GENERAL PHARMACOLOGICAL Notes / pharmacodynamics and pharmacokinetics notes / what is pharmacokinetics

 GENERAL PHARMACOLOGICAL PRINCIPLES

Pharmacology 

 Pharmacology is the science of drugs (Greek: Pharmacon-drug; logos-discourse in). In a broad sense, it deals with interaction of exogenously administered chemical molecules with living systems, and any single chemi cal substance which can produce a biological response is a 'drug'. Pharmacology encompasses all aspects of knowledge about drugs, butlrQ importantly those that are relevart_ to ef(ecti\l_e and safe use of drugs for medicinal purposes. 

 For thousands of years most drugs were crude natural products of unknown composition and limited efficacy. Only the overt effects of these substances on the body were rather imprecisely known, but how the same ere produced was entirely unknown. Animal experiments, primarily aimed at understanding pn siological processes, were started in the 18th century. These were pioneered by F. Magendie and Claude Bernard, who also adapted them to study effects of certain drugs. Pharmacology as an experimental science was ushered by Rudolf Buchheim who f ounded the first institute of pharmacology in 1847 in Germany. In the later part of the 19th century, Oswald Schmiedeberg, regarded as the 'father of pharmacology', together with his many disciples like J Langley, T Frazer, P Ehrlich, AJ Clark, JJ Abel propounded some of the fundamental concepts in pharmacology. 

 Since then drugs have been purified, chemically characterized and a vast variety of highly potent and selective new drugs have been developed. The mechanism of action including molecular target of many drugs has been elucidated. This has been possible due to prolific growth of pharmaco ogy which forms the backbone of ational therapeutics.

 The two main divisions of pharmacology are pharmacodynamics and pharmacokinetics.

 Pharmacodynamics 

(Greek: dynamis-power) -What the drug does to the body. This includes physiological and biochemical effects of drugs and their mechanism of action at organ system/subcellular/macromolecular levels, e.g.-Adrenaline ➔ interaction with adrenoceptors ➔ G-protein mediated stimu lation of cell membrane bound adenylyl cyclase ➔ increased intracellular cyclic 3 ',5' AMP ➔ cardiac stimulation, hepatic glycogenolysis and hyperglycaemia, etc.

 Pharmacokinetics (Greek: Kinesis-move ment)-What the body does to the drug. This refers to movement of the drug in and alteration of the drug by the body; includes absorption, distribution, binding/localization/stor age, biotransformation and excretion of the drug, e.g. paracetamol is rapidly and almost completely absorbed orally attaining peak blood levels at 30-60 min; 25% bound to plasma proteins, widely and almost uniformly distri buted in the body (volume of distribution ~ 1L/kg); exten sively metabolized in the liver, prima rily by glucuronide and sulfate conju gation into inac tive metabolites which are excreted in urine; has a plasma half life (t½) of 2–3 hours and a clearance value of 5 ml/kg/min.

 SECTION 1 Drug (French: Drogue—a dry herb) It is the single active chemical entity present in a medicine that is used for diagnosis, prevention, treatment/cure of a disease. This disease oriented definition of drug does not include contraceptives or use of drugs for improvement of health. The WHO (1966) has given a more comprehensive definition—“Drug is any substance or product that is used or is intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient.”

 The term ‘drugs’ is being also used to mean addictive/abused/illicit substances. However, this res tric ted and dero gatory sense usage is unfor tunate degradation of a time honoured term, and ‘drug’ should refer to a substance that has some health promoting/therapeutic/ diagnostic application. Nevertheless, to avoid any misinterpretation, the term ‘medicine’ is being employed to designate such a substance in place of the term ‘drug’. Some other important aspects of pharmacol ogy are:
 
 Pharmacotherapeutics It is the application of phar ma cological information together with know ledge of the disease for its prevention, mitigation or cure. Selection of the most appro priate drug, dosage and duration of treatment taking into account the stage of disease and the specific features of a patient are a part of pharmacotherapeutics.

 Clinical pharmacology

 It is the scientific study of drugs (both old and new) in man. It includes pharma codynamic and pharmacokinetic investigation in healthy volun teers as well as in patients. Evaluation of efficacy and safety of drugs and comparative trials with other forms of treatment; surveillance of patterns of drug use, adverse effects, etc. are also part of clinical pharmacology. The aim of clinical pharmacology is to gen erate data for optimum use of drugs and the practice of ‘evidence based medicine’. 

Chemotherapy It is the treatment of sys temic infection/malignancy with specific drugs that have selective toxicity for the infecting orga nism/malignant cell with no/minimal effects on the host cells. Drugs in general, can thus be divided into:

Pharmacodynamic agents These are designed to have pharmacodynamic effects in the reci pient.

 Chemotherapeutic agents These are designed to inhibit/kill invading parasites/malignant cell, but have no/minimal pharmacodynamic effects in the recipient. 

Pharmacy It is the art and science of compoun ding and dispensing drugs or prepar ing suitable dosage forms for administration of drugs to man or animals. It includes collection, identification, purification, isolation, synthesis, standardization and quality control of medicinal substances. The large scale manufacture of drugs is called Pharmaceutics, which is primarily a technological science. 

 Toxicology It is the study of poisonous effect of drugs and other chemicals (household, environ mental pollutant, industrial, agricultural, homi cidal) with emphasis on detection, pre vention and treatment of poisonings. It also includes the study of adverse effects of drugs, since the same substance can be a drug or a poison, depending on the dose

 nature of drugs
All drugs are chemical entities with simple or complex molecules. While majority are organic compounds, some are purely inorganic, like lithium carbonate, ferrous sulfate, magnesium hydroxide, etc. Organic drugs may be weakly

acidic (aspirin, penicillin) or weakly basic (mor phine, chloroquine) or nonelectrolytes (alcohol, diethyl-ether). Most drugs are normally solids, e.g. paracetamol, propranolol, furosemide, ampi cillin, etc., but some such as ethanol, glyceryl trinitrate, propofol, castor oil are liquids, and few like nitrous oxide are gaseous. The molecular weight of majority of drugs falls in the range of 100-1000 D, because molecules smaller than 100 D do not generally have sufficiently specific features in terms of shape, size, configuration, chirality, distribution of charges, etc. to selectively bind to only one/ few closely related target biomolecules, to the exclusion of others. On the other hand, larger molecules than 1000 D do not readily pass through membranes/barriers in the body to reach the target sites in various tissues/cells. However, few drugs are as small as lithium ion (7D), and some like heparin (10-20 KD), gonadotropins (>30 KD), enzymes, proteins, antibodies (>50 KD) are much bigger. Bulky molecule drugs have to be administered parenterally. Drugs are generally perceived to be chemical substances foreign to the body (Xenobiotics). However, many endogenous chemicals like hormones, autacoids, metabolites and nutrients are also used as drugs. Chemical congeners of these metabolites/signal molecules are an im portant class of drugs which act by modifying the synthesis, storage, degradation or action of these metabolites/signal molecules.  
sources of drugs
 Drugs are obtained from a variety of sources: 1. Plants Many plants contain biologically active substances and are the oldest source of drugs. Clues about medicinal plants were obtained from traditional systems of medicine prevalent in various parts of the world; e.g. use of opium, belladonna, ephedra, cinchona, curare, foxglove, sarpagandha, qinghaosu has been learnt from Egyptian, Greek, Aztec, Ayurvedic, Chinese and other systems of medicine. Chemically the active ingredients of plants fall in several categories:
 a. Alkaloids: These are alkaline nitrogenous bases having potent activity, and are the most important category of vegetable origin drugs. Prominent examples are: morphine, atropine, ephedrine, nicotine, ergotamine, reserpine, quinine, vincristine, etc. They are mostly used as their water soluble hydrochloride/ sulfate salts 

b. Glycosides: These compounds consist of a heterocyclic nonsugar moiety (aglycone) linked to a sugar moiety through ether linkage. Cardiac glycosides (digoxin, ouabain) are the best known glycosidic drugs. The active principle of senna and similar plant purgatives are anthraquinone glycosides. Aminoglycosides (gentamicin, etc.) are antibiotics obtained from microorganisms, and have an aminosugar in place of a sugar moiety. 

c. Oils: These are viscous, inflammable liquids, insoluble in water. Fixed (nonvolatile) oils are calorie yielding triglycerides of higher fatty acids; mostly used for food and as emollients, e.g. groundnut oil, coconut oil, sesame oil, etc. Castor oil is a stimulant purgative. Essential (volatile) oils, mostly obtained from flowers or leaves by steam distillation are aromatic (fragrant) terpene hydrocarbons that have no food value. 

They are used as flavouring agents, carminatives, counterirritants and astringents; examples are eucalyptus oil, pepermint oil, nilgiri oil, etc. Clove oil is used to allay dental pain. Menthol, thymol, camphor are volatile oils that are solids at room temperature. Mineral oils are not plant products, but obtained from petroleum; liquid paraffin is a lubricant laxative, soft and hard paraffin are used as emollient and as ointment bases. 

Other plant products like tanins are astringent; gums are demulcents and act as suspending agents in liquid dosage forms. Glycerine is a viscous, sweet liquid used as vehicle for gum/throat paint. Resins and balsams are used as antiseptic and in  cough mixtures. The antimalarial drug artemisinin is a sesquiterpene endoperoxide obtained from a Chinese plant.

2. Animals Though animal parts have been used as cures since early times, it was exploration of activity of organ extracts in the late 19th and early 20th century that led to introduction of animal products into medicine, e.g. adrenaline, thyroxine, insulin, liver extract (vit. B12 ). Antisera SECTION 1 and few vaccines are also produced from animals.

 3. Microbes Most antibiotics are obtained from fungi, actinomycetes and bacteria, e.g. penicillin, gentamicin, tetracycline, erythromycin, polymyxin B, actinomycin D (anticancer). Some enzymes, e.g. diastase from a fungus and streptokinase from streptococci have a microbial source. Vaccines are produced by the use of microbes.

 4. Minerals Few minerals, e.g. iron salts, calcium salts, lithium carbonate, magnesium/ aluminium hydroxide, iodine are used as medicinal substances. 

 5. Synthetic chemistry Synthetic chemistry made its debut in the 19th century, and is now the largest source of medicines. Synthetic drugs have the advantage of purity and uniformity of the product. They can be manufactured in any quantity as per need, in contrast to drugs from natural sources whose availability may be limited. Not only diverse congeners of naturally obtained drugs (atropine substitutes, adrenergic b2 agonists, synthetic glucocorticoids/progestins/ cephalosporins, etc.) have been introduced to achieve greater selectivity of action or even novel type of activity, but many entirely synthetic families of drugs, e.g. benzodiazepines, thiazides, benzimidazoles, f luoroquinolones, etc. have been produced. Many drugs are being synthesized to target specific biomolecules, e.g. ACE inhibitors, glycoprotein IIb/IIIa receptor antagonists, HIV-reverse transcriptase inhibitors, etc. Synthetic drugs that are chiral can also be produced as single active enantiomer products, which may be therapeutically superior. 

 6. Biotechnology Several drugs, especially peptides and proteins are now produced by recombinant DNA technology, e.g. human growth hormone, human insulin, altaplase, interferon, etc. Monoclonal antibodies, regulator peptides, erythropoietin and other growth factors are the newer drugs of biotechnological origin. Protein therapeutics is rapidly expanding, because specifically designed and customized proteins can now be produced.

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