits phosphodiesterase enzyme (PDE 3,4,5) →
increase ▲cAMP
1. ►Broncho-dilatation (compare with B2 agonists)
2. ►Mast cell stabilization→ decrease release of
mediators
3. ▲Mucociliary clearance
Block adenosine receptors A1, A2B (Not enprophylline)
1.
2.
3.
4.
Moderate anti-inflammatory effect: inhibit synthesis and
secretion of inflammatory mediators (Mast cells, basophils)
Increase release of catecholamines.
Improvement of diaphragmatic contractions (▲Ventilation)
Inhibiting pulmonary edema by ▼vascular permeability
▲clearance
Pharmacological Actions:
1.
2.
3.
4.
5.
6.
7.
Smooth muscles: Relax smooth muscles (bronchial)
CNS:
A. Caffeine (150-250 mg), Stimulant (alertness,
▲intellectual effort, motor activity )
B. ▲Doses ►irritability, nervousness, tremors,
confusion,▼ motor tasks, convulsions)
C. ▲ all, medullary centres, CTZ, VM, VC
CVS:. Direct myocardial and direct peripheral dilatation.
With large doses the peripheral effects predominate. Except
Cerebral BV? Why?
Diuretic action: Why? 2 causes
GIT: ▲Volume and gastric secretion.
SKM: +ve skeletal muscles (▼Fatigue of diaphragm)
Others: ▲ BMR, FFA
Pharmacokinetics
Absorption: Irritant, Food↓, SR, Rectal (unreliable),
Variable & irritant.
 Distribution: protein bound, Widely distributed Vd
(0.4-0.6 L/kg)
 Metabolism; liver (CYP1A2, 3A4): 80-90%
(Importance?)
Factors: diseases & drugs, genetic, environmental.
 Not metabolized to uric acid. (importance?)
 Excretion: kidney 10%
 First order kinetics→ Zero order kinetics
 t1/2: 8h Non-Smokers, 4h, Smokers, 4h Children
 In premature infants; t1/2 up to 50 h
 Therapeutic level: (10-20 ug/ml). Narrow TI

Indications of methylxanthines:
1.
2.
3.
Bronchial asthma: Why it is delayed to 3-4th
line?
1. Acute attack & Status asthmaticus (only
in impending respiratory failure)
2. Prophylaxis (nocturnal asthma) Vs
salmeterol & ICS
3. Bronchospasm + bronchitis (COPD)
Apnea in premature infants (caffeine)
Headache & migraine (caffeine)
Adverse effects: Narrow safety margin
1.
2.
3.
4.
5.
6.
7.
8.
CNS: Headache, restlessness, agitation, insomnia,
nervousness, convulsions> 20 ug/dl (treat?),
hyperactivity in some children. Habituation
Behavioral toxicity: Anxiety, fear, panic, dysphoria,
depression, hyperactivity.
CVS: Tachycardia, arrhythmia > 20 ug/dl, hypotension,
Rapid IV of therapeutic doses→ syncope and death.
GIT: N,V, D, PU (hematemesis), hyperglycemia,
hypokalemia
Respiratory: Tachypnea, hyperventilation, respiratory
arrest.(used in asthma of premature infants)
Learning difficulty and increased activity in children.
Tolerance
Drug interactions:
A. Drugs inhibit liver metabolism:
e.g. cimetidine, ciprofloxacin, erythromycin, zafirlukast, heart
and hepatic diseases, ketoconazole, COPD, Viral infections,
extremes of age
B. Metabolism is increased by:
Protein diet, Rifampicin, antiepileptics, tobacco smokers (↑50100%)
C. Aminophylline inhibits metabolism of other drugs
like Warfarin
Contraindications to methylxanthines:
1.
2.
3.
4.
Caffeine in hypertensives (large, prolonged doses).
Cardiac dysrhythymias and IHD
Oral therapy in peptic ulcer
History of epilepsy & convulsions
Preparations and doses of theophylline:
 Dose in acute attack: IV infusion
1.
2.

Loading dose = (5 mg /kg/15-30 min)
Maintenance dose = 0.2-0.8 mg/kg/h
Dose in prophylaxis: Orally
Adults: 5-15 mg/kg/day (SR tablets)
 300-600 mg/day (increased gradually/3 days) up to
800 mg/day


What about the dose in smokers, children,
neonates, old age?
II. Anti-inflammatory drugs
Cromolyn and nedocromil: (mast cell stabilizers)
 Inhalation only
 Prophylaxis only
Mechanism of action: unknown (only 1/3 patients
respond)
1.
2.
3.
Stabilization of mast cells (▼inflammatory mediator release)
Inhibition of axon-mediated release of neuropeptides
(▼cl channels)(▼cough-bronchospam-hyperreactivity)
▼Inflammtory cells
Pharmacokinetics:


Inhalation (aerosol-nebulizer-powder)
0.5-1% absorbed excreted in bile & urine
Indications:
1. Prophylaxis of mild to moderate persistent asthma (added
or alternative therapy)
2. Allergic type of asthma & exercise-induced asthma
Used in:
1.
Short term: immediate before (exercise-allergies-Cold air)
2.
Long term: (▼bronchial hyper-reactivity)
Doses:

Cromolyn for all ages- Nedocromil for > 12 years

Inhalations: Cromolyn 2mg/6h –Nedocromil 4 mg/6h

Preparations: for nose, eye, mouth
Side effects:
1.
Safe for children and pregnant women
2.
Bitter taste, Irritation (Bronchospam-cough-wheezespharyngeal). Solve?
3.
Rarely: Allergy
Corticosteroids
Mechanism of action of corticosteroids in asthma
1.
2.
3.
4.
5.
6.
7.
Inhibition of synthesis of inflammatory cytokines &
chemokines. How? ▼Phospholipase A2 E, ↓lysosomal
Inhibition of production and accumulation of
inflammatory cells (esinophils & basophils in lung tissue)
Inhibition of release & response to inflammatory
mediators (T-cells-macrophages-esinophils)►↓late response
Inhibition of ag/ab reaction
Inhibition of ab formation
Increase No & sensitivity of B2-receptors # down
regulation
Prolonged administration ▼Hyper-responsiveness of
airway smooth muscles
Uses of corticosteroids in asthma:


Improvement begins after 6-8 h, substantial after
2-3 days, maximum after 1-2 weeks
Must be given continuously (can you stop it?)
1.
Acute severe asthma: given orally or IV for one
week
2.
Chronic asthma: Drug of choice for persistent
asthma (mild-moderate-severe)

Given by inhalation

Given orally in severe asthma (short
course)

Could be combined with Bronchodilators
Status asthmaticus: Orally Or IV
3.
Administration of corticosteroids in asthmatic patients:
1. Inhalation: in chronic asthma
Advantages:
1.
Decrease systemic absorption
2.
Decrease side effects
Dosage form:

MDI, Nebulizer, Dry powder.

All inhalations are given twice daily
Types & doses
1.
Fluticasone: Flexicort; the best (100-300-600)
2.
Budesonide: (pulmicort
(200-600-1200)
Side effects:
1.
Oropharyngeal candidiasis
2.
Dysphonia (Solve)
3.
Systemic effects in children with > 500 ug/day
2. Oral administration:


Drugs: prednisone or prednisolone
doses: begin with 60-80 mg/day for 1-2 days then decrease
to 40-60 mg/day later on decreased gradually if > 2 weeks
Indications:
1.
2.
3.
Acute severe astma: (failure of bronchodilators)for 3-10 days
Severe chronic persistent asthma (failure of aerosols)
Status asthmaticus: Maintenance after IV hydrocortisone
Side effects of oral corticosteroids & High ICS in children
1.
Adrenal suppression 2. Cushing syndrome 3. weight gain
4. Osteoporosis 5. Hyperglycemia 6. Infection (TB) 7.
Hypertension 8. Psychosis 9. ▼Growth of children 10. Peptic
ulcer 11. Myopathy 12. cataract & glucoma 13. Withdrwal
syndrome 14. Thinning of the skin
What are the contraindications of corticosteroids?
Leukotriene pathway inhibitors:
Zafirlukast
Montelukast
Mechanism
Block LTC4, D4 receptors
Block LTC4,D4 receptors
Kinetics
T1/2
Oral
PPB
Liver-bile
10 h
Oral
PPB
Liver-bile
5h
Dose
20/2
4-10 /1
Age
> 5y
> 1y
Indications
Side effects
Prophylaxis only
1.
2.
3.
4.
Weaker than ICS
Mild PA & Moderate PA (additives or alternative to ICS)
NSAID-induced asthma
Exercise-induced asthma & irritant (cold air)-allergic asthma
1.
2.
3.
4.
▲Liver enzymes, Headache, NV, dyspepsia
Hypersensitivity, edema
Churg-Straus syndrome (vasculitis)
DDI: Zafirlukast (CYP450) # warfarin (+hepatitis)
Anti-IGE treatment (Omalizumab)
Mechanism: RH monoclonal antibody binds to IgE ▼its
binding to mast cells and eosinophils ▼allergic reaction
Pharmacokinetics:
1.
2.
3.
Administration: SC
Half life: 26 days
Elimination : liver, RES.
Indications: expensive & injection
1. > 12 years with moderate & severe asthma (failure of
others)
2. Other allergies: Food allergy- nasal allergy
Side effects: Very expensive (600$ for vial)
1.
2.
3.
Local reactions (redness-induration-bruising-stinging)
Anaphylaxis (0.1%)
Cancer?
Dose: 175-350 mg/1month