Bronchial Asthma (reversible airway obstruction)

Consist of

1. Narrowing of airway due to muscle spasm

2. Mucosal edema due to inflammation
3. Tenacious mucous production

Classification of anti-asthmatic drugs

A. Bronchodilators
1. Beta 2 adrenergic agonists (use as reliever)
(a) Selective beta 2 action
- Short acting: Salbutamol, Terbutaline, Orciprenaline
- Long acting: Salmeterol, Formoterol
(b) Both alpha and beta action: Adrenaline (SC) , Ephedrine (oral)
(c) Both beta 1 and beta 2 acting: Isoprenaline (inhalation)
2. Xanthine derivatives (oral, parenteral)
- Aminophylline, Enpyrophyllne
3. Muscarinic receptor antagonist (inhalation)
- Ipratropium, Tiotropium, Oxitropium
4. Magnesium sulfate
B. Drugs that the bronchial hyperactivity (anti-inflammatory agents)
1. Corticosteroids
- Inhaled corticosteroids (use as controller): belomethasone, fluticasone, triamcinolone, budesonide, ciclesonide,
flunisolide, mometasone
- Oral: prednisolone, dexamethasone
- Parenteral (use for permissive action): hydrocortisone sodium succinate, dexamethasome
2. Cromolyn sodium
C. Mucolytics
- Acetylcysteine, bromhexine
D. Newer drugs
- Leukotriene receptor antagonists: Zafirlukast, Montelukast
- Leukotriene synthesis inhibitor: Zileuton (report liver toxicity)
- Monospecific anti-IgE antibody: Omalizumab
1. Beta 2 adrenergic agonist
- Drug of choice in sthma

Mechanism of action

- Directly stimulate beta 2 receptor by activating adenylate cyclase – increasing cyclic AMP and reduction smooth
muscle tone
- Increase conductance of large Ca2+ -sensitive K+ channel – membrane hyperpolarization – relax bronchial smooth
muscle
- Indirectly inhibit the release of
1. Bronchoconstrictor mediators from inflammatory cells
2. Bronchoconstrictor neurotransmitters from airway nerves

Uses

- Acute attack and non-acute asthma

- Short acting agents (salutamol, terbutaline) –“ as needed” basis
- Long acting agent (salmeterol, formeterol) – not used on “as needed” basis, regularly, twice daily inhalation, as
adjunct therapy – maintainance therapy in asthma, exercise induced asthma and nocturnal asthma
Untoward effects
- Palpitation, headache, tachycardia, fine tremor (hand), hypokalaemia
2. Methylxanthines
 - Theophylline, theobromine and caffine – among them theophylline used therapeutic agent in the treatment of
asthma

Mechanism of action

- At high concentration – inhibit cyclic nucleotide phosphodiesterase family (PDE4), prevent breakdown of cAMP
- Therapeutic concentration –competitive inhibition of adenosine
- Anti-inflammatory
- Increase in circulating catecholamine, inhibition of calcium influx into inflammatory cells, inhibition of
prostaglandin effects

Pharmacological actions

1. Bronchial smooth muscle relaxation – relive asthma

2. CVS – positive chronotropic and inotropic actions of heart –tachycardia, increase cardiac output, even arrhythmia
- Generalized vasodilator except cerebral blood vessels where they cause constriction (malignant vasodilatation)
3. CNS – stimulate CNS – restlessness, nervousness, insomnia, anxiety, tremors and even seizures
- Useful in COPD, apneic preterm infants and prevention of nocturnal asthma
4. Kidney – mild diuretic actions
5. GIT – stimulation of secretion of both gastric acid and digestive enzymes

Pharmacokinetics

- Well absorb orally, cross the placenta, half-life about 8 hours

- Elimination is increase in liver disease and cardiac failure and decrease in heavy smoker and drinker (enzyme
induction)
- Narrow therapeutic index (aminophylline, digoxin, lithium)
- Long term therapy (oral)
- less effective bronchodilator than beta 2 agonist
- Primarily used to treat not controlled other drug alone

Untoward effects

- Major GI, CNS, CVS

- GI: abdominal pain, nausea, vomiting (minimized by taking food, antacid, full glass of water and milk)
- CNS: tremor, nervousness, insomnia, convulsion
- CVS: palpitation, arrhythmia
- Overdose: hypotension, arrhythmia, seizures

Drug interaction

- Increase plasma theophylline with enzyme inhibitors (isoniazid, cimetidine, erythromycin, clarithromycin,
ciprofloxacin, diltiazem and fluconazole)
- Decrease plasma theophylline with enzyme inducers (rifampicin, carbamazepine, phenobarbitone, phenytoin)

3. Muscarinic receptor antagonist (ipratropium by aerosol inhalation)

Mechanism of action
- Competitively antagonize ACh binding to muscarinic cholinergic receptor (M 3)
- Reduce cGMP – reduce of mediator release
- little systemic absorption
Use
- Not first- line drug, more effective in fixed airway obstruction (COPD) (bronchodilator of choice)
- Adjunct to beta 2 agonist and steroid in asthma
- Use intolerant to inhaled beta 2 agonist
- Bronchospasm due to beta blocker
Untoward effects
- Unpleasant bitter taste, glaucoma in elderly by ipratropium, dry mouth by tiotropium, rarely constipation and
urinary retention
4. Magnesium sulfate
 Mechanism of action
- Reduce cytosolic Ca2+ by inhibit calcium influx into cytosol
- Inhibit histamine release from mast cells
- By increasing receptor affinity – increase effect of beta 2 agonist
Uses
- Adjunct therapy for severe and life-threatening exacerbation asthma
Untoward effects – flushing and nausea
5. Corticosteroids
- Inhaled corticosteroid (ICS) – beclometasone, fluticasone, budesone, ciclesonide, flunisolide, mometasone and
triamcinolone
Mechanism of action
- Inhibit phospholipase A2 – inhibit PGs and leukotriene synthesis
- Inhibit release of mediator from mast cells – reduce edema and inflammation
- Permission action
Uses
- Severe acute asthma (crisis asthma) (status asthmaticus) (iv hydrocortisone)
- Non-acute asthma (oral prednisolone or inhaled cortisteroids)
Untoward effects
- Local untoward effects (ICS) – dysphonia, oropharyngeal candidiasis (reduced by rinsing mouth and throat by
water)
- Systemic untoward effects – fewer with ICS, growth retardation in children
- Oral corticosteroid for long-term use – fluid retention, weight gain, osteoporosis, capillary fragility, hypertension,
peptic ulceration, diabetes, cataracts psychosis
6. Cromolyn sodium (sodium cromoglycate) and Nedocromil
Mechanism of action – unknown
Pharmacological action
- Inhibit release of inflammatory mediators
- inhibit leukocytes trafficking in asthmatic airways
- no direct effect on airway smooth muscle tone
- by inhalation (poor absorption from GI, well absorb from lungs)
Uses
- long term prophylaxis and allergic reaction, e.g, allergic rhinoconjunctivitis (Primary use) and exercise induced
asthma
- no role in relieving acute bronchospasm
Untoward effects – minor symptom such as throat irritation, cough, and mouth dryness
7. Leukotriene receptor antagonists ( Montelukast and Zafirlukast )
Mechanism of action
- Antagonize cysteinyl leukotriene receptors: LTC4, LTD4, and LTE4
- Do not block LTB4 (involved in severe asthma and asthma exacerbation)
Pharmacological Action
- Inhibit early and late response to inhaled allergy
- Inhibit exercise induced asthma
- Action additive with beta 2 agonist
- Rapid onset of action with ORAL administration
Uses
- Allergic asthma and aspirin sensitive asthma
- Monothreapy for prophylaxis of exercise induced asthma
- Adjunct to inhaled corticosteroids in chronic asthma
- Allergic rhinitis
- Beneficial effect in children than adult
Montelukast – children 6 months to 5 years
Zafirlukast – not recommended in children under 12 years (enzyme inhibitor)
Untoward effects – liver dysfunction (rarely), Churg-Strauss syndrome (blood vessel inflammation)
8. Anti-IgE therapy (Omalizumab) (S.C)
- Recombinant humanized monoclonal antibody
- Use – moderate to severe persistent asthma, other allergic disorders: nasal allergy and food allergy
- Untoward effect
 - Injection site – redness, stinging, bruising and induration

Not useful for acute attacks: - Antihistamines (may be harmful)

- Sedative and cough suppressants (contraindicated)

Drugs to be avoided in asthmatics:

1) Adrenergic antagonist, e.g. propranolol

2) Drug release histamine, e.g. opiates, curare
3) Parasympathomimetic agents, e.g. methacholine
4) NSAIDs, e.g. aspirin, ibuprofen, naproxen
5) PGF2 , e.g. carboprost, dinoprost, latanoprost

Drug treatment of cough

Classification
A. Cough stimulants (should not be uses in children 6 years)
I. Expectorants: stimulate cough reflex directly and indirectly
1. Saline expectorants
- Sodium salts (Cl- ,HCO3- ,citrate)
2. Stimulant expectorants (by inhalation)
- volatile oils, e.g. eucalyptus oil, menthol, tincture of benzoin
3. Expectorant Creosotes and Guaiacols
II. Mucolytics: less viscosity of respiratory exudates
1. Bromhexine (contraindication – peptic ulcer, pregnancy)
2. Acetylcysteine (Methylcysteine, Carbocysteine)
B. Cough Suppressants (antitussives) (avoid children under 12 years)
I. Opiates
Codeine, (Pholcodeine and Dextromethophan – avoid in children under 6 years), Methadone
II. Non-opiates (suppress cough centre)
Sedating antihistamines –diphenhydramine, chlorpheniramine
III. Demulcents (local action): Glycerol, Linctus (useful for children)

Drug use in Renal

Classification of Diuretics

1. Inhibitors of Na+ -Cl- symport (Thiazide and Thiazide-like Diuretics)

- Chlorothiazide
- Trichlormathiazide
- Hydrochlorothiazide
- Hydroflumethiazide
- Metolazone
- Indapamide,Xipamide
- Polythiazide
- Chlorthalidone
2. Inhibitors of Na+-K+-Cl- symport ( High-Ceiling Diuretics; Loop Diuretics)
- Frusemide
- Bumetanide
- Ethacryic acid
- Piretanide
 - Tripamide
- Torsemide
- Azosemide
3. Potassium Sparing Diuretics
- Inhibitors of renal epithelial Na+ channel: Amiloride and triamterene
- Aldosterone antagonists: spironolactone, eplerenone
4. Osmotic Diuretics
- Manitol
- Urea, glycerine, isosobride
5. Carbonic Anhydrase inhibitors
- Acetazolamide
- Dichlorphenamide
- Methazolamide
6. Micellaneous Agents
- Acidifying salts (ammonium chloride)
- GFR raising agents: xanthines (theophylline)
- ADH antagonist: demeclocycline

Thiazide and thiazide-like diuretics ( Sulfonamide group (allergy)- SO2NH2 ) ( luminal side of early distal tubule)

Pharmacological Action

1. Diuretics ( use - generalized or localized edema – CHF, Nephrotic syndrome)

Mechanism of action
- Blockade of sodium and chloride symport (early diatal tubule)
- Carbonic amhydrase inhibition acidosis
2. Reduction of blood pressure ( use alone or with others, sub diuretic dose – hypertension )
- Vasodilation - sodium loss in urine
3. Antidiuresis in (Diabetes insipidus)
- Paradoxical antidiuretic effect – reduce polyuria and polydipsia
4. Effect on electrolyes
- Increase excretion Na+ and water – diuresis, hyponatraemia and dehydration
- Increase excretion of K+ (hypokalaemia) (hypokalaemic alkalosis)
- Increase excretion of Cl+ (hypochloremic alkalosis)
- Increase excretion of magnesium, iodide and bromide
- Decrease excretion of Ca++ (use – idiopathic hypercalciuria – to reduce urinary stone formation) and Uric acid
(precipitate gout)
5. Increase in blood glucose level
- Hyperglycaemia
- Hyperuricemia
- Hypercholesterolaemia

Pharmacokinetics

- Incomplete absorption

Clinical Toxicity

1. Related to diuresis
2. Impotency in men
3. Common side effect: allergy, purpura, dermatitis with photosensitivity, thrombocytopenia, acute pancreatitis,
necrotizing vasculitis, cholestatic hepatitis
4. Reduce lithium clearance (contraindicated in lithium overdose)
5. Potentiate skeletal muscle relaxants (muscle cramps, fatigue)

Drug interactions
 1. Digoxin and thiazides in cardiac failure: Synergism in treatment of congestive heart failure
2. Thiazide and antihypertensive: synergistic
3. Thiazide and NSAIDs: blunt diuresis due to sodium retention effect of NSAIDs

Furosemide

- Furodemide, bumetanide and torsemide –sulfonamide derivatives

- Ethacrynic acid not sulfonamide

Pharmacological actions

1. Diuresis (site: ascending limb of loop of Henle)

- Powerful diuresis even with low GFR
- Time of onset and duration of action shorter than thiazide
- Steep dose response curve

Mechanism of Action

- Inhibit Na+ - K+ - 2Cl—symport

- Frusemide inhibit carbonic anhydrase ( not ethacrynic acid)
2. Reduction of blood pressure
3. Decrease left ventricular filling pressure (Furosemide)
- Systemic vasodilation, required intact kidney
- Benefit patient with pulmonary edema even before diuresis ensues
4. Effect on electrolytes
- Increase Na+ , K+ , Cl-- , Ca+ and Mg2+ excretion
- Decrease urate excretion - gout
- Frusemide has weak carbonic anhydrase-inhibiting activity – increase excretion of HCO3 and phosphate
- Alternation of electrolyte of endolymph of inner ear (ethacrynic acid) - deafness
5. Effect on renal haemodynamics
- Increase total renal blood flow
6. Increase blood glucose

Pharmacokinetics

- Good GI absorption, bioavailability 60% frusemide, 100% bumetanide

- Oral absorption of torsemide (1 hr) more rapid than furosemide (2-3 hrs)
- Not excreted in glomerular filtrate. Secreted into proximal tubule by organic acid transporter system( inhibit by
probenecid)

Uses

1. Acute pulmonary edema (emergency iv)

2. Acute cerebral edema (danger of medullary herniation)
3. Hypertensive emergency ( not for routine use)
4. Edema of cardiac, renal or hepatic origin
5. Refractory edema together with thiazides or K+ -sparing agents
6. Oliguria in early renal failure (contraindicated in anuria)
7. Force diuresis in drug over dose
8. Hypercalcaemia, mild hyperkalaemaia

Clinical toxicity

1. Related to diuresis
2. Hypotension
3. Hyperglycaemia, hyperuricemia, increase LDL cholesterol and triglyceride and decrease HDL
4. Allergy (sulfonamide diuretics) – skin rash, paraesthesia, hepatic dysfunction, intestinal nephritis, bone marrow depression
5. Deafness, GI haemorrhage (ethacrynic acid)
 6. Nephrotoxicity (use with gentamicin/cephaloridine – increase ototoxicity)
Indacrinone (uricosuric diuretic) – derivative of ethacrynic acid

Drug interaction

1. Digoxin and frusemide – hypokalaemia – increase arrhythmias

2. Sulfonylurea and frusemide –hyperglycaemia
3. NSAIDs, probenecid – blunt diuretic response
4. Lithium, propranolol – increase plasma level of lithium
5. Anticoagulant – increase anticoagulant effect of warfarin
6. Thiazide diuretics – Synergism
7. Amphotericin B – increase potential for nephrotoxicity and ototoxicity and intensification of electrolyte imbalance

Amiloride and Triamterene (potassium sparing diuresis)

- Late segment of nephron

- Amiloride at high dose decrease excretion of Ca+ , Mg2+ , H+ ( inhibit Na+ - H+ - Ca2+ antiport)
- Use with other diuretics that cause K+ loss : mildly uricosuric
- Triamterene – 50% absorbed , metabolized in liver
- Amiloride – slow onset, excreted unchanged in urine

Side effects

- Hyperkalaemia, leg cramp, dry mouth, skin rash, increase blood urea, decrease BP, confusion, megaloblastic
anemia (inhibit DHFR/folate deficiency) and nephrolithiasis with triamterene

Spironolactone

- Synthetic steroid – structure similar to aldosterone – competitive antagonist aldosterone in distal tubule

Mechanism of action

- Competitively inhibits to MR (mineralocorticoid receptor-MR) – prevent formation of mediator protein (AIP –

aldosterone induced protein) – interfering with sodium retaining action

Pharmacological Action

- Increase sodium excretion, H+ ion and uric acid excretion, Potassium is conserved (hyperkalaemia)
- Canrenone is active metabolite
- Other actions: synthetic steroids- endocrine abnormalities
- Onset of action very slow

Therapeutic uses

1. Primary hyperaldosteronism ( Conn’s syndrome, ectopic ACTH production)

2. Secondary aldosteronism ( edema and ascities in cirrhosis of liver, nephritis syndrome and refractory edema)
3. Edema and hypertension
Side effect
1. Hyperkalaemia, mild acidosis
2. Steroid like effects: gynaecomastia, impotence, decrease libido, hirsutism, deeping voice, rregular menses, GI
disturbances (abdominal pain, gastritis, gastric bleeding)
3. CNS: ataxia, drowsiness, lethargy, confusion

Contraindication

- Hyperkalaemia, Addison’s disease, severe renal impairment, porphyria, pregnancy and breast feeding, peptic ulcer
Manitol (I.V)

- Osmotic diuretics, not absorbed to any greater extent and pharmacologically inert
Mechanism of Action
a. In the plasma – increase osmotic pressure – attract water into blood from interstitium and tissues (eye and
brain) cause expansion of ECF and decrease blood viscosity
b. In the renal tubule – acts both proximal tubules and loop of Henle

Therapeutic uses

1. By increasing osmotic pressure in the plasma

a. Raise intraocular pressure (pre- and post- eye operation, acute attack of glaucoma)
b. Increase intracranial pressure (due to space occupying lesion, tumour, abscess, encephalitis)
2. Maintenance of urine flow
a. Prophylaxis and early treatment of acute renal failure
b. Acceleration elimination of poison and drug in urine
3. Treatment of dialysis disequilibrium syndrome

Side effects of Manitol

- Expansion of ECF (hazard in heart failure and pulmonary congestion), headache, nausea, vomiting, allergy,
dehydration
- Hyperkalaemia, hypernatremia
Urea – thrombosis, pain if extravasation
Glycerine – metabolized hyperglycemia, glycosuria
Contraindication
1. Cardiac failure
2. Hypertension
3. Marked pulmonary congestion or edema
4. Marked dehydration
5. Potential anuria due to severe renal disease
6. Intracranial haemorrhage

Carbonic anhydrase Inhibitor (Acetazolamide)

- Sulfonamide in nature
- Metabolic acidosis

Therapeutic uses (NOT as diuretic agent)

1. Open-angle glaucoma (major indication) – also acute angle closure glaucoma – dorzolamide, brinzolamide:
topically
2. Patient with increase ICP (reduce CSF formation)
3. Prophylaxis of mountain sickness
4. Epilepsy in childhood
5. Periodic paralysis ( both hyperkalaemic and hypokalaemic)
Side effect
1. Paraesthesia, fatigue, somnolence, malaise
2. Renal potassium wasting
3. Hypersensitivity and blood dyscrasias (fever, bone marro depression, interstial nephritis)
4. Alkalinization of urine – calculus formation and ureteral colic
5. Divert ammonia of renal to systemic circulation – worsen or induce hepatic encephalopathy (contraindicated
in hepatic cirrhosis)
6. Increase lithium excretion, reduce quinidine excretion
7. Reduce urinary excretion of weak organic bases
Choice of diuretics for different clinical settings

1. For increased intracranial pressure:

- Space occupying lesion: manitol IV infusion
- Cerebral edema: frusemide IV
2. For increased intraocular pressure(glaucoma): acetazolamide
3. For removal of edema (heart failure, cirrhosis of liver): thiazide, furosemide
4. Renal failure (as treatment, before anuria sets in): furosemide (to maintain urine flow / prophylaxis of renal failure): maintol IV
infusion
5. Refractory edema to routine diuretic treatment
- IV furosemide – use combination therapy to sequential block – synergistic interaction e.g. loop diuretic with K+
sparing diuretic or thiazide
- If due to secondary aldosteronism): furosemide + spironolactone
6. For hypertension: thiazide alone or with K+ sparing diuretics
7. For acute pulmonary edema: IV furosemide