General Pharmacological Principle
General Pharmacology
Pharmacology is the science dealing with biochemical and physiologic aspects of drug effects, including absorption, distribution, metabolism, elimination, toxicity doses, and specific mechanisms of drug action.
Pharmacology includes three major divisions: theoretical (general), experimental, and clinical. Theoretical pharmacology touches upon common regularities of interactions of drugs with an organism. Experimental pharmacology investigates drugs influence on the organism of animals. Clinical pharmacology examines drugs influence on the organism of patient. Pharmacotherapy studies the use of medicaments for cure of a concrete illness. Some branches of pharmacology are different sciences: phytotherapy, toxicology, vitaminology, endocrinology, and chemotherapy.
Pharmacology is closely connected with pharmacy. Pharmacology is based on the advances of physics, chemistry, biology, biochemistry, physiology for the explanation of drugs mechanism of action. Pharmacology is the basis for therapy and other clinical disciplines.
The pharmacological effect is the changes of metabolism and function of cells. Mechanism of action is the way by means of which the initial reaction is realized. The initial pharmacological reaction is characterized by biochemical, physiological, physical and chemical changes of metabolism and function of systems and organs. The two main areas of pharmacology include pharmacokinetics and pharmacodynamics. Pharmacokinetics refers to the way the body handles drug absorption, distribution, biotransformation, and excretion. Pharmacodynamics is the study of biochemical and physiological effects of drugs and their mechanisms of action
Drug transport : The movement of drug molecules in the body is subject to absorption, distribution, and excretion. Drugs can cross cellular membranes by various mechanisms. The mechanisms of absorption are similar to the mechanisms of membrane transport: passive diffusion, carrier-mediated diffusion, filtration, active transport, or pinocytosis. Being a bimolecular lipid layer, the cell membrane can also act as a barrier to some drugs.
Passive diffusion : Most compounds penetrate into cells by diffusing as the un- ionized moiety through the lipid membrane. Factors affecting the passage of a molecule through a membrane are the molecule's size and charge, the lipid-water partition coefficient, and the concentration gradient. The two types of passive drug transport are simple diffusion and filtration.
Filtration is a character of urea pure. Water, ions, and some polar and no polar molecules of low molecular weight can diffuse through membranes, suggesting that pores or channels may exist. The capillaries of some vascular beds (e.g. in the kidney) have large pores, which permit the passage of molecules as large as proteins.
Carrier-mediated facilitated diffusion is character of amino acids, vitamins and other drugs. In this type of transport, movement across the membrane is facilitated by a macromolecule. It is a saturable process; that is, external concentrations can be achieved in which increasing the external/internal concentration gradient will not increase the rate of influx. It is selective for the chemical structure of a drug; that is, the carrier mechanism transports only those drugs having a specific molecular configuration. It requires no energy. It cannot move against a concentration gradient and, therefore, is still diffusion.
Active transport is a character of cardiac glycosides and others. Active transport is similar to carrier-mediated diffusion in several ways: movement across the membrane is mediated by macromolecules. It is a saturable process, selective for chemical structure. Several important features distinguish active transport from diffusion processes. Active transport requires metabolic energy; this is often generated by the enzyme known as Na+ -K + -ATPase. It transports molecules against a concentration gradient.
Pinocytosis is typical of lipid soluble vitamin drugs. A vacuolar apparatus in some cells is responsible for this process. There exist both fluid-phase pinocytosis for substances such as sucrose and adsorptive-phase pinocytosis for substances such as insulin.
Bioavailability is the relative rate and extent by means of which a drug reaches the general circulation; this is especially important when a drug is administered orally. Factors that influence bioavailability are: solubility of the drug in the contents of the stomach, dietary patterns, tablet size, quality control in manufacturing and formulation.
Routes of Drug Administration
A. LOCAL ROUTES
- Topical
- Deeper tissues
- Arterial supply
B.SYSTEMIC ROUTES
- Oral
- Sublingual or buccal
- Rectal
- Cutaneous
- Inhalation
- Nasal
- Parenteral: (s.c),(i.m),(i.v),Intradermal inj.
Absorption
Absorption is the rate at which a drug leaves the site of administration and the extent to which this occurs. The absorption of a drug through the mucosal lining of the gastrointestinal tract or through capillary walls depends on the physical and chemical properties of the drug.
Route of administration is an important determinant of the rate and efficiency of absorption.
Enteral routes are the most common routes of administration. Examples of enteral routes are peroral, rectal, sublingual, subbuccal, and duodenal. Advantages of peroral administration. An alimentary route is physiological, generally the safest route of administration. The delivery of the drug into the circulation is slow after oral administration, so that rapid, high blood levels are avoided and adverse effects are less likely. The dosage forms available for alimentary administration are convenient and do not require sterile technique.
Disadvantages of alimentary administration : It is not convenient for the first aid. The main disadvantage is that the rate of absorption varies. It becomes a problem if a small range in blood levels separates a drug desired therapeutic effect from its toxic ones. Irritation of mucosal surfaces can occur. A patient compliance is not ensured. With peroral administration of some drugs extensive hepatic metabolism may occur before a drug reaches its site of action. This is known as a first-pass effect. Passage through the liver and the resulting initial hepatic metabolism are avoided by administering the drug sublingually. But only some drugs may penetrate through mucose surfaces.
Parenteral routes : The main merit is that the medicine bypasses the alimentary tract. Examples of parenteral routes: intravenous, intramuscular, subcutaneous, intraperitoneal, intra-arterial, intrathecal, transdermal, intranasal, and inhalational etc.
Advantages of parenteral administration : A drug gets to the site of action faster, providing a rapid response, which may be required in an emergency. The dose can often be more accurately delivered. Parenteral administration can be used when the alimentary route is not feasible (e.g. when a patient is unconscious). Large volumes can be delivered intravenously.
Disadvantages of parenteral administration: More rapid absorption can lead to increased adverse effects. A sterile formulation and an aseptic technique are required. Local irritation may occur at the site of injection. Parenteral administration is not suitable for insoluble substances. Parenteral administration may lead to HIV infection and phlebitis.
Topical administration is useful in the treatment of patients with local conditions; with topical administration there is usually little systemic absorption. Drugs can be applied to various mucouse membranes and skin. Inhalation provides a rapid access to circulation; it is the common route of administration for gaseous and volatile drugs. It is managed well. In the case of inhalation there may occur allergic reaction and any disease may be aggravated.
Factors affecting drug absorption
A. Factors Related to Drugs:
1. Lipid water solubility
Lipid water solubility coefficient is the ratio of dissolution of drug in lipid as compared to water. Greater the lipid water solubility coefficient, more is the lipid solubility of the drug and greater is the absorption. Less the coefficient, less is the lipid solubility and less is the absorption.
2. Molecular size
Smaller the molecular size of the drug, rapid is the absorption. There exist different processes involved in absorption for different molecular sizes. Those with a large molecular size undergo endocytosis or facilitated diffusion, while those with smaller molecular sizes utilize aqueous diffusion or lipid channels.
3. Particle size
Particle may be composed either of a single molecule or more than hundred molecules. Larger is the particle size, slower will be the diffusion and absorption and vice versa.
4. Degree of Ionization
Different drugs are either acidic or basic and are present in ionized or unionized form, which is given by their pKa values. In the body, the ratio of the ionized and unionized forms depend on the pH of the medium. Acidic drugs are unionized in the acidic medium and basic drugs are unionized in the basic medium. Acidic drugs are better absorbed from the acidic compartment.
5. Physical Forms
Drugs may exist as solids, liquids or gases. Gases are rapidly absorbed than the liquids, while the liquids are rapidly absorbed than the solids. Thus the drugs in syrup or suspension form are rapidly absorbed than the tablets or capsules. Volatile gases used in general anesthesia are quickly absorbed through the pulmonary route.
6. Chemical Nature
Chemical nature is responsible for the selection of the route of administration of drug. Drugs that cannot be absorbed through the intestines are given by the parenteral route. Examples include heparin which is large molecular weight, and cannot be given orally. Simililarly, benzyl penicillin is degraded in the GIT, so is given parenterally.
Salt forms of drugs are better absorbed than the organic compounds when given orally. The organic compounds are given by routes other than the oral or enteral route.
Drugs in inorganic form are better absorbed than organic forms e.g. iron in Fe+2 is better absorbed than Fe+3, d-tubocurarine exists in ionized form and is a quaternary ammonium compound. Neostigmine is also a quaternary ammonium compound.
7. Dosage Forms
Dosage forms affect the rate and extent of absorption. A drug can be given in the form of tablets, capsules or transdermal packets. Injections may be aqueous or oily. This changes the rate of absorption. Examples include nitroglycerin which when given by sublingual route, disintegrates rapidly but stays for a shorter duration. When it is given orally, it disintegrates slowly and stays for longer duration. When given by transdermal route, the drug can cover an even longer duration.
8. Formulation
When the drugs are formed, apart from the active form some inert substances are included. These are the diluents, excipients and the binders. Normally they are inert, but if they interact, they can change the bioavailability. Examples include Na+ which can interact to decrease the absorption.
Atropine is required by some patients only in amounts of 0.2 to 0.6 mg.
9. Concentration
According to Fick’s law, higher the concentration more flux occurs across the membrane. The rate is less affected than the extent of absorption.
B. Factors Related to Body
1. Area of Absorptive Surface
Area of absorptive surface affects oral as well as other routes. Most of the drugs are given orally because of the large area of absorptive surface, so that greater absorption occurs. Intestinal resection decreases the surface area leading to a decreased absorption. Similarly, when the topically acting drugs are applied on a large surface area, they are better absorbed.
Eg : Organophosphate compounds are highly lipid soluble and poisoning can occur even by absorption through skin.
2. Vascularity
More the vascularity, more is the rate and extent of absorption and vice versa. In shock, blood supply to the GIT is less so the oral route of drug administration is affected. The blood flow to the peripheries is decreased, so absorption in those areas is diminished as well. Therefore, intravenous route is preferred in case of shock.
Vasoconstrictors decrease the blood supply of an area, thus are useful to restrict the local anesthesias so that they remain for a longer duration. Their wash away as well as their toxic effects are decreased in this way.
3. pH
Acidic pH favors acidic drug absorption while basic pH is better for basic drugs.
4. Presence of other Substances
Foods or drugs may interact with the drugs to alter their rate of absorption. Especially for the drugs given orally, food can increase or decrease the absorption.
- Antihyperlipidemic drugs like the statins are better absorbed when taken with the food.
- Iron when given with milk has decreased absorption.
- Vitamin C enhances the absorption of iron.
- Phytates decrease iron absorption.
- Milk decreases the absorption of tetracyclines.
- Epinephrine when given with local anesthetics decreases their absorption.
- Calcium salts when given with iron salts or tetracyclines interfere with their absorption
- Aspirin is given with food while antibiotics are given in empty stomach. Liquid paraffin may affect drug absorption. Some acidic drugs bind with cholestyramine to from a complex which is not absorbed in GIT.
5. GI Mobility
GI mobility must be optimal for absorption of oral drugs. It should be neither increased nor decreased which may affect the rate or extent of absorption.
Different diseases or drugs may alter the mobility. Diarrhea causes rapid peristalsis, decreasing contact time and thus the extent of absorption is affected more. Constipation affects disintegration and dissolution so decreases motility.
6. Functional Integrity of Absorptive Surface
Flattening and edema of mucosa decreaes absorption. Dysfunctional breach in the skin affects the absorption of topical drugs.
Parasympathomimetic drugs can decrease drug absorption and parasympatholytic drugs can increase absorption. Metodopramide prevents vomiting and accelerates gastric emptying. It increases gastric emptying increasing drug absorption.
7. Diseases
a. Diarrhea
- Decreases absorption because of decreased contact time.
b. Malabsorptive syndrome
- Decreases absorption
c. Achlorhydria
- Acidic medium for acidic drugs is affected.
d. Cirrhosis
- Cirrhosis affects portal circulation. Thus affecting metabolism of drugs.
e. Emphysema
- Emphysema affects the absorption of volatile gases through the pulmonary route.
f. Lipodystrophy
- Lipodystrophy decreases absorption. In diabetics, insulin might lose its affect.
Distribution
One-compartment model: This is the simplest and most commonly used pharmacokinetic model system. Usually distribution of a drug within a compartment is assumed to be uniform. The apparent volume of distribution (Vd) is a quantitative estimate of the tissue localization of a drug. It can be determined by measuring the plasma level of the drug:
In general, a high Vd indicates high lipophilicity or many receptors for a drug. The total body clearance is a volume of blood or plasma that is effectively cleared a drug in a specified unit of time. Clearance is related to Vd and to the time required for plasma drug concentration or the amount in the body to decrease by 50%, which is called half-life (t1/2). Clearance is, therefore, related to the elimination rate constant (k):
This formula assumes a specific Vd, but the Vd changes over the time.
Two-compartment model is generally used for drugs which are not administered intravenously because it can better describe both distribution and elimination. The multicompartment model is used for drugs which are stored in body depots and for drugs with extensive metabolism or elimination mechanisms.
Drug metabolism /biotransformation
It is the process of a chemical alteration of drugs in a body. The main principles are: a liver is a major site of metabolism for many drugs or other xenobiotics, but other organs, such as lungs, kidneys and adrenal glands can also metabolize drugs. Many lipid-soluble, weak organic acids or bases are not readily eliminated from a body and must be conjugated or metabolized to compounds which are more polar and less lipid-soluble before being excreted. Metabolism results in inactivation of a compound (e.g. morphini hydrochloridum). Some drugs are activated by metabolism. Some of these substances are called prodrugs (e.g. enalaprilum). Some drugs become more toxic by biotransformation.
Biochemical reactions involved in drug metabolism occur in two phases:
Phase 1: reactions are divided into:
a) microsomal oxidation;
b) nonmicrosomal oxidation (e.g. oxidation, reduction, hydrolysis) after chemical reactivity and increase aqueous solubility;
Phase 2: reactions (e.g. conjugation) further increase solubility, promoting elimination.
Drug excretion
It is the process of elimination of a drug or metabolite from a body. Elimination of drugs from the blood follows exponential (a first-order) kinetics. The elimination process can be saturated after high doses of some drugs and elimination will then follow a zero-order kinetics. Ethanol is a prototypic example. For drugs which are eliminated by a first-order kinetics, the fractional change in the amount of a drug in plasma or blood per unit of time is expressed by the half-life (t1/2), or by the elimination rate constant (k), which is equal to 0.693/t1/2.
Routes of elimination
Kidney is the most important organ for excretion of drugs. Excretion of drugs and their metabolites into urine involves three processes:
Glomerular filtration: Water-soluble and polar compounds are filtrated under hydrostatic pressure unable to diffuse back into circulation. Drugs dissolved in blood plasma are excreted in this way.
Active tubular secretion: Mechanisms for active tubular secretion exist in the proximal tubule. Drugs such as organic acids (e.g. quinine sulfas) are transported by these systems.
Passive tubular reabsorption is typical for lipophylic nonpolar drugs.
Biliary tract and faeces are important routes of excretion for some drugs which are metabolized in a liver (e.g. digitoxinum).
Drugs and their metabolites can also be eliminated with expired air, sweat, saliva, tears, and breast milk. Drugs eliminated through these routes tend to be lipid- soluble and nonionized.
PHARMACODYNAMICS
Mechanisms of drug action :
Most drugs interact with macromolecular components (called receptors) of a cell or an organism to begin biochemical and physiologic changes which causes drugs observed effects, or response, or primary pharmacological reaction. Receptors bind ligands and transduce signals. A drug is called an agonist if it interacts with specific receptor, causes its conformation biochemical reactions, produces some of the effects of endogenous compounds. Agonists (e.g. acetylcholine) have intrinsic activity. Intrinsic activity is a drug ability to stimulate receptor and cause specific effects. An antagonist is a drug which has no intrinsic activity, even when it can reduce or abolish the effect of an agonist, protect from neuromediators and hormones action. Examples of pure antagonists are atropini sulfas and tubocurarini chloridum, which inhibit the effect of acetylcholine. If antagonists occupy the same receptors as agonists they are called concurrent antagonists (e.g. atropini sulfas). If antagonists occupy other sites of macromolecules which do not belong to a specific receptor they are called nonconcurent antagonists. Some drugs (e.g. nalorphini hydrochloridum) are agonists-antagonists or synergoantagonists; they have some intrinsic activity and may activate one type of receptors and block another one. There are drugs which may not cause a response by interacting with receptors. These drugs may combine with small molecules or ions found in a body (e.g. chelating agents).
Certain receptors when exposed to an agonist repeatedly can become desensitized or down-regulated. For example, -adrenergic bronchodilators used in the treatment of patients with asthma can become less effective over time when administered at the same concentration. Super sensitivity of receptors to agonists can occur with chronic administration of an antagonist. For instance, the abrupt discontinuation of propranolol in a patient who has been taking it constantly could precipitate dysrhythmias. Super sensitivity may result from the synthesis of additional receptors.
Toxicology
Science of poisons. Poisons are substances that cause harmful, dangerous or shows fatal symptoms in animals and human beings; many drugs in large dose acts as poisons Like, aspirin in less dose acts as anticoagulant by inhibiting thromboxane A2, useful for heart patients and in high dose causes the ulceration
Chemotherapy
It is concerned with the effect of drug upon microorganisms and parasites, living & multiplying in living organisms. It is now also useful for treatment of cancer by targeting cancerous cells.
Pharmaco-epidermiology
It is study of the effect of the drugs in large number of people in community
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