introduction to pharmacology

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PHARMACOLOGY:

PHARMACOLOGY DERIVATION:- The word pharmacology is derived from two Greek words i.e. PHARMAKON (an active principle or equivalent to drug, medicine or poison) and LOGIA (meaning study). MEANING:- Pharmacology means “The Science of Drugs”

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DEFINITION:- Pharmacology may be defined as the study of Effect of a drug (chemical) on the body (living system) It includes, History, Source, Physical and chemical properties, Compounding, Biochemical and Physiological effects, PK and PD, Therapeutic and other uses, precautions, Adverse effects, Interactions and Contra-indications of Drugs.

Subdivisions of pharmacology:

Subdivisions of pharmacology Pharmacotherapeutics deals with the use of drugs in the prevention and treatment of diseases and it utilizes or depends upon the information of drug obtained by pharmacodynamic studies. 3

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Toxicology – is the study of harmful effects of chemical on living organisms. Experimental Pharmacology – deals with the study of drug effects in laboratory animals. Clinical Pharmacology – deals with drugs effects in human beings. Neuropharmacology – deals with effects of drugs on Nerves. Chemotherapy deals with the effects of drugs upon microorganisms and parasites without destroying the host cells . 4

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Pharmacology is not concerned primarily with what the drug may be used for , but with what actions it has and what fate it encounters in the living organisms. 5

Pharmacology:

Pharmacology Pharmacokinetics What the body does to the drug (movement of the drug) Absorption Distribution Biotransformation Excretion Pharmacodynamics What the drug does to the body Mechanism of action Pharmacological actions Adverse effects Drug interactions

Drug:

Drug is a word derived from a French word ‘ Drogue’ which means dry herb . Any substance that brings about a change in biologic function through its chemical action Alters state in the body can’t create new function but alter existing function Are poisons if they used irrationally

DRUG NAMES:

DRUG NAMES Every drug has at least three names—a chemical name, a generic (nonproprietary or official) name, and a trade (proprietary or brand) name. The chemical name describes the atomic or molecular structure of the drug. This name is usually too complex and cumbersome for general use.

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So an official body assigns a generic name to a drug. The generic names for drugs of a particular type (class) usually have the same ending. For example, the names of all beta-blockers, which are used to treat such disorders as high blood pressure, end in "lol."

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The trade name/proprietary name is chosen by the pharmaceutical company that manufactures or distributes the drug. Patented drugs are usually sold under a trade name. Generic versions of trade-name drugs—manufactured after expiration of the pharmaceutical company's patent—may be sold under the generic name (for example, ibuprofen) or under the manufacturer's own trade name (for example, Advil).

DRUG GROUPS:

DRUG GROUPS Understanding what group a drug belongs to is also useful. Broadly, drugs are classified by therapeutic group—that is, by what disorder or symptom they are used to treat. For example, drugs used to treat high blood pressure are called antihypertensive, and drugs used to treat nausea are called antiemetic (emesis is the medical term for vomiting).

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Within each therapeutic group, drugs are categorized by classes. Some classes are based on how the drugs work in the body to produce their effect. For example, diuretics, calcium channel blockers, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors are all classes of antihypertensives that work differently.

DRUG USAGES:

DRUG USAGES Drugs have 3 medical uses. Therapeutic use : Drugs are used to control, improve or cure symptoms, conditions or diseases of a physiological or psychological nature. E.g of the therapeutic use of drugs include the following: Antibiotics to kill the bacteria that cause an infection Analgesics to control the pain and inflammation of arthritis Hormone replacement therapy for the symptoms of menopause

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Preventive use : Drugs are used to prevent the occurrence of symptoms, conditions or diseases. E.g of the preventive use of drugs include the following Vaccination for immunization against childhood diseases Drugs taken to prevent motion sickness prior to flying on an aeroplane

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Diagnostic use : Drugs are used by themselves or in conjunction with radiological procedures and other types of medical tests to provide evidence of a disease process. E.g.Radiopaque dyes used during x-ray procedures Drugs given to stimulate cardiac exercise in patients who cannot undergo regular exercise stress testing

Sources of drugs. :

Sources of drugs. Drugs are obtained from various sources. According to sources they are:- Natural drugs A/ Plants E.g. .Digoxin from Digitalis purpurea .Atropine from Atropa belladonna .Quinine from Cinchona officinalis B/ Animals E.g.. Insulin from pig .Cod liver oil from Cod fish liver. 16

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C/ Minerals E.g.. Iron, Iodine, Potassium salts. D/ Micro – organisms E.g. .Penicillin from penicillium notatum. .Chloramphenicol from Streptomyces venezuelae (Actinomycetes). 2. Synthetic drugs - prepared by chemical synthesis in pharmaceutical laboratories E.g.. Sulphonamides, quinolones, barbiturates 17

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3. Semisynthetic drugs - prepared by chemical modification of natural drugs. E.g.. Ampicillin from penicillin G. .Dihydroergotamine from ergotamine. 4. Biosynthetic drugs - prepared by cloning of human DNA in to the bacteria like E.coli. E.g.. Human insulin. 18

pharmacokinetics:

pharmacokinetics Pharmacokinetics and Dosage Regimens Determine: How much drug is in the body at any given time How long it takes to reach a constant level of drug in the body during chronic drug administration How long it takes for the body to rid itself of drug once intake of drug has stopped

Pk principles:

Pk principles In practical therapeutics, a drug should be able to reach its intended site of action after administration by some convenient route.so,drug should be absorbed into the blood from its site of administration distributed to its site of action, permeating through the various barriers that separate these compartments After bring about its effect, a drug should be eliminated at a reasonable rate -by metabolic inactivation or -by excretion from the body, or by a combination of these processes

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Drug at site of administration Drug in plasma Drug / metabolites in tissues Drug / metabolites in urine, feces , bile Absorption Distribution Elimination Metabolism Kidney Liver

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1,000 500 250 125 1 3 2 Half-life (plural half-lives) t 1/2 Half-life What is the percentage of drug left after 4.5 hours if its half-life is 1.5 hours? Question Conc

absorption:

absorption The transfer of substances from sites of administration to sc . Drugs get absorbed to systemic circulation after crossing different barriers -orally mucous membrane of gut capillary membrane of BV -injections capillary membrane of BV

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Mechanisms by which Drugs Cross Biological Membranes……..Cont Passive Diffusion: Vast majority of drugs cross membranes by passive diffusion Most lipid soluble drugs readily move across membranes (lipid diffusion) Drug moves across membranes according to concentration gradient No carrier is involved Not saturable Low structural specificity

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Mechanisms by which Drugs Cross Biological Membranes……..Cont Passive Diffusion…cont: Water-soluble drugs (MW 20,000 – 30,000) cross membrane through aqueous channels or pores (Aqueous diffusion) Drugs bound to large molecules such as albumin do not penetrate aqueous pores The capillaries of the brain and testes are characterized by absence of pores that permit aqueous diffusion of many drug molecules into the tissues (protection)

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Mechanisms by which Drugs Cross Biological Membranes……..Cont Active transport: Involves specific carrier protein A few drugs that closely resemble the structure of naturally occurring metabolites (structural specificity) Involves energy expenditure Drugs can move against concentration gradient Saturable

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Mechanisms by which Drugs Cross Biological Membranes……..Cont Endocytosis and Exocytosis: For large molecules Substance is engulfed by the cell membrane and carried into the cell by pinching off of the newly formed vesicle inside the membrane The substance can then be released inside the cytosol by breakdown of the vesicle membrane Iron and vitamin B 12 Exocytosis is a reverse process for the excretion of some substances outside the cell

Factors deciding Choice of Route:

Factors deciding Choice of Route Type of desired effect : systemic or local Physiochemical properties : solid or insoluble Rapidity of effect : oral, intramuscular (IM), intravascular (IV) Condition of patient : conscious or unconscious, vomiting 29

Classification of the Routes of Drug Administration:

Classification of the Routes of Drug Administration Enteral: Oral Sublingual Administration Rectal Administration Parenteral Injection: Intravenous (IV) Intramuscular (IM) Subcutaneous (SC) Intraarterial Intrathecal/intraventricular

Classification of the Routes of Drug Administration……Cntd:

Classification of the Routes of Drug Administration……Cntd Other Routes: Inhalation Intranasal Transdermal Topical Application: Mucous Membranes Skin Eye

Enteral Routes:

Enteral Routes The Oral (Per Os, PO): The most common route Most variable and requires the most complicated pathway to tissues Some drugs are absorbed from the stomach However, the duodenum is the major site of absorption Absorbed drugs enter the liver through the portal circulation before they are distributed in the general circulation: First-pass metabolism First-pass metabolism by intestine or liver limits the efficacy of many drugs e.g. Nitroglycerline

Enteral Routes……Cont:

Enteral Routes……Cont Advantages of the Oral Route: Most convenient Safe Economical

Enteral Routes……Cont:

Enteral Routes……Cont Disadvantages of the Oral Route: Needs patient cooperation Some drugs may become destroyed by -the gastric acidity e.g. penicillin -enzymes eg.insulin -micro flora Irritant drugs need to be coated Presence of food may delay absorption First pass effect limits availability of some drugs Presence of GIT diseases may limit absorption

Enteral Routes……Cont:

Enteral Routes……Cont Sublingual Route: Placement of the drug under the tongue Drug bypasses the intestine and the liver and therefore not inactivated by the metabolism (no first-pass effect)

Enteral Routes……Cont:

Enteral Routes……Cont Rectal Route: 50% Bypasses portal circulation (Drug avoids destruction by the liver enzymes) Good absorption Prevents drug destruction by low pH of the stomach and intestinal enzymes Good for drugs that might induce vomiting if given orally May be used for unconscious patients or if the patient is vomiting (commonly used to administer antiemitics)

Parenteral Routes:

Parenteral Routes Used for drugs poorly absorbed from the GIT Used for drugs unstable in the GIT Used for treatment of unconscious patients Used in circumstances that require rapid onset of action Only sterile solutions can be injected

Parenteral Routes…Cont:

Parenteral Routes…Cont Intravenous Route (IV): The most common parenteral route Used for drugs not absorbed orally Avoids first-pass effect Permits rapid onset of effect May be used for irritant drugs May be used inject large volumes like iv fluids May be used to administer drugs over a long period of time

Parenteral Routes…Cont:

Parenteral Routes…Cont Disadvantages of the IV Route: Only used for sterile solutions Difficult to control an administered dose Possibility of bacterial contamination Possibility of hemolysis Possibility of adverse reactions by too rapid delivery of high drug concentrations

Parenteral Routes…Cont:

Parenteral Routes…Cont Intramuscular Route (IM) : Aqueous solutions are injected IM Used for depot preparations (oily preparations, or special nonaqueous vehicles such as ethylene glycol). Irritant drugs may be given IM. Deltoid, vastus lateralis and gluteus maximus muscles are commonly used

Parenteral Routes…Cont:

Parenteral Routes…Cont Subcutaneous Route (SC) : Only used for drug not irritating to tissues. May be used for: depot drugs (implants; silastic capsules containing the contraceptive levonorgestrel) or sustain release drugs Absorption may be controlled through co-administration of a vasoconstrictor (Epinephrine)

Parenteral Routes…Cont:

Parenteral Routes…Cont Intraarterial (IA): Occasionally used when a drug effect is intended to be localized in a particular organ or tissue (treatment of liver cancer; diagnostic agents)

Parenteral Routes…Cont:

Parenteral Routes…Cont Intrathecal: Used for injection of certain drugs directly in the cerebrospinal fluid (CSF) when rapid and localized effect is intended in the meninges or the cerebrospinal axis: methotrexate in acute leukemia treatment of brain tumor spinal anesthesia acute CNS infections

Other Routes of Drug Administration:

Other Routes of Drug Administration Inhalation: Provides rapid delivery of drugs over the large surface area of the mucous membranes of the respiratory tract and pulmonary epithelium For Drugs which are gases (general anesthetics), or as aerosols. Convenient for patients with respiratory complaints such as asthma. Rapid onset of effect (as the IV)

Other Routes of Drug Administration:

Other Routes of Drug Administration Intranasal: Drugs taken by sniffing Desmopressin for the treatment of diabetes insipidus (banned in USA in 2007, pills are the alternative) Salmon calcitonin for treatment of ospeoporosis

Other Routes of Drug Administration:

Other Routes of Drug Administration Topical application: Mucous membranes: Drugs are applied on the mucous membranes of the conjunctiva, nasopharynx, oropharynx, vagina, urethra, urinary bladder to produce a local effect Good absorption to sites of action

Other Routes of Drug Administration:

Other Routes of Drug Administration Topical application: Skin: Drugs applied directly on the skin. Used when a local effect is desired. Absorption through the skin can be enhanced by preparing the drug in a cream or as an oily preparation. May be used for sustain release preparations (dermal patches) to achieve systemic effects. Eye: Used for ophthalmic drugs to produce local effects on the eye

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The process of drug absorption Absorption is the transfer of a drug from its site of administration to the blood stream The rate and efficiency of absorption depend on the route of administration For IV administration, absorption is complete as the total dose reaches the systemic circulation Other routes result in partial absorption and thus lower bioavailability

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The Effect of pH on drug absorption Most drugs are either weak acids or weak bases. Acidic drugs (HA) release a H + causing a charged anion (A - ) to form in basic media: HA H + + A - A weak acid is defined as a neutral molecule that can reversely dissociate into an anion (a negatively charged molecule) and a proton (a hydrogen ion) Factores affecting drug absorption

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The Effect of pH on drug absorption…Cont Weak bases (BH + ) can also release a H+; however, the protonated form of basic drugs is usually charged and loss of a proton produces the uncharged base (B). BH + B + H + A weak base is a is defined as a neutral molecule that can form a cation (a positively charged molecule) by combining with a proton

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Passage of unchanged drug through a membrane A drug passes through membranes more readily if it is unchanged as either weak acids or weak bases The effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms The ratio between the two forms is determined by the pH at the site of absorption and by its pk a value

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Determination of how much drug will be found on either side of a membrane Henderson-Hasselbalch equation: pH = pk a + log For acids: pH = pk a + log For bases: pH = pk a + log The equation is useful in determining how much drug will be found on either side of a membrane that separates two compartments that differ in pH [non-protonated species] [protonated species] [A - ] [HA] [B] [BH + ]

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Ion Trapping At steady state: An acidic drug will accumulate on the more basic side of the membrane. A basic drug will accumulate on the more acid side of the membrane. The phenomenon has obvious implications for the absorption and excretion of drugs

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Physical factors influencing drug absorption Blood flow to the absorption site. - Blood flow to the intestine is much greater than the flow to the stomach Total surface area available for absorption. - Intestine surface is rich in microvilli, it has a surface area about 1000 times that of the stomach. Contact time at the absorption surface. -Speed of movement through the GIT (diarrhea).

Other factors affecting absorption:

Other factors affecting absorption Dosage forms of the drugs Drug solubility Stress/pain Food Routes of administration The presence of other drugs

bioavailability:

Designated by: By ‘F’ Serum Concentration Time Injected Dose Oral Dose bioavailability Fraction of a drug that reaches systemic circulation after a particular route of administration

Bioavailability:

Bioavailability Dose Destroyed in gut Not absorbed Destroyed by gut wall Destroyed by liver systemic circulation

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Intravenous route of drug administration gives 100% bioavailability as it directly enters the circulation. “ F ” is equal to 1 Non i.v - ranges from 0 to 100%; value of “ F ” is equal or less than 1 e.g. lidocaine bioavailability - 35% → due to destruction in gastric acid and liver metabolism, hence not given orally The term bioavailability is used commonly for drugs given by oral route.

Why less Bioavaililbity for drugs given other than IV route?:

Why less Bioavaililbity for drugs given other than IV route? Because they undergo ….. FIRST PASS METABOLISM

Hepatic ‘First-Pass’ Metabolism:

Hepatic ‘First-Pass’ Metabolism Metabolism of drug in gut (liver) before drug reaches systemic circulation Drug absorbed into portal circulation, must pass through liver to reach systemic circulation Reduce the bioavailability of drug Orally administered drugs will have high FIRST PASS METABOLISM Parenteraly administered drugs will bypass the FIRST PASS METABOLISM to the major extent

distribution:

Circulation Membrane permeability Protein binding distribution After a medication is absorbed, it is distributedwithin the body to tissues and organs and ultimately to its specific site of action Rate and extent of distribution depend on the physical and chemical properties of medications and the physiology of the person taking the medication

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Apparent volume of distribution (aVd) :- is the hypothetical volume of body fluid into which a drug is uniformly distributed at a concentration equal to that in plasma, assuming the body to be a single compartment.

Factors affecting drug distribution / Vd:

Factors affecting drug distribution / Vd Physicochemical properties of the drug: Lipid soluble and unionized form of drugs readily cross the cell membrane and are widely distributed e.g.. lignocaine, propranolol, tricyclic antidepressants etc. Drugs like heparin (strongest acid in the body) is confined only to intravascular compartment as it exists in ionized form.

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Plasma protein binding : Acidic drugs bind to albumin, Basic drugs bind to  1 acid glycoprotein etc Clinical importance of Plasma protein binding : Free form Bound form Free form – Pharmacologically active Bound form - Pharmacologically inactive, acts as a “temporary store” of the drug

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Plasma protein binding favours drug absorption. Drugs which are highly bound to plasma proteins have a low volume of distribution. Plasma protein binding delays the metabolism of drugs. Bound form is not available for filtration at the glomeruli, hence delays its excretion.

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Highly protein bound drugs have a longer duration of action. In cases of poisoning, highly plasma protein bound drugs are difficult to be removed by Hemodialysis.

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Plasma protein binding can cause displacement interactions More than one drug can bind to the same site on albumin. The drug with higher affinity will displace the one having lower affinity and may result in a sudden increase in the free concentration of the drug

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Disease states: Eg: In CHF, the Vd of some drugs can increase due to increase in ECF volume or it could decrease due to reduced perfusion of tissues. Fat: lean body mass ratio : If the ratio is high, fat acts as a reservoir for certain drugs

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Redistribution Highly lipid soluble thiopentone → IV administration immediately gets distributed to areas of high blood flow - brain → general anaesthesia. In few minutes, it re crosses the BBB gets distributed to less perfuse tissues such as muscle, adipose tissue → termination of action Thiopentone Has a very short duration of action (5-10 min) and is used for induction of general anaesthesia.

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Drug reservoirs or tissue storage Tetracyclines : bones, teeth Thiopentone, DDT : adipose tissue Chloroquine : liver, retina Digoxin : heart Clinical importance of drug storage : Because of such storage, repeated exposure to some chemicals like DDT in small quantities may lead to chronic toxicity

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Blood Brain Barrier (BBB) The capillary boundary that is present between the blood and brain is called BBB Barbiturates, diazepam, volatile anesthetics, amphetamine etc – cross BBB

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Meningitis, encephalitis - increase the permeability of the BBB eg. penicillin in normal conditions has poor penetration through BBB, but its penetrability increases during meningitis and encephalitis.

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Placental Barrier : The lipid membrane between the mother and fetus is called placental barrier. Unionized and lipid soluble drugs can freely cross the placental barrier. e.g.. anesthetics, alcohol, morphine etc. Quaternary ammonium compounds cannot cross the placental barrier.

METABOLISM:

METABOLISM Mechanism by which a drug interacts with and is processed by the body. Process by which a drug is converted by the liver to inactive compounds (deactivated) through a series of chemical reactions. Also called biotransformation

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Metabolism First Pass Metabolism Occurs Primarily in the Liver and Gut

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Elimination After medications are metabolized, they exit the body through: Kidneys – most common (in urine) Liver Bowel Lungs Exocrine glands Bile Breast milk Elimination of a drug is usually affected by: Renal filtration Secretion Reabsorption The mechanism by which a drug leaves the body

Renal clearance:

Renal clearance Is the sum total of three renal process Rcl=RF+S-R Drug clearance -is the measure of the ability of the body to eliminate drug -it is the apparent volume of blood that is cleared of drug per unit time CL= rate of elimination/plasma concentration

Common terms:

Common terms Onset: The time after administration when the body initially responds to the drug Peak Plasma Level: The highest plasma level achieved by a single dose when the elimination rate of a drug equals the absorption rate Drug Half-Life (Elimination half-life): The time required for the elimination process to reduce the concentration of the drug to one-half what it was at initial administration

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88 PHARMACODYNAMICS Pharmacodynamics can be defined as the study of the biochemical and physiological effects of drugs and their mechanisms of action. How do drugs act? 1. Most drugs must bind to a molecular target in order to produce their actions. - most drug targets are protein molecules. - protein targets for drug binding. a- receptors b- ion channels c- enzymes d- carrier molecules (transporters).

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89 a) Ion channels minute pores present in the cell membrane. common ion channels are of Na+, K+, Ca +2 and Cl – are selective – for particular ion species have gating properties . Ligand – gated channels – activated by binding of a chemical ligand. . Voltage – gated channels – open when the cell membrane is depolarized.

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90 Ion – channels: Blockers . Calcium channel blockers. e.g. diltiazem . Sodium channel blockers. e.g. phenytoin, carbamazepine, lidocaine

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91 b) Enzymes Biocatalysts present in the cell Common target enzymes: cholinestrase (ChE) , monoamine oxidase (MAO), cyclooxygenase, (cox) angiotensin converting enzyme (ACE) etc. Inhibitor – normal reaction inhibited - competitive inhibitor e.g. captopril – acting on ACE normal reaction inhibited - non – competitive and irreversible inhibitor. e.g. aspirin – acting on COX. Activator . E.g. nitroglycerine activates guanylyl cyclase

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92 c) Carrier molecules (transporters). - T he transport of ions and small organic molecules across cell membranes generally requires a carrier protein, because permeating molecules are often too polar. Normal transporter Transport glucose and aminoacid, transport Na +1 and Ca +2 out of cells. Uptake of neurotransmitters precursor (e.g.choline). Inhibitor Na + /K + / 2Cl - – cotransporter e.g. diuretics – transport blocked (furosemide) Selective serotonine reuptake inhibitors (SSRI) e.g. fluoxetine

d)receptors:

d)receptors A receptor is a protein, which is embedded in a cell membrane that facilitates communication between the outside and the inside of a membrane It is the initial site of action of a biologically active agent such as neurotransmitter, hormone, or drug (all referred to as ligands )

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94 d) Receptors A macromolecular component of an organism that interacts with a drug and initiates the chain of events leading to the drug’s effect. Receptors are responsible for selectivity of drug action. (Size, shape, electrical change of drug determines binding to a receptor.) Receptors mediate the actions of both pharmacologic agonists and antagonists. Function as regulatory proteins & components of chemical signaling mechanisms that provides targets for important drugs. Receptors largely determine the quantitative relations between dose or concentration of drug and pharmacologic effect.

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95 Chemical bonds established during interactions between drug and its receptor * Ionic bond *Hydrogen bond *Hydrophobic interaction *Covalent bond is responsible for irreversible interaction.

Agonists vs antagonists:

Agonists vs antagonists After a medication binds to a receptor, the receptor helps to communicate specifics about the medication to the inside of the cell by generating a signal in the cell about the medication. A drug must be a close mimic of the neurotransmitter By binding to the receptor, medications can either augment or block the signal normally brought about by binding of the endogenous substance to the receptor Medications that augment or enhance a signal normally communicated in a cell are called agonist. Conversely, medications that block the transmission of a signal normally communicated in a cell are called antagonist

agonists:

= = = agonists An agonist is a drug which produces a stimulation type response. It activates or enhances cellular activity once bound to the receptor. The agonist is a very close mimic and fits with the receptor site and is thus able to initiate a response An agonist causes a particular effect by binding to the correct receptor

antagonist:

≠ ≠ ≠ What are competitive antagonists and partial antagonists? antagonist Antagonist drug interacts with the receptor site and blocks or depresses the normal response for that receptor because it only partially fits the receptor site and can not produce an effect. However, it does block the site preventing any other agonist or the normal neurotransmitter from interacting with the receptor site

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99 Response (effect) of drug Receptor interaction - If a drug has affinity for the receptor and if it is in close proximity of the receptor site, then receptor occupancy takes place. This drug, receptor interaction (coupling) leads to a variety of response (effects) depending on the nature of drug molecules, which are:- 1- Agonists:- are drugs that have the ability to activate a receptor by binding to a receptor. - have affinity for the receptors and efficacy/ intrinsic activity.

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100 a) Full agonists:- bind to the receptor and elicit maximal possible response. b) Partial agonists:- have affinity for the receptors but sub maximal efficacy. - Competitively antagonize the effect of a full agonists but in the absence of the agonist they can produce some responses (effect). E.g. Succinylcholine for acetylcholine.

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101

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102 2) Antagonists:- are drugs that antagonists or block responses (effects) of the concerned agonists. - They have affinity for receptors but no intrinsic activity. - Antagonism can be produced:- Binding of an antagonist to the same site on the receptor normally occupied by the agonist. The binding of the antagonist blocks the agonist occupancy of the site. Binding of an antagonist to site different from that normally occupied by the agonist (allosteric site). This either provents the agonist from binding or prevents the bound agonist from eliciting a response.

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103 Regulation of receptors Down regulation of receptors (Desensitization) - Prolonged administration of an agonist leads to decrease in number of receptors. - cause decreased tissue sensitivity. - leads to hypo activity (hyposensitivity) of receptors to an agonist after prolonged treatment. Mechanism of desensitization - A conformational change in the receptor, resulting in tight binding of the agonist molecule with out the opening of the ionic channel.

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104 Tolerance – a more gradual decrease in responsiveness to a drug, taking days or weeks to develop. Tachyphylaxis – a rapid decrease in responsiveness to a drug. Drug resistance – loss of effectiveness of antimicrobial or antitumor drugs.

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105 2) Upregulation of receptors (sensitization) - Prolonged administration of an antagonist leads to formation of new receptors causing increased tissue sensitivity. - Leads to hyperactivity (super sensitivity) of receptors to an against following sudden withdrawal of the antagonist after prolonged treatment. E.g. rebound hypertension, appearance of angina pectoris or cardiac arrhythmias following sudden withdrawal of propranolol. Withdrawal effect – an effect due to sudden discontinuation of the treatment.

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106 2.Some drugs don't bind to molecular targets, but act. I. By reacting chemically. e.g. antacids II. By chelating e.g. E D T A III. Due to physical properties. e.g. mannitol (osmotic diuretics.)

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IV. By targeting DNA, cell wall constituents as well as protein of bacteria, virus etc e.g. Chemo therapeutic drugs V. Being nutrients. e.g. Vitamins VI. Unknown mechanism. 107

Dose Response Relationships:

Dose Response Relationships Threshold (minimal) dose Least amount needed to produce desired effects Maximum effect Greatest response produced regardless of dose used

Dose Response Relationships:

Dose Response Relationships Loading dose Bolus of drug given initially to rapidly reach therapeutic levels Maintenance dose Lower dose of drug given continuously or at regular intervals to maintain therapeutic levels

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110 Therapeutic index - an index for measuring safety of drugs. Therapeutic index (TI) = LD 50 ED 50 LD50 = is the lethal dose that causes death in 50% a animal under experiment. If TI is wide – the drug is safe. If TI is narrow – the drug is toxic. Must be >1 for drug to be usable Digitalis has a TI of 2 Penicillin has TI of >100

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Margin of safety = LD 1 ED 99 The therapeutic window - a more clinically relevant index of safety - describes the dosage range between the minimum effective therapeutic concentration or dose, and the minimum toxic concentration or dose. 111

Some terms:

Some terms Side Effects : non-desired effects of a drug Drug Allergy : itching, burning, skin rash or severe reactions (anaphylactic shock) Efficacy – the ability of a bound drug to change the receptor in such a way to elicit a tissue response. Potency – the amount of drug we can use to produce the desired effect. Potency is determined mainly by the affinity of the receptor for the drug. - doesn’t measure effectiveness.

Types of drug concentration– response relationship:

Types of drug concentration– response relationship A. Graded drug concentration-Response Relationships As the dose of a drug is increased, the response (effect) of the tissue or organ is also increased. The efficacy ( Emax ) and potency (ED50) parameters are derived from these data. 113

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GRADED DOSE- RESPONSE CURVE 114 QUANTAL DOSE-RESPONSE CURVE

B. Quantal or all or none dose response relation ship. :

B. Quantal or all or none dose response relation ship. The Plot of the fraction of the population that responds at each dose of the drug versus the log of the dose administered. responses follow all or none phenomenon – that means the individual of the responding system either respond to their maximum limit or not at all to a dose of drug and there is no gradation of response. population studies. relates dose to frequency of effect . The median effective (ED50), median toxic (TD50) ,and median lethal doses (LD50) are extracted from experiments carried out in this manner. 115

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116 M edian effective dose (ED 50 ) : the dose at which 50% of individuals exhibit the specified quantal effect. M edian toxic dose (TD 50 ) : the dose required to produce a particular toxic effect in 50% of animals . M edian lethal dose (LD 50 ) : is the lethal dose that causes death in 50% animal under experiment.

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117 Factors affecting response 1) Age 2) Body weight -The concentration of a drug at the site of action depends on the ratio between the body weight or surface area and the amount of drug administered. 3) Sex 4) Psychological/ Emotional state 5) Pathological state 6) Physiological state 7) Time of drug administration. 8) Environment 9) Idiosyncratic – a different response for unknown reason(mostly due to genetic variation) . 10)route of drug administration 11)drug interaction 12)tolerance

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Drug – drug interaction that occurs inside the body are of two types:- I – Pharmacokinetic interaction II – Pharmacodynamic interaction I – Pharmacokinetic interaction - It occurs by altering the concentration of one drug by the other in the tissue or fluid. 1 . Gastrointestinal absorption changes in gastrointestinal PH. e.g. antacids/PPI/H 2- antagonists + ketoconazole/digoxin/ampicillin/iron salts. 118

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Complex formation *Irreversible binding of drugs in the GI tract e.g. Tetracyclines,quinolone antibiotics + ferrous sulfate (Fe +2 ),antacids (Al +3 , Ca +2 ,Mg +2 ), dairy products(Ca +2 ) 119

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2. Distribution - Displacement from tissue binding site. e.g. - Phenylbatazone + wartarin 3. Metabolism - Inducers e.g. – Navirapine + oral contraceptives - Rifampin + Nevirapine - Inhibitors e.g. – Ritonavir + sildenafil - Ketoconazole + saquinavir/ anperenavir/ indinavir. 120

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4. Excretion - Alteration of urine PH. e.g. Phanobarbitone + NaHCo 3 - Alteration of active tubular secretion e.g. Probenecid + peincillin . II – Pharmcodynamic interaction - It occurs by modification of pharmacological response of one drug by another without altering the concentration of the drug in the tissue or tissue fluid. 1. Additive – Occurs when the combined effect of two drugs is equal to the sum of the effects of each agent given alone. 2 + 2 = 4 e.g H 1 antagonist + CNS depressant 121

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2 . Potentiation:- - a situation where by one drug enhance the action another drug without having an effect by itself. e.g. 0 + 1 > 1 e.g. Caffeine +ergot alkaloid 3. Synergism - when the combined effects of two drugs are much greater than the sum of the effects of each agent given alone. e.g. 1 + 1 >>> 2 penicillin + aminoglycosides 122

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4. Antagonism a) Pharmacological antagonism - It is due to opposite effects of two drugs binding to the same receptor. It can be competitive antagonism or non – competitive antagonism. Competitive antagonist - Produce receptor blockade by competing with an agonist for the same receptor . The binding of agonist and antagonist is mutually exclusive, possibly because both agents bind to the same receptor site. - Reversibly bind to the receptor usually the concentration of the agonist. - The effect can be overcome by increasing the concentration of the agonist . 123

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E.g. diazepam (agonist) and flumazenil antegonist. acetylcholine (agonist) and atropine. d – tubocurarine (antagonist ). Non – competitive antagonist - bind at different site from agonist binding site brings conformational change. - binding is irreversible . The irreversible mechanism reduces the total number of receptors available for an agonist action. The irreversible binding doesn’t last forever. 124

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b) Chemical antagonism Occur when antagonist react chemically with agonist and inactivate it independently from receptor interaction. E.g. - Neutraliztion - Antacids - 125

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c) Physiological antagonism - It is due to opposite effects of two drugs on the same physical function. E.g. – Histamine and adrenaline - Insulin and glucagon. d) Physical antagonism -It is due to physical properties of drugs. E.g. activated charcoal in alkaloidal posioning 126

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C- Drug – herb interaction e.g. Grape fruit juice + saquinavir / BDZ/ Ca +2 channel blocker (grape fruit juice is inhibitor) 127 B – Drug – food interaction e.g. - MAOI + Tyramine - TTC + milk

Adverse Drug Reactions / ADR /:

Adverse Drug Reactions / ADR / Response to a drug that is noxious and unintended and that occurs at doses used in humans for prophylaxis, diagnosis, or therapy of disease, or for the modification of physiologic function. WHO 128

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Allergic reaction - an immunologically mediated adverse reaction to a chemical resulting from previous sensitization to that chemical or to a structurally similar one. Tertogenecity - some drug taken during pregnancy can cause congenital abnormalities. e.g. Thailodomide CARCINOGENICITY Certain drugs affect the genes and structural changes in the chromosomes . The drugs that cause cancer are called as carcinogenic drugs, for example, oral contraceptives increase the incidence of benign liver tumors, vaginal adenocarcinoma in the female offsprings of women who have taken diethylstilboesterol (DES) during her pregnancy for abortion purpose. e.g.anticancer / antineoplastic drugs. 129

Definition of different terms:

Definition of different terms SIDE EFFECTS: There are undesirable and unavoidable pharmacological effect of the drug, which occur at therapeutic dose. e.g. Atropine causes dryness of mouth. TOXIC EFFECTS: Toxic effects develop due to excessive pharmacological action of drug, which may be due to overdose or continuous use of drug for prolonged period. IDIOSYNCRASY: It is genetically determined abnormal reactivity to a drug. Drug abuse : using drugs not for the intended purpose , but for psychological or emotional effect. 130

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