GENERAL PHARMACOLOGY (OLD SYLLABUS)

 

GENERAL PHARMACOLOGY

PREPARED BY MR. ABHIJIT DAS

INTRODUCTION

Pharmacology means studies of drugs. It is a branch of medicine that deals with the interaction of drugs with the systems of  living animals, in particular, the mechanisms of drug action as well as the therapeutic uses of the drug.

The word pharmacology is derived from Greek word ‘pharmacon’ which means ‘drug’ and ‘logia’ which means ‘study of’.

The two main divisions of pharmacology are pharmacodynamics and pharmacokinetics.

Pharmacodynamics: What the drug does to the body.

Pharmacokinetics: what the body does to the drug.

 

DRUG

Drug is any component that provides pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man or animals.

 

PHARMACOLOGY VS PHARMACY

Pharmacology is not synonymous with pharmacy. Pharmacology, a branch of medicine, deals with the research, discovery, and characterization of chemicals which show biological effects (treat diseases). On the other hand, pharmacy, a health service profession,  is concerned with the application of principles learned from pharmacology.

ROUTES OF ADMINISTRATION

A route of administration is the path by which a drug is taken into the body. The choice of appropriate route in a given situation depends both on drug as well as patient related factors. In addition, some drugs are maximally absorbed through a particular route as compared to another route.

 There are several routes of drug administration, each with its own advantages and disadvantages. The choice of route depends on various factors, such as the drug's properties, the condition being treated, and the patient's age and health status.

The routes can be broadly divided into:

·        Local/topical route

·        Systemic route

LOCAL ROUTE

Drugs may be applied on the skin for local action as ointment, cream, gel, powder, paste etc.

Drugs may also be applied on the mucous membrane as in the eyes, ears and nose as ointment, drops and sprays.

ADVANTAGES

1.     Precise targeting: Local administration allows for precise targeting of the drug to the site of action, which minimizes systemic exposure and reduces the risk of side effects.

2.     Rapid onset of action: Local administration provides a rapid onset of action as the drug is delivered directly to the site of action.

3.     Minimal systemic side effects: Local administration reduces the risk of systemic side effects, as the drug is not distributed throughout the body.

4.     Lower doses: Local administration requires lower doses of the drug compared to systemic administration, which reduces the risk of toxicity and side effects.

5.     Convenient: Local administration is often more convenient than systemic administration, as it can be easily self-administered.

DISADVANTAGES

1.     Limited scope of action: Local administration is limited to the site of administration, which may not be sufficient for treating certain diseases that require a systemic approach.

2.     Difficulty in reaching certain sites: Some areas of the body may be difficult to access with local administration, such as the brain or spinal cord, which may require systemic administration.

3.     Short duration of action: Some drugs delivered through local administration may have a short duration of action, requiring repeated administration to maintain therapeutic effects.

4.     Irritation and tissue damage: Local administration may cause irritation, tissue damage, or other local side effects, particularly with prolonged use.

SYSTEMIC ROUTE

Systemic route of drug administration refers to the delivery of drugs to the bloodstream, where they are distributed throughout the body to exert their effects. They are of two types such as enteral and parenteral.

ENTERAL ROUTES

Enteral routes of drug administration refer to the delivery of drugs via the gastrointestinal tract, including oral, sublingual, and rectal routes.

ORAL ROUTE

The oral route of drug administration is one of the most commonly used methods of delivering drugs to the body. It involves ingestion of the drug through the mouth, which then travels through the gastrointestinal tract and is absorbed into the bloodstream. This route is convenient, non-invasive, and allows for a sustained release of the drug over time.

ADVANTAGES

·        Safest route

·        Most convenient

·        Economical

·        Self-administration is possible

·        Non-invasive route

DISADVANTAGES

1.     Variable absorption: The absorption of drugs through the gastrointestinal tract can vary depending on factors such as food, pH levels, and individual patient factors, leading to inconsistent and unpredictable drug effects.

2.     First-pass metabolism: Some drugs are metabolized by the liver before they reach the systemic circulation, reducing their bioavailability and requiring higher doses to achieve therapeutic effects.

3.     Gastrointestinal side effects: Oral drugs can cause gastrointestinal side effects such as nausea, vomiting, and diarrhea due to irritation of the digestive tract.

4.     Slow onset of action: The onset of action for orally administered drugs can be slower compared to other routes of administration, as the drug must travel through the digestive tract before it can be absorbed into the bloodstream.

SUBLINGUAL ROUTE

Sublingual drug administration involves placing medication under the tongue, where it is rapidly absorbed through the sublingual mucosa into the bloodstream, bypassing the liver and digestive system.

This route provides a fast onset of action and avoids first-pass metabolism, making it suitable for drugs with poor oral bioavailability.

Common drugs administered sublingually include nitroglycerin for angina and buprenorphine for pain management and opioid addiction.

ADVANTAGES

1.     Rapid onset of action: Sublingual administration provides a rapid onset of action as the drug is absorbed directly into the bloodstream without having to pass through the digestive system or liver.

2.     High bioavailability: Sublingual administration provides high bioavailability of the drug, as it bypasses first-pass metabolism in the liver.

3.     Precise dosing: Sublingual administration allows for precise dosing, as the drug is absorbed directly into the bloodstream and its effects can be monitored more accurately.

4.     Patient convenience: Sublingual administration is a convenient and non-invasive route of drug administration that can be easily self-administered by patients.

5.     Reduced risk of gastrointestinal side effects: Sublingual administration reduces the risk of gastrointestinal side effects, such as nausea, vomiting, and diarrhea, that may occur with oral administration.

DISADVANTAGES

1.     Limited drug types: Sublingual drug administration is only suitable for a limited number of drugs. It is not possible to administer every medication through this route.

2.     Drug taste and irritation: Some medications can have an unpleasant taste or cause irritation when held under the tongue. This can be uncomfortable for the patient and may discourage compliance with the medication regimen.

3.     Dose accuracy: It can be challenging to achieve accurate dosing with sublingual administration, as the amount of medication that is absorbed can vary depending on factors such as the size of the dose, the patient's saliva production, and how long they hold the medication under their tongue.

4.     Slow onset of action: While sublingual administration can have a faster onset of action than oral administration, it may be slower than other routes of administration, such as intravenous injection. This may not be suitable for medications that require rapid onset of action.

RECTAL ROUTE

The rectal route of drug administration involves the insertion of medication into the rectum via the anus. Suppositories are the most common dosage form used for rectal drug delivery. They are designed to melt or dissolve when inserted and release the medication for absorption through the rectal mucosa.

PARENTERAL ROUTE

The parenteral route of drug administration refers to the delivery of medication through a route other than the gastrointestinal tract.

It also bypasses the digestive system, allowing for more predictable absorption and bioavailability of the medication.

Parenteral route is of 3 types such as injections, inhalation and transdermal.

ADVANTAGES

1.     Rapid onset of action: Parenteral administration allows for rapid delivery of medication directly into the bloodstream, bypassing the digestive system, and allowing for immediate onset of action.

2.     Increased bioavailability: Because parenteral administration bypasses the digestive system, medication is not subject to first-pass metabolism, which can reduce its bioavailability. As a result, a higher proportion of the medication reaches its target site, leading to improved efficacy.

3.     Accurate dosing: Parenteral administration allows for precise control of the dose of medication administered, ensuring accurate dosing and reducing the risk of under- or overdosing.

4.     Alternative to oral administration: Parenteral administration is an alternative route of drug administration when oral administration is not feasible or effective, such as in patients with vomiting, swallowing difficulties, or gastrointestinal disorders.

5.     Suitable for poorly soluble drugs: Some drugs have poor solubility in water and are poorly absorbed through the gastrointestinal tract. Parenteral administration allows for the delivery of these drugs directly into the bloodstream, improving their efficacy.

DISADVANTAGES

The parenteral route of drug administration also has several potential disadvantages, including:

1.     Risk of infection: Parenteral administration carries a risk of infection, as the skin is breached during administration, and the medication is delivered directly into the bloodstream.

2.     Pain and discomfort: Some forms of parenteral administration, such as intramuscular and subcutaneous injections, can cause pain and discomfort at the injection site.

3.     Cost and complexity: Parenteral administration can be more expensive and complex than oral administration.

4.     Limited self-administration: Most forms of parenteral administration require administration by trained healthcare professionals, limiting the ability of patients to self-administer their medication.

5.     Risk of tissue damage: Some forms of parenteral administration, such as intramuscular injections, carry a risk of tissue damage or nerve injury if not administered correctly.

6.     Rapid onset of action: When medication is administered through this route, it enters directly into the bloodstream, bypassing the digestive system. As a result, the medication can quickly reach its target site and produce a rapid therapeutic effect.

INJECTIONS

Injections are a common form of parenteral drug administration that involve the use of a needle and syringe to deliver medication into the body.

There are several types of injections used in clinical practice, each with different indications and injection sites. Here are some key points about the different types of injections:

1.     Intramuscular (IM) injections: These injections are administered into the muscle tissue, typically in the deltoid, gluteus maximus, or vastus lateralis muscles. IM injections are commonly used for vaccines, antibiotics, and some hormonal medications.

2.     Subcutaneous (SC) injections: These injections are administered into the fatty tissue beneath the skin, typically in the abdomen, thigh, or upper arm. SC injections are commonly used for insulin, heparin, and some vaccines.

3.     Intradermal (ID) injections: These injections are administered into the dermis layer of the skin, typically on the forearm or upper back. ID injections are commonly used for tuberculosis screening and some allergy testing.

4.     Intravenous (IV) injections: These injections are administered directly into a vein, typically in the arm or hand. IV injections are commonly used for medications that require immediate onset of action, such as anesthesia, emergency medications, and chemotherapy.

5.     Intra-articular (IA) injections: These injections are administered directly into a joint, typically for the treatment of inflammation or pain. IA injections are commonly used for arthritis, tendonitis, and bursitis.

6.     Intrathecal (IT) injections: These injections are administered directly into the cerebrospinal fluid. IT injections are commonly used for anesthesia, chemotherapy, and treatment of neurological disorders.

INHALATION

Inhalation is a route of drug administration that involves the delivery of medication directly to the lungs through inhalation of a gas or volatile liquid. Some key points about inhalation route of administration include:

1.     Rapid onset of action: Inhalation allows for rapid delivery of medication directly to the lungs, where it is rapidly absorbed into the bloodstream, leading to a quick onset of action.

2.     Local and systemic effects: Inhalation can provide both local and systemic effects, depending on the medication and its intended use. For example, inhalation of bronchodilators can provide local effects on the airways, while inhalation of systemic corticosteroids can provide systemic effects for the treatment of inflammation.

3.     Targeted delivery: Inhalation allows for targeted delivery of medication to the lungs, where it is needed most for respiratory conditions such as asthma, chronic obstructive pulmonary disease (COPD) etc.

4.     Reduced systemic side effects: Because inhalation delivers medication directly to the lungs, it can reduce the risk of systemic side effects that can occur with other routes of administration.

5.     Convenient and non-invasive: Inhalation is a convenient and non-invasive route of administration that can be performed easily by patients in their own homes using appropriate inhalation devices.

6.     Risk of adverse effects: Inhalation carries a risk of adverse effects, including bronchospasm, cough, and throat irritation, which can be reduced by using appropriate inhalation devices and techniques.

TRANSDERMAL

The transdermal route of drug administration involves the delivery of medication through the skin. Here are some key points about this route of administration:

1.     Transdermal administration provides a non-invasive, convenient, and painless method of drug delivery, with the potential for improved patient compliance.

2.     Medication is typically delivered through a patch or other type of delivery system that is applied directly to the skin, allowing for sustained and controlled release of the medication over a period of time.

3.     Transdermal administration is particularly useful for medications that require continuous or long-term administration, such as hormone replacement therapy, pain management, and smoking cessation.

4.     Transdermal patches can be designed to release medication at a constant rate, depending on the medication and the desired therapeutic effect.

5.     Transdermal delivery allows for systemic drug delivery, bypassing the gastrointestinal tract and reducing the risk of gastrointestinal adverse effects.

6.     Some of the potential disadvantages of transdermal administration include skin irritation or allergic reactions, limited absorption of some medications due to their molecular size or properties, and difficulty in achieving consistent drug delivery across different individuals.

PHARMACOKINETICS

 

Pharmacokinetic means movement of drugs inside our body, during which it passes through four different phases:

Absorption

Distribution

Metabolism/biotransformation

Excretion

In short ADME

 

ABSORPTION

Absorption is a process of transfer of drug from the site of administration to the systemic circulation.                                             

DIFFERENT PROCESSES OF ABSORPTION OF DRUGS

A. Passive transfer:

1.     Simple diffusion

2.     Filtration

B. Specialized transfer:

1.     Active transport

2.     Facilitated diffusion

3.     Pinocytosis

                                                                          

Ø SIMPLE DIFFUSION/PASSIVE TRANSPORT

Substances can be transported from higher concentration to lower concentration.

It does not require the assistance of membrane proteins.

Ex- passive transport of small non polar drugs

Ø FILTRATION

Only water soluble substances can be transported through this process through aqueous pores present in the cell membrane.

Molecules will move from area of higher concentration to area of lower concentration.

Ø ACTIVE TRANSPORT

Active transport is the movement of drug molecules from an area of lower concentration to an area of higher concentration against the concentration gradient.

Active transport requires cellular energy(ATP) to make this happen.

 Ø FACILITATED DIFFUSION

It is the process of transport done by the help of carrier protein.

Being passive, facilitated diffusion doesn’t require chemical energy from ATP.

Ø PINOCYTOSIS

In this process cells engulf fluids or macromolecules from the surroundings. 

FACTORS AFFECTING THE ABSORPTION PROCESS

1.     LIPOPHILICITY

Lipid solubility of the drug affect drug absorption from the GI tract.

Lipid soluble drugs are absorbed more rapidly than water soluble drugs.

PHYSICAL STATE

Physical state of drugs is one of the most important factors affecting their absorption.

It has been observed that liquid drugs are well absorbed than solid drugs. Also, aqueous solutions are more quickly absorbed than oily solutions. Gasses are more quickly absorbed through lungs.

DEGREE OF IONIZATION

Unionized drugs are easily absorbed than ionized drugs.

Different drugs are either acidic or basic and are present in ionized or unionized form.

Acidic drugs are unionized in the acidic medium and basic drugs are unionized in the basic medium. That’s why acidic drugs are quickly absorbed from the acidic compartment.

 PARTICL SIZE

It has been studied that smaller particle sized drugs are better absorbed than larger particle sized drugs.

Smaller particle size provides greater surface area of a given weight of drug thus improving the process of absorption.

1.     PH

Acidic pH favors acidic drug absorption and basic pH is better for basic drugs. That means, acidic drugs are rapidly absorbed from stomach.

On the other hand, basic drugs are not absorbed until they reach the small intestine.

CONCENTRATION

Passive diffusion depends on concentration gradient. So, concentrated forms of drugs are quickly absorbed than dilute solutions. Higher concentration of drugs helps better absorption of those drugs.

SURFACE AREA

Larger the surface area of the absorbing membrane, more will be the absorption.

Drugs can be easily absorbed from the small intestine than the stomach due to large surface area of the small intestine.

The absorption of drugs through sublingual route is faster. That means absorption of drugs from highly vascular membrane will be faster.

 ROUTE OF ADMINISTRATION

Some drugs are well absorbed through parenteral route than oral route.

Bioavailability of drugs administered through parenteral route is always more than the bioavailability of drugs administered through oral route.

Certain drugs are degraded in the GI tract by acid and are ineffective orally. So enteric coated tablets can be used to overcome acid lability.

1.     PRESENCE OF FOOD

Foods can interact with the drugs to alter their rate of absorption.

Ex-antihyperlipidemic drugs are better absorbed when taken with the food.

1.     PHARMACEUTICAL FACTORS

DISINTEGRATION:

Disintegration is the breaking up of the dosage form into smaller particles. So, when disintegration occurs rapidly, rapid will be the absorption.

DISSOLUTION:

After disintegration, drugs dissolve in the gastric juices, which is called dissolution. When rapid is the dissolution, rapid will be the absorption.

1.     GI MOBILITY

GI mobility should be optimal for oral drug absorption. That means it should be neither increased nor decreased.

Different situations may alter the GI mobility. Diarrhea causes rapid peristalsis (GIT movement), thus the process of absorption is affected. Constipation affects disintegration so decreases mobility.

BIOAVAILABILITY

It is the fraction of unchanged portion of drug that reaches the blood circulation after administration by any route.

When we take drug through oral route drug will be metabolized in liver so the bioavailability won’t be 100%.

But after an IV route of administration the bioavailability is always 100%.

 Bioavailability = (AUC Oral/AUC IV)X100

 

 

DISTRIBUTION

Movement of drug through the blood stream to reach target cells.

The distribution is complete when the drug has reached all the possible sites, including blood.

FACTORS AFFECTING DRUG DISTRIBUTION

1.     LIPOPHILICITY

Highly lipophilic drug will dissolve through some membrane much easier than the hydrophilic drug.

2.     BLOOD FLOW

Some organs such as brain receives more blood flow than for example skin so if a drug can pass through blood-brain-barrier it will accumulate much faster in the brain as compared to the skin.

3.     CAPILLARY PERMEABILITY

For example capillaries in the liver have lots of slit junctions through which large proteins can pass on the other hand in the brain there are no slit junctions at all so it’s more difficult for a drug to pass through.

4.     PLASMA PROTEIN BINDING

Many drugs will bind to albumin which is a major drug binding protein. That will significantly slow the distribution process.

VOLUME OF DISTRIBUTION

It is theoretical volume that the drug would have to occupy in order to produce the concentration that’s present in blood plasma.

Vd = Amount of drug in blood/Plasma concentration

This is extremely helpful in estimating drug dosing. For example if a drug has large volume of distribution we would need to administer a larger dose to achieve desired concentration.

 

 

METABOLISM/BIOTRANSFORMATION

Modification of drug by enzymes to make the drug ineffective.

It is needed to convert lipid-soluble compounds to water soluble compounds so that they will be easily excreted. That’s why most hydrophilic(water-soluble) drugs are little biotransformed and are largely excreted unchanged.

The primary site for drug excretion is liver. Other sites are kidney, intestine, lungs etc.

Liver does it mainly through two metabolic reactions called phase 1 and phase 2.

PHASE 1 REACTIONS

Phase 1 reactions are all about making a drug more hydrophilic. These reactions involve introduction or unmasking of a polar functional group so in phase 1 we are going to see oxidation, reduction, hydrolysis, cyclization and decyclization.

OXIDATION

Ø The enzyme system which oxidizes the drug is called ‘cytochrome P-450 system’.

Ø This reaction involves addition of oxygen/negatively charged radical or removal of hydrogen/positively charged radical.

Ø Oxidations are the most important drug metabolizing reactions.

Ø Types of oxidation: Microsomal oxidation and NON-microsomal oxidation.

Ø Microsomal Oxidation- Catalyzed by enzymes present in the microsome of liver

a)     Hydroxylation – addition of hydroxyl group.

Ex – phenytoin à hydroxyl phenytoin

b)    Dealkylation – removal of alkyl group

Ex - codeinà morphine

c)     S-Oxidation – addition of sulfoxide group

Ex- Cimentidineà cimentidine sulfoxide

Ø Non-microsomal Oxidation- catalyzed by enzymes present in the endoplasmic reticulum of liver.

Ø Barbiturates, imipramine, phenothiazines, imipramine, ibuprofen, paracetamol etc are oxidized in this way.

 

REDUCTION

Ø This reaction involves removal of oxygen or addition of hydrogen.

Ø Warfarin, halothane, chloramphenicol etc are reduced.

 

HYDROLYSIS

Ø Hydrolysis is any chemical reaction in which a molecule of water breaks one or more chemical bonds.

Ø Hydrolysis occurs in liver, intestine, plasma etc.

Ø Ex- aspirin, procaine, lidocaine etc are hydrolyzed

 

 

CYCLIZATION

Ø This is formation of ring structure from a straight chain compound.

Ø Ex- proguanil

 

DECYCLIZATION

Ø This is opening up of ring structure of the cyclic drug molecule.

Ø Ex- phenytoin, barbiturates etc.

 

 

PHASE 2 REACTIONS

If metabolites from phase 1 are still too lipophilic they can undergo conjugation reaction which involves addition of a polar group.

GLUCURONIDE CONJUGATION

Ø Compounds with a hydroxyl or carboxylic acid group are easily conjugated with glucuronic acid.

Ø Ex- chloramphenicol, aspirin, paracetamol, morphine, metronidazole etc.

Ø Glucuronidation increases the molecular weight of the drug which favours it’s excretion in bile.

ACETYLATION

Ø Compounds having amino or hydrazine residues are conjugated with the help of acetyl coenzyme-A

Ø Ex- sulfonamides, isoniazide, hydralazine, clonazepam, procainamide etc.

METHYLATION

Ø The amines and phenols can be methylated.

Ø Ex- adrenaline, histamine, nicotinic acid, methyl dopa, captopril, etc.

SULFATE CONJUGATION

Ø The phenolic compounds and steroids are sulfated by sulfotransferase.

Ø Ex- chloramphenicol, methyl dopa, sex steroids etc.

GLYCINE CONJUGATION

Ø Drugs having carboxylic acid group are conjugated with glycine.

Ø Ex- salicylates

 

EXCRETION

Excretion is the clearing of a drug from the body.

Drugs and their metabolites are excreted in urine, faeces, saliva, sweat, milk etc.

CL_total= CL_hepatic+CL_renal+CL_biliary+CL_other

PHARMACODYNAMICS

Pharmacodynamics is the study of effects of drugs and the mechanism of their action. It is the science of how the body reacts to drugs.

PRINCIPLES OF DRUG ACTION

Drugs don’t impart new functions to any system, organ or cell; they only alter the pace of ongoing activity. The basic types of drug action are stimulation, depression, irritation, replacement, and cytotoxic action.

STIMULATION

Ø It refers to selective enhancement of the level of activity of specialized cells.

Ø Ex- Adrenaline stimulates heart, caffeine stimulates CNS

DEPRESSION

Ø It means depression of activity of specialized cells.

Ø Ex- Barbiturates depress CNS, Quinidine depress heart

IRRITATION

Ø Mild irritation may stimulate associated function.

Ø Ex- bitters increase salivary and gastric secretion.

REPLACEMENT

Ø This means use of natural metabolites or their derivatives in deficiency states.

Ø Ex- Insulin in diabetes mellitus, Iron in anaemia.

CYTOTOXIC ACTIONS

Ø This means selective cytotoxic action for invading parasites or cancer cells.

Ø Drugs destroy those toxic cells without affecting the host cells.

Ø Ex- Penicillin

 

 

 

MECHANISM OF DRUG ACTION

Majority of drugs produce their effects by interacting with a target biomolecule, which usually is a protein.

Proteins that are targets of drug action can be classified into four categories such as enzymes, ion channels, transporters and receptors.

 

ENZYMES

Ø Almost all biological reactions are carried out under catalytic influence of enzymes. That’s why enzymes are very important target of drug action.

Ø Drugs can either increase or decrease the rate of enzymatically mediated reactions.

Ø Ex- Aspirin inhibits cyclooxygenase enzyme

ION CHANNELS

Ø Ion channels regulate the intracellular ionic composition.

Ø Drugs can affect ion channels either through specific receptors(G-Protein operated ion channels) or by directly binding to the channel and affecting ion movement through it.

Ø Ex- Phenytoin inhibits voltage sensitive neuronal NA⁺ channel

       Amiloride inhibits renal epithelial NA⁺ channel

TRANSPORTERS

Ø Several drugs are translocated across membranes by binding to specific transporters (carriers).

Ø Many drugs produce their action by directly interacting with the transporter proteins to inhibit the ongoing physiological transport of the metabolites.

Ø Ex- Amphetamines block dopamine reuptake in brain neurons by dopamine transporter.

RECEPTORS

Ø The largest number of drugs bind to receptors to show their pharmacological actions.

Ø Receptor- It is defined as a binding site located on the surface or inside the effector cell that serves to recognize the drug and initiate the response to it.

There are few terms used in describing drug-receptor interaction.

AGONIST

An agent (drug) which activates a receptor to produce an effect similar to that of the physiological signal molecule.

INVERSE AGONIST

An agent (drug) which activates a receptor to produce an effect in the opposite direction to that of the agonist.

ANTAGONIST

An agent (drug) prevents the action of an agonist on a receptor

PARTIAL AGONIST

Partial agonists are drugs that bind to and activate a given receptor but have only partial efficacy at the receptor as compared to a full agonist.

 

The receptors that have the most therapeutic relevance can be divided into four types.

1.     Ligand-gated ion channels

2.     G-protein-coupled receptors

3.     Enzyme-linked receptors

4.     Intracellular receptors

 

LIGAND-GATED ION CHANNELS

Ø Ligand: any molecule (drug) or ion that binds to the receptor.

Ø So ligand-gated ion channel has a ligand binding site and when the ligand binds to it the channel opens very briefly which allows ions such as sodium, potassium, chloride, calcium etc. to pass through the membrane.

G-PROTEIN-COUPLED RECEPTORS

Ø This is also known as seven transmembrane receptor and this is because it passes through the cell membrane seven times.

Ø These receptors are composed of three sub units such as alpha, beta, and gamma, all together known as G-protein.

Ø In its inactive form the alpha subunit has GDP attached to it. However when ligand binds to the receptor the affinity for GTP increases so then GTP replaces GDP.

 

 

Ø This in turn causes the alpha subunit to dissociate from beta-gamma complex and then both of these complexes (alpha-GTP) go to interact with other enzymes or proteins which they can alter or regulate ultimately leading to some kind of response.

Ø There are three kinds of g-proteins. These are G_s, G_i, and G_q.

Ø G_s is a stimulative g-protein that activates enzyme called adenylyl cyclase which produces cyclic AMP from ATP.

Cyclic AMP is a very important second messenger that initiates biological action.

Ø G_i is an inhibitory G-protein which inhibits adenylyl cyclase thus lowers levels of cyclic AMP in the cell.

 

 

Ø The last one is G_q which activates class of enzymes called phospholipase C (PLC).

Ø Now PLC produces two second messengers such as Diacylglycerol (DAG) and Inositol triphosphate (IP₃).

Ø Now DAG just like cAMP leads to different responses through activation of protein kinase.However, IP₃ produses various responses by mediating intracellular release of calcium.

 ENZYME-LINKED RECEPTORS

Ø These receptors just like G-protein receptors have extracellular binding site where ligand, typically hormone or growth factor, can attach and thus stimulate enzymatic activity inside the cell.

Ø Most enzyme linked receptors are tyrosine kinase type which simply means that they display kinase activity and that there is an amino acid tyrosine involved in that.

Ø So the way it works is that when ligand binds to two of these receptors it causes conformational change that results in aggregation of both receptors.

Ø Once the dimer is formed the tyrosine regions get activated and cause ATP to become ADP which results in auto phosphorylation of the receptors.

Ø Now once each tyrosine picks up phosphate group different inactive intracellular proteins comes up and attach to phosphorylated tyrosine.

Ø This in turn causes conformational change in the attached protein ultimately showing cellular response.

 

INTRACELLULAR RECEPTORS

Ø Unlike the other three this receptor is located entirely inside the cell rather than on cell membrane. Therefore the ligand has to cross first lipid membrane and then once it’s inside it can then bind to the receptor.

Ø Now the activated ligand-receptor complex can move into the nucleus, bind to DNA and regulate gene expression ultimately leading to synthesis of specific  proteins.

 

 

FACTORS MODIFYING DRUG ACTION

A variety of host and environmental factors affect the drug response. Hence knowing various factors modifying drug action is essential as it will help in deciding proper desired drug effects with the optimum dosage of drugs.

The important factors which modify the effect of a drug are :

ROUTE OF ADMINISTRATION

Ø Bioavailability of a particular drug when given through IV route is greater than the bioavailability of that particular drug when given through oral route. So when a drug is given through IV route shows better action.

Ø A drug may have entirely different uses through different routes.

Ex- Magnesium sulfate when given orally causes purgation but when given intravenously it produces hypotension.

CUMULATION

Ø Accumulation of a drug in the body following its repeated administration is termed as cumulation. So if rate of administration is more than the rate of elimination, then the drug will accumulate in the body. Hence slowly eliminated drugs produce cumulative toxicity.

Ø Ex- prolonged use of chloroquine causes retinal damage.

Ø Sometimes cumulative effect is desired.

Ex- Phenobarbitone in the treatment of epilepsy.

AGE

Ø The newborn has low glomerular filtration rate and tubular transport is immature.

Ø Similarly, hepatic drug metabolizing system is not properly developed in newborns. Infants below one year are devoid of enzymes that metabolize drugs.

Ø Drug absorption may also be altered in newborns because of lower gastric acidity.

Ø Similarly, in geriatric patients (older patients), administered drug dosages should be selected carefully due to their inability to metabolize drugs.

The dosage of children is calculated on the basis of their age.

YOUNG’S FORMULA

Child Dose= (Age/Age+12) X Adult Dose

DILLING’S FORMULA

Child Dose= (Age/20) X Adult Dose

GENDER

Ø Generally, males weigh more than females. So females get lesser dose than males.

Ø Females have a higher percent of body fat than males which can affect the volume of distribution of certain drugs.

Ø In women consideration must be given to menstruation, pregnancy and lactation. For example drugs having strong stimulant effect on uterus or foetus should not be given to menstruating and pregnant ladies.

Ø Drugs like morphine can cross the placental barrier and depresses the foetal respiration. So morphine should be avoided during pregnancy.

BODY WEIGHT

Ø The average adult dose refers to individuals of medium built (adult weighing between 50-100 Kg.).

Ø So for obese or lean individuals and for children dose can be calculated on body weight basis.

 

Dose= (Body Weight in Kg/70) X Adult Dose

GENETIC FACTOR

Ø Some patients are unable to metabolize certain medicines because of the absence of certain enzymes required for their metabolism. Absence of certain enzymes in some individual is the result of lack of specific genes encoding them from their genetic set up.

Ø Deficiency of enzyme ‘Glucose-6 Phosphate dehydrogenase’ can not metabolize primaquin in some individuals.

 

PRESENCE OF FOOD

Ø Sometimes presence or absence of food in GIT can modify the drug absorption process.

Ø Example

Milk decreases the absorption of Tetracyclin.

Fat increases the absorption of Griseofluvin.

DISEASE

Ø In liver disease first pass metabolism of some drugs will be reduced. So the bioavailability of drugs having high first pass metabolism will be increased and that will produce toxicity.

Ø In some gastrointestinal disease, the absorption of some orally administered drugs can be altered.

METABOLISM

Ø If a drug undergoes first pass metabolism the concentration of that drug is generally reduced before it reaches the systemic circulation. That’s why it shows less action. If the drug will be administered in ways to bypass first pass metabolism then the drug will show good efficacy.

Ø Metabolic disturbance in one’s body can drastically affect drug action. Changes in physiological factors such as water balance, body temperature, electrolyte balance also modify the drug effects.

Ø Example- in case of iron deficiency anaemia, absorption of iron from the gastrointestinal tract is maximum.

RACE (ETHNICITY)

Ø Ethnic differences in drug response may be due to the interaction of genetic factors and the environmental factors. It also depends on the pathogenesis of the disease.

Ø So different race require different dose of a particular drug.

Ø Example- Blacks require higher and Mongols require lower concentration of atropine and ephedrine to dilate their pupil.

RATE OF ABSORPTION

Ø The rate of drug absorption determines the onset of action.

Ø Drugs which are highly lipid soluble are absorbed fast and will show better action than polar drugs.

PSYCHOLOGICAL FACTOR

Ø Efficacy of a drug can be affected by patient’s attitude and expectations.

Ø Placebo effect: Placebo is an inert substance. It works by psychological rather than pharmacological means and often produces responses equivalent to the active drug.

Ø Nocebo effect: It refers to negative psychodynamic effect evoked by loss of faith in the medication or the doctor. Nocebo effect can oppose the therapeutic effect of active medication.

TIME OF ADMINISTRATION

Ø Effects of some drug may be influenced by the setup in which it is taken.

Ø Example- Hypnotics taken at night and in quiet atmosphere may work more easily.

EFFECT OF OTHER DRUGS

Ø ADDICTIVE EFFECT: when the total pharmacological effect of two drugs administered together is equal to the sum of their individual pharmacological effects, the phenomenon is called addictive effect.

2+2=4

Example- Ephedrine and aminophylline show addictive effect in the treatment of bronchial asthma.

Ø SYNERGICTIC EFFECT: It is the result of two or more drugs interacting together to produce an effect that is greater than the cumulative effect that those drugs produce when used individually.

2+2=10

Example- Codeine and aspirin as analgesic.

Ø ANTAGONISTIC EFFECT: It is defined as the opposite actions of two drugs on the same physiological system.

2+2=0

Example- Protamine reverses the action of heparin.

TOLERANCE

Ø On repeated administration, some drugs may prove to be ineffective at the usual therapeutic dose.

Ø That’s why progressive increase in the dose is required to produce the desired effect. This phenomenon is known as drug tolerance.

Ø Example- When Morphine or Alcohol is used for a long time, larger and larger doses must be taken to produce the same effect.