Medicinal chemistry -1 for 3rd Sem University of Rajasthan syllabus UNIT 3

 Unit 3
 Pharmacodynamics and Pharmacokinetics

Objectives :

            The aim of this unit is to study the drug movement inside the outside the body. We also get knowledge about Pharmacokinetics, the quantitative study of drug movement inside, through and outside of the body is done. We also studied drug absorption by different ways, Distribution & disposition of drugs, excretion and elimination of drugs & Pharmacokinetics  of elimination and different Pharmacokinetics  in drugs development process has also studied.

            We will get knowledge of pharmacodynamics that deals enzyme stimulation, enzyme inhibition, sulphonamides, membrane active drug metabolism, xenobioties & significance of Drugs metabolites in medicinal chemistry.

Introduction

    Definition 
Pharmacodynamics is the study of drug effects, attempts to elucidate the complete effect of action, sequence and the dose effect relationship.

              Modification of the effects of one drug by another drug and by other factors is also a part of pharmacodynamics.

     Drug Action:

(a)  Stimulation:

(b) Depression:

(c)  Irritation:

(d) Replacement:

(e)  Cytotoxic Action

Drugs acting on receptors:

A drug which binds to a receptor and produces a maximum effect is called a full agonist. 

A drug which binds and produces less than a maximal effect is called a partial agonist. Partial agonists produce an effect if no agonist is present but act as antagonists in the presence of a full agonist.

Drugs which bind but do not activate a secondary messenger system are called antagonists. Antagonists can only produce effects by blocking access of the natural transmitter (agonist) to the receptor. Ion channel blockers act on the ion channel receptors associated with transporting ions (sodium, potassium, calcium) to and from cells. Drugs react with the receptors in channels to prevent the transport of ions. For drugs that are receptor agonists -when a drug is administered the response usually increases in proportion to the dose until the receptors are saturated.

 Example OLANZAPINE and NIFEDIPINE

Mechanism of Drug Action: Drug Action mechanism is classified into four parts:

(a)  Physical Action:

(b) Chemical Action:

(c)  Through Enzymes:

Enzyme stimulation:

     1 .Drugs are truly foreing substances. 

     2 .Stimulation of enzymes by drugs is unusual 

  3.The endogenous mediators mediators simulate the enzymes, e.g, pyridoxine acts as a cofactor and increase decarboxylase activity similarly aderenaline stimulates adenylyl cyclase 

    4.Stimulation of an enzyme enhances its affinity for the substrate, thus rate constant (Km) of the enzyme reaction decreases.

    5. Many drugs induce the microsomal enzymes e.g, enzyme penicilinase is obtained from a mould, and is induced by methicilin.

   6.Many insecticides, carcinogens, and drugs interact with DNA and increase the synthesis of microsomal enzyme protein, particularly glucuronyl transferase and cytochriome P-450

 Enzyme Inhibition

Enzymes are inhibited generally by drugs. Inhibition is of two types:

(a)   Non specific inhibition: Strong acids heavy metal Salts, phenols, alcohol, formaldehyde and alkalies inhibit enzymes inhibit enzymes non specifically. The chemicals and drugs change the tertiary structure of enzymes and denafure their protein portion and thus inhibit them.

(b)  Specific inhibition: Many drugs inhibit a specific enzyme without affecting others. This type of inhibition is categorized in two parts:

(1) Competitive inhibition (Equilibrium Type)

(2) Non competitive Inhibition

In this type, the drug competes with the normal substrate or coenzyme to get a new equilibrium. Substrate concentration is increased sufficiently, it can displace the drug and the same maximal reaction velocity can be obtained.

(A) Sulfonamides compete with para aminobenzoic acid (PABA) for bacterial folate synthetase.

(B) Carbidopa and methyldopa compete with levodopa for dopa decarboxylase.

(C)  Neostigmine and physostigmine compete with acetylcholine for cholinesterase.

(D) A Drug may also compete with coenzyme e.g, Warfarin competes with vitamin k which acts as a coenzyme for enzyme which synthesize clotting factors in the liver

(3) Noncompetitive inhibiton: in noncompetitive inhibition, the inhibiters react with an adjacent site but not with the catalytic site of enzymes. Inhibitor also changes the enzyme in such a way that it loses its catalytic property in such typc of inhibition km remains unchanged,

 Sulphonamides:

          In 1935 the daughter of Gerhand Domagk a doctor working in a German dye factory, suffered from severe streptococcal infection contracted from a pin prick. Domagk gave her an oral dose of a dye called prontosil which had shown to inhibit the growth of streploccci in  mice.Ernest fourneau in 1936 demonstrated that prontosil brcaks down to produce sulphanilamide in human body which is the actual active agent specifically lethal to streptococci.

 Membrane Active Drugs

          Membrane active drugs are volatile anesthetics and also known as general anesthetics. General anesthetics are depressant drugs which produce partial or total loss scnsc of pain, and may be accompanied by loss of consciousness. This state of insensibility is known as anesthesia; Membrane active drugs or general anesthetics act by depressing nervous function.

          To administer gas or volatile liquid anesthetics, various equipment and techniques have been used such as open drop method in which liquid anesthetic is dropped on gauze of other absorbent material supported on the patient’s nose and mouth by wire frame During the intake of an anesthetic, its concentration in the  blood supply and thus the brain rapidly acquires high concentration of anesthetic.

Types of membrane active Drugs: A number active drugs are described below.

Cyclopropane is also a currently used membrane active drug. But due to explosive nature its use has declined now a days.

1 Ethers:  alkane, alkene and alicylic eithers are potent membrane active drugs, but only vinly-substituted and ethyl-substituted ethers have been investigated as anesthetic drugs. Chain length increases, the anesthetic activity of low-molecular-weight hydrocarbon ethers increase. Divinyl ether and its analogs are not much important as anesthetic.

2 Halogenated anesthetic agents: Introduction of halogen atoms (Cl,Br,F) in membrane active increases anesthetic potency and decreases flammability. These drugs are as follows.

    Fluorinated hydrocarbons: Fluorinated hydrocarbons such as flurorene, methoxy flurane, isoflurane, and sevofluane are developed as perfect anesthetic.

3 Nitrous oxide: Nitrous  oxide is a lcast potcnt and least toxic membrane active drug.

4 ketamine hydrochloride: Ketamine hydrochloride e.g, 2-(o-chloropheny1)-2 methy 1- aminocyclo hexanone hydrochloride is a rapid-acting, potent, and a short duration membrane active drug. Accidental inhalation of trichloroethylene and 1, 1,1- trichloethane has been associated with brain damage,

 Drug Metabolism

After the pharmacological response, the drugs are required then excreted from the body, by enzymes of liver and various other tissue, the drugs may undergo a variety of chemical changes.

 The study of drug- metabolism and other xenobiotics,

Drug metabolism usually leads to detoxication, oxidation, reduction and other enzyme catalyzed reaction, therefore, may form a metabolite having toxic or therapeutic effects. Thus drugs and other chemicals such as some nature products. Food additives, insecticides, preservatives, environmental and agrochemicals etc, undergo enzymic transformation in the body, which generally cause the loss of pharmacological activity.

Although liver is the major site of drug metabolism however, some drug metabolizing enzymes are also found in kidney, lung, plasma, nervous tissue and the gastrointerstnal tract.

Liver disease should have an important effect on the metabolism of drugs. The capacity of drug metabolism is greatly affected in damaged or chronic diseased liver.

The ability of the liver to metabolize a substance in one pass is called first-pass effect or presystemic hepatic elimination.

The river can remove chemicals from the blood after their absorption from the gastrointestinal tract.

The principal route of drugs and their metabolites excretion occurs in the urine. If drugs  and other compounds are not metabolized.

Urine is not the only route for excreting drugs and their metabolites from the animal body. The other routes for excretion are:

(a) Bile

(b) Saliva

(c)  Lungs

(d) Sweat and

(e)  Milk

The bile has been recognized as a major route of excretion for various exogenous and endogenous substances.

Pathways of drugs Metabolism

(1)  Phase I Reaction : This is a biotransformation process and consists of oxidation, hydroxylation, reduction, and hydrolysis-enzymatic reactions. In phase I reaction, either a new functional group is introduced into the drug molecule or an preexisting functional group undergoes modification. Hence, drug becomes more polar and therefore it can be excreted more readily.

(2)  Phase 2 Reaction: The phase 2 reactions are conjugation reactions. These are enzymatic synthesis in which a functional group Is masked by the addition of a new group. Such groups are glucuronic acid. Certain amino acids, acetyl of sulfate groups. These groups increase the polarity of the drug and caused rapid excretion.

(3)  Dealkylation of Ether and Thioether : By a hydroxylation of the sulphur and oxygen alkyl groups, an acetal or thio-acetal are formed.

Microsomal Reductions: For the metabolism of drugs, some enzymes are capable of reducing azo nitro gropes of the drugs. These enzymes are found in microsomal systems. For example, the nitro group of hypnotic benzodiazepine, nitrazepam, gets reduced into the 7-amino derivative.

   The most important of these has been alcohol dehydrogenase which catalyses the oxidation of ethanol to acetaldehyde.

    Hydrolysis: In the brain, Kidney, blood liver microsomes and many other tissues esters and amides get hydrolysed by enzymes. The esters get slowly hydrolysed and may often get excreted unchanged or unhydrolysed.

Phase 2reactions-Conjugation

        

  The added group helps in blocking the functional group as well as.  Decreasing the lipophility of the molecule, hence facilitating its excretion. Formation of glucuronide, is a most common encountered conjugation reaction.

          Alcohols and phenols form ether type glucuronides, acids from acid type glucuronide, amines form N-glucuronides, while thiols give S-glucuronides. These glucuronides are more soluble in water and are more acidic than the starting drug, hence at normal pH they are more likely to be ionized and consequently even less lipophilic. Most of the elimination into the urine occurs via kidney.

          Glycine conjugation, acetylation and mercapturic acid formation are other types of conjugation of lesser importance.

Biotransformation

Chemical changes of the drug in the body is called biotransformation. It is important to convert non-polar, i.e., lipid soluble compounds into polar, i,e,. lipid insoluble, so that they may not be reabsorbed in the renal tubules and are exerted from the body. Many of the hydrophilic drugs, for example, neostigmine, decamethonium and streptomycin etc. can not be biotransformed and are excreted unchanged.

Types of Biotransformation Reactions

(1) Non synthetic reactions

(2) Synthetic reactions

(1)  Non synthetic Reactions

Non synthetic reactions form metabolite which may be either active of inactive. These are phase 1 reactions and can be classified as:

(A) Oxidation: Oxidation is the most important drug metabolizing reaction. This reaction involves addition of oxygen of removal of hydrogen. The example are oxygenation at C, N or S atoms, hydroxylation, Nor O-dealkylation, oxidative deamination etc.

Generally oxidative reactions are occurred by a group of monooxygenases in the liver.

Phenothiazines, barbituratcs, steroids, paracetamol; benzodiazepines, phenytoin, theophylline an many other drugs are oxidized in this way. Rate of metabolism of drugs.

(1)   CyP 3A 4/5 : About 50% drugs are blotransformed by this isoenzyme. It is available in liver, kidney and intestine.

Inhibitors : This is inhibited by many compounds such as clarithromycin, erythromycin, itraconazole, verapamil etc.

(2)CYP 2 D6: About 20% drugs get transformed by this isoenzyme.

(3)CYP 2C 8/9 Nearly>15 commonly used drugs including narrow safety margin drugs such as warfarin and phenytoin etc. Are metaboliced  by this enzyme.

(4) CYP 2 C 19: This enzyme metabolized about >12 frequently used drugs such as lansoprazole and omeprazole etc.

(2) Synthetic Reactions

These are phase 2 conjugation reactions. The metabolites formed by this biotransformations are mostly inactive. Synthetic reactions have high energy requirement. These involve conjugation of drug or its phase 1, metabolite with an endogenous substrate such as amino acids, of carbohydrate.

(a)   Glucuronide conjugation: This is a most important synthetic reaction where a compound which contains hydroxyl or carboxylic acid group can be easily conjugated with glucuronic acid.

(b) Acetylation: Compounds containing amino or hydrazine residues are conjugated with the help of acetyl coenzyme-A and show acetylation reaction e.g. sulfonamides, hydralazine, p-amino sulfanilamide, isoniazid etc.

Significance of Drug-metabolism In Medicinal Chemistry

The metabolic changed drugs have been of considerable interest and of great practical value in the search for new and improved medicines.

          The azodye, prontosil, which is inactive in vitro, is converted in the development of compounds which are acetylated t a lesser extent and whose acetylated derivatives are more soluble, hencereduce kidney damage to crystallization in the renal tubules.

          Other significance of drug development related to metabolism is analgesic properties of phenacetin i.e., p-ethoxy acetanilide which depends on its conversion by O-dealkylation to produce an active metabolite, acetaminophen I,e,. p-hydroxyacetanilide.

          Cholroguanide (paludrine), 1 (p-chlorophenyl)-5- isopropylbiguanide, shows its antimalarial activity only when it is converted into 1-(p_chlorophenyl)-2, 4-dimino-6-dimethyl-dihydro-3,3, 5-triazine by the human body.

          Arsine-oxide is a therapeutically useful compound resulted from arseno compound-As=As-, when it undergoes oxidation reaction. Arsine-oxide is although more toxic but a superior therapeutic compound developed by drug metabolism process. The introduction of mandelic acid as a genitor-urinary antiseptic drug showed the observation that it gets excreted unchanged and in the pH of urine, it has significant bactericidal properties.

          After metabolism process, the drugs may lead to the following way:

(a)  Inactivation: Most drugs and their active metabolites are rendered inactive or less active. For example chloramphenicol, morphine etc.

(b) Active metabolite from an active drug:

They also exhibit better bioavailability and other desirable pharmacokinetic properties.

Prodrug          active form

Sulindac        Sulfide metabolic.

Let us sum up:

After going through this unit, you would have achieved the objectives stated earlier. 

Let us recall what we have discussed so far:

·        Pharmacokinetics is the study of action and metabolism on drugs in the body. It deals with different aspects of absorption, distribution, biotransformation and elimination of drugs.

·        Drug elimination through lungs is important for gaseous anesthetics. The rate of elimination of drugs from the lungs is based on blood/air partition coefficient.

·        The transport mechanisms for acids &elimination is often termed drug disposition.

·        Clearance (CL) of a drug is theoretical volume of plasma from which the drug is completely removed in unit time.

·        The pharmacokinetic parameters consists of items like the determination of biological half-life, the apparent volume distribution, the rate consists for compartmental analysis includes the blood and urine.

·        Pharmacodynamics is the study of drugs effects attempts to elucidate the complete action-effect sequence and the dose effect relationship.

·        The stimulation of enzymes by drugs, that are truly foreign substances is unusual. Enzyme stimulation is relevant to may endogenous mediation and modulators. Stimulation of an enzyme increases its affinity for the substrate see that rate constant of the reaction decreases:

·        Inhibition of enzyme is a common mode of drug action, these are non specific and specific.

·        The prontosil breaks down to produce sulphanilarnide in human body. The sulpha drugs are derivatives of sulphanilamide & these were the first synthetic compounds found to be effective against pathogenic organisms.

·        Drug which inhibits cell wall synthesis si called active drug e.g. antibiotics.

·        Xenobiotics word is derived from greek ‘xenos’ word, means foreign and ‘bios’ means life. Any foreign substance to living systems is called xenobiotics. It include drugs, pesticides and carcinogens. Detoxification of such substances occur mainly in liver.

·        Biotransformation means chemical alteration of the drug is the body. The primary site for drug metabolism is liver, kidney intestine, lungs & plasms. Metabolic enzymes exist mainly is liver.