1. PHARMACOLOGY
It is the study of interaction of drug with biological system. The pharmacology is broadly defined as the knowledge of the history, source, physical and chemical properties, compounding, biochemical and physiological effects, mechanism of action, absorption, distribution, biotransformation, elimination, therapeutics and other uses of drugs.
2. CLASSIFICATION OF PHARMACOLOGY
2.1. PHARMACOKINETICS
It is simply defined as “what the body does to the drug” i.e. absorption distribution, localization, biotransformation and elimination of drug.
2.2. PHARMACODYNAMICS
- Simply it is defined as “what the drug does to the body” i.e. the biochemical and
physiological effects of drugs and their mechanism of action on the body.
- It is the study how drugs alter the functions of living cells.
2.3. PHARMACY
It is the art of preparing, compounding and dispensing drug in a form which is suitable for human use.
2.4. PHARMACOTHERAPEUTICS
It is the knowledge concerned with the application of drugs for the treatment of diseases.
2.5. TOXICOLOGY
It is that branch of pharmacology that deals with adverse effects of drugs.
2.6. DRUGS
A drug can be defined as a chemical substance which shows biological activities.
2.7. PRODRUG
Prodrug is a precursor of drug. It is a compound that must undergo chemical conversion by metabolic processes to become an active pharmacological agent.
3. PHARMACOKONETICS
3.1. ROUTES OF ADMINISTRATION
There are 4 main routes of drug administration.
3.1.1. Enteral (involving gastrointestinal tract)
• Oral
• Sublingual
• Rectal.
3.1.2. Parenteral
• I/M ( intramuscular )
• I/V ( intravenous )
• S/C ( subcutaneous )
• Intrathecal
• Intraperitoneal
• Intracardial
• Intra-arterial
3.1.3. Topical
• Skin
• Mucous membrane
3.1.4. Pulmonary or inhalation
4. ENTERAL
4.1. ORAL ROUTE
4.1.1. Merits
- Easy administration.
- Cheapest and economical.
- Irritant drug which cannot be given by parenteral route can be given through it.
- Provides largest surface area for absorption.
- Larger quantity of drug can be given.
- Suitable for producing local action on GIT e.g. antacid.
4.1.2. Demerits
- Cannot be used in patient with emergency.
- Cannot be used in unconscious.
- Absorption may not be proper.
- Drugs which are poorly lipid soluble are not absorbed e.g. neostigmine.
- Drugs that are destroyed in GIT cannot be used e.g. insulin.
- Drugs undergo in enterophepatic circulation and some or major portion is metabolized by the liver, therefore amount of drug entering into the circulation (called bioavailability) is low.
- Any pathological condition in GIT can interfere with absorption e.g. peptic ulcer.
4.2. SUBLINGUAL ROUTE
4.2.1. Merits
- Drugs do not go in entero-hepatic circulation.
- Maximum therapeutic concentration can be achieved rapidly. Therefore, in emergency this route is used e.g. nitroglycerin is given sublingually in angina attacks.
4.2.2. Demerits
- Large doses cannot be given.
- Repeatedly use damages the oral mucosa.
4.3. RECTAL ROUTE
4.3.1. Merits
- Highly irritant drugs can be given by this route.
- Less entero-hepatic metabolism (about 50% drugs will bypass the liver).
- Can be used in unconscious patient or in vomiting.
4.3.2. Demerits
Absorption is incomplete and irregular. Cannot be used frequently.
5. PARENTERAL ROUTES
5.1. INTRAVENOUS ROUTE
5.1.1. Merits
- Drug enters directly into blood so it is rout of emergency.
- Max. therapeutic concentration can be achieved rapidly.
- Highly irritant drugs which cannot be given by mouth can be given through it but requires dilution.
- Larger doses can be given.
- Bioavailability is 100%.
5.1.2. Demerits
- Drug once administered can’t be recovered back.
- Highly irritant drugs can produce thrombophlebitis.
- Defective technique can lead to pain and inflammation.
- Requires lot of skill.
- There is increased risk of side effects.
- Not suitable for oily solutions and insoluble substances.
5.2. INTRAMUSCULAR ROUTE
5.2.1. Merits
- It is easier for administration than l/V.
- Absorption is quicker than subcutaneous route.
- Suitable for moderate volumes and oily drugs.
5.2.2. Demerits
- Highly irritant drugs cannot be given.
- Insoluble drugs cannot be given because they are not absorbed.
- Defective technique can result in damage to nerve or blood vessel.
5.3. SUBCUTANEOUS ROUTE
5.3.1. Merits
- Absorption is low so the duration of action is prolonged.
- Suitable for some insoluble suspensions.
5.3.2. Demerits
Irritant drugs can produce inflammation, necrosis, and pain.
5.4. INTRAPERITONEAL ROUTE
5.4.1. Merits
Surface area is larger. Used in cases of poisoning.
5.4.2. Demerits
Repeated administration results in peritonitis.
5.5. INTRATHECAL ROUTE
5.5.1. Merits
Uses in cases of severe brain infection when drug cannot pass CSF barrier.
5.5.2. Demerits
Defective technique may result in damage to nervous system.
5.6. INTRA-ARTERIAL ROUTE
Through this route drug is injected in particular artery to localize the effect of drug on an organ or tissue..
5.7. INTRA-ARTICULAR ROUTE
Steroids and antibiotics are injected into the inflamed joints to produce potent effect.
6.TOPICAL ADMINISTRATION
6.1. Skin
Solution, emulsion, ointments, powders and creams are applied for their local topical action on skin and mucous membrane.
6.2. Mucous membrane
Some drugs are applied to the mucus membrane of conjunctiva, nasopharynx, oropharynx, vagina, colon, urethra, and urinary bladder for local effects.
6.3. Eye
Ophthalmic drugs are used primarily for their local effects.
7. INHALATION ROUTE
This route is used to produce local effects on lung or bronchi as in case of asthma and it is also used in general anaesthesia.
8. PASSAGE OF DRUG ACROSS CELL MEMBRANES
The ability of drug to cross cell membrane will determine whether the drug
will be absorbed or not. Important characteristics of drugs that influence their passage across the membrane are their molecular size and shape, solubility at the site of absorption, degree of ionization and lipid solubility. The passage of drug across membrane takes places by any of the following processes:
- Passive Transport: involving
• Simple diffusion: In this transport drug will pass from one side of the cell membrane to other along its concentration gradient. This process depends upon lipid solubility and ionization. Greater the lipid solubility greater will be diffusion. Unionized drugs are more lipids soluble than ionized ones so there rate of diffusion are also greater than ionized drugs.
• Filtration: In this process passage of drugs occurs through porous membrane by means of their hydrostatic or osmotic pressure.
- Specialized Transport: involving
• Active transport: In this process the drug is transferred against a concentration or electrochemical gradient with the expenditure of energy. Absorption takes place by this transport in renal tubules, choroid plexus and neuronal membrane.
• Facilitated diffusion: In this process drugs are transported along their concentration gradient with the help of a carrier e.g. absorption of glucose and amino acids.
• Pinocytosis: This refers to the ability of the cells to engulf fluid material by local invagination of the cell membrane and subsequently formation of vesicle containing fluid or solute within the cell.
Drug absorption is defined as the passage of a drug from its site of administration into the blood stream.
Factors that modify drug absorption:
1. Solubility:
• Drugs with higher lipid solubility are absorbed at a greater rate.
• Drugs given in aqueous solution are more rapidly absorbed than these given in oily solution, suspension or solid form.
2. Degree-of ionization:
Greater the degree of ionization, lesser the absorption. Drugs which are lipid soluble are in unionized form, and readily absorbed, while the water soluble drugs are in ionized form and can be absorbed if they have very small molecular size.
Pka: Pka is the pH at which drug is ionized to the extent of 50%.
3. Pharmaceutical Preparations:
• Solution are better absorbed than suspensions.
• Smaller the particle size of powders the more efficient their absorption.
4. Route of Administration:
Absorption form intramuscular route is rapid than from subcutaneous route Absorption from parenteral route is rapid than oral route.
5. Surface Area
Grater the surface area, larger will be the amount of drug absorbed e.g. surface area of mucous membrane of small intestine is greater than that of buccal or gastric mucosa, thus providing large area for absorption.
6. Concentration of Drug:
Greater the concentration of the drug, greater will be the conc. Gradient across the cell membrane, and thus higher the rate of absorption.
7. Local Blood Flow:
Rate of absorption is directly proportional to the local blood circulation.
Factors modifying absorption from Gut
Solubility, surface area and local circulation are already discussed. Other factors are:
• Motility of the Gut:
Motility of the gut helps in dissolution of tablets, therefore increased motility also increase rate of absorption.
• pH of the Gut:
Most of the drugs are either weak acids or weak base. Weak acids are mostly unionized in acidic medium and therefore better absorbed in acidic medium while the weak bases are unionized in alkaline medium and therefore better absorbed in it.
• Disease Conditions:
Different disease conditions also effect the rate of absorption e.g. in congestive cardiac failure edema of the gut delays absorption.
• Presence of other substances in Gut:
Food or other substances present in the gut may delay the absorption e.g. Tetracyclines are absorbed if given with calcium or iron salts.
DISTRIBUTION OF DRUGS
After the drug is absorbed it is distributed through different tissues and the body fluid compartments such as plasma, extracellular and intracellular and intracellular fluid depending upon its physicochemical properties.
The drugs are not equally distributed in the body. There are four basic patterns of drug distribution.
• Substances of high molecular weight like dextran almost remain in plasma water.
• Drugs that can pass the capillary wall but cannot pass across the cell membrane are localized mainly in extracellular fluid e.g. mannitol after IV administration.
• Some drugs are concentrates especially in one or more tissues of the body e.g. iodide in thyroid gland, chloroquine in liver and calcium in bone.
FACTORS THAT DETERMINE DRUG DISTRIBITION
1. Protein blinding.
2. Blood flow.
3. Membrane permeability
4. Tissue solubility (lipid solubility).
Protein Binding:
After entering the blood, a drug maybe bound to plasma proteins (chiefly albumin) to varying extent; this is called plasma protein binding of drug. The binding of drugs to albumin is reversible and may show low or high capacity. Albumin has strongest affinity for anionic drugs and neutral drugs do not bind to albumin. Following are the properties of protein bound drug.
• Binding is reversible, bound form does not go out into tissue; it remain in blood.
• The protein bound fraction of drug is inactive ( not available for interaction with
receptors ) and acts as deposit from which a small proportion of drug is constantly released to maintain equilibrium with free drug which is being utilized.
• Bound form if not freely filtered from the renal glomeruli.
• Only the unbound or free drug is liable to degradation, utilization and excretion.
• When two drugs are given, each with high affinity for albumin, they compete for available sites. Protein bound drug can be displaced by another drug that competes for protein binding e.g. when sulfonamide is given with tolbutamide, sulfonamide compete s with tolbutamide for albumin biding and displaces tolbutamide from albumin binding sites resulting in rapid rise in plasma tolbutamide level than can be very harmful for the body. This type of drug interactions is clinically very significant.
Blood Flow:
Blood flow determines how rapidly drug molecules are delivered to a given tissue and how effectively the concentration gradient between blood and tissue is maintained. Therefore, drugs equilibrate rapidly between the blood and organs with a high blood flow.
Membrane permeability and tissue solubility
Already discussed in previous section.
PASSAGE OF DRUG TO CNS
The passage of drug into the CNS is limited by the blood brain barrier. Only non-ionized lipid soluble drugs can pass through that barrier, while soluble drugs do not reach the CSF because blood brain barrier has not intercellular pores that are necessary for the passage of water-soluble drugs.
REDISTRIBUTION:
Termination of drug effect is usually by its metabolism and excretion but it may also result form redistribution of the drug from its site of action into other tissues or sites. Redistribution is a factor in termination drug affects primarily when a highly lipid-soluble drug affects primarily when a highly lipid-soluble drug that acts on the brain or CVS is administered rapidly by l/V or by inhalation.
Example
Intravenous anesthetic thiopental is a highly lipid soluble drug. Because blood flow to the brain is so high, the drug reaches its maximum concentration in train within a minute after it is injected intravenously. After injection is stopped, the plasma concentration falls as thiopental diffuses of drug follows that of plasma, because there is little binding of drug to brain constituents.
VOLUME OF DISTRIBUTION (Vd)
Volume of distribution is a relation between amount of drug in the body to the concentration of drugs in the blood or plasma.
V/d =
Total drug in the body Cone. of drug in the blood
Vd = Volume of distribution.
Volume of distribution depends upon the:
• PKa of the drug
• Degree of plasma protein binding
• Degree of binding to other tissue within the body.
Example
Total body water =42liters
Plasma volume =5.5liters
When a drug in the body of a person is 400mg and plasma conc. Of this drug is 40mg/lit then the
volume of distribution will be:
V/d =
400 mg
40mg/lit
= 10liters
Now consider that
• If Vd 5.5 liter, then the whole drugs will remain in plasma and no portion will go to the tissues.
• If the Vd is 11liters, then half of drug will remain in plasma and half is distributed to the tissues.
• If the Vd of drug is 42 liters, It will be distributed in the whole body fluid -----5.5liters in plasma and remaining to the tissue. i.e. major portion of the drug is distributed to the tissue and concentration of drug in the blood is less.
• If Vd is 300liters, then very little drug is present in blood and maximum is concentrated i
the tissues i.e. drug with short plasma half life has high volume of distribution.
Note: As I have mentioned above that the distribution of drug mainly depends on protein binding. Therefore the drug that has tendency to extensively bind to plasma protein, will be retained in the blood, distribution to the tissues is least and therefore the volume of distribution will also be towards lower limit e.g. 7liters, 9liters. The drug which has greater affinity for tissue proteins than that of plasma protein will be very less cons. In blood and major portion will be distributed to the tissues and then the volume of distribution will also be towards upper limit e.g. 40liters, 300liters.
BIOAVAILABILITY
Bioavailability is the extent of absorption of a drug following its acministration by routes other than intravenous injection. Bioavailability is expressed as the fraction of administered drug that gains access to the systemic circulation in a chemically unchanged form. For example, if 100mg of a drug is administered unchanged , the bioavailability is 70%.
Bioavailability is determined by comparing plasma levels of drug after a particular route of administration (e.g. oral) with plasma drug levels achieved by intravenous administration.
FACTORS AFFECTING BIOAVAILABILITY
• Route of administration
When a dose of a drug is given intravenously, the whole drug reaches in circulation and the bioavailability is equal to one.
When a drug is administered through other route (such as orally) bioavailability maybe less than one for the following reasons:
• Incomplete absorption
• Solubility of drug
After oral administration, a drug maybe incompletely absorbed because of too hydrophilic that cannot pass through the lipid cell membrane, or too lipophilic that the drug is not soluble enough to cross the water layer adjacent to the cell.
• First-pass hepatic metabolism
Metabolism liver prior to entry into the systemic circulation is called first-pass metabolism. After absorption in the gut drug enters in to the portal circulation. If the drug is rapidly metabolized by the liver, the amount of unchanged drug that enter into
the systemic circulation is decreased. Drugs such as propranolol and nitrates undergo significant hepatic metabolism during a single passage through the liver.
• Chemical instability
Some drugs such as penicillin G is unstable in the of gastric contents.
Lec.3 : BIOTRANSFERMATION OF DRUGS
The series of chemical alterations of a drug that occurs within the body is called biotransformation or metabolism of drug. This is how the activity of drug is terminated or altered. Some drugs are filtered through the kidney and do not need biotransformation while the majority requires metabolism before they loose their function and elimination from the body.
The lipophilic characteristic of drugs that promote their passage through biological membranes and subsequent access to their site of action hinder their elimination from the body. Therefore these lipophilic drug are converted into hydrophilic metabolites for the termination of their biological activity and elimination of their metabolites from the body.
SITES
Major site of biotransformation is liver, while other organs involved are kidneys, gastrointestinal tract, skin and lung. Phase I reaction occurs mainly in smooth endoplasmic reticulum and phase II in cytosol.
ENZYMES
The metabolic conversion of drugs requires certain enzymes. The important enzyme system is cytochrome P-450 system that includes:
• Cytochrome P-450 enzyme
• NADPH-cytochrome P-450 reductase
P-450 is a family of enzymes that occur in most cells, but that are particularly abundant in the liver.
Enzyme induction
Many drugs area able to induce elevated levels of cytochrome P-450, resulting in an increased rate of metabolism of the inducing drug, as well as other drugs, therefore reducing action and duration of the drugs.
Enzyme inhibition
Many drugs inhibit the P-450 system and may potentate the action of other drugs that are metabolized by this system.
PHASES OF BIOTRANSFORMATION
There are two phase of biotransformation, majority or drugs undergo first phase I and then phase II, but some drugs pass through phase II and then phase I. Some drugs
directly undergo through phase II without prior phase I metabolism.
1. Phase I reaction
2. Phase II reaction
PHASE I REACTION
The phase I reaction may result in:
1. Phase I reaction generally result in loss of pharmacological activity of a drug, although it can increase pharmacological activity such as prodrugs that are pharmacologically inactive become active after metabolism.
2. Conversion of the drug to a toxic compound.
Reaction included in type I reaction are:
Oxidative reaction ( cytochrome P-450 ) dependent)
• Deamination
• Desulfuration
• S-Oxydation
• N-Oxydation
• O-Dealkkylation
• N-Dealkylation
• Aliphatic hydroxylation
• Aromatic hydroxylation
Oxidative reaction ( cytochrome P-450 independent )
• Dehydogenation
Reduction reaction
• Azo reduction
• Nitro reduction
• Carbonyl reduction Hydrolysis
PHASE II REACTION
Phase II reaction involve “conjugation” of the parent compound with certain; radical or amino acids. If the metabolite phase I metabolism is sufficient polar, it can excreted by the kidneys. However many metabolites are too lipophilic to be excreted and they must undergo conjugation reaction with an endogenous substrate such as glucuronic acid, sulfuric acid, acetic acid or an amino acid resulting in polar, usually more water soluble compounds that are most often therapeutically inactive. Conjugation with glucuronic acid is the most common reaction.
Phase II reactions results in inactivation of the parent drug but not always.
• Chloramphenicol conjugates with glucuronic acid
• Phenol conjugates with sulfate
• Salicylates conjugate with glycine.
Note: The microsomal exzymes produced by the hepatic smooth endoplasmic reticulum, catalyze glucuronide conjugation and mowtof the oxidation of drug. While he readution and non- microsomal Enzymes. These enzymes are also present in kidney and GIT.
Phase II reaction are:
• Glucuronidation
• Acetylation
• Glutathione conjugation
• Sulfate conjugation
• Methylation
• Water conjugation
FACTORS AFFECTING BIOTRANSFORMATION
Different people have different in drug distribution metabolism and elimination due to the following factors:
Individual differences
Different people have different level of metabolism.
Genetic factors
Genetic factors influence enzyme levels resulting in difference drug metabolism.
Diet and environmental factors
Certain vegetable ad fruits induce or inhibition enzymes affecting the drug metabolism Cigarette smokers metabolize some drugs are rapidly than non-smokers do.
Age & Sex
Drugs have more effect and more toxicity in very young and old patients due to decreased drug metabolism. In newborn the enzymes in the liver are not developed. If drug like chloramphenicol is given to the newborn, it proves toxic as glucuronide is not fully developed. Males have more rapid drug metabolism than females.
Drug-Drug interaction
Some drugs induce and some inhibit enzymes those results in decreased or increased metabolism of the same or other drugs. Phenobarbitone induces enzymes and increases the metabolism of several drugs.
Interaction between drugs and endogenous compounds
Various drugs require conjugation with endogenous substrates such as glutathione, glucuronic acid, and sulfate for their inactivation. Different drug may compete for the same endogenous substrates, and the faster-reacting drug may effectively deplete endogenous substrates levels and impair the metabolism of slow -reacting drug.
Disease affecting drug metabolism
Acute or chronic disease that affect liver architecture or function markedly affect hepatic metabolism of some drugs.
Pharmacokinetic factors
As long as drug is bounds to plasma protein, it will not be metabolized .
Drugs which are localized in tissue are protected from metabolism e.g. Chloroquine in liver.
DRUG ELIMINATION
Drugs in the free form and in the form of their degradation products are eliminated though on or more of the following channel of excretion.
1. RENAL EXCRETION:
In renal excretion three processes are evolved:
• Filtration: Rate of filtration is determined by degree of drug bound to plasma Protein.
Only free fraction for the dug in filtrated.
• Active tubular secretion and reabsorption: Many drugs are actively secreted by the tubules e.g. penicillin and uric acid. There is competition between different drugs e.g. probenecid competes with penicillin for excretion and stops excretion of penicillin, thus increasing its duration of action.
• Passive diffusion: It depends upon whether it is ionized or unionized. Drugs which are unionized are reabsorbed.
2. LUNGS:
The lungs excrete gaseous and volatile general anesthetics as well as gaseous drug
product such as CO 2
3. ALIMENTARY SYTEM
Thiocynate and iodides are excreted though saliva while morphine is excreted in bile.
CLEARANCE OF DRUG
Rate of elimination of drug by all route normalized to the concentration of drug in some biological fluid is called drug clearance. Major organs that clear the drug are kidney and liver Initially the clearance of each organ is calculated, then they are added target total body clearance.
The clearance of most drugs is of two types:
First order kinetics:
If a constant fraction of drug is eliminated per unit time it is called first order kinetics e.g. 5% or 10%/min.
Zero-order Kinetics:
If a constant amount of drug is eliminated per unit time it is called first order kinetics 5mg of 10mg/min.
Importance
Assuming complete bioavailability, the steady state will be achieved when the rate of drug elimination equal the rate of drug administration. Thus if the desired steady-state concentration of drug in plasma or blood is known, the rate of clearance of drug by the patient will decade the rate at which the drug should be administered.
FIRST PASS EFFECT:
The enzymes systems concerned in the metabolism of many drugs are located in liver. A drug
that is absorbed from the stomach and intestine must fist pass through the liver before it reaches the systemic circulation. If the metabolic system of the liver is over active for this drug, the drug will be metabolized before reaching the circulation e.g. nitroglycerine. To avoid this , such drugs are given sublingually.
ENTEROHEPATIC CIRCULATION:
Drugs and their metabolites that are secreted into bile are carried by the bile duct and the
common duct to the duodenum. Some drug may then be absorbed from the lumen of the intestine and appear again unchanged in the blood. This recycling of drug is termed enterohepatic circulation.
HALF-LIFE
The time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50% is called half-life of a drug.
Half-life provides a good indication of the time required to reach steady state after a dosage
regimen is initiated, the time of a drug to be removed from the body, and means to estimate the appropriate dosing interval.
0.693
Half-life =
x volume of distributi on Clearance of drug
FACTORS AFFECTING HALF-LIFE
• As the clearance decreases due to some disease process the half-life increases, as in renal failure.
.If the volume of distribution is increased, half-life is increase e.g. half-life of diazepam increases in old age due to increased volume of distribution.
• Change in the protein binding may result in change in the volume of distribution and
drug clearance in the leads to change in the half-life. Increased plasma binding increases half-life.
STEADY STATE
A steady state concentration of drug occurs when the rate of drug elimination is equal to the rate of drug administration. Steady state plasma concentration is directly proportional to rate of infusion and inversely proportional to the total body clearance of the drug.
DOSAGE OF DRUGS
The minimum quality of the drug needed to produce measurable biological response is called dose of a drug. A rational dosage regimen is based on the assumption that there is a target concentration that will produce desired therapeutic effect.
Dose usually has range i.e minimum and maximum limits. Dose is not always fixed amount and it can be change according to the severity of the disease.
THERAPEUTIC DOSE OR EFFECTIVE DOSE (ED50)
The average dose required to produce therapeutic effect in 50% of the population treated is called therapeutic for effective dose.
MAXIMAL TOLERATED DOSE
The largest dose of a drug that can be taken safely is called maximal tolerated dose.
INITIAL DOSE
The dose used at the start of treatment is called initial dose.
MAINTENANCE DOSE
The dose required to maintain the therapeutic effects (steady state of target level) attained by the initial dose is called maintenance dose.
LOADING DOSE
The loading dose is one or a series of doses that may be given at the onset of therapy with the aim of achieving the target concentration rapidly. A loading dose may be desirable if the time required to attain steady state by the admonition of drug at a constant rate (four elimination half-lives) is long relative to the demand of the condition. It is unnecessary for drugs having short half-life. In loading dose the amount of the drug should be increased not the of administration.
Loading dose = Vd × TC
Vd = volume of distribution TC = target concentration
INEFFECTIVE DOSE
The dose below the effective dose is called ineffective dose.
TOXIC DOSE
The dose above the effective dose produces undesirable effects and is called toxic dose.
LETHAL DOSE (LD50)
The dose which produces death in 50% of population treated is called lethal dose.
THERAPEUTIC INDEX
The relationship between the dose of the drug required to produce desired and undesired effects is termed as therapeutic index or margin of safely.
Therapeutic index =LD50/ED50
Higher the therapeutic index, safer will be the drug
FACTORS MODIFYING THE DOSAGE OF DRUGS
Age, weight, and body surface area:
• Children require smaller doses of drug than adult
• Greater the body weight, the bigger the dose required.
• Greater the body surface area, larger the dose required. Sex:
• Females usually require smaller dose than males
Routes of Administration
• Intravenous dose is less then oral dose
• Subcutaneous and intramuscular dose are also smaller the oral dose but larger than intravenous dose.
Time of Administration
• Absorption of drugs occurs more rapidly in an empty stomach than after meals. However,
it is better to take irritant drugs after meals.
Diseased condition
Drug metabolized in liver are not destroyed during liver disease. Drugs excreted by kidney are not excreted in renal disease; therefore the dose should be reduced.
Drugs Interactions:
When two or more drugs are combined together one of the following four phenomena may be observed:
• Summation:
The resultant action is the algebraic sum of the individual actions of the two drugs
combined. In such cases only one half of the normal dose of each drug is required to produce the desired effects.
• Synergism:
When combined the net effect is greater than the sum of their individual effect e.g. ethyl alcohol and barbiturates.
• Potentiation:
When one drug has no apparent action by itself on one system but increase the effect of another drug is termed potentiation e.g. barbiturates potentiate the analgesic action on their own.
• Antagonism:
This occurs when drugs with opposing actions are administered simultaneously. It may be of several types:
Physiological
Histamine + Adrenaline
Chemical
Protamine + Heparin
Pharmacological: Competitive:
Acetylcholine + Atropine
Non-competitive: AcetylcholineSuxamethonium.
Placebo Effect:
This is the influence of the emotional state of the patient on response to drugs. Placebos are inert dosage forms usually tablets or capsules containing sucrose or lactose. They have no pharmacological effect but produce improvement due to psychological effects.
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