A. What are drugs? Pharmacology is the study of the interaction of chemical with the living systems.

Drugs are chemical substance which, by interacting with biological systems, are able to change them in some way.

*Contraction of muscles *Secretion by glands *The release of hormones *Alterations in nervous activity *killing cells , and many more The interactions are divided into two different subjects:

a. Pharmacodynamics : To study the effects of drug on the body i.e. what the drug does to the body. e.g. mechanism of drug action, side effects b. Pharmacokinetics: To study the process concerned with the distribution of drugs in the body and theirs absorption, excretion and , metabolism (ADME). i.e. what the body does to the drug (the conc.-time course of drug in the body) kinetikos = relating to motion pharmacokinetics=drug kinetics Since the drugs must get into the target site in order to act, the usefulness of a drug depend on both the above factors Drugs can be existed as *Inorganic substance e.g. mercury. lithium, gold, iodine, fluorine, and many simple molecules *Various organic substance e.g. hormone. Proteins, polysaccharides, polynucleotides The fact that drugs differ in their actions means that they must be selective in the biological structures with which they interact. The selective action (specificity) of a drug depends on forming a combination(binding) with certain tissue components (receptors).

B. Drug Mechanisms Major drug mechanisms: 1. Act by their physicochemical properties e.g. general anaesthetics, osmotic diuretics. (With non-specific actions) 2. Some act as false substrates or inhibitors for certain transport systems or enzyme. e.g. angiotensin converting enzyme (ACE) inhibitors, proton pump inhibitors (e.g. Losec) 3. Most drugs produce their effects by acting on specific protein molecules (receptors), usually located in the cell membrane.

For example, acetylcholine is a transmitter substance released from motor nerve endings and it activates receptors in skeletal muscle initiating a sequence of events that results in contraction of muscle * Agonist is the drug, hormone or transmitter substance that elicit a cellular response when it combines with receptors. * Antagonist combines with the receptor, but do not activate them. Antagonist s reduce the probability of the transmitter substance ( or another agonist) combining with the receptors and so reduce or block its action C. Drug - Receptors Interactions *Receptors are protein molecules which are normally located in the cell membrane . *They are normally activated by transmitters or hormone. *The interaction between a drug and the binding site of the receptor depends on the complementarity of fit the two molecule ( Lock and Key Hypothesis) *The closer the fit, the greater the number of bonds (usually non-covalent), the stronger will be the attractive forces between them, and the higher the affinity of the drug for the receptor. *The ability of a drug to combine with one particular type of receptor is called specificity . However , no drug is truly specific, if the drugs can also act on other receptors or systems, side effects are produced. D. Dose-Response Curve If the response is plotted against the drug concentration, a hyperbolic curve is often produced. If using the response against the logarithm of the agonist concentration, a sigma shaped log dose-response curve is plotted. However, the response = the occupancy????????? Rarely valid, the response is a complex, non-linear function of the occupancy. Thus , in addition to having affinity for the receptor, an agonist has another chemical property called intrinsic efficacy which is its ability to elicit a response when binds to a receptors. E. Receptor Interactions a. The agonists Agonists: activate the receptors when they occupy it. The ability of a drug molecule to activate the receptor is a continuously graded, rather than all-or-nothing. i.e. The maximal response (the largest response that can be produced by the drug in high concentration) differs from one drug to another. A full agonist is a drug that is capable, at a sufficiently high concentration, of producing a maximal cellular response. A partial agonist is an agonist whose maximum effect is less than the maximal response of which the tissue is capable. i.e. Even with the same affinity, the response at any given occupancy is much smaller, so

that it cannot produce a maximal response even at 100% occupancy. A decrease in efficacy. (When acting at receptors alone, partial agonists stimulate a physiological response, but antagonize the effects of a full agonist) b. The antagonist

( the antagonism by receptor block.) Antagonists: no activation when they occupy the receptor. i. Reversible competitive antagonism Reversible competitive antagonist : *A receptor antagonist also binds to the agonists receptor site and equilibrates sufficiently rapidly with the receptors that its occupancy is reduced when the agonist concentration is increased. *It causes the agonist log-conc. Parallel shifting the curve to the right without change in slope or maximum. ii. Irreversible competitive antagonism Irreversible competitive antagonist : *Bind to the agonist receptor site & forming strong bonding. *A receptor antagonist that dissociates from the receptor slowly or not at all. *The slope & maximum of the agonist log conc.-effect curve are likely to be reduced. iii. Non-competitive antagonism Non-competitive antagonist: *Do not bind to the same receptor sites as the agonist *Blocks the chain of event at some point that reduce its effect in some other way. So, the efficacy that varies between different agonists & expresses the ability of the agonistreceptor complex to elicit a physiological response. Efficacy is high for full agonist; low for partial agonist; zero for competitive antagonists. Also termed intrinsic activity. F. Receptor-Effector Linkage The cellular effects may be rapid e.g. synaptic transmittion (in ms) intermediate e.g. catecholamine (in sec.) very slow e.g. thyroid hormone (hours/ days) Three types of receptor-effector linkage can be recognized: a.. Direct regulation of membrane permeability to ions. *The fastest type of receptor- mediated response. *When a neurotransmitter acts on the post synaptic membrane of a nerve or muscle cell, and transiently increase its permeability to a particular ions by control the opening or closing of the ions channels. *Most excitatory neurotransmitters such as acetylcholine(Ach) at the neuromuscular junction, glutamate in the CNS---> cause increase of the Na+ & K+ permeability--> a net incurrent carried mainly by Na+ ions which depolarizes the cell & increases the probability of generating an action potential, their action reaches a peak in fraction of a microsecond and usually decays within a few millisecond.

b. Mechanisms involving a second messenger *The effect of an agonist on extracellular receptors is transmitted to the interior of the cell through the involvement of a second messenger: i. Cyclic-adenosine-3 5-monophosphate (cAMP) ii. Calcium ion *They regulate many different kinds of cellular activity, including: muscle contraction, relaxation, secretion, change in membrane permeability to various ions, transport mechanism & cell division. *In many cases, these cellular response are due to change in the state of phosphorylation of various intracellular protein by various specific protein kinases. c. Regulation of DNA Transcription * A characteristic of steroid hormones. *Certain regions of DNA sequence show a high affinity for particular steroid-receptor complexes *The binding of the complex to DNA switches on the process of gene transcription at a region of the DNA molecule several hundred base residues away from the region that binds the steroid-receptor complex. *An increase in RNA polymerase activity and the production of specific mRNA occur within a few minutes of adding steroid. *One steroid may result in the production of several different proteins, that leads to the great diversity of steroid actions.