derived from the Greek word for drug

A science that studies drug effects within a living system, biochemical and physiological aspects

Deals with all drugs used in society today, legal or illegal, including street, prescription, and non-prescription or over –the-counter medications

What is Pharmacology?

A drug is defined as any substance; chemical agent; used in the

• Diagnosis• Cure• Treatment• prevention of a disease or condition

Drug

Chemical NameGeneric NameTrade Name

Drug Names

Describes its molecular structure and distinguishes it from other drugs

Chemical Name

Determined by the pharmaceutical company along with a special organization known as the U.S. Adopted Names Council (USAN)

Generic name

Or brand name- the manufacturer selects alone…can become a registered trademark.

They are the only one who can advertise and market the drug under that name.

Trade Name

The particular spelling of a brand name drug is proposed by a manufacturer for one of several reasons.

How is the Trade Name Chosen?

Azmacort- treats asthma

Rythmol- treats cardiac arrhythmias

1. To indicate the disease process being treated

Pseudoephedrine to Sudefed

Haloperidol to Haldol

Ciprofloxacin to Cipro

2. To simplify the generic name

Slow-K slow release potassium supplement

3. To indicate the duration

Or legend drugs Means in order to obtain drug, you

must have a legal prescription

Prescription Drugs

Or Over-the-Counter (OTC) drugs Drug that may be purchased

without a prescription

Non-Prescription Drugs

Drugs have been identified or derived from four main sources:

Plants Animals Minerals and Mineral Products Synthetic or Chemical Substances

Made in the Laboratory

Sources of Drugs

Routes of drug administration

The route of administration (ROA) that is chosen may have a profound effect upon the speed and efficiency with which the drug acts

Routes of Drug Administration

ImportantInfo

The main routes of drug entry into the body may be divided into two classes:

◦Enteral◦Parenteral

Enteral - drug placed directly in the GI tract:

◦sublingual - placed under the tongue

◦oral - swallowing (p.o., per os)

◦rectum - Absorption through the rectum

Enteral Routes

Some drugs are taken as smaller tablets which are held in the mouth or under the tongue.

Advantages ◦ rapid absorption◦ drug stability◦ avoid first-pass effect

Sublingual/Buccal

Disadvantages

◦inconvenient◦small doses◦unpleasant taste of some drugs

Sublingual/Buccal

Disadvantages◦Sometimes inefficient - only part of the drug may be absorbed

◦First-pass effect - drugs absorbed orally are initially transported to the liver via the portal vein

◦irritation to gastric mucosa - nausea and vomiting

Oral

Disadvantages

◦destruction of drugs by gastric acid and digestive juices

◦effect too slow for emergencies

◦unpleasant taste of some drugs

◦unable to use in unconscious patient

Oral

The first-pass effect is the term used for the hepatic metabolism of a pharmacological agent when it is absorbed from the gut and delivered to the liver via the portal circulation.

The greater the first-pass effect, the less the agent will reach the systemic circulation when the agent is administered orally

First-pass Effect

First-pass Effect Magnitude of first pass hepatic effect: Extraction ratio (ER)ER = CL liver / Q ; where Q is hepatic blood flow (usually about 90 L per hour. Systemic drug bioavailability (F) may be determined from the extent of absorption (f) and the extraction ratio (ER): F = f x (1 -ER)

First-pass Effect

Absorption across the rectal mucosa occurs by passive diffusion.

This route of administration is useful in children, old people and unconscious patients.

Eg., drugs that administered are: aspirin, acetaminophen, theophylline, indomethacin, promethazine & certain barbiturates.

08/10/2010KLECOP, Nipani 28

RECTAL ADMINISTRATION:

Advantages: 1. Suitable for unconscious patients and

children 2. suitable if patient is nauseous or vomiting 3. easy to terminate exposure 4. good for drugs affecting the bowel such

as laxativesDisadvantages: 2. absorption may be variable 3. irritating drugs contraindicated

Rectal

◦Intravascular (IV, IA)- placing a drug directly into the blood stream

◦Intramuscular (IM) - drug injected into skeletal muscle

◦ ◦Subcutaneous - Absorption of drugs from

the subcutaneous tissues

◦Intrathecal : into CSF

Parenteral Routes

IntravascularAbsorption phase is bypassed (100% bioavailability)1.precise, accurate and almost immediate onset of

action, 2. large quantities can be given, fairly pain free

Disadvantages a-. greater risk of adverse effects b- high concentration attained rapidly C- risk of embolism

Intramuscular

1. very rapid absorption of drugs in aqueous solution 2. Slow release preparations Disadvantages

pain at injection sites for certain drugs

Subcutaneous

1. slow and constant absorption 2. absorption is limited by blood flow, affected if circulatory problems exist

3. concurrent administration of vasoconstrictor will slow absorption

1. gaseous and volatile agents and aerosols 2. rapid onset of action due to rapid access to circulation a. large surface area b. thin membranes separates alveoli from

circulation c. high blood flow

Inhalation

Topical•Mucosal membranes (eye drops, antiseptic) •Skin a. Dermal - rubbing in of oil or ointment (local action, sun screen, an callus removal) b. Transdermal - absorption of drug through

skin (systemic action) i. stable blood levels ii. no first pass metabolism iii. drug must be potent or patch becomes too large

o Intra nasal administration

Drugs generally administered by intra nasal route for treatment of local condition such as perennial rhinitis, allergic rhinitis and nasal decongestion etc.

37

intravenous 30-60 seconds intraosseous 30-60 seconds endotracheal 2-3 minutes inhalation 2-3 minutes sublingual 3-5 minutes intramuscular 11-30 minutes subcutaneous 14-30 minutes rectal 5-30 minutes ingestion 30-90 minutes transdermal (topical) variable (minutes to hours)

Route for administration -Time until effect-

Aspects of Drug Pharmacokinetics (ADME)

Drug at site of administration

Drug in plasma

Drug/metabolitesin urine, feces, bile

Drug/metabolites in tissues

Absorption

Distribution

Elimination

Metabolism

Definition :The process of movement of

unchanged drug from the site of administration to systemic circulation.

The ultimate goal is to have the drug reach the site of action in a concentration which produces a pharmacological effect.

No matter how the drug is given (other than IV) it must pass through a number of biological membranes before it reaches the site of action.

Absorption

08/10/2010KLECOP, Nipani 42

LIPID BILAYER

the Rate dependent on polarity and size.

Polarity estimates partition coefficient.

The greater the lipid solubility – the faster the

rate of diffusion

Smaller molecules penetrate more rapidly.

Highly permeable to O2, CO2, NO and H2O .

Large polar molecules – sugar, amino acids,

phosphorylated intermediates – poor permeability

These are essential for cell function – must be

actively transported

43

DIFFUSION THROUGH MEMBRANES

KLECOP, Niani 44

MOVEMENT OF SUBSTANCES ACROSS CELL MEMBRANES

1) Passive diffusion2) Carrier- mediated transport a) Facilitated diffusion

b) Active transport3) PINOCYTOSIS

08/10/2010KLECOP, Nipani 45

MECHANISMs OF DRUG ABSORPTION

46

1) PASSIVE DIFFUSION

Also known as non-ionic diffusion.

It depends on the difference in the drug concentration on either side of the membrane.

Absorption of 90% of drugs.

The driving force for this process is the concentration or electrochemical gradient.

Involves a carrier (a component of the membrane) which binds reversibly with the solute molecules to be transported to yield the carrier solute complex which transverses across the membrane to the other side where it dissociates to yield the solute molecule

The carrier then returns to its original site to accept a fresh molecule of solute.

There are two types of carrier mediated transport system:

a) facilitated diffusion b) active transport

47

2) CARRIER MEDIATED TRANSPORT MECHANISM

48

a) Facilitated diffusion

This mechanism driving force is concentration gradient.

In this system, no use of energy is involved (down-hill transport), therefore the process is not inhibited by metabolic poisons that interfere with energy production.

49

b) Active transport More important process

than facilitated diffusion. The driving force is

against the concentration gradient or uphill transport.

Since the process is uphill, energy is required in the work done by the barrier.

As the process requires energy, it can be inhibited by metabolic poisons that interfere with energy production.

Drug Absorption Active vs. Passive

Active transport:• Carrier-mediated• Energy-dependent• Against conc gradient• Shows carrier

saturation kinetics Passive transport• Energy-independent• No carrier involved• Along conc gradient• No saturation kinetics

ATP

ADP + Pi

A-

BH+

Passive diffusion of a water-sol drug via aqueous channel

Carrier-mediated energy-dependent active transport

Passive diffusion of a lipid-sol drug

AH

B

51

3) Pinocytosis

This process is important in the absorption of oil soluble vitamins & in the uptake of nutrients.

Drug transported by passive diffusion depend upon:

dissociation constant, pKa of the drug lipid solubility, K o/w pH at absorption site. Most drugs are either weak acids or weak

bases whose degree of ionization is depend upon pH of biological fluid.

PHYSICOCHEMICAL FACTORS

For a drug to be absorbed, it should be unionized and the unionized portion should be lipid soluble. Only non-ionized fraction of drugs (acids or bases is absorbed

The fraction of drug remaining unionized is a function of both

Dissociation constant (pKa) and pH of solution.

HENDERSON HASSELBATCH EQUATION For acid, pKa - pH = log[ Cu/Ci ]For base, pKa – pH = log[ Ci/Cu ] Eg. Weak acid aspirin (pKa=3.5) in stomach (pH=1) will have > 99%of unionized form so gets absorbed in stomach

Weak base quinine (pKa=8.5) will have very negligible unionization in gastric pH so negligible absorption

Several prodrugs have been developed which are lipid soluble to overcome poor oral absorption of their parent compounds. 08/10/2010KLECOP, Nipani 54

Factors Affecting GIT Absorption

Blood Flow To Absorptive Site:o Greater blood flow raises absorptiono Intestine has greater BF than stomach

Total Surface Area of Absorptive Site: Intestinal microvilli increases surface area to

1000-fold that of the stomach favoring intestinal absorption

Contact Time at Absorptive Site: Diarrhea reduces absorption Accelerated gastric emptying→ faster delivery to

intestinal large surface → increased absorption

Factors Affecting GIT Absorption

Food: Presence of food in the gut reduces/delays drug absorption from GIT

Increased splanchnic blood flow during eating increases drug absorption

Ionized drugs as tetracycline can form insoluble complexes with Ca2+ in food/milk.

Formulation Factors: Solid dosage forms dissolution & solubility are

essential Aqueous solutions are absorbed more quickly

than tablets or suspensions56

Stomach:

The surface area for absorption of drugs is relatively small in the stomach due to the absence of macrovilli & microvilli.

Extent of drug absorption is affected by variation in the time it takes the stomach to empty, i.e., how long the dosage form is able to reside in stomach.

Drugs which are acid labile must not be in contact with the acidic environment of the stomach

Factors affecting absorption from GIT

PHYSIOLOGICAL FACTORS: Gastrointestinal (Gi) Physiology Influence Of Drug Pka And Gi Ph On

Drug Absorbtion Git Blood Flow Gastric Emptying………………..contact

time Disease States Total surface area

Intestine Major site for absorption of most drugs due to its large

surface area (0.33 m2 ). It is 7 meters in length and is approximately 2.5-3 cm in

diameter. These folds possess finger like projections called Villi which

increase the surface area 30 times ( 10 m2). From the surface of villi protrude several microvilli which

increase the surface area 600 times ( 200 m2). Blood flow is 6-11 times that of stomach. PH Range is 5–7.5 , favorable for most drugs to remain

unionized. Peristaltic movement is slow, while transit time is long. Permeability is high.

All these factors make intestine the best site for absorption of most drugs.

Large intestine :

The major function of large intestine is to absorb water from ingestible food residues which are delivered to the large intestine in a fluid state, & eliminate them from the body as semi solid feces.

Only a few drugs are absorbed in this region.

Bioavailability the proportion of the drug in a

dosage form available to the body

i.v injection gives 100% bioavailability.

BIOAVAILABIITY Fraction of a drug reaching

systemic circulation in chemically unchanged form after a particular route

First pass metabolism, i.e., rapid hepatic metabolism, reduces bioav. (lidocaine, propranolol, nitrates)

Drug solubility Chemical instability in

gastric pH (penicillin G, insulin)

Drug formulation: Standard & SR formulations

Bio = AUC oral/AUC IV x 100

62

Seru

m

Con

cen

trati

on

Time

Injected Dose

Oral Dose

DISTRIBUTION

The body is a container in which a drug is distributed by blood (different flow to different organs) - but the body is not homogeneous.

Factors affecting drug delivery from the plasma:A- blood flow: kidney and liver higher than skeletal

muscles and adipose tissues.

B- capillary permeability: 1- capillary structure: blood brain barrier 2- drug structure C- binding of drugs to plasma proteins and tissue

proteins

DEFINITION OF PHARMACOKINETICS AND PHARMACODYNAMICS

Renal Excretion

Glomerular filtration depends on: Renal blood flow & GFR; direct relationship Plasma protein binding; only free unbound drugs are

filtered

Tubular Secretion in the proximal renal tubule mediates raising drug concentration in PCT lumen

Organic anionic & cationic transporters (OAT & OCT) mediate active secretion of anionic & cationic drugs

Passive diffusion of uncharged drugs Facilitated diffusion of charged & uncharged drugs Penicillin is an example of actively secreted drugs

74

Renal Excretion

Tubular re-absorption in DCT: Because of water re-absorption, urinary D concentration

increases towards DCT favoring passive diffusion of un-ionized lipophillic drugs

It leads to lowering urinary drug concentrationo Urinary pH trapping: Chemical adjustment of urinary pH can inhibit or enhance

tubular drug reabsorption For example, aspirin overdose can be treated by urine

alkalinization with Na Bicarbonate (ion trapping) and increasing urine flow rate (dilution of tubular drug concentration)

Ammonium chloride can be used as urine acidifier for basic drug overdose treatment

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Drug Elimination

Pulmonary excretion of drugs into expired air: Gases & volatile substances are excreted by this route No specialized transporters are involved Simple diffusion across cell membrane predominates. It depends on: Drug solubility in blood: more soluble gases are slowly excreted Cardiac output rise enhance removal of gaseous drugs Respiratory rate is of importance for gases of high blood solubility Biliary excretion of few drugs into feceso Such drugs are secreted from the liver into the bile by active

transporters, and then into duodenumo Examples: digoxin, steroid hormones, some anticancer agentso Some drugs undergo enterohepatic circulation back into systemic

circulation

CLEARANCE:-

Is defined as the hypothetical volume of body fluids containing drug from which the drug is removed/ cleared completely in a specific period of time. Expressed in ml/min. CL = kVD, k: elimination rate constant

09-12-2010 77KLECOP, Nipani

Clearance It is ability of kidney, liver and other organs to eliminate drug

from the bloodstream Units are in L/hr or L/hr/kg Used in determination of maintenance doses Drug metabolism and excretion are often referred to

collectively as clearance The endpoint is reduction of drug plasma level Hepatic, renal and cardiac failure can each reduce drug

clearance and hence increase elimination T1/2 of the drug

78

TOTAL BODY CLEARANCE:-

Is defined as the sum of individual clearances by all eliminating organs is called total body clearance/ total systemic clearance.

Total Body Clearance = CLliver + CLkidney + CLlungs +CLx

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Metabolism & Excretion Kinetics

Elimination (metabolism + excretion) of most drugs follow first-order kinetics at therapeutic dose level

Amount of drug cleared in a given unit of time is directly proportional to the concentration of the drug according to Michaelis-Menten (linear) kinetics:

Only few drugs (e.g., phenytoin, alcohol) show saturation clearance (Zero-order, non-linear) kinetics Clearance mechanisms become saturated at therapeutic level,

and clearance remain constant even with increased drug plasma level

SLOW ELIMINATION at therapeutic levels leadsto toxic reactions

E = Vmax x C km + C

Minimum effective conc.

Therapeutic success of a rapidly & completely absorbed drug.

Therapeutic failure of a slowly absorbed drug.

Subtherapeutic level

Time

Plasma

Drug

Conc.

Not only the magnitude of drug that comes into the systemic circulation but also the rate at which it is absorbed is important this is clear from the figure.

81

Loading Dose

Loading Dose = Target Plasma C x VD

What Is the is the loading dose required fro drug A if:

target concentration is 30 mg/L

VD is 0.75 L/kg, patients weight is 75 kg

Answer VD = 0.75 L/kg x

75 kg = 56.25 L Target Conc. = 10

mg/L Dose = 30 mg/L x

56.25 L = 1659 mg

Maintenance Dose

Maintenance Dose = CL x target steady state drug concentration

The units of CL are in L/hr or L/hr/kg Maintenance dose will be in mg/hr

2004-2005

Pharmacodynamics (how drugs work on the body)

It is the study of biochemical and physiological effects of drugs and their mechanism of action at organ level as well as cellular level.

LONGITUDNAL SECTION OF KIDNEY

09-12-2010 85KLECOP, Nipani

Half-life (t1/2)

Half-life: is a derived parameter, completely determined by volume of distribution and clearance.

(Units = time) As Vd increases t1/2 increases

Steady-State Steady-state occurs

after a drug has been given for approximately 4-5 t1/2

At steady-state the rate of drug administration equals the rate of elimination

Plasma concentration after each dose is approximately the same

C

t

Cpav

Four half lives to reach steady state

Importance of Steady State (SS) At SS Rate in = Rate Out Steady state is reached usually within 4 – 5

half-lives at linear kinetics It is important for drug concentrations

interpretation in: Therapeutic Drug Monitoring (TDM) Evaluation of clinical response

Dosing and Steady State

• Dosing: Administration of medication over time, so that therapeutic levels can be achieved.

• Steady-state: o drug accumulates and plateaus

at a particular level o rate of accumulation determined

by half lifeo reach steady state in about five

times the elimination half-life

How Drugs Act: Pharmacodynamics

2004-2005

Pharmacodynamics (how drugs work on the body)

It is the study of biochemical and physiological effects of drugs and their mechanism of action at organ level as well as cellular level.

Do NOT impart new functions on any system, organ or cell Only alter the PACE of ongoing activity

STIMULATION DEPRESSION REPLACEMENT CYTOTOXIC ACTION

Principles of drug action

Majority of drugs interact with target biomolecules: Usually a Protein

ENZYMES

ION CHANNELS

TRANSPORTERS RECEPTORS

Targets of drug action

I- Ion Channels

DirectPhysical blocking

of channel local anesthetic & amiloride

ModulatorBind to the channel

protein itselfCa channel blockers

II- Enzymes

ChE inhibitors

α-Methyl dopa

II- Enzymes (cont.)

Drug acts as

Substrate leading to reversible OR irreversible inhibition of enzymereversible inhibition of cholinesterase by

neostigmine Irreversible inhibition of cyclo-oxygenase by aspirin

True/False substrateL-DOPA converted into dopamine α-methyldopa converted into α-

methylnorepinephrine (false transmitter)

III- Carrier Molecules What is carrier molecule? Carrier protein molecules function to

transport ions & small organic molecules (too polar to penetrate) across cell membranes.

III- Carrier Molecules

They possess a recognition site that confers specificity for a particular carried agent.

Such recognition sites can be targets for drugs where they block the transport system.

An example is the inhibition of cardiac Na+K+-ATPase by cardiac glycosides.

IV- Receptors cellular macromolecular proteins located

either in the cell membrane or less frequently in the cytoplasm.

Definition: It is defined as a macromolecule or binding site located on cell surface or inside the effector cell that serves to recognize the signal molecule/drug and initiate the response to it, but itself has no other function, e.g. G-protein coupled receptor.

They have specific recognition sites that bind selectively with a structurally-related group of synthetic drugs and endogenous mediators (ligands).

They responsible for transducing extracellular signals into intracellular response

IV- Receptors

There are FOUR types of receptors, classified according to their molecular structure and the nature of

the receptor-effector linkage

Receptor structure

Membrane receptors are usually composed of three parts:more than one hydrophobic membrane-

spanning α-helical segment the extracellular ligand-binding domain the intracellular transduction domain

Ligand-gated ion channel (inotropic)

They are responsible for regulation of ions across cell membrane

Binding of ligand to receptor → opening or closure of channel

Response is very rapid (few milisec)

E.g. Nicotinic receptors in the skeletal muscleδ-aminobuteric acid (GABA)

receptors in the brain

nAch receptor: pentamer protein (α2βγδ),

Class 2: G-protein-Coupled (Metabotropic) Receptors

Membrane bound receptors which are bound to effector system through G-proteins.

These are hetero trimeric molecules having 3 subunits α,β and ϒ. Based on α-sub unit they are further classified into 3 main varieties Gs, Gi and Gq

G-protein controls the activity of an effector protein; a membrane enzyme or an ion channel

Activation/inhibition of the effector enzyme increase/decrease the release of a diffusible second messenger such as cAMP or IP3

Subtypes of G-proteins - Targets (Second messenger systems)

Ion chanels: Na+ / H+ exchange Enzyms: Gi Inhib. Adenylyl cyclase Gs Stimul. Adenylyl cyclase Gq Stimul. Phospholipase C One ligand can bind to more than one type

of G-proteins coupled receptors second messenger pathways

2nd Messenger

Adenylate cyclase Phospholipase C

cAMP

Activation of protein Kinase C

DAG IP3

Regulation of free Ca in the cell

Enzyme linked receptors They have cytosolic enzyme in their

structure.

Binding of a ligand to extracellular domain activate or inhibit the enzyme.

Duration of response is minutes to hrs.

They are two main groups Tyrosine-kinase-linked receptors

such as receptors for insulin, growth factors and many cytokines,

Guanylate cyclase-coupled receptors for atrial natriuretic peptide (ANP)

Class 4: Gene Transcription-Regulating Receptor

This is the only intracellular cytoplasmic protein receptors, NO membrane segments.

The drug should diffuse into the cell to interact with receptor i.e. the drug should be lipid soluble.

E.g. Steroid & thyroid hormones.

It takes time for onset of action i.e. time for protein synthesis and longer duration of action (hrs to days)

Drug (D) + Receptor (R) K1 K2

DR complex

Pharmacologic Response

Drug-Receptor Interactions

Lock and key theory

Drugs binding to the receptors is governed by Law of Mass Action.

The number of receptors [R] occupied by a drug depends on the drug concentration [D] and the drug-receptor association and dissociation rate constants (K1 & K2).

Affinity: Ability of a substrate to bind with receptor Intrinsic activity (IA): Capacity to induce functional change

in the receptor

Affinity & Efficacy

Drug Receptor DR complex

Biological response

Key & Lock theory

Affinity

Efficacy Affinity is the tendency of drug to combine with its receptorEfficacy is the ability of a drug to initiate a cellular effect

According to Efficacy, the drug may be Agonist

An agent which activates a receptor to produce an effect similar to a that of the physiological signal molecule, e.g. Muscarine and Nicotine) response.◦ it has affinity & intrinsic activity i.e. the drug binds to a

receptor and produce biological response like endogenous ligand.

Antagonist an agent which prevents the action of an agonist on a

receptor or the subsequent response, but does not have an effect of its own, e.g. atropine and muscarine no response.◦ It has affinity but without intrinsic activity◦ Efficacy = zero

Partial agonist or antagonist◦ It has efficacy > zero but < full agonist, even if all receptors

are occupied◦ It has affinity greater, less or the same as full agonist◦ It decrease the response of the agonis.• Inverse agonist: an agent which activates receptors to

produce an effect in the opposite direction to that of the agonist, e.g. DMCM on bzp receptors opposite response

Ligand: any molecule which attaches selectively to particular receptors or sites (only binding or affinity) If explained

◦ Agonist: Affinity+ IA ◦ Antagonist: Affinity+ IA (0)◦ Partial agonist: Affinity + IA (0 to 1)◦ Inverse agonist: Affinity + IA (0 to -1)

Types of drug antagonist at the receptor

Competitive antagonism◦ Ag & Antag have the same binding site on the

receptor.◦ Increasing agonist concentration can restore the

agonist occupancy and hence the response. ◦ They increase the ED50 of the agonist, but not Emax or

the slope.◦ e.g. NA & prazocin on α1 receptor

Non competitive antagonism = allosteric◦ Ag & Antag have different site of binding.◦ Increasing the agonist does not affect antagonist

occupancy or the receptor blockade.◦ They cause a reduction of the slope & the max of the

agonist concentration-response curve

Dose-response (DR) curve: Depicts the relation between drug dose and magnitude of drug effect

Drugs can have more than one effect Drugs vary in effectiveness

◦ Different sites of action◦ Different affinities for receptors

The effectiveness of a drug is considered relative to its safety (therapeutic index)

Drug Effectiveness

Dose-Response Curves

By raising the dose above the “threshold dose level”, a gradual increase in response occurs.

Thus, DR of similarly active drugs produce parallel DR curves, enabling us to compare between the potencies of qualitatively similar drugs.

Potency Amount of the drug necessary to produce

certain magnitude of the effect e.g. 50% of the max. effect (EC50)

Efficacy = Intrinsic activity

Efficacy: the maximum effect of a drug

Depends on:◦ No. of complex formed◦ Efficiency of coupling between the complex and

the biological response (Emax)

Greater efficacy is more important therapeutically

Dose-Effect Curves

A) Additive: 1+1= 2

B) Synergism: 1+1= 4

C) Potentiation: 1+0= 2

Enhancement of drug effects

Therapeutic index The ratio of the dose that produce toxicity to the dose that

produce effective response It is obtained from quantal DRC (all-or-none effect)

TD50/ED50 TD50 = The drug dose that produce toxic effect in 50% of

population ED50 = The drug dose that produces a therapeutic or desired

response in 50% of population Examples

◦ Warfarin (narrow index)◦ Penicillin (wide index)

2- Standard safety margin (SSM): SSM= LD1 - 1 x 100 ED99

Therapeutic Index

1- Extracellular Sites of Drug Action Stomach: neutralize acid with base

(antacids) Blood: bind metals (chelation) like lead

with EDTA GI Tract: bind drugs (adsorption) with

Cholestyramine. GI Tract: increase water by osmotic

effects (laxatives) Kidney: increase water elimination

(osmotic diuretics)

Targets for drug action

Allergy: antigen-antibody………unpredictable

Idiosyncrasy: genetic abnormality…….. Unpredictable

Side effects: unavoidable, undesirable, normal actions by therapeutic doses.

Over-dose: high dose of drugs

Supersenstivity: exaggerated response to normal dose due to upregulation of receptors.

Dependance: habituation and addiction.

Adverse effects of drugs

Desensitization and Tachyphylaxis

tachyphylaxis ◦ When it is developing in the course of few

minutes.

Tolerance ◦ To describe a more gradual loss of drug-induced

clinical effects that develops in the course of days or weeks.

Refractoriness ◦ Used to indicate the loss of therapeutic response.

Drug resistance ◦ Describes the loss of the effect of antitumor and

antimicrobial drugs

Mechanisms of Desensitization

Receptor phosphorylation◦ Usually by phosphorylating serine or threonine residues

in the C-terminal domain of GPCRs leading to reduce efficiency and alter their binding affinity.

Down-regulation of receptors

◦ Phosphorylation also signals the cell to internalize the membrane receptor leading to decrease the number of receptors on the cell membrane.

◦ In contrast, continuous or repeated exposure to antagonists initially can increase the response of the receptor (supersensitivity or up-regulation)

Mechanisms of Desensitization

Receptor phosphorylation◦ Usually by phosphorylating serine or threonine residues

in the C-terminal domain of GPCRs leading to reduce efficiency and alter their binding affinity.

Down-regulation of receptors

◦ Phosphorylation also signals the cell to internalize the membrane receptor leading to decrease the number of receptors on the cell membrane.

◦ In contrast, continuous or repeated exposure to antagonists initially can increase the response of the receptor (supersensitivity or up-regulation)

Mechanisms of Desensitization

Depletion of mediators◦ Drugs acting indirectly via transmitter release can cause

depletion of that transmitter and hence loss of action e.g. amphetamine or ephedrine act by releasing catecholamines from nerve terminals.

Pharmacokinetic desensitization◦ Drugs which stimulate hepatic metabolism may enhance

their own metabolism and hence a lower plasma concentration with repeated administration of the same dose e.g. barbiturates

Pumping of drugs out from intracellular site (chemotherapy)

MCQs

MCQs The description of molecular events

initiated with the ligand binding and ending with a physiologic effect is called ----------

(A) receptor down-regulation (B) signal transduction pathway (C) ligand-receptor binding (D) law of mass action (E) intrinsic activity or efficacy

MCQs The description of molecular events

initiated with the ligand binding and ending with a physiologic effect is called ----------

(A) receptor down-regulation (B) signal transduction pathway (C) ligand-receptor binding (D) law of mass action (E) intrinsic activity or efficacy

MCQs A partial agonist is best described as an agent

that ---- (A) has low potency but high efficacy (B) acts as both an agonist and antagonist (C) interacts with more than one receptor type (D) cannot produce the full effect, even at high

doses (E) blocks the effect of the antagonist

THANK YOU

Do NOT impart new functions on any system, organ or cell Only alter the PACE of ongoing activity

STIMULATION DEPRESSION REPLACEMENT CYTOTOXIC ACTION

Principles of drug action

Majority of drugs interact with target biomolecules: Usually a Protein

ENZYMES ION CHANNELS TRANSPORTERS RECEPTORS

Targets of drug action

All Biological reactions are carried out under catalytic influence of enzymes

Drugs – increases/decreases enzyme mediated reactions In physiological system

Enzyme stimulation is less common by drugs – common by endogenous substrates

Enzyme inhibition – common mode of drug action

Enzymes – drug targets

take part in transmembrane signaling and regulates ionic composition

Drugs also target these channels:

Ligand gated channels, G-protein operated

channels,

Direct action on channels

Ion Channnels

•are translocated across membrane•binding to specific transporters (carriers) –,Pump the metabolites/ions In the direction of concentration gradient or against it

Transporters

 Drugs usually do not bind directly with enzymes, channels, transporters or structural proteins, but act through specific macromolecules-

RECEPTORS Definition: It is defined as a macromolecule or

binding site located on cell surface or inside the effector cell that serves to recognize the signal molecule/drug and initiate the response to it, but itself has no other function, e.g. G-protein coupled receptor

Receptors

Membrane bound receptors which are bound to effector system through G-proteins.

These are hetero trimeric molecules having 3 subunits α,β and ϒ. Based on α-sub unit they are further classified into 3 main varieties Gs, Gi and Gq

G-Protein coupled receptor

Subtypes of G-proteins - Targets (Second messenger systems)

Ion chanels: Na+ / H+ exchange Enzyms: Gi Inhib. Adenylyl cyclase Gs Stimul. Adenylyl cyclase Gq Stimul. Phospholipase C One ligand can bind to more than one type of

G-proteins coupled receptors second messenger pathways

Receptors intracellular domain is either protein kinase or guanyl cyclase Ex: Insulin, EGF, NGF

Tyrosine Kinase binding receptors have no intrinsic catalytic domain but agonist induced dimerization affinity for cytosolic tyrosine kinase protein Ex:cytokines,growth hormone

ENZYME LINKED RECEPTORS

  Receptors regulating gene expression Intracellular- cytoplasmic or nuclear Ex:All

steroid hormones,thyroxine, Vit A

TRANSCRIPTION RECEPTORS

To propogate signals from outside to inside To amplify the signal To integrate various extracellular and intracellular regulatory signals To adapt to long term changes in maintaining homeostasis

FUNCTIONS OF RECEPTORS

Drug+receptor drug-receptor complex effect

Lock and key theory

Affinity: Ability of a substrate to bind with receptor

Intrinsic activity (IA): Capacity to induce functional change in the receptor

Agonist: An agent which activates a receptor to produce an effect similar to a that of the physiological signal molecule, e.g. Muscarine and Nicotine) response.

Antagonist: an agent which prevents the action of an agonist on a receptor or the subsequent response, but does not have an effect of its own, e.g. atropine and muscarine no response.

 

Partial agonist: An agent which activates a receptor to produce submaximal effect but antagonizes the action of a full agonist, e.g. pentazocine Partial  

Inverse agonist: an agent which activates receptors to produce an effect in the opposite direction to that of the agonist, e.g. DMCM on bzp receptors opposite response

Ligand: any molecule which attaches selectively to particular receptors or sites (only binding or affinity) If explained

Agonist: Affinity+ IA Antagonist: Affinity+ IA (0) Partial agonist: Affinity + IA (0 to 1) Inverse agonist: Affinity + IA (0 to -1)

Desenstization or down-regulation Supersenstivity or up-regulation

Receptor regulation

A) Additive: 1+1= 2

B) Synergism: 1+1= 4

C) Potentiation: 1+0= 2

Enhancement of drug effects

Allergy: antigen-antibody………unpredictable

Idiosyncrasy: genetic abnormality…….. Unpredictable

Side effects: unavoidable, undesirable, normal actions by therapeutic doses.

Over-dose: high dose of drugs

Supersenstivity: exaggerated response to normal dose due to upregulation of receptors.

Dependance: habituation and addiction.

Adverse effects of drugs

Desensitization and Tachyphylaxis

tachyphylaxis ◦ When it is developing in the course of few

minutes.

Tolerance ◦ To describe a more gradual loss of drug-induced

clinical effects that develops in the course of days or weeks.

Refractoriness ◦ Used to indicate the loss of therapeutic response.

Drug resistance ◦ Describes the loss of the effect of antitumour and

antimicrobial drugs

MCQs G protein-coupled receptors that activate an

inhibitory Gα subunit alter the activity of adenylyl cyclase to --------

(A) increase the coupling of receptor to G protein

(B) block the ligand from binding (C) initiate the conversion of GTP to GDP (D) generate intracellular inositol

triphosphate(E) decrease the production of cAMP

MCQs The law of mass action explains the

relationship between --------- (A) dose of drug and physiologic response (B) the concentration of drug and the

association or dissociation of drug-receptor complex

(C) receptors and the rate of signal transduction

(D) an enzyme and ligands that inhibit the enzyme

(E) graded and quantal dose-response curves

Apparent Volume of Distribution

Vd = Amount of drug in the body Plasma drug concentration

VD = Dose/Plasma Concentration It is hypothetical volume of fluid in which the drug

is disseminated. Units: L and L/Kg We consider the volume of fluid in the body = 60%

of BW 60 X 70/100 = 42 L

Drug DistributionWater Body Compartments

Drugs may distribute into Plasma (Vascular)

Compartment: Too large mol wt Extensive plasma protein binding Heparin is an example Extracellular Fluid Low mol wt drugs able to move via

endothelial slits to interstitial water Hydrophilic drugs cannot cross cell

membrane to the intracellular water Total Body Water; Low mol wt

hydrophobic drugs distribute from interstitial water to intracellular

Plasma(4 litres)

Interstitial Fluid(11 litres)

Intracellular Fluid

(28 litres)

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Plasma Compartment

Extracellular Compartment

IntracellularCompartment

Drug has large Mol. Wt.OR

Bind extensively to pp

Vd = 4L6% of BW

e.g. Heparin

Drug has low Mol. Wt.Hydrophilic

Distributed in plasma & Interstitial fluid

Vd = 14L21% of BW

e.g. Aminoglycosides

Drug has low Mol. Wt.Hydrophobic

Distributed in three comp.Accumulated in fat

Pass BBB

Vd= 42L60% of BW

e.g. Ethanol

Plasma protein binding Many drugs bind reversibly to plasma proteins

especially albumin D + Albumin↔ D-Albumin (Inactive) + Free D Only free drug can distribute, binds to receptors,

metabolized and excreted.

Clinical Significance of Albumin Biding

Class I: dose < available albumin binding sites (most drugs)

Class II: dose > albumin binding sites (e.g., sulfonamide)

Drugs of class II displace Class I drug molecules from binding sites→ more therapeutic/toxic effect

In some disease states → change of plasma protein binding

In uremic patients, plasma protein binding to acidic drugs is reduced

Plasma protein binding prolongs duration

Sulfonamide

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Displacement of Class-I Drug

Alter plasma binding of drugs

1000 molecules

% bound

molecules free

999 900

100 1

100-fold increase in free pharmacologically active concentration at site of action.

Effective TOXIC

Capillary permeability Endothelial cells of capillaries

in tissues other than brain have wide slit junctions allowing easy movement of drugs

Brain capillaries have no slits between endothelial cells, i.e tight junction or blood brain barrier

Only carrier-mediated transport or highly lipophilic drugs enter CNS

Ionised or hydrophilic drugs can’t get into the brain

Liver capillary

Endothelial cells

Glial cell

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Brain capillary

Slit junctions

Tight junctions

Barriers to Drug Distribution

Blood-Brain barrier: Inflammation during meningitis or

encephalitis may increase permeability into the BBB of ionised & lipid-insol drugs

Placental Barrier: Drugs that cross this barrier reaches fetal

circulation Placental barrier is similar to BBB where

only lipophilic drugs can cross placental barrier

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Metabolism• It is enzyme catalyzed conversion of drugs to their metabolites.

• Process by which the drug is altered and broken down into smaller substances (metabolites) that are usually inactive.

• Lipid-soluble drugs become more water soluble, so they may be more readily excreted.

Most of drug biotransformation takes place in the liver, but drug metabolizing enzymes are found in many other tissues, including the gut, kidneys, brain, lungs and skin.

Metabolism aims to detoxify the substance but may activate some drugs (pro-drugs).

Reactions of Drug Metabolism

Conversion of Lipophyllic molecules

Intomore polar molecules

by oxidation, reduction and hydrolysis

reactions

Phase I Phase II

Conjugation with certain substrate

↑↓or unchanged Pharmacological

ActivityInactive compounds

Phase I Biotransformation Oxidative reactions: Catalyzed mainly by family of

enzymes; microsomal cytochrome P450 (CYP) monoxygenase system.Drug + O2 + NADPH + H+ → Drugmodified + H2O + NADP+

Many CYP isoenzymes have been identified, each one responsible for metabolism of specific drugs. At least there are 3 CYP families and each one has subfamilies e.g. CYP3A.

Many drugs alter drug metabolism by inhibiting (e.g. cimetidine) or inducing CYP enzymes (e.g. phenobarbital & rifampin).

Pharmacogenomics

Oxidative reactions: A few drugs are oxidised by cytoplasmic enzymes.◦ Ethanol is oxidized by alcohol dehydrogenase◦ Caffeine and theophylline are metabolized by xanthine

oxidase◦ Monoamine oxidase

Hydrolytic reactions: Esters and amides are hydrolyzed by:◦ Cholineesterase

Reductive reactions: It is less common.◦ Hepatic nitro reductase (chloramphenicol)◦ Glutathione-organic nitrate reductase (NTG)

Phase I Biotransformation (cont.)

Phase II Biotransformation Drug molecules undergo conjugation reactions with an

endogenous substrate such as acetate, glucuronate, sulfate or glycine to form water-soluble metabolites.

Except for microsomal glucuronosyltransferase, these enzyems are located in cytoplasm.

Most conjugated drug metabolites are pharmacologically inactive.◦ Glucuronide formation: The most common using a

glucuronate molecule.◦ Acetylation by N-acetyltransferase that utilizes acetyl-Co-

A as acetate donar.◦ Sulfation by sulfotransferase. Sulfation of minoxidil and

triamterene are active drugs.

Drug Excretion Excretion is the removal of drug from body

fluids and occurs primarily in the urine.

Other routes of excretion from the body include in bile, sweat, saliva, tears, feces, breast, milk and exhaled air.