Management of status asthmaticus and Chronic Asthma

Treatment of  Status asthmaticus

Propped up position.

Oxygen inhalation by mask

Injection Hydrocortisone 200-500mg I/V routes 6 hourly Or Sodium succinate.

Nebulizer – over 5 minute repeated in 15 minutes.

Injection adrenaline subcutaneously 0.5mg (1000 dilution) 1:1000ml.

Ipratropium bromide ( 0.5mg should be added in nebulizer)

Injection Aminophylline ( 5 mg/kg intravenously very slowly)

If improved this condition then oral prednisolone 30.-60mg daily with inhaler sulbutamol.

Antibiotics if necessary.

No sedative of any kind.

Chest X-ray to exclude pneumothorax

Treatment on discharge:

• Complete the course of antibiotic
• Short course of oral prednisolone
• Inhaled beta agonist + inhaled steroid 

Treatment plan of chronic asthma

It is also called step care management of Asthma.
Step – I : Occasional use  of inhaled short acting β2 agonist bronchodilator ( once daily)
Step – II: Regular inhaled anti-inflammatory agent ( Chromolin or low dose leukotrien antagonist)
Step – III: Regular inhaled corticosteroid + regular long acting inhaled β2 agonist
Step – IV: High dose of inhaled steroid & regular bronchodilator
Step – V: Best of step + oral prednisolone

Bronchodilators administered by inhalation\

• Salbutamol
• Sulmeterol
• Formeterol
• Albuterol
• Isoproterenol
• Metaproterenol
• Terbutaline
• Ipratropium bromide
• Dexamethasone
• Beclomethasone
• Budesonide
• Flunisolide
• Di – sodium chromoglycate
• Fluticasone
• Triamcinolone

Approaches of bronchial asthma treatment, Drugs used

Approaches of bronchial asthma treatment:

1. Prevention of exposure to allergens
2. Reduction of bronchial inflammation and hyper reactivity
3. Dilatation of narrowed bronchi

Drugs used in Bronchial asthma

A. Bronchodilators:

1. Sympathomimetic drugs:

a. Selective β2 agonist.
Short acting (duration 4-6 hrs) –

• Salbutamol
• Terbutaline
• Metaproterenol

Long acting (duration 12 hrs or more) –

• Salmeterol
•  Fenoterol
• Formeterol
• Rimeterol
• Bitolterol

b. Non selective (β1 & β2)

•  Adrenaline
•  Ephedrine
• Isoproterenol (Isoprenaline).

2. Methyl xanthene group:

Natural –

• Theophylline
• Theobromine
• Caffeine (also used in neonatal apnoea)

Synthetic –

• Aminophylline. (Na salt of Theiophylin)

3. Antimuscarinic bronchodilator:

• Ipratropium
• Oxitropium

B. Anti-inflammatory

1. Corticosteroids: 

• Hydrocortisone. (Inj.)
• Prednisolone. (Oral)
• Beclomethasone
• Budesonide
• Triamcinolone
• Flunisolide
• Fluticasone
• Mometason

   

2 . Mast cell stabilizer:

• Nedocromil sodium
• Cromolyn sodium ( disodium chromoglycate) drugs 

C. Others:

1. Leukotrine pathway inhibitor –

• Zileuton
• Zafirlukast
• Montelukast

2.  Calcium channel blocker –

•  Nifedipine
• Verapamil
• Amlodipine

3. Anti IgE monoclonal antibody:

• Omalizumab

4. Histamin (H1 ) receptor blocker:

• Ketotifen

Drugs Used In Prostatic Hyperplasia and Erectile Dysfunction

Drugs Used in Benign Enlargement of Prostate

Principle:  

Capsular and stromal tissue of Prostate gland is rich in α1 adrenoceptors, and glandular tissue under the influence of androgens. Both these, the α receptors and androgens, and androgens, are targets for drug therapy. Because the bladder itself has a few α receptors, it is possible to use selective α1-blockade without affecting bladder contraction.

Drugs:

α –adrenoceptor blockers:

•     Prazosin
•     Alfuzosin
•     Indoramin
•     Terazosin
•     Doxazosin
•     Tamsulosin

All are selective for α1 receptor.

Others:

•     Finasteride

Mechanism of drugs used in BHP: 

α1 receptor blockers cause significant increases (compared to placebo) in objective measures such as maximal urine flow rate and drugs also improve semi-objective symptom scores. In normotensive men, falls in blood pressure are generally negligible; in hypertensive patients, the decline in pressure can be regarded as an added bonus.

Tamsulosin is a competitive α1 receptor blocker with a structure quite different from that of most other α1 receptor blockers. Long half life of 9-15 hrs. it has higher affinity for α1A and α1D receptors than for the α1B subtype.

Advantages of tamsulosin over other alfa receptor blockers:

•     Long half life
• Greater potency in inhibiting contraction in prostate smooth muscle versus vascular smooth muscle
• Drug efficacy in BHP suggests that the α1A subtype may the most important alfa subtype mediating prostate smooth muscle contraction.
• Less effect on standing blood pressure

Adverse effects:

• Dizziness
• Asthenia
• Nasal stuffiness

But Tamsulosin has fewer side effects.

Finasteride: 

An alternative drug is the type II 5α-reductase inhibitor; it inhibits conversion of testosterone to its more potent metabolite, dihydrotestosterone.  It doesn’t affect serum testosterone, or most non-prostatic responses to testosterone. It reduces prostatic volume by 20% and increases urinary flow rates by a similar degree.

Drug used in erectile dysfunction:

• Sildenafil
• Tadalafil
• Vardenafil

Sildenafil
Mechanism of action:

Erectile response mediated by release of nitric oxide (NO) from nerves supplying vessels in corpora cavernosa. This increases intracellular cGMP levels which cause vasodilatation. Effects terminated by phosphodiesterase type 5 enzymes. Which is inhibited selectively by sildenafil, which enhances vasodilatory action of NO.

Contra indications:

• Severe hepatic impairment
• BP<90/50 mmHg
• Recent stroke or MI
• Patient who are taking organic nitrates

Adverse effects:

• Headache
• Flushing
• Dyspepsia
• Nasal congestion
• Green / blue tingling of vision (3%)

Drugs used for osteoporosis:

• Alendronate
• EtidronateIbandronate
• Pamidronate
• Risedronate

Drugs for obesity:

• Orlistat
• Phentermine
• Sibutramine

Oral Hypoglycemic Drug- Sulphonylureas: Mechanism, Indication, Side Effects

Mechanism of action of Sulfonylureas (Glibenclamide) / oral hypoglycemic drug:

I. Pancreatic action: 

a. They are effective only in the presence of functioning pancreas at least 30% β- cell should be active.
At pancreatic beta cell membrane there is ATP dependent K+ channel. Sulfonylurea bind to sulfonylurea receptor and blocks the ATP dependent K+ channel. So inhibits the efflux of K+ ion, through the channel resulting depolarization. Depolarization causes opening of voltage gated Ca++ channel leading to influx. This Ca++ then induces insulin secretion. This endogenous release insulin then lowers the blood glucose level. Sulfonylurea acts only in presence of viable pancreatic beta cell that is when at least 30% pancreatic beta cell is viable. It is indirect action of sulfonylurea.

b. Reduction of serum glucagons concentration:
Increase release of both insulin and somatostatin causes inhibition of α cells which leads to reduction of glucagons release

II. Extra pancreatic action:
Sulfonylurea binds to its receptor in K+ channel in extrapncreatic tissue also and may potentiate the action of insulin by –
o    Increase number of insulin receptors in tissue
o    Increase binding affinity of insulin receptor for insulin
o    Increase glucose transport into the cell by glucose transporter
o    Decrease release of catecholamines
o    Inhibit glycogenolysis by inhibiting phosphorylase enzymes

Three mechanism of Sulfonylureas action have been proposed. Sulfonylureas indirectly decrease blood sugar:
By –
1. Release of insulin from pancreatic beta cell.
2. Reduction of serum Glucagon level.
3. Potentiate the action of insulin on its target tissue & extra pancreatic effect.

Adverse effect of Sulfonylureas:

1. Hypoglycaemia.
It is not frequently occurs but when occurs tends to be prolong. It is particularly seen with Chlorpropamide, Glibenclamide & elderly patient with impaired hepatic & renal function.

2. GIT upset.

• Nausea
• Vomiting.
• Diarrhea

3. Haemotological reaction.

• Neutropenia
• Agranulocytosis
• Thrombocytopenia
• Aplastic anemia

4. Cholestatic jaundice & intolerance to alcohol Chlorpropamide can induce hepatic microsomal enzyme particularly in high doses & due to disulfiram like reaction.

5. Allergic skin reaction – skin rash, exfoliative dermatitis

6. Weight gain – due to increase appetite

7. Muscular weakness, ataxia, dizziness, mental confusion

8. Teratognensis

9. Drug interaction:  Sulfonylureas are protein-binding drug so drug interaction occurs with protein binding drugs.

• Sulfonamide
• Salicylate
• Phenylbutazone
• Warfarin

These drugs displace Sulfonylureas & produce antidiabetic effect & cause hypogylcaemia.

Indications of Sulfonylureas:

1. Sulfonylureas are used for the treatment of NIDDM who can’t be controlled by diet, exercise & weight reduction. It is usually used in non-obese non-insulin dependent patient.

Contraindications of Sulfonylureas:

1. In insulin dependent diabetes mellitus (IDDM).
2. Diabetes with complication e.g. diabetic keto acidosis, diabetic nephropathy etc.
3. Diabetes with surgery.
4. Diabetes with pregnancy & lactation.
5. Hepatic & renal impairment.

N.B:
Combined therapy with Sulfonylureas & insulin: 
It is used in cases where daily insulin requirement is very high. Since Sulfonylureas drug not only increase the pancreatic beta cell secretion of insulin but also increase peripheral tissue sensitivity to insulin. So use of Sulfonylureas has been advocated to reduce the total insulin dose.

How Insulin Reduces Blood Glucose Level; Indication of Insulin

Insulin reduce blood glucose level by –

1. Increase glycogenesis by increase glucose uptake & increase deposition of glycogen.
2. Decrease glycogenolysis by decrease phosphorylase & decrease cAMP.
3. Decrease neoglucogenesis by decrease enzymes concerned with neoglucogenesis

Indications of insulin

1. Insulin dependent diabetes mellitus (IDDM-Type I).
2.  Non -insulin dependent diabetes mellitus (NIDDM- Type II) when oral hypoglycemic drug failed.
3. Diabetes with complication such as -
•    Diabetic keto acidosis
•    Diabetic retinopathy
•    Diabetic nephropathy
•    Diabetic neuropathy
•    Diabetic acidosis.
These are emergency condition. Here we use short acting insulin & it is administered in I/V route.

4. Diabetes with acute infection & acute MI.
5. Diabetes with surgery. Before surgery, during surgery & after surgery insulin is required.
6. Diabetes with pregnancy (gestational diabetes). During pregnancy diabetes is controlled by insulin, here oral hypoglycaemic drug should not be used because it can cross-placental barrier & have teratogenic effect.
Insulin has large molecular weight & does not cross placenta & have no teratogenic effect.
7. Diabetes with pancreatectomy.

Synthesis and Pharmacological Properties of Insulin

Islets of langerhans of pancreas contains 4 types of cells –

I. α / A cell	20%	Secretes glucagons ( increase blood glucose level)
II. β/ B cell	68%	Secretes insulin ( decreases blood glucose level)
III. δ / D cell	10%	Secretes somatostatin ( inhibit both insulin and glucagons release)
IV. PP/ F cell	2%	Secretes pancreatic polypeptide ( stimulation of gastric and intestinal enzymes and inhibition of intestinal motility)

   

Insulin is a large polypeptide hormone. It is synthesized in beta cell of pancreas. It consists of 51 amino acid & they are arranged in A chain & B chain. A chain contains 21amino acid & B chain contains 30 amino acid. A chain & B chain are linked together by disulfide bond. In addition, A chain contains another disulfide bond. Disulfide bond are essential for biological activity. Oral administration of insulin; disulfide bond are destroyed by proteolytic enzyme pepsin not by HCl.

Source:

a. Human.

b. Porcine.

c. Bovine

Synthesis of insulin:

Site: Rough endoplasmic reticulum of β cell.

Steps:  Glucose enters in to the cell → converts into glucose metabolites → stimulates RER (rough endoplasmic reticulum)→ synthesis of preproinsulin → which converted to proinsulin → proinsulin transported into golgi complex → & converted into insulin by the enzyme trypsin like enzyme.(These trypsin like enzyme are transmitted genetically into the individual , the person had lack of these enzyme who has suffer  DM). Then insulin is packaged into the granules→ granule fused with cell membrane →exocytosis of insulin →release of insulin into the capillary blood.

Insulin exists in our body in 3 forms:

1. Monomers-single molecule active form.

2. Dimer –double molecule inactive form.

3. Hexamer- It is storage form of insulin in granules of β cell. It is stored in the form of crystal & consists of 2 molecule of zinc & 6 molecule of insulin.

Daily release of insulin is 18- 40 units.

It is metabolized by enzyme insulinase.

M/A of insulin (cellular/molecular mechanism):

Insulin receptor is a tetramer made up of two alpha (α) & two beta (β) glycoprotein subunits & binds by disulfide bonds. The a subunit binds with insulin extra cellularly & β subunit is transmembrane protein & its intracellular end has tyrosine kinase activity. Binding of insulin triggers the tyrosine activity of the β subunits producing autophosphorylation of the β subunits on the tyrosine residue.

Autophophorylation of the β subunit leads to phosphorylation of some enzyme in the cytosol .The activated enzyme then produce action.

Pharmacological properties of insulin

Insulin promotes storage of fat, as well as glucose (both are sources of energy) in target cell & influences growth of cells & metabolic function of tissue.

A. Action of insulin on glucose transports: Insulin has an important effect on several transport molecules that facilitates glucose transport or movement across the cell membrane. These transporters play a role in etiology as well as manifestation of diabetes. There are 5 types of transporters.

GLUT -4 is important for lowering blood glucose.

Defect in GLUT-2 mediates transport of glucose into pancreatic β-cells may cause reduced insulin liberation that characterized NIDDM.

B. Action of insulin on liver:

1. Decreased blood glucose level by –

a. Increase glycogenesis by increase glucose uptake & increase deposition of glycogen.

b. Decreased glycogenolysis by decrease phospholipase & increased cAMP.

c. Decreased neoglucogenesis by decrease enzymes concerned with neoglucogenesis

2. Decrease TG synthesis & VLDL formation?

3. Decrease protein catabolism.

4. Increased K⁺ & phosphate uptake by liver.

5. Inhibit formation of keto acid, fatty acid & protein.

C. Action of insulin on muscle:

1. Increase protein synthesis by amino acid transport & increased ribosomal protein synthesis.

2. Increase glycogen synthesis by glucose transport. Induce glycogen synthetase & inhibit phosphorylase.

D. Action of insulin on adipose tissue:

Decrease circulating free fatty acid & promotes TG storage in adipose tissue by-

1. Lipoprotein lipase is induced & activated by insulin to hydrolyze TG from lipoprotein.

2. Glucose transport into cell to form glycerophosphate as a metabolic product which permits esterification of fatty acid.

3. Intracellular lipase is inhibited by insulin & inhibition of lipolysis of stored TG

Antidiabetic Drugs or Hypoglycemic Agents

A. Injectible hypoglycaemic drug:

Insulin preparations are:

a. Ultra short acting insulin, very rapid onset of action –

• Insulin lispro (duration of action 3-4hrs)
• Insulin Aspart
• Insulin glulisine

b. Short acting insulin, rapid onset action, Soluble insulin –

• Regular humulin (D/A 6-8 hrs)
• Regular novolin
• Velosulin BR
• Semilente insulin (prompt insulin zinc suspension) (D/A 12-14hrs)

c. Intermediate acting insulin (slower action) – Isophane insulin suspension (NPH- neutral protamine hydrogen) (D/A is 7-14 hrs), Lente insulin (insulin zinc suspension)

d. Long acting insulin (slower onset of action) –

• Insulin detemir
• Insulin glargine
• Protamine zinc insulin suspension (PZI) D/A is 24-36hrs
• Ultralente insulin (Extended insulin zinc suspension)

e. Premixed insulin (%NPH + % regular), Biphasic insulin -

• Humulin 70/30
• Novolin 70/30
• 50/50 NPL, Lispro
• 75/25 NPL, Lispro
• 70/30 NPA, Aspart

  

B. Oral hypoglycaemic drug:

I. Insulin secretagogues:

1. Sulfonylureas:

a. First generation-

·         Tolbutamide.                                           

·         Chlorpropamide.

·         Acetohexamide.                                      

·         Tolazamide.

b. Second generation-

·         Glyburide

·         Glibenclamide.                         

·         Glipizide.

·         Glimepiride

·         Gliclazide

2. Meglitinides:

• Repaglinides

3. Diphenylalanine derivative

• Nataglinide

II. Biguanide:

·         Phenformin.                                                             

·         Metformin.

·         Buformin.