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 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
Drugs affecting hair growth
Means to ‘smooth down’. These are protective agents applied over skin to treat irritation.
-Carboxy methyl cellulose
External protective which provide lubrication.
– Olive oil
– Cotton seed oil
– Corn oil
– Peanut oil
– Theobroma oil
Vegetable oils may be applied over skin to fight dryness to prevent itching due to thick dry skin.
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.
– Tannic acid
D. Counter Irritants
Those locally acting drugs used over skin cause feeling of hotness and burning so that they mask the pain.
They are of three types:
Mechanism of Action
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.
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.
Diapedesis of leucocytes occurs and a crop of painful pustules around skin glands form
2. Black mustard
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).
1.Obliterate varicose veins
2. Fibrosis of Haemorrhoids
Na tetradecyle sulfate
Valvular or deep venous incompetence
F.Caustics and Escharoitics
Topical agents which destroy upper thick layer of skin, and are thus not commonly used.
1.Glacial acetic acid
Destroy warts (viral infection causing raised thick layer over skin)
Moles or Hyperplastic tissues
Fungal infections & Eczema
Desquamating agents, can cause desquamation of dermis.
Softening & removing horny layer of skin
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.
1. Benzoic acid
2. Salicylic acid
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.
1. Al Chlorohydrate
2. Al Cl3
3. Buffered AlSO4
4. Al Ziriconium
5. Al Formate
6. Methyl Benzethonium Cl
7. Neomycin SO4
2.Inactivated by Soaps
I. Anti Seborrheics
These locally applied drugs are used to decrease seborrheia.
1. Quarternary NH4 surfactants
2. Chlorinated phenols
3. Salicylic acid
5. Zn pyrithione (Head & Shoulders)
6. Selenium sulphide ( Exsel, Selsun)
Present over skin e.g.
Hair lice (pediculus capitis)
Scabies(sarcoptes scabei) (lies over skin causes itching especially at bed time especially winters)
K. Anti Acne Drugs
Management of acne
Topical preparations for acne
Retinoic acid &derivatives
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)
Irritation of skin, patient is asked to apply small quantity gradually increasing strength.
Inactivated by exposure to light, applied before going to bed.
Sunscreens – Absorb UV light.
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:
Prevent the development of resistance
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.
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
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
Drugs + Epinephrine
Drugs + Methacholine (vasodilator –effective drug levels not achieved)
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
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
Block vasodilatation in endothelial smooth muscles. However, they are not effective in preventing bronchoconstriction because there are leukotrines and platelet activating factors involved.
Prevent capillary permeability, thus effective in preventing edema.
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.
Decrease secretions of endocrine glands, including lacrimal gland, but not effective in decreasing gastric secretions.
Prevent triple response, but not effective in preventing bronchoconstriction and hypotension.
Most of 1st generation antihistamines are capable of antagonizing muscarinic receptors, having anticholinergic effects including
blurring of vision,
dilatation of pupils,
Among 1st generation antihistamines, Promethazine has strongest anticholinergic activity and Mepyramine has least anticholinergic activity.
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.
Asthma is most common respiratory tract infection. It is the reversible obstruction of large and small airways.
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.
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.
2 phases are present:
Immediate –release of histamine leading to antigen-antibody reaction on surface of mast cells
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.
2 groups are present:
Bronchodilators/relievers –address acute phase
Anti inflammatory/controllers –address undelying
Theophylline (anhydrous) (oral preparation with erratic solubility)
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
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.
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.
Dephosphorylation of MLC
2. Translocation of intracellular calcium
Increased intracellular calcium lead to increased diaphragmatic contractility
3. Blockade of adenosine receptors
Decrease contractility of bronchiolar smooth muscles
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.
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
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.
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.
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.
Systemic toxicity occurs when steroid is inhaled, more than 1500 mcg.
Even with 500 mcg dose there are chances are
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)
b. Acute asthma – oral
c. Chronic asthma –(Prophylaxis) Inhalation
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 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
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.
Cause opening and re-alignment of trabecular meshwork
Facilitate drainage of aqueous humor
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.
Latanoprost (0.005%) bid
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.
Thickening and darkening of eye lashes
Darkening of iris
Redness of eyelids
Redness of eyes
Blurring of vision
Carbonic Anhydrase Inhibitors
Acetazolamide (125, 250 mg) bid to qid (500mg)
Acetazolamide (500 mg) 6-8 hr
Dichlorphenamide (50mg) bid, tid
Methazolamide (25, 50 mg) bid, tid
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.
Systemic effects are common with drugs used parentally.
Dorzolamide has more topical adverse effects than Brinzolamide.
Renal stone formations
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.