Locally acting drugs are applied onto the skin and sometimes on mucous membranes, the benefits include:
Concentration of drug at site of application is high
Systemic absorption is negligible
Adverse effects are minimum as compared to systemic preparations.
Types of applications
Tinctures
Wet dressings
Lotions
Gels
Aerosols
Powders
Pastes
Creams
Ointments
Tinctures and wet dressings are usually applied over oozing lesions because of drying of lesions and in descending order these preparations are applied over dry thick skin to act as lubricant.
Names of groups
Demulcents
Emolients
Irritants/counter irritants
Antiseborrheics
Astringents
Ectoparasiticides
Anti-acne drugs
Anti-warts drugs
Anti-pigmentation drugs
Sunscreens
Drugs affecting hair growth
Antiseptics/disinfectants
A. Demulcents
Definition
Means to ‘smooth down’. These are protective agents applied over skin to treat irritation.
Examples:-
Gum acacia
Tragacanth
Glycyrrhiza
Synthetic cellulose
-Methyl cellulose
-Carboxy methyl cellulose
Glycerine
Starch
-Barley starch
-Wheat starch
B. Emolients
External protective which provide lubrication.
Examples:-
Animal fat
Vegetable oils:
– Olive oil
– Cotton seed oil
– Corn oil
– Peanut oil
– Theobroma oil
Paraffin
Vegetable oils may be applied over skin to fight dryness to prevent itching due to thick dry skin.
C. Astringents
These are locally applied protein precipitants i.e. when applied over skin, they cause precipitation of proteins present over surface but do not destroy cells. They just cause contraction of tissues and wrinkling of tissues. Females apply astringents over oily skin because of precipitation of superficial proteins, which is helpful especially during summer season.
Examples
Metallic salts
-ZnSO4
-Al subacetate
-ZnO
Vegetables
– Tannic acid
D. Counter Irritants
Those locally acting drugs used over skin cause feeling of hotness and burning so that they mask the pain.
Degrees:
They are of three types:
1.Rubefacients
2.Vesicants/blisters
3.Pustulants
Mechanism of Action
First degree:
When applied to the skin, there is rubfacient effect with feeling of heat, leading to dilation by axon reflex and paralysis of sensory receptors, which cause stimulation of cerebral centers of perception and consciousness by painful impression.
2nd degree:
Reddened area +inflammation
Plasma escapes from capillaries more rapidly but cannot escape through the stratum corneum with the result that epidermis is raised producing vesicles.
Third degree:
Diapedesis of leucocytes occurs and a crop of painful pustules around skin glands form
1. Camphor
2. Black mustard
3.Cantharides
4.Turpentine oil
5.Methyl cellulose
6.Iodine
7.Eucalyptous oil
These are not rubbed as effects appear which are unpleasant.
E. Sclerosing Agents
Agents used to obliterate varicose veins (dilated veins due to lack of valves).
Uses:
1.Obliterate varicose veins
2. Fibrosis of Haemorrhoids
Examples:
Morhuate Na
Na tetradecyle sulfate
Contraindications:
Acute thrombophlebitis
Valvular or deep venous incompetence
F.Caustics and Escharoitics
Topical agents which destroy upper thick layer of skin, and are thus not commonly used.
Examples:
1.Glacial acetic acid
2.Exzicated alum
3.Phenol
4.AgNO3
5.Trichloracetic acid
Uses:
Destroy warts (viral infection causing raised thick layer over skin)
Keratosis
Moles or Hyperplastic tissues
Fungal infections & Eczema
G. Keratolytics
Desquamating agents, can cause desquamation of dermis.
Characteristics:
Softening & removing horny layer of skin
Uses:
1. Fungal infections
2. Warts & Corns
3. Eczema & certain forms of acne
4. Psoriasis (white silvery spots over skin especially over extensor surfaces, knees, elbows, scalp due to rapid turn over of epidermis.
These agents are applied to reduce thickness.
Examples:
1. Benzoic acid
2. Salicylic acid
3. Resorcinol
4. Tar (applied to patients of psoriasis)
As damage to skin occurs, these are carefully applied to warts especially salicylic acid.
H. Anti-Perspirants and Deodrants
Agents used to decrease formation of sweat are called anti-perspirants
Agents used to decrease smell from areas where sweating occurs are called deodrants.
Agents:
1. Al Chlorohydrate
2. Al Cl3
3. Buffered AlSO4
4. Al Ziriconium
5. Al Formate
6. Methyl Benzethonium Cl
7. Neomycin SO4
Side Effects:
1.Contact dermatitis
2.Inactivated by Soaps
I. Anti Seborrheics
These locally applied drugs are used to decrease seborrheia.
Agents:
1. Quarternary NH4 surfactants
2. Chlorinated phenols
3. Salicylic acid
4. Sulphur
5. Zn pyrithione (Head & Shoulders)
6. Selenium sulphide ( Exsel, Selsun)
7. Tar
J. Ectoparasiticides
Present over skin e.g.
Hair lice (pediculus capitis)
Scabies(sarcoptes scabei) (lies over skin causes itching especially at bed time especially winters)
Lindane
Crotamiton
Sulfur
Permethrin
Malathion
K. Anti Acne Drugs
Management of acne
Topical preparations for acne
Oral antibiotics
Hormonal treatment
Retinoic acid &derivatives
Tretinoin
All-trans-retinoic acid
L. Melanizing Agents
In hypopigmentation caused by vertiligo, TRIOXSALEN is applied over skin but requires direct sunlight for action, patient is asked to sit in sun after applying cream over lesion. Oral preparations are also available, patient is asked to sit in sun after 2 hours of administration.
M. Anti Pigmentation Drugs
Commonly used especially in Melasina for very long time. These preparations contain:
1.Hydroxyquinones (reversible pigmentation)
2. Monobenzene (irreversible pigmentation)
Side Effects
Irritation of skin, patient is asked to apply small quantity gradually increasing strength.
Inactivated by exposure to light, applied before going to bed.
N. Sunscreens
Sunscreens – Absorb UV light.
Chemical compounds:
1.p-aminobenzoic acid
2.Benzophenones
3.Physical sunscreens
PF stands for production factor. Very fair people require up to 15 SPF, below this level are not effective.
Drug interactions may create alarming situations. In most cases, monotherapy is preferred but sometimes drugs need to be given in combination e.g. in treatment of congestive cardiac failure, diuretics and vasodilators need to be combined, or in patients suffering from malignancy, coma, chemotherapy or tuberculosis. The aim is to:
Reduce dose
Prevent the development of resistance
Definition
When pharmacological action of a drug is altered by concurrent administration of another drug.
The adverse drug interactions may be of great clinical importance when margin of safety of drugs is small.
Sometimes clinicians allow drug interactions to occur for better actions, but adverse reactions occur with drugs having low therapeutic index.
Types
1. In Vitro
2. In Vivo
Drugs interactions can occur outside the body, e.g.
1. Incompatibilities of drug in an IV infusion
2. Use of wrong vehicle for infusion:
a) no drug should be added to blood plasma, aminoacid solutions, fat emulsions, sodium bicarbonate solution, mannitol solution (mannitol may crystalize) and to heparin infusion.
b) Mannitol should not be mixed with electrolytes, KCl or other drugs
Highly acidic solution such as dextrose, or fructorse are unsuitable as vehicle for sodium and potassium salts of weakly acidic drugs. Such as sulfonamides, barbiturates, methicillin and novobiocin
Benzyl penicillin, ampicillin, heparin and aminophylline are unstable at the pH of these solutions.
Isotonic saline is slightly acidic or neutral and is suitable vehicle for most drug like phenytoin, diazepam
Most antibiotics become unstable and deteriorate in large volumes of fluids exceptions are amphotericin B and erythromycin.
Erythromycin lactobionate is unstable in electrolyte solution but may be diluted with 5% dextrose solutions
Amphotericin B should be diluted with 5% dextrose
Calcium salts should not be added to sodium bicarbonate
Incompatibilities in syringe
Soluble and protamine zinc insulin: soluble insulin interacts with excess of zinc and protamine and its onset of action may be delayed
Barbiturates,, phenytoin, phenothiazine, frusemide should not be mixed with any other drug in solution
Penicillin is incompatible with gentamicin, tetracycline and hydrocortisone
Tetracycline is incompatible with calcium salts
Heparin sodium is incompatible with gentamicin and hydrocortisone
Thiopentone sodium is incompatible with succinylcholine
In Vivo
Pharmacokinetic Drug Interactions
Differences in plasma levels of a drug achieved by a given dose of that drug.
Pharmacodynamic Drug Interactions
Differences in pharmacological effects produced by a given plasma level of a drug
Pharmacokinetic Drug Interactions
Drug absorption e.g. antacids
Interactions due to changes in protein binding of drugs – distribution (if highly protein bound, displace other drugs, free levels increase, leading to toxicity)
Interactions affecting drug metabolism
Interactions affecting renal excretion of drugs
Interactions Affecting Absorption
Parenteral administration
Drugs + Epinephrine
Drugs + Methacholine (vasodilator –effective drug levels not achieved)
Oral administration
Chelation / Adsorption
Tetracycline + Ca++
Cholestyramine (adsorption) + Cardiac Glycosides
Sucralfate adsorbs, cannot give other drugs
Altered Intestinal Motility
Atropine + Acetaminophen
Metoclopramide (prokinetic) + Cimetidine (anti ulcer) (increased gastric emptying, less drug absorbed)
Inhibition of Absorption
Phenytoin and oral contraceptives + Folic acid
Colchicine + Vit B12
P-glycoproteins in intestinal wall can influence absorption, present in different cells of body, some drugs may be expelled out.
Influence of Diet
Food in Stomach
Fatty Meal
Griseofulvin has increased absorption with fally meal -EXCEPTION
pH Dependent Absorption
Weak acidic drugs e.g. NSAIDS
Weak basic drugs
Interactions Affecting Distribution
Competition for Plasma Protein Binding
Sulfisoxazole and Bilirubin (may lead to kernicterus)
Displacement from Tissue Binding Sites
Phenylbutazone and Warfarin (displace, also at level of metabolism, thus vitamin K dependent factors are impaired)
Methotrexate + Aspirin (efficacy decreased, PG inhibition, increased levels of methotrexate) so aspirin is stopped before treatment otherwise may cause methotrexate toxicity
Chemical Messenger having a wide range of cellular responses, causing allergies, inflammatory reactions, increased gastric acid secretion, acting as a neurotransmitter in brain
Synthesized from HISTADINE through decarboxylation.
Stored in mast cells
Released in response to various stimuli like after insect bites, can be released in response to bees sting, and in anaphylactic reaction.
Histamine Receptor Subtypes
H1 – Most abundant, present in:
Smooth muscles, responsible for smooth muscle contraction
Endothelium, vasodilatation of blood vessels
Brain neurotransmitters
Act through hydrolysis of inositol triphosphate diacyl glycerol second messenger system.H1 receptors are present on post synaptic neurons.
H2
Gastric mucosa, increase gastric acid secretion
Cardiac muscle, produce hypotension, producing reflex tachycardia
Mast cells,
Brain
H2 receptors act through stimulation of cAMP 2nd messenger system. H2 receptors are also present on post synaptic neurons.
H3 and H4 are present pre-synaptically.
H3 – Presynaptic: brain, myenteric plexus, other neurons
Act through inhibition of cAMP
H4 – Eosinophils, neutrophils, CD4 T cells
Play a role in allergies.
Antihistamines
By antihistamines we mainly refer to H1 blockers. H2 blockers are called the drugs which decrease gastric acid secretion.
Classification of Antihistamines
Antihistamines are broadly divided into two groups:
1st generation antihistamines
2nd generation antihistamines
Drugs having hysteric signs are included in 2nd generation,, rest are in 1st generation.
Ethanolamines
Carbinoxamine maleate
Clemastine fumarate
Dimenhydrinate
Diphenhydramine HCl
Ethylaminediamine
Tripelennamine HCl
Pyrilamine Maleate
Antazoline
Piperazine Derivatives
Hydroxyzine HCl
Cyclizine HCl
Meclizine HCl
Cetrizine*
Alkylamines
Brompheniramine maleate
Chlorpheniramine maleate
Pheniramine
Acrivastine*
Phenothiazine
Promethazine HCl
Piperidine
Fexofenadine*
Levocabastine*
Loratidine*
Miscellaneous
Cyproheptadine
Pheniramine
Structure of antihistamines
Structure resembles that of histamine.
Have ethylamine or carbon chain
Linked with Tertiary amine group through glycosidic bond.
Block vasodilatation in endothelial smooth muscles. However, they are not effective in preventing bronchoconstriction because there are leukotrines and platelet activating factors involved.
Capillary Permeability
Prevent capillary permeability, thus effective in preventing edema.
Triple response
Antihistamines are effective in preventing triple response seen after intradermal injection of histamine, in which there is redness due to dilatation of small vessels and there is veil formation i.e. edema.
Flare is the redness around wheel. Antihistamines are effective in preventing all components of triple response.
Exocrine glands
Decrease secretions of endocrine glands, including lacrimal gland, but not effective in decreasing gastric secretions.
Allergy
Prevent triple response, but not effective in preventing bronchoconstriction and hypotension.
Anticholinergic Effects
Most of 1st generation antihistamines are capable of antagonizing muscarinic receptors, having anticholinergic effects including
blurring of vision,
dilatation of pupils,
urinary retention,
constipation and
tachycardia.
Among 1st generation antihistamines, Promethazine has strongest anticholinergic activity and Mepyramine has least anticholinergic activity.
Motion Sickness
Vestibular apparatus has M1 and H1 receptors, so antihistamines and anticholinergics are effective in motion sickness.
Drugs used are Diphenhydramine and Dimenhydrinate.
1st generation antihistmaines having anticholinergic activity are effective in motion sickness.
Local Anesthetic Effect
1st generation antihistamines possess local anesthetic effect in higher doses. They can block sodium channels and this local anesthetic effect is equal to procaine and lignocaine.
Mostly seen with Promethazine and Diphenhydramine.
Serotonin blocking effect
1st generation antihistamines have ability to antagonize serotonin receptors e.g. Cyproheptadine.
Appetite stimulant effect
Because of blockage of serotonin receptors, Cyproheptadine has appetite stimulant effect.
Central Nervous System
1st generation antihistamines cross BBB and produce CNS depressant effect,
Sedation
Drowsiness
Dizziness
Fatigue
Almost all 1st generation antihistamines produce CNS depression except Fenandamine which produces CNS stimulation. 2nd generation antihistamines do not cross BBB.
Pharmacokinetics
Routes of Administration
Usually given through oral route and parenteral route. Topical preparations are available in form of nasal drops, eye drops. Levocabastine can be given topically.
Peak plasma concentration
Usually in 1-2 hours.
Duration of action
1st generation up to 6 hours
2nd generation up to 24 hours
However, Astimazole has more than 24 hours.
Distribution
1st generation antihistamines are widely distributed as are lipid soluble. 2nd generation have far less distribution.
Metabolism
Antihistamines are metabolized by CYT P450. Most are metabolized by cyt CA4.
Excretion-as metabolites
As a result converted into metabolites, e.g. Loratidine is converted into Desloratidine, Hydroxyzine is converted into Cytrazine and Terphendadrine is converted into Fexophendaine.
Mostly excreted in urine in form of metabolites. However, Cytrazine and Acrevestine are excreted as such. Sexophenadine is eliminated in feces.
Therapeutic Uses
Allergy
All kinds of allergies,
acute allergies,
acute rhinitis
acute conjunctivitis
chronic allergies
chronic urticarial
drug induced allergies
contact dermatitis
insect bites
serum sickness
Common Cold
Provide symptomatic release and decrease secretions.
Anti Emetic Effect
Pregnancy induced vomiting
Radiation induced vomiting
Cancer chemotherapy induced nausea, vomiting
Motion sickness
Diphenhydramine and Dimenhydrinate are used.
Meniere’s disease
Idiopathic disease of inner ear, affecting hearing and balance.
Promethazine and Dimenhydrinate are used.
Parkinsonism
Antihistamines effect rigidity and tremors and decreases cholinergic activity. Drugs used are Orphenadrine and Diphenhydramine.
Sedative, Hypnotic, Anxiolytic, Pre anesthetic medication
Can be used for sedation, hypnosis, anxiolytic effect. Can be given as pre anesthetic medication. Mostly Promethazine and Diphenhydramine are used.
Appetite Stimulant
Block serotonin receptors, having appetite stimulant effect (Cyproheptadine)
Carcinoid Syndrome
Cyproheptadine is used having serotonin blocking effect.
There is group of symptoms secondary to carcinoid tumor, flushing, diarrhea, bronchoconstriction.
Adverse Effects
Central Nervous System
1st generation antihistamines cross BBB and produce CNS depression except Phenadrine which produces CNS stimulation. 2nd generation do not cross BBB being devoid of CNS effects.
Gastrointestinal Tract
Can produce abdominal discomfort
Can alter bowel habits
Anorexia
Cycloheptidine has appetite stimulant effect.
Cardiovascular Effects
Two drugs Astamizole and Terphenadrine prolong QT interval, can produce ventricular arrhythmias. These drugs should not be given to individuals taking enzyme inhibitors.
Anticholinergic effects
1st generation antihistamines can enter cholinergic receptors, producing anti cholinergic effects:
Dilatation of pupil
Dryness of mouth
Urinary retention
constipation
Allergy
Topical preparations can produce allergic manifestations:
Dermatitis
Articaria
Rash
Hematological Complications
Can produce:
Hemolytic anemia
leukopenia
Teratogenic
With Piperazine derivatives, teratogenic effects are seen in experimental animals (not in humans).
Mutagenicity
Some antihistamines have been found to be mutagenic, can induce fibrosarcomas and melanomas in experimental animals.
Drug Interactions
Sedative Hypnotics
Can potentiate the effects
Alcohol
Can potentiate the effects
MAO Inhibitors
MAO inhibitors can enhance anticholinergic effects of antihistamines
Ketoconazole, Itraconazole, Erythromycin
These are enzyme inhibitors, when these are combined, metabolism of antihistamines is reduced.
Astamizole and Terphenaline cardiac effects are enhanced.
Grape fruit juice
Enzyme inhibitor.
Slight over dosage
With slight overdosage, there is sedation.
High Doses
In higher doses, CNS stimulation and anticholinergic effects are enhanced.
1st generation
2nd generation
Name of drug
Chemical properties
Aromatic groups and ethylamine group
Aromatic group
Mechanism of action
Competitive antagonism of H1
Non competitive antagonism
Pharmacological actions
Can cross BBB causing CNS depression(except Pheniramine)
Cannot cross BBB so no CNS effects
PharmacokineticsDistributionMetabolism
Lipid soluble so distributed in all compartmentsNo active metabolite
Less lipid soluble so cannot enter CNS, CSFMostly converted to active metabolite e.g.Terfenadrine à FenofexadineLoratidine à Desloratidine
Local Anesthetic/Membrane Stabilizing Activity
Local anesthetic having effect like procaine and lidocaine
No effect
Adrenoceptor blockage
Alpha 1 blockage
None
Duration of action
Short (4-6 hours) except Meclizine 12-24 hours
Long 12-24 hours except Estemizole more than 24 hours.
Asthma is most common respiratory tract infection. It is the reversible obstruction of large and small airways.
Pathophysiology
Bronchial asthma is characterized by hyperresponsiveness of tracheo-bronchial smooth muscle to a variety of stimuli, resulting in narrowing of air tubes, often accompanied by increased secretions, mucosal edema and mucus plugging.
Inflammation
Hyper reactivity
Bronchospasm
Bronchial hyper reactivity results in inflammation of bronchial wall because of increased leakiness from micro circulation, leading to edema of bronchial wall.
Because of leakage, there is plugging of bronchi with thick mucous, symptoms include wheezing breathlessness.
Parasympathetic innervation is present in fibers of walls of bronchi, when inflammation occurs, increased parasympathetic tone due to release of acetylcholine leads to bronchospasm.
Vascular smooth muscle has sympathetic innervation. Increased pulmonary blood flow occurs because of vasodilatation, ultimately leading to bronchodilatation.
Hyper reactivity is due to release of chemical mediators.
Mediators are also released from certain cells, storage granules, besides certain other cells are recruited including eosinophils, neutrophils, monocytes, which themselves release mediators contributing to inflammatory response.
The strategy these days is to address inflammation.
Phases
2 phases are present:
Immediate –release of histamine leading to antigen-antibody reaction on surface of mast cells
Late
IgE antibodies are synthesized within mast cells in lungs. Antigen interacts with IgE on mast cells leading to release of mediators.
IL 4 and IL 13 are mainly responsible for bronchoconstriction and bronchospasm.
Mast cells release platelet activating factors, responsible for late phase eosinophilia.
For control of asthma, antihistamines are least beneficial especially exercise induced and allergic asthma and should be avoided. Normally leukotriene antagonists are given because:
Leukotrines are contributing more in process
Antihistamines cause more dryness
Bronchial inflammation differs because here hyper reactivity is the main problem.
Main goal is to treat underlying inflammation by use of anti inflammatory drugs.
Types of Bronchial Asthma
1. Extrinsic Asthma: (allergic)
It is mostly episodic, less prone to status asthmaticus
Atopic (immediate due to IgE antibody).
Nonatopic delayed for some hours, associated with production of precipitating antibodies
2. Intrinsic Asthma
It tends to be perennial, status asthmaticus is more common. Associated with COPD.
Classification
2 groups are present:
Bronchodilators/relievers –address acute phase
Anti inflammatory/controllers –address undelying
Bronchodilators
Sympathomimetics:
Salbutamol, Albuterol
Terbutaline,
Bambuterol,
Salmeterol,
Formoterol.
b. Methylxanthines:
Theophylline (anhydrous) (oral preparation with erratic solubility)
Aminophylline
500 mg diluted in 5% dextrose is given I/V very slowly, as can cause tachycardia, arrhythmias, having less therapeutic index.
Preferentially directly into airways by inhalation.
Onset of action via inhalational route is 1-5 minutes. Action is for 2-6 hours.
Oral administration is not preferred for bronchodilation although having prolonged action, up to 8 hours. Also
Systemic side effects are produced
Metabolic side effects
Although some absorption occurs through inhalational route as well, but there is not much toxicity. Beta2 drugs given in syrup form in children under 5 or elderly chronic asthmatics with symptoms aggravating. Can be given orally. Albuterol syrup
Mechanism of Action
1. Beta-2 adrenoceptor agonist, when administered binds beta 2 receptors
Stimulation of adenylate cyclase
Increase cAMP
Bronchodilation and decreased muscular tone
2. Increase potassium conductance leading to hyperpolarization and relaxation of bronchial muscle cells.
Terbutaline subcutaneous preparation is available. Usually beta 2 agonists are preferred in dyspnea with bronchoconstriction, providing symptomatic relief.
Short term drugs have quick onset of action. Salmetrol reduces possible bronchodilation for 12 hours.
3. Inhibit release of chemical mediators from mast cells, lymphocytes which have beta 2 receptors in different cells in lungs àincrease cellular cyclic AMP contributing to inflammation by preventing release of cytokines.
4. Mucociliary action -Increase mucus clearance by an action on cilia
Chronic treatment decreases receptor sensitization and decreases action of drug. Effective in young asthmatics, but desensitization is not observed in beta 2 receptors present on bronchial smooth muslces (resistant). Desensitization is cell specific.
Beta 2 receptors on mast cells are desensitized.
COPD (less benefit due to toxicity)
Salmetrol also has anti inflammatory action. It acts on eosinophils. As controller Salmetrol can be added to corticosteroids, dose of which is decreased when combined.
There is risk of side effects due to genetic variations in beta 2 receptors. Patients homozygous for arginine genotype especially African-Americans. Salbutamol, Salmetrol have greater risks, affecting transcription, increasing the mortality rate.
Methylxanthine
Aminophylline, Theophylline
Theophylline is least expensive, very old drug and effective.
It is ethylated xanthine (dioxy purine) structurally related to uric acid.
Solubility of methyl xanthine is low and is enhanced by formation of complex with ethylene diamine in 1:1
Theophylline + Ethylene diamine = Aminophylline
Mechanism of Action
1. Inhibit Phosphodiestrase Enzyme (which catalyzes breakdown of cAMP). Many isoenzymes are present but isoenzyme III and IV are most effective.
Increase cAMP
Dephosphorylation of MLC
Bronchodilation
2. Translocation of intracellular calcium
Increased intracellular calcium lead to increased diaphragmatic contractility
3. Blockade of adenosine receptors
Decrease contractility of bronchiolar smooth muscles
Uses
Drug is slowly given over 20-40 minutes, otherwise death occurs due to cardiac arrhythmias.
Acute asthma- I/V (slowly)
Chronic asthma (prophylaxis) Oral
Treatment of apnea of preterm infants as metabolized in liver and:
Converted in caffeine behaving as stimulant, which is exploited in treatment
Volume of distribution is very large
2nd line drug in bronchodilation, having narrow therapeutic window.
Adverse effects
Dose has to be maintained between 5-20 mcg/l, if it crosses 20 mcg/l severe CNS toxicity and convulsions occur.
After 15 mcg/l GIT symptoms including pericardial pain occurs
Tachycardia, palpitations
Drug monitoring is mandatory, given only in facilities having monitoring facilities.
Still theophylline is preferred in children over corticosteroids as growth retardation occurs by corticosteroids.
Sustained release preparations including 8 hourly, 12 hourly and 24 hourly preparations maintaining plasma levels for peak symptoms.
Pharmacokinetics
Absorbed readily after oral administration, per rectal suppository has erratic absorption.
Peak plasma concentration is achieved within 2 hours
Volume of distribution is 0.4-0.6 l/kg, important fact is that infants have much larger Vd than adults.
In viral infections there are chances of toxicity as clearance is decreased.
Antibiotics, macrolides and cimetidine are not given with methyl xanthine as clearance is decreased
With Anti T.B drug rifampicin clearance of methyl xanthine is increased.
Anticholinergics
Ipratropium
Oxytropium
Tiotropium
Selective in action, atropine is very potent but not selective so not used because of toxicity.
Mechanism of Action
Blockade of muscarinic receptors present in bronchi and bronchioles
Decrease mucus viscosity
Increase mucociliary clearance
In therapeutic doses, does not overcome bronchoconstriction as non muscarinic in nature.
Given as aerosol inhalation.
In lungs relieves bronchospasm.
Duration of action is up to 5 hours.
Minimal systemic effects as poorly absorbed from lungs.
Uses
Chronic asthma/prophylaxis (Inhalation) (More effective & less toxicity)
Limited role in asthma, main role is to decrease bronchoconstriction in bronchitis caused by stimulation of muscarinic receptors. Antibiotics are given for secondary infections.
Mainly for COPD.
Adverse effects
Dry mouth –since not as effective given in combination with beta 2 agonists and corticosteroids, when not controlled by beta agonists alone.
Leukotriene Receptor Antagonists
Montelukast – oral
Zafirlukast – (Cingular) oral administration for control of asthma
Leukotrines are products of arachidonic acid metabolism. They are released at the site of inflammation producing bronchoconstriction having contributory effect to inflammation and bronchoconstriction.
Mechanism of Action
Montelukast and Zafirlukast are competitive antagonists.
Inhibits cysteinlyl leukotriene Cys LT1 receptor relieving bronchospasm and bronchoconstriction.
Inhibit physiologic actions of LTC4, LTD4, LTE4
One drug blocks synthesis of 5 lipooxygenase and is hepatotoxic Zileuton. Half like is 2.5 hours
When Montelukast is administered, it binds cysteine leukotriene 1 receptor
Montelukast is 60-70% metabolized, having plasma life about 3-6 hours.
Side effects
Rare.
Inflammation at site in lungs
Rarely hypersensitivity reaction
Patients already treated with glucocorticoids have decreased dose.
Chraug Stauss Syndrome
This is not due to drug but due to pre existing underlying disease, eosinophilia and vasculitis is seen.
Drug Interactions
Zafirleukast has drug interaction with warfarin sodium, leading to increased prothrombin time, thus dose has to be monitored.
Increase in theophylline levels, which is itself bronchodilator
Monteleukast is commonly used.
Mast Cell Stabilizers
Na chromoglycate inhalation
Nedocromil
Ketotifen- (5HT action) oral
Nedocromil and Ketotifen are not bronchodilators, not having direct effect. They are ineffective once antigen antibody reaction takes place.
Mechanism of Action
Inhibit transmembrance influx of Ca provoked by antigen antibody interaction on the surface of mast cells. this is prophylactic use and have to be given before antigen enters.
Stabilize mast cells membrane and inhibit release of chemical mediators
Depress exaggerated neuronal reflexes triggered by stimulation of irritant receptors
Depress axonal reflexes which release inflammatory neuropeptides.
Inhibit release of cytokines from T-CELLS
Only 5% sodium chromoglycate reaches lungs, rest get accumulated leading to irritation.
Allergic conjunctivitis –nasal sprays, eye drops
Uses
Prophylaxis of allergic exercise, irritant induced asthma.
Adjuvant therapy, dose limited.
Now limited role due to leukotrines, was drug of choice in children.
Corticosteroids
Hydrocortisone I/V
Prednisolone oral
Betamethosone
Beclomethasone inhalation
Budesonide
Flucitasone having affinity for glucocorticoids receptors in airways
Mechanism of Action
Anti inflammatory action
Decrease mucosal oedema, mucus secretion and reduce capillary permeability
Antagonise histaminergic and cholinergic responses
Enhance beta-2 adrenoceptor responsiveness to agonists (Catecholamines)
Effects appear after 1 week, and it takes nearly 10 weeks for control of disease.
Beneficial effects are observed with inhalted 500 mcg.
Maximum therapeutic range is 500 mcg/ml.
Toxicity
Systemic toxicity occurs when steroid is inhaled, more than 1500 mcg.
Even with 500 mcg dose there are chances are
Osteoporosis
Dysphonia
Oropharyngeal candidiasis
Uses and Routes of Administration
Bronchodilator is given immediately because:
It takes about 1 week for effects to appear.
Due to constriction, drug cannot reach lungs so bronchodilator is given
a. Acute severe asthma (status asthmaticus)
Hydrocortisone I/V
b. Acute asthma – oral
Prednisolone
c. Chronic asthma –(Prophylaxis) Inhalation
Beclomethasone etc
Ciclesonide
Prodrug, when absorbed drug is acted upon by esterases in bronchial epithelial cells, less amount of drug absorbed gets bound to glucocorticoid receptors, bones, skin, eyes, and there are less chances of osteoporosis and cutaneous thinning.
It has some role in people predisposed to cataract and osteoporosis.
Status Asthmaticus
Status asthmaticus is an acute exacerbation of asthma that remains unresponsive to initial treatment with bronchodilators.
It is a life threatening form of asthma, because it can lead to respiratory failure and cardiac arrest.
Status Asthmaticus requires immediate treatment (corticosteroids are essential as immediate treatment)
Air trapping strains on breathing muscle which are fatigue and exhausted
Status asthmaticus is frequently associated with metabolic acidosis, and acidosis reduces the effectiveness of beta agonist.
I/V NaHCo3 added if pH is below 7.5 in patient with refractory status asthmaticus, but there is risk of hypercapnia, in children.
decrease in PCO2 level corrected with nasal/Face mask oxygen (Helium)
Continuous nebulization of albuterol for the first few hrs
Switched to intermittent albuterol very 02 hrs. I/V
corticosteroids, inhaled ipratropium every 06 hrs
Treatment of last resort used in status asthmaticus include:-
Providing G.A with inhaled anaesthetic which are potent bronchodilators.
I/V ketamine, is also helpful.
However help of an anesthesiologist is required.
CAN STATUS ASTHMATICUS BE PREVENTED?
The best way to decrease the possibility of having a severe attack is to take medication regularly as prescribed:-
Never to stop taking inhaled steroids
Leukotriene modifiers / “Controller” unless instructed to do so
Monoclonal Antibodies
Can be given to patients having severe forms of disease.
They bind to IgE antibodies present on mast cells. If administered I/V or subcutaneously, humanized monoclonal antibodies decrease levels of IgE antibodies, decreasing tendency of severe asthma, in both phases (immediate/delayed).
Also improve nasal/conjunctival symptoms, allergic manifestations. These are reserved for severe cases, if want to reduce dose of corticosteroids as there are undetectable levels of IgE antibodies in plasma and no antigen antibody reaction occurs.
Severe throbbing pain in eye along with blurring of vision.
Dilated pupil not responding to light
Cornea discoloured or steamy.
Redness of eye.
May be accompanied by abdominal discomfort, nausea, vomiting
Diagnosis
Made on basis of symptoms and tonometry.
Treatment
Definitive treatment is surgery or laser iridotomy.
Vigorous medical therapy is employed to decrease intraocular pressure.
Drugs used are:
Acetazolamide 500 mg I/V followed by 250 mg.
Mannitol I/V à decongests eye, once I/V given
Pilocarpine, drug is instilled after every 10 minutes for 1st one hour, then 4 times daily.
Topical beta blockers like Timolol are instilled after every 12 hours.
Apraclonidine
Latanoprost
PGF2 alpha analog
Once intraocular is decreased then surgery or laser iridotomy is done, hole is made in iris which facilitates flow of aqueous humor.
Open Angle Glaucoma
More common/dangerous than closed angle because of no signs/symptoms usually.
Reason
Due to changes in trabecular meshwork that occurs with advancing age
Genetic Predisposition
Genetically predisposed condition due to mutations in myocilin, genes are present on chromosome 1, which encodes myocilin glycoproteins present in meshwork.
Optic nerve/optic disc damage, increase in cup disc ratio, if more than .2-.3 then suspicion of glaucoma is made.
Signs/symptoms
Usually no complains of hallows around light, central vision remains intact till last and there is loss of peripheral vision.
Diagnosis
Made on visual field examinations, on tonometry and optic disc examination.
Drug Treatment of Glaucoma
Beta-adrenergic Antagonists
Are one of the 1st line drugs. However, nowadays, PGF2 alpha analogs have replaced them.
Beta-1 nonselective
Timolol maleate (0.25, 0.5%) bid
Timolol Hemihydrates (5-12 mg/ml) bid
Levobunolol HCL (0.25, 0.5%) bid
Metopranolol (0.3%) bid
Carteolol HCL (1.0%) bid
Beta-1 selective
Betaxolol HCL (0.25, 0.5%) bid
Mechanism of Action
These block beta receptors in ciliary epithelium and decrease aqueous humor production by inhibiting adenylyl cyclase, so decrease intraocular pressure.
Have secondary effect, i.e. decrease intra ocular blood flow.
Advantages
There are a few advantages over meiotics:
No change in pupil size
No headache or pain
No fluctuations in IOP
Convenient to be used, given once daily or twice daily.
Disadvantages
Ocular
Dryness
Redness of eye
Blurring of vision
Corneal hypo esthesia
Allergic blepharoconjunctivitis
Systemic
Systemic effects occur when beta blockers act through nasolacrimal duct.
Severe bronchospasm in asthmatics
Bradycardia
Enhancement of heart blocks
Congestive heart failure
Adrenergic agonists
Nonselective adrenergic agonists
Epinephrine (0.25,0.5,1.0,2.0%) bid
Epinephrine HCL (1.0,2.0%) bid
Epinephryl borate (0.5, 1.0,2.0%) bid
Epinephrine bitartrate (2.0%) bid
Dipivefrin (0.1%)
Alpha2– selective adrenergic agonist
Apraclonidine HCL (1.0%) (0.5%) pre and post laser tid
Brimonidine tartrate (0.2%)
Brimonidine has selective actions on alpha 2 receptors than apraclonidine, has lesser adverse effects than apraclonidine.
Mechanism of Action
Initially produce vasoconstriction and decrease aqueous humor production,
later on also increase outflow of aqueous humor
Dipivefrin is prodrug, activated while it transverses the cornea, has less systemic effects than epinephrine.
Cause opening and re-alignment of trabecular meshwork
Facilitate drainage of aqueous humor
Adverse effects
Contact allergy is possible to pilocarpine. Since produce meiosis, interfere with visual acuity and should not be given for longer time since Echothiophate produces cataract formation if given for prolonged period because of degradation of proteins.
Prostaglandins
Latanoprost (0.005%) bid
Bimatoprost
Travoprost
Mechanism of Action
Increase uveoscleral outflow of aqueous humor, exact mechanism is not known.
Said to be due to relaxation of ciliary muscles as well as remodeling of elements of ciliary muscles.
Side effects
Thickening and darkening of eye lashes
Darkening of iris
Redness of eyelids
Redness of eyes
Blurring of vision
Macular edema
Carbonic Anhydrase Inhibitors
Systemic
Acetazolamide (125, 250 mg) bid to qid (500mg)
Acetazolamide (500 mg) 6-8 hr
Parenteral
Dichlorphenamide (50mg) bid, tid
Methazolamide (25, 50 mg) bid, tid
Topical
Dorzolamide (2.0%) tid
Brinzolamide (1.0%) tid
In health it is production of bicarbonates that drain sodium and then water follows by osmosis.
These carbonic anhydrase inhibitors inhibit production of bicarbonate inhibiting aqueous humor production.
Side effects
Systemic effects are common with drugs used parentally.
Dorzolamide has more topical adverse effects than Brinzolamide.
Anorexia
Hypokalemia
Metabolic acidosis
Renal stone formations
Lethargy
paresthesias
Hyperosmotic agents
Mannitol parenteral (5-25% solution) 2g/kg
Mechanism of Action
Osmotic agents are inert in humans. They increase blood plasma osmolarity and in this way drain water from eyes into plasma and decrease vitreous volume and intraocular pressure.
