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Introduction
Pharmacology can be broadly defined as the science dealing with interactions between living systems and molecules, especially chemicals introduced from outside the system. This definition thus includes medical pharmacology, the science of materials used to prevent, diagnose and treat disease as well as the important role played by chemicals in the environment that cause disease and the use of certain chemicals as molecular probes for the study of normal biochemistry and physiology. Toxicology is that branch of pharmacology that deals with the undesirable effects of chemicals in biologic systems.

The nature of drugs

A drug is any small molecule that, when introduced into the body, alters the body's function by interactions at the molecular level. Hormones are properly considered drugs whether introduced from outside the body (exogenous) in any amount or released internally in increased amounts by administration of a stimulant agent. Xenobiotics (from Gr. Xenous "stranger") are chemicals that are not synthesized in the living system but must be introduced into it from the outside. Drugs vary in molecular size: Molecules as small as carbon monoxide and lithium ion and as large as thrombolytic enzymes fall within the above functional definition. The great majority of drugs fall into the molecular weight range of 100-1000. There is a reason for this: As noted below, a drug is often introduced for practical reasons into a part of the body remote from the target tissue. To be absorbed and distributed to the target organ, the drug molecule must be capable of diffusion (or transport by carrier mechanisms). With some excep ons, molecules within the narrow range of MW100 -1000 are capable of convenient administration and efficient absorption and distribution. Drugs vary in shape: The shape of a drug is important because the vast majority of drugs interact with specific receptor sites on macromolecules in the body. The shape of the receptor site determines what kinds of drugs molecules may interact with it; the shape of the drug must be complementary to the shape of the receptor site to produce an optimum fit.

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While variation in shape is an obvious result of differences in the number, identity, and interconnections of the atoms that comprise the drugs, more than 25% of the drugs in use are chiral molecules; that exist in stereo isomeric pairs. Just as right and left gloves are usually not interchangeable, members of chiral drug pairs usually differ markedly in their effects on the body and often differ in the way they are eliminated from the body. For example, the S (+) enan omer of methacholine, a parasympathomime c drugs, is over 250 mes more potent that the R (-) enantiomer. Drugs also vary in their chemical nature On one hand, there are highly reactive anticancer alkylating agents such as mechlorethamine; on the other, nearly "inert" anesthetic gases such as xenon. The various classes of organic compounds, carbohydrates, proteins, and lipids, are all represented. Many drugs are weak acids or weak bases. This fact has important implications for the way they are handled by the body, since the pH differences between different compartments of the body may alter the degree of ionization of such compounds (see below).

Drug-body interactions
The interactions between a drug and the biologic system are divided into two classes: a- Pharmacodynamic interactions: the effects of the drugs on the body; and b- Pharmacokinetic interactions: the way in which the body handles the drugs The quantitative aspects of pharmacodynamics, the drug receptor concept and dose- response relationships, the principles of pharmacokinetics, absorption, distribution, metabolism, and elimination are presented later. Some of the introductory concepts used in discussing these interactions are presented in this chapter.

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Types of therapy
Specific, rational, or causal therapy: means the treatment of the cause of the disease, e.g. antimalarials. Prophylactic therapy: this is mainly directed to prevent the incidence of the disease, before exposure to the infection e.g. the vaccines or the prophylactic use of antimalarials. Suppressive therapy: means prevention of the appearance of the clinical picture of the disease, although the subject may have already been infected by an invading organism e.g. the use of antimalarials as suppressive agents. Empirical therapy: sometimes the drug may be used with a certain degree of success for treating the manifestations of the disease but its exact mechanism of action is not known e.g. the use of ergotamine in treatment of migraine. Substitution therapy (replacement therapy): includes the substitution and replacement of a substance lost e.g. chlorides in vomiting, blood transfusion, etc. Supportive therapy: is a supplementary type of therapy aiming at maintaining the general conditions and the vital body functions of the patient while carrying on the specific treatment, until the critical episode of the disease passes off. Expectant therapy: It aims at maintaining a good general condition of the patient and taking care of him until a diagnosis is made. Symptomatic therapy (palliative therapy): means the treatment or the relief of the symptoms regardless the cause of the disease e.g. relieving headache by aspirin.

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PHARMACODYNAMICS Definition
means what drugs do to the body (pharmacological effects) and how drugs do it (mechanisms of drug action).

Mechanisms of drug action

Most drug acts by altering the body's control systems that mediate body functions. Other drugs may act through chemical or physical mechanisms or interference with normal metabolic pathways.

Body control systems:

These are the targets for drug action or called the regulatory proteins e.g. a) Receptors b) Ion channels c) Enzymes d) Carrier molecules

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A Receptors
Definition:
are protein macromolecules on the surface or within the cell that combine chemically with small molecules (ligands) and produces physiological regulatory functions. Receptors could be isolated and characterized biochemically

N.B.

Ligand is any chemical substance that combines with the receptors and produces an effect. The receptor produces an effect only when the ligand is bound, otherwise it is functionally silent. Ligands that activate the receptors are called agonists, ligands that combine the same site without causing activation are called antagonists. The combination of the agonist with the receptor result in a molecular change in the receptor and thereby triggers a chain of events leading to a response.

Types and molecular structure of receptors There are four types of receptor families classified according to the nature of the receptor-effector linkage or cellular signaling system. In general receptors are composed of multiple subunits, each subunit is a glycoprotein. The subunits are arranged as interacting helices that penetrate the cell membrane completely.

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Each receptor is composed of extra-cellular amino terminus (ligand binding domain) and an intracellular carboxy terminus (effector domain) and some contains another long cytoplasmic loop. A. Direct ligand-gated channel type receptors Are receptors for fast neurotransmitters (milliseconds) e.g. nicotinic ACh receptors and GABA receptors couples directly to an ion channel. composed of five subunits, each a glycoprotein. These subunits are arranged as interacting helices that penetrate the cell membrane completely and surround a "central pit" that is a sodium ion channel. The binding sites for A.Ch are located on one of the subunits that project extracellulary from the cell membrane. This binding induces a conformational change in the glycoprotin whereby the side chains move away from the center of the channel, allowing sodium ions to enter the cell through the channel i.e. the glycoproteins of the nicotinic receptors forms the walls and the gate of the ion channel.

G-protein coupled receptors Are receptors for many hormones and slow transmitters (seconds). They couple to effector systems via G-protein e.g. muscarinic acetylcholine receptors, adrenergic receptors, dopamine receptors, 5-H.T receptors, opiate receptors, peptide and purine receptors.

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Structure: o Most of these receptors consist of seven transmembrane subunits. o Both the extracellular amino terminus and the intracellular carboxy terminus vary greatly in length. o Another highly variable region is the long third cytoplasmic loop which is the site that couples to the G-protein (guanine nucleotide binding proteins). The family of G-proteins is subdivided into stimulatory G-protein and inhibitory G-protein subfamilies.

Stimulatory G-protein (GS): o receptors which trigger Gs include 1 and 2 adrenoceptors, H2 histamine, A2 adenosine, D1 dopamine...etc. o Activation of adenylate cyclase (effector) through Gs enables it to catalyze the conversion of ATP to cAMP, which in turn can activate a number of enzymes known as kinases. Each kinase phosphorylates a specific protein(s). o Such phosphorylation reactions are known to be involved in the opening of some calcium channels as well as activation of other enzymes. Receptor coupled G-proteins can directly influence ion channel functions. Receptor coupled G-proteins can activate membrane phospholipase C enzyme (PLC): o PLC catalyses the forma on of two intracellular messengers, Ins. P3 (inositol triphosphate) and DAG (diacylglycerol) from membrane phospholipids. o Inositol P3 acts to increase free cytosolic calcium by releasing calcium from intracellular compartments.

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o Increased free calcium initiates many events, including contraction, secretion, enzyme activation and membrane hyperpolarization. DAG activates protein kinase C, which controls many cellular functions by phosphorylating a variety of proteins. Receptor-coupled-G-proteins also controls the following: o Phospholipase A2 (and thus the forma on of arachidonic acid and eicosanoids). o Guanylate cyclase (which forms cGMP). o Ion channels (e.g. K+ and Ca++ channels, thus affecting membrane excitability, transmitter release, contractility... etc.) Fig. 7 shows that G-proteins have the capacity to bind guanosin triphosphate (GTP) and hydrolyze it to guanosine diphosphete (GDP). The energy liberated allows G-proteins to couple a target protein (effector) e.g. enzyme or ion channel.

Inhibitory G-protein (GI): o receptors which trigger GI include 2 adrenoceptor, A1 adenosine, D2 dopamine, muscarinic receptors, opiate receptors...etc. o Stimulation of these receptors trigger GI which inhibits adenylate cyclase (effector) leading to decrease cAMP and inhibition of specific protein kinase o GI also mediate stimulation of phospholipase C and regulation of K+ and Ca++ channels.

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Gq is not yet well defined.

B. Tyrosine kinase-linked receptors are receptors for various hormones (e.g. insulin) and growth factors that incorporate directly to tyrosine kinase in their intracellular domain. have very large extracellular binding domain connected via a single-helix to a catalytic region (intracellular protein kinase). involved mainly in events controlling gene transcription by phosphorylating target protein on tyrosine residues. C. Intracellular steroid receptors are receptors for corticosteroids and thyroid hormones. regulate DNA transcription.

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are soluble cytosolic or nuclear proteins, so ligands must first enter cells. Effects are produced as a result of increased protein synthesis and thus are slow in onset.

DRUG-RECEPTOR BINDING
Chemistry of drug receptor binding
The drug molecule, following its administration and passage to the area immediately adjacent to the receptor surface (BIOPHASE) must form bonds with the receptor before it can initiate a response. There are 3 main types of bonds: The ionic bonds: It is the first force that draws the ionized drug molecules towards the oppositely charged receptor surface. It is exerted over a long distance. It is reasonably strong bond (5 Kcal / mol) It is reversible (can dissociate). It is responsible for most drug receptor interactions. The hydrogen bonds: It reinforces the ionic bond for significant receptor activation to occur. It is exerted over a short distance. It is a weak and reversible bond (2 Kcal / mol). It has a significant role in establishing the selectivity & specificity of receptors and the structure activity relationships The covalent bonds: It is a union between two atoms by sharing a pair of electrons. It is very strong bond (100 Kcal / mol). It is irreversible at body temperature (can not dissociate). It is useful in anticancer and antibiotic drugs.

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It is dangerous when environmental pollutants combine covalently with cellular constituents resulting in mutagenesis and carcinogensis.

Biological responses to drug receptor binding

A. Agonist effect The first step in drug action on specific receptors is the formation of a reversible drug-receptor complex The reaction is being governed by the " Law of Mass Action " which states that ( the rate of a chemical reaction is proportional to the product of the concentrations of reactants). K1 K3 A+R AR Response K2 A: Agonist R: Receptor K1: Rate of association between the agonist and the receptor. K2: Rate of dissociation of the agonist from the receptor. K3: Is the response of the effector organ to the AR complex i.e. the efficacy. K1/K2: Associa on and dissocia on between A & R i.e. affinity( which is the capacity of the the agonist to combine with the receptor).

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From both curves you can notice that, as the dose increases the response increases and binding increases tell certain extent after which the response remains unchanged. B. Antagonist effects This means that the effect of one drug diminishes or completely abolished in the presence of another. Antagonism could be produced by a lot of mechanisms e.g. chemical, physiological, pharmacokinetis and by receptor block. Receptor block: o Pure pharmacologic antagonists bind to receptors without directly altering the receptor function, but it prevents the binding and blocks the biologic actions of agonist molecules. o Antagonism produced is either reversible or irreversible. 1- Reversible antagonism (Competitive antagonism): This means that in presence of a fixed concentration of agonist, increasing the concentration of competitive antagonist progressively inhibit the agonist response. In presence of a fixed dose of antagonist the agonist concentration effect curve has the same maximal response (E.max) i.e. surmountable as does the curve seen in the absence of antagonist, however, concentrations of agonist required for producing any given level of effect are increased, and the curve is shifted to the right. 2- Irreversible antagonism (Non-competitive antagonism): Here the antagonist affinity to the receptor is very high that the receptor is unavailable for binding of the agonist because the antagonist dissociates from the receptor very slowly or not at all. High concentrations of the agonist can not overcome the antagonism and the maximal agonist response can not be obtained i.e. non surmountable The duration of action of irreversible antagonist is relatively independent of its own rate of clearance and more dependent upon the rate of turnover of receptors molecules i.e. regeneration of new receptors.

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Partial agonist It is that agonist that produces a lower maximal response, at full receptor occupancy, than do full agonist i.e. (resemble curves of full agonist in the presence of irreversible antagonist).

B Ion Channels
They are protein structures located on the cell membrane. Ion channel modulation by drugs: o Ion channels could be physically blocked by the drug molecule (voltage gated ion channel) e.g. blocking of the Na+ channel by local anaesthetic. o Ion channel opens only when the receptor that forms the ion channel in its center (as part of its structure) is occupied by an agonist (Ligand gated ion channel) e.g. nicotinic ACh receptor associated Na+ channel. o The gating (opening or closure) of the ion channel could be influenced by a drug whose receptor is part of the ion channel. It is a chemical change in the channel and not a simple physical block as mentioned in item 1. o Ion channels could open when the intracellular ATP concentration drops. This is called ATPase sensitive ion channel e.g K+ channels in the membrane of the pancreatic beta cells which secretes insulin when the plasma glucose rises.

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C Enzymes
Drugs may alter enzyme activity by several mechanisms. The alteration of the enzyme activity produced is reflected on the patient as the pharmacological effect of the drug e.g. 1) The drug may act on the enzyme itself by competition with its normal substrate for the active binding sites on the enzyme. e.g the action of neostigmine on acetylcholine esterase enzyme. 2) The drug molecule may inhibit the enzyme by covalent binding with the structure of the enzyme (irreversible binding). e.g effect of organophosphorus compounds on the acetyl choline esterase enzymes. 3) The drug may act as false substrate on which the enzyme acts and produces a totally different chemical. e.g -methyl dopa which is transformed into -methyl nor-epinephrine. 4) The drug may stimulate the formation of the enzyme or the activity of the enzymes (enzyme inducers) or inhibit the activity of the enzyme or decrease its formation (enzyme inhibitors).

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N.B.

In step No.1, increasing the dose of either the drug or the normal substrate reverses the effect of each other. In step No.2, the inhibition of the enzyme is irreversible, and for the body to gain the function of the enzyme again, it has to resynthetize it again instead of the irreversibly inhibited enzymes.

D Carrier Molecules
These are proteins, which has recognition sites specific for a particular permeating species. Drugs could block these transport sites. In general carrier proteins are usually needed when the ions or small organic molecules that will cross the cell membranes are insufficiently lipid soluble i.e. too polar e.g. i. Transport of glucose and amino acids into the cell. ii. Transport of ions and many organic molecules by the renal tubules. iii. Transport of Na+ and Ca++ out of the cells. iv. The uptake of neurotransmitter precursors e.g. choline or the neurotransmitter themselves.

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PHARMACOLOGICAL EFFECTS OF THE DRUGS

Whatever the mechanism of action of the drug is, there are dose response relationship between the different concentrations of the drug used and the response of the tissues to the drug. Study of these relationships is very important for clinical practice.

Dose response relationship curves and their importance A. Graded dose-response curves
In general, biological responses to drugs are graded, that is, the response continuously increases (up to the maximal responding capacity of the organ) as the administered dose is continuously increased. This means that the response to the drug is directly proportional to the number of

receptors interacting with the drug.

Importance
a) Calcula on of the ED50 (Eec ve dose 50%) : ED50 means the dose that produces 50% of the maximum response in one animal. If dierent drugs having a similar eect are given to the same animal, comparison of their ED50 gives an idea about their relative potency( i.e. the drug that produces the given effect with a smaller dose is more potent than the other). Potency is of limited clinical value because one might simply increase the dose of a less potent drug to obtain an identical therapeutic response. Other factors such as the severity and

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frequency of undesirable effects associated with each drug are more relevant factors in the choice between similar drugs. In Fig. 10A, drug (a) is more potent than drug (b). Comparing ED50 of dierent drugs on the same animal gives an idea about the equieffective doses i.e. the doses that produce the same effect. Comparing the ED50 of the same drug in dierent animals or (pa ents) gives an idea about the relative sensitivity of animals to the same drug i.e. the degree of biological variation in a population of such animals(Fig. 10B). b) Calculation of the maximum response: Maximum response means the maximum responding capacity of the responding system. Drug (c) has a lesser maximum effect than either drug (a & b) Intrinsic activity: o Comparing the maximum response obtained by different drugs on the same organ gives an idea about their intrinsic activity. o Drug (c) has a lesser maximum effect than either (a) or (b). Drug (c) has a lower intrinsic activity than the other two drugs. In other words, drugs (a & b) are full agonists with an intrinsic ac vity of 1; drug (c) is called par al agonist and has an intrinsic ac vity of because it has half the maximum effect of (a) or (b). c) Determination of the steepness of the dose response: steep dose response curve like curve (a) indicates that any small change in the drug concentration produces significant increase in the tissue response. This means that the maximum response to the drug could be reached very fast and the toxicity could be reached very fast too. Disadvantages of graded dose-response curve Graded dose response curve cannot be consulted if the effect of the drug is a quantal event i.e. prevention of convulsions or arrhythmias (all or non-effect). For this reason the quantal dose-response curve has been designed.

B. Quantal dose-response curve

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Here we determine the dose of the drug required to produce a specified magnitude of effect in a large number of individuals and plotting the percent of responders versus the log dose i.e. (all or non-effect). Anticonvulsants are an example of drugs that can be suitably studied by use of quantal doseresponse curves. For example, to assess the potential of a new anticonvulsant to control epileptic seizures in humans, these drugs are initially tested for their ability to protect animals against experimentally induced seizures. In the presence of a given dose of the drug, the animal either exhibits the seizure or does not; that is, it either has or has not been "protected". Thus in the design of experiment, the effect of the drug (protection) is all or none

Importance
a) Calcula on of the ED50 (eec ve dose 50%): ED50 means the dose that would protect 50% of the animals. The ED50 in Fig. 12A is approximately 4 mg/kg. b) Calcula on of the LD50(lethal dose 50%): LD50 means the dose that kills 50% of the population. Fig. 12B illustrates LD50 of phenobarbital. c) Determination of the therapeutic index of the drug: Since the degree of safety associated with drug administration depends on an adequate separation between doses producing a therapeutic effect and doses producing toxic effect one can use comparison between ED50 and LD50 to es mate drug safety i.e. the therapeu c index.

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LD50 Therapeutic index = ED50 As a general rule, a drug should have a high therapeutic index. This index is a very rough estimate of safety. d) Estimation of safety index: LD1 Safety index = ED99 LD1 = lowest dose that produces toxicity. ED99 = highest dose that produces a maximal therapeu c response. The higher the ratio, the safer is the drug. Fig (12A&B) indicates that phenobarbital ra o is approximately 2. A ratio less than unity would indicate that a dose eec ve in 99% of the popula on will be lethal in more than 1% of the individuals taking that dose. e) Estimation of the protective index: LD50 (undesirable eect) Protective index = ED50 (desirable eect) A drug with a protec ve index of 1 is useless, since the dose that treats the pa ent causes an unacceptable degree of side effects, while a drug with a high protective index would be more promising for clinical use. From the previous discussion it is easy to see that data derived from dose-response curves can be used in a variety of ways to compare the clinical usefulness of different drugs.

Factors modifying doseresponse relationship:

1- Age
response to drugs varies at the extremes of age. So a specific formulas for calculation of the dose of the drug are used in these ages.

2- Weight

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To gain the same response obtained in normal weight patients, the dose should be increased for over weight and decreased for under weight persons according to special formulas also.

3- Sex
Sometimes females are more susceptible to some drugs than males.

4- Pathological status
Liver diseases or kidney diseases could alter significantly the response of the patient to the therapeutic doses of drugs. This may be due to altered metabolism or elimination of the drug.

5- Time and route of drug administration

The time of administration is also related to the drug action e.g. o Irritant drugs should be given after meals to avoid gastric irritation. o Drugs required to produce immediate effects are given on empty stomach, e.g. antiemetics and anthelmintics. o Tetracyclines should not be given with milk or antacids since they form insoluble chelates with magnesium, calcium and aluminum salts (see chelation) Usually the intravenous dose is smaller than the oral one, and the onset of action is also quicker. The intramuscular and subcutaneous doses are also smaller than the oral but larger than the intravenous doses. Chronopharmacology: o Some enzymes responsible for metabolism of drugs are more active either in the morning or evening. o This must be considered in deciding the time of administration of drugs. o The drug which is metabolized to inactive metabolite by enzymes activated in the evening is better given in the morning and vice versa. o This approach helps us to reduce the dose given to the patient and to decrease the risks of the drug if these enzymes transform the drug to toxic metabolite.

6- Pharmacogenetic Factors (IDIOSYNCRASY)

Some heritable conditions due to genetic defects could alter the response of the individuals to drugs e.g.: A. Heritable conditions causing increased or toxic drug response: a. Pseudo cholinesterase deficiency: This leads to suxamethonium toxicity. (See neuromuscular blockers)

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b. Hereditary methemoglobinemia: It is due to deficiency of methemoglobin reducates enzyme. This enzyme is responsible for reduction of the oxidized hemoglobin (methemoglobin) to reduced hemoglobin. When methemoglobin accumulates in the circulation especially in presence of some drugs e.g. nitrates, it cannot be reduced and the patient gets cyanosed. c. Poor oxidation: Some persons have a limited capacity to oxidize drugs, thus they are at high risk of side effects of these drugs e.g. phenytoin, nortryptyline. d. Glucose -6- phosphate dehydrogenase deficiency: This enzyme is an important source of reduced NADPH which maintains erythrocyte glutathion in its reduced form. Reduced glutathion is necessary to keep Hb in the reduced form (ferrous) rather than in its (ferric) form i.e. methemoglobin, which is useless for oxygen carriage. Build up of methemoglobin in RBCs impairs the function of sulphhydryl groups, especially those associated with the cell membrane and leads to hemolysis of RBC's if they are exposed to certain oxidant drugs e.g. nitrates, some antimalarials, some antimicrobials and others. e. Malignant hyperthermia: It is a result of an inherited muscle disorder. After exposure to general anaesthetic agents, the patient develops muscular rigidity, high fever and lactic acidosis.(See CNS) f. Acetylator phenotypes: Acetyla on is an important route of metabolism of many drugs that possess an NH2 group. Two types of abnormal acetylators could be detected; Rapid acetylators and slow acetylators. Isoniazide causes two distinct forms of toxicity: i. One is peripheral neuropathy whose incidence is greater in slow acetylators due to interference with pyridoxine metabolism; for this reason, pyridoxine is added to the antituberculosis regimen. ii. The other is acute hepatocellular necrosis occurs more commonly in rapid acetylators and is related to formation of a hepatotoxic metabolite. Slow acetylators of procainamide develop systemic lupus erythematosus. B. Heritable conditions causing decreased drug response: a) Resistance to cumarin anticoagulants:

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Those patients have a variant of the enzyme that converts Vit.K to its reduced (active) form. Cumarins normally inhibits this step. Presence of this variant of the enzyme antagonizes the effect of cumarines and those patients need 20 mes the usual dose to get the response. b) Resistance to suxamethonium: due to increased cholinesterase activity. c) Resistance to Vit. D: individuals who exhibit this condition develop rickets that responds only to huge doses of Vit. D. d) Resistance to mydriatics: dark eyes are less responsive to mydriatics.

7- Hyporeactivity to drugs(tolerance, desensitization and drug resistance)

Tolerance: decreased response to the same dose of the drug after repeated administration. The same response may be obtained by higher doses. It occurs over a long period Tachyphylaxis: it is a type of tolerance, which occurs very rapidly. Desensitization: decreased response to the agonist after its repeated injection in small doses. These groups of hyporeactivity syndromes are still with poorly understood mechanisms. The most probable mechanisms for tolerance and tachyphylaxis are: i. Change in receptors o Slow conformational change in the receptor, resulting in tight binding of the agonist to the receptor without opening of the ion channels. ii. Loss of receptors: (down regulation) o Prolonged exposure to agonists results in gradual reduction of the number of receptors (slow process than the change in receptors) starts a er 8 hrs and the recovery takes several days n i case of isoprenaline. o Receptors are taken into the cell by endocytosis of patches of the membrane. iii. Exhaustion of mediators: o e.g. depletion of catacholamines e.g. amphetamine. iv. Increased metabolic degradation by enzyme induction:

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o Increased amount and activity of some enzymes by some drugs e.g (barbiturates). v. Physiological adaptation: o homeostatic response e.g. carbonic anhydrase inhibitors could diminish the effect of a drug. (See renal pharmacology). vi. Other factors: e.g racial, species, individual etc o Racial tolerance: e.g. ephedrine may not produce mydriasis when installed into the conjunctival sac of mongols. o Species tolerance: some animals are tolerance to certain drugs even in doses lethal to man, e.g. rabbits tolerate large amounts of atropine. o Individual tolerance: there may be, in some individuals, genetic variations enhancing certain drug metabolism.

8- Hyperreactivity to drugs(up-regulation of the receptors and overshoot phenomena or

hypersusceptibility) Known also as drug intolerance Antagonists and decreased number of agonists may raise the number of receptors in a cell by preventing down regulation caused by endogenous agonists. When the antagonist is withdrawn, the elevated receptor number allows an exaggerated response to physiological concentration of agonists e.g. severe tachycardia or arrhythemias which could occur after sudden withdrawal of propranolol. In this case, the dose must be reduced gradually. Adrenergic neuron blockers and ganglion blockers may produce the same phenomena. Adrenaline in thyrotoxic patients may produce the same phenomena.

9- Cumulation
This occurs when the rate of drug administration exceeds the rate of excretion or metabolism. Consequently, drugs accumulate in the body and eventually produce toxic effects. Cumulative drugs are thus those with a relatively slow excretion rate e.g. digitalis, thyroxin and heavy metal salts.

10- Drug Dependence

Drug dependence is a phenomenon that is related to tolerance. It may either take the form of habituation or addiction.

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a- Habituation: It describes the emotional or psychological dependence (psychic craving) for a drug. If the drug is stopped, the individual might develop some emotional distress for a relatively short period of time, but will finally recover, e.g. tobacco smoking, coffee and tea habits. b- Addiction: Addiction involves psychic craving for and physical dependence on a drug. Through the repeated administration of the drug, the body tissues gradually become accustomed to it to the extent that they even require the drug to function normally. When the drug is stopped, withdrawal symptoms or an abstinence syndrome occurs. Some of these symptoms are the reverse of the normal pharmacological actions of the drug and may sometimes be very severe. Examples of addictive drugs include morphine, ethyl alcohol, barbiturates... etc.

11- Drug Combination

More than one drug may be given to the patient either separate or in combination, in a mixture or in one preparation; this combination may be of value to produce a better therapeutic effect due to many reasons. Sometimes one drug may antagonize the side effects of the other, or the combined effects of one or more drugs may be more manifest. However, drug combinations should be practiced with care, otherwise, one drug may interfere with the metabolism of the other, increasing its toxicity. Drug combination may result in one of the following phenomena: Summation and addition: It means that the combined effects of two drugs are equal to the sum of their individual effects. If the mechanism of action of the drugs is the same, we usually define it as addition. Synergism or potentiation: This means that the combined effects of drugs may be greater than the sum of their individual effects. The two drugs usually have different mechanisms of action but they facilitate the pharmacological response of each othere.g. penicillin and aminoglycosides tThe use of ethyl alcohol with barbiturates or aspirin with phenobrobiton. Phenobarbiton has no analgesic action, but it potentiates the action of aspirin. Antagonism:

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Antagonism means the opposition of the actions of two drugs on the same physiological system and this can be of the following types: 1- Chemical antagonism: e.g. the antagonism between acids and alkalies, between potassium oxalate and calcium, etc. 2- Physical antagonism: e.g. the use of protamine sulfate, which is positively charged as an antidote for heparin, which is negatively charged. Also, the use of the dehydrating agents 3- Physiological antagonism: this occurs when the physiological effects of two endogenous substances acting on different receptors are opposing to each other, e.g. adrenaline and histamine. 4- Receptor Block(pharmacological antagonism): i- Competitive antagonism: (reversible antagonism): see before. ii- Non-competitive antagonism (Irreversible antagonism): see before.

12- Drug Interactions

See later.

Types of drug action:

A- Local action: At the point of application, e.g. demulcents, emollients, local anesthetics. B- General (systemic) action: By being transported by the blood e.g. diuretics. It may act also by reaching a certain concentration in a particular tissue, e.g. inhalation anesthetics. C- Reflex action: This usually a result of local application It may be central reflex action or segmental.

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