Drug Absorption and Distribution

Unless a drug acts topically (i.e., at its site of application), it first must enter the bloodstream and then be distributed to its site of action.The mere presence of a drug in the blood,however,does not lead to a pharmacological response.To be effective, the drug must leave the vascular space and enter the intercellular or intracellular spaces or both.The rate at which a drug reaches its site of action depends on two rates: absorption and distribution.Absorption is the passage of the drug from its site of administration into the blood; distribution is the delivery of the drug to the tissues.To reach its site of action, a drug must cross a number of biological barriers and membranes, predominantly lipid. Competing processes, such as binding to plasma proteins, tissue storage,metabolism,and excretion (Fig.3.1),determine the amount of drug finally available for interaction with specific receptors

PROPERTIES OF BIOLOGICAL MEMBRANES THAT INFLUENCE DRUG PASSAGE :-

                      Although some substances are translocated by specialized transport mechanisms and small polar compounds may filter through membrane pores, most foreign compounds penetrate cells by diffusing through lipid membranes. 

 =A smaller component consists of glycoproteins or lipoproteins that are embedded in the lipid matrix and have ionic and polar groups protruding from one or both sides of the membrane.

= This membrane is thought to be capable of undergoing rapid local shifts,whereby the relative geometry of specific adjacent proteins may change to form channels, or pores.

=The pores permit the membrane to be less restrictive to the passage of low-molecularweight hydrophilic substances into cells.

= In addition to its role as a barrier to solutes,the cell membrane has an important function in providing a structural matrix for a variety of enzymes and drug receptors.The model depicted is not thought to apply to capillaries.

Physicochemical Properties of Drugs and the Influence of pH:-

=The ability of a drug to diffuse across membranes is frequently expressed in terms of its lipid–water partition coefficient rather than its lipid solubility per se.

=This coefficient is defined as the ratio of the concentration of the drug in two immiscible phases: a nonpolar liquid or organic solvent (frequently octanol),representing the membrane; and an aqueous buffer, usually at pH 7.4, representing the plasma.The partition coefficient is a measure of the relative affinity of a drug for the lipid and aqueous phases. 

=Increasing the polarity of a drug, either by increasing its degree of ionization or by adding a carboxyl, hydroxyl, or amino group to the molecule, decreases the lipid–water partition coefficient. 

=Alternatively, reducing drug polarity through suppression of ionization or adding lipophilic (e.g.,phenyl or t-butyl) groups results in an increase in the lipid–water partition coefficient. 

Metabolism and Excretion of Drugs

⇒Both metabolism and excretion can be viewed as processes responsible for elimination of drug (parent and metabolite) from the body. Drug metabolism changes the chemical structure of a drug to produce a drug metabolite, which is frequently but not universally less pharmacologically active. Metabolism also renders the drug compound more water soluble and therefore more easily excreted.

Drug excreation

⇒Drug metabolism reactions are carried out by enzyme systems that evolved over time to protect the body from exogenous chemicals. The enzyme systems for this purpose for the most part can be grouped into two categories: phase I oxidative or reductive enzymes and phase II conjugative enzymes. Enzymes within these categories exhibit some limited specificity in relation to the substrates acted upon; a given enzyme may interact with only a limited number of drugs.Some nonspecific hydrolytic enzymes, such as esterases and amidases, have not received much research attention. The focus of this discussion therefore is on phase I and phase II reactions and the enzymes that carry out these                                                                             processes.

MEtabolism of drugs

⇒The cytochrome P450 (CYP450) enzyme superfamily is the primary phase I enzyme system involved in the oxidative metabolism of drugs and other chemicals.These enzymes also are responsible for all or part of the metabolism and synthesis of a number of endogenous compounds,such as steroid hormones and prostaglandins. 

⇉Substrate Specificity of the CYP Enzymes፦

                                                                 CYP3A4 is thought to be the most predominant CYP isoform involved in human drug metabolism, both in terms of the amount of enzyme in the liver and the variety of drugs that are substrates for this enzyme isoform.

⇒This isoform may account for more than 50% of all CYP-mediated drug oxidation reactions,and CYP3A4 is likely to be involved in the greatest number of drug–drug interactions. The active site of CYP3A4 is thought to be large relative to other isoforms, as evidenced by its ability to accept substrates up to a molecular weight of 1200 (e.g., cyclosporine). 

⇒This active site size allows drugs with substantial variation in molecular structure to bind within the active site.However,the fact that two drugs are metabolized predominantly by CYP3A4 does not mean that coadministration will result in a drug–drug interaction, since drugs can bind in different regions of the CYP3A4 active site, and these binding regions may be distinct.In fact,it is believed that two drugs (substrates) can occupy the active site simultaneously,with both available for metabolism by the enzyme.

✱Regulation of the CYP Enzymes ፦

CYP450 enzymes can be regulated by the presence of other drugs or by disease states.This regulation can either decrease or increase enzyme function, depending on the modulating agent. These phenomena are commonly referred to as enzyme inhibition and enzyme induction,respectively.

1.Enzyme Inhibition፦

                                Enzyme inhibition is the most frequently observed result of CYP modulation and is the primary mechanism for drug–drug pharmacokinetic interactions. The most common type of inhibition is simple competitive inhibition, wherein two drugs are vying for the same active site and the drug with the highest affinity for the site wins out.

=A second type of CYP enzyme inhibition is mechanism-based inactivation (or suicide inactivation).In this type of inhibition, the effector compound (i.e., the inhibitor) is itself metabolized by the enzyme to form a reactive species that binds irreversibly to the enzyme and prevents any further metabolism by the enzyme. 

                     

 2.Enzyme Induction ፦          

                                   Induction of drug-metabolizing activity can be due either to synthesis of new enzyme protein or to a decrease in the proteolytic degradation of the enzyme.Increased enzyme synthesis is the result of an increase in messenger RNA (mRNA) production (transcription) or in the translation of mRNA into protein. Regardless of the mechanism,the net result of enzyme induction is the increased turnover (metabolism) of substrate.

☆CONJUGATIVE ENZYMES: PHASE II REACTIONS ፦

⇒Phase II conjugative enzymes metabolize drugs by attaching (conjugating) a more polar molecule to the original drug molecule to increase water solubility, thereby permitting more rapid drug excretion.This conjugation can occur following a phase I reaction involving the molecule, but prior metabolism is not required. The phase II enzymes typically consist of multiple isoforms, analogous to the CYPs, but to date are less well defined.

 

✱Glucuronosyl Transferases፦

⇒Glucuronosyl transferases (UGTs) conjugate the drug molecule with a glucuronic acid moiety,usually through establishment of an ether, ester, or amide bond. 

Glucuronosyl Transferases 

⇒Typically this conjugate is inactive, but sometimes it is active. For example, UGT-mediated conjugation of morphine at the 6- position results in the formation of morphine-6-glucuronide,which is 50 times as potent an analgesic as morphine.

✱N-Acetyltransferases፦

⇒As their name implies, the N-acetyltransferase (NAT) enzymes catalyze to a drug molecule the conjugation of an acetyl moiety derived from acetyl coenzyme A. 

N-Acetyltransfrases

⇒The net result of this conjugation is an increase in water solubility and increased elimination of the compound.The NATs identified to date and involved in human drug metabolism include NAT-1 and NAT-2.Little overlap in substrate specificities of the two isoforms appears to exist. 

Mechanisms of Drug Action

DYNAMICS OF DRUG–RECEPTOR BINDING፦ 

 The drug molecule, following its administration and passage to the area immediately adjacent to the receptor surface (sometimes called the biophase), must bond with the receptor before it can initiate a response. Resisting this bond formation is a random thermal agitation that is inherent in every molecule and tends to keep the molecule in constant motion. Under normal circumstances, the electrostatic attraction of the ionic bond, which can be exerted over longer distances than can the attraction of either the hydrogen or van der Waals bond,is the first force that draws the ionized molecule toward the oppositely charged receptor surface. This is a reasonably strong bond and will lend some stability to the drug–receptor complex. 

DOSE–RESPONSE RELATIONSHIP ፦

To understand drug–receptor interactions, it is necessary to quantify the relationship between the drug and the biological effect it produces.Since the degree of effect produced by a drug is generally a function of the amount administered, we can express this relationship in terms of a dose–response curve. Because we cannot always quantify the concentration of drug in the biophase in the intact individual, it is customary to correlate effect with dose administered.

The principles derived from dose–response curves are the same in animals and humans. However, obtaining the data for complete dose–response curves in humans is generally difficult or dangerous.We shall therefore use animal data to illustrate these principles.

Mechanisms of Drug Action

☆THE CHEMISTRY OF DRUG–RECEPTOR BINDING ፦     

⇨Biological receptors are capable of combining with drugs in a number of ways, and the forces that attract the drug to its receptor must be sufficiently strong and long-lasting to permit the initiation of the sequence of events that ends with the biological response. Those forces are chemical bonds, and a number of types of bonds participate in the formation of the initial drug–receptor complex.

⇨The bond formed when two atoms share a pair of electrons is called a covalent bond. It possesses a bond energy of approximately 100 kcal/mole and therefore is strong and stable; that is, it is essentially irreversible at body temperature. Covalent bonds are responsible for the stability of most organic molecules and can be broken only if sufficient energy is added or if a catalytic agent that can facilitate bond disruption,such as an enzyme,is present.Since bonds of this type are so stable at physiological temperatures, the binding of a drug to a receptor through covalent bond formation would result in the formation of a long-lasting complex. 

⇨The formation of an ionic bond results from the electrostatic attraction that occurs between oppositely charged ions.The strength of this bond is considerably less (5 kcal/mole) than that of the covalent bond and diminishes in proportion to the square of the distance between the ionic species.Most macromolecular receptors have a number of ionizable groups at physiological pH (e.g., carboxyl, hydroxyl, phosphoryl, amino) that are available for interaction with an ionizable drug. 

Mechanisms of Drug Action

           ➤A fundamental concept of pharmacology is that to initiate an effect in a cell, most drugs combine with some molecular structure on the surface of or within the cell. This molecular structure is called a receptor.The combination of the drug and the receptor results in a molecular change in the receptor,such as an altered configuration or charge distribution,and thereby triggers a chain of events leading to a response.
           ➞ This concept applies not only to the action of drugs but also to the action of naturally occurring substances,such as hormones and neurotransmitters.Indeed,many drugs mimic the effects of hormones or transmitters because they combine with the same receptors as do these endogenous substances.
           ➞It is generally assumed that all receptors with which drugs combine are receptors for neurotransmitters,hormones, or other physiological substances.

           ➞ Thus, the discovery of a specific receptor for a group of drugs can lead to a search for previously unknown endogenous substances that combine with those same receptors.For example, evidence was found for the existence of endogenous peptides with morphinelike activity.A series of these peptides have since been identified and are collectively termed endorphins and enkephalins .

 ☆DRUG RECEPTORS AND BIOLOGICAL RESPONSES∶➞ 

         ➞ Although the term receptor is convenient, one should never lose sight of the fact that receptors are in actuality.

➞molecular substances or macromolecules in tissues that combine chemically with the drug. Since most drugs have a considerable degree of selectivity in their actions, it follows that the receptors with which they interact must be equally unique.

➞Thus,receptors will interact with only a limited number of structurally related or complementary compounds. The drug–receptor interaction can be better appreciated through a specific example.

➞The end-plate region of a skeletal muscle fiber contains large numbers of receptors having a high affinity for the transmitter acetylcholine. 

➞Each of these receptors, known as nicotinic receptors, is an integral part of a channel in the postsynaptic membrane that controls the inward movement of sodium ions.

➞.The acetylcholine combines with the receptors and changes them so that channels are opened and sodium flows inward. 

➞The more acetylcholine the end-plate region contains, the more receptors are occupied and the more channels are open.When the number of open channels reaches a critical value, sodium enters rapidly enough to disturb the ionic balance of the membrane,resulting in local depolarization. 

➞The local depolarization (end-plate potential) triggers the activation of large numbers of voltage-dependent sodium channels, causing the conducted depolarization known as an action potential.

➞The action potential leads to the release of calcium from intracellular binding sites.