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What is Pharmacology?. derived from the Greek word for drug A science that studies drug effects within a living system, biochemical and physiological aspects

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what is pharmacology
What is Pharmacology?
  • 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
slide2
Drug
  • A drug is defined as any substance; chemical agent; used in the
  • Diagnosis
  • Cure
  • Treatment
  • prevention of a disease or condition
drug names
Drug Names
  • Chemical Name
  • Generic Name
  • Trade Name
chemical name
Chemical Name
  • Describes its molecular structure and distinguishes it from other drugs
generic name
Generic name
  • Determined by the pharmaceutical company along with a special organization known as the U.S. Adopted Names Council (USAN)
trade name
Trade 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.
how is the trade name chosen
How is the Trade Name Chosen?
  • The particular spelling of a brand name drug is proposed by a manufacturer for one of several reasons.
1 to indicate the disease process being treated
1. To indicate the disease process being treated
  • Azmacort- treats asthma
  • Rythmol- treats cardiac arrhythmias
2 to simplify the generic name
2. To simplify the generic name
  • Pseudoephedrine to Sudefed
  • Haloperidol to Haldol
  • Ciprofloxacin to Cipro
3 to indicate the duration
3. To indicate the duration
  • Slow-K slow release potassium supplement
prescription drugs
Prescription Drugs
  • Or legend drugs
  • Means in order to obtain drug, you must have a legal prescription
non prescription drugs
Non-Prescription Drugs
  • Or Over-the-Counter (OTC) drugs
  • Drug that may be purchased without a prescription
sources of drugs
Sources of 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
routes of drug administration1

Important

Info

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

enteral routes
Enteral Routes
  • Enteral- drug placed directly in the GI tract:
    • sublingual - placed under the tongue
    • oral - swallowing (p.o., per os)
    • rectum - Absorption through the rectum
sublingual buccal
Sublingual/Buccal

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 buccal1
Sublingual/Buccal
  • Disadvantages
    • inconvenient
    • small doses
    • unpleasant taste of some drugs
slide23
Oral
  • 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
slide24
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
first pass effect
First-pass Effect
  • 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 effect1
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)

rectal administration
RECTAL ADMINISTRATION:
  • 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.

KLECOP, Nipani

rectal
Rectal

Advantages:

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 laxatives

Disadvantages:

absorption may be variable

irritating drugs contraindicated

parenteral routes
Parenteral Routes
  • 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
intravascular
Intravascular

Absorption 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
Intramuscular

1. very rapid absorption of drugs in aqueous solution

2. Slow release preparations

Disadvantages

pain at injection sites for certain drugs

subcutaneous
Subcutaneous

slow and constant absorption

2. absorption is limited by blood flow, affected if circulatory problems exist

3. concurrent administration of vasoconstrictor will slow absorption

inhalation
Inhalation

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

topical
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
slide37

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.
slide38

Route for administration

-Time until effect-

  • 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)
aspects of drug pharmacokinetics adme
Aspects of Drug Pharmacokinetics (ADME)

Drug at site

of administration

Absorption

Drug in plasma

Distribution

Drug/metabolites

in tissues

Metabolism

Elimination

Drug/metabolites

in urine, feces, bile

absorption
Absorption
  • 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.
lipid bilayer
LIPID BILAYER

KLECOP, Nipani

diffusion through membranes
DIFFUSION THROUGH MEMBRANES

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
mechanisms of drug absorption
MECHANISMs OF DRUG ABSORPTION
  • Passive diffusion
  • Carrier- mediated transport

a) Facilitated diffusion

b) Active transport

  • PINOCYTOSIS

KLECOP, Nipani

passive diffusion
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.

2 carrier mediated transport mechanism
2) CARRIER MEDIATED TRANSPORT MECHANISM
  • 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

a facilitated diffusion
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.

b active transport
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
Drug AbsorptionActive 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

Carrier-mediated energy-dependent active transport

ADP

+ Pi

Passive diffusion of a water-sol drug via aqueous channel

AH

B

Passive diffusion of a lipid-sol drug

A-

BH+

3 pinocytosis
3) Pinocytosis

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

physicochemical factors
PHYSICOCHEMICAL FACTORS
  • 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.
slide53

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.
slide54

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.

KLECOP, Nipani

factors affecting git absorption
Factors Affecting GIT Absorption
  • Blood Flow To Absorptive Site:
  • Greater blood flow raises absorption
  • 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
  • Acceleratedgastric emptying→ faster delivery to intestinal large surface → increased absorption
factors affecting git absorption1
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 suspensions
factors affecting absorption from git
Factors affecting absorption from GIT

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
slide58

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
slide59

Intestine

  • Major site for absorption of most drugsdue 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 Villiwhich increase the surface area 30 times( 10 m2).
  • From the surface of villi protrude several microvilliwhich 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.

slide60

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
Bioavailability
  • the proportion of the drug in a dosage form available to the body

i.v injection gives 100% bioavailability.

bioavailabiity
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

Injected Dose

Serum Concentration

Oral Dose

Time

distribution
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

renal excretion
Renal Excretion
  • Glomerular filtration dependson:
  • 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
renal excretion1
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 concentration
  • 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
drug elimination
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 feces
  • Such drugs are secreted from the liver into the bile by active transporters, and then into duodenum
  • Examples: digoxin, steroid hormones, some anticancer agents
  • Some drugs undergo enterohepatic circulation back into systemic circulation
slide77

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

KLECOP, Nipani

clearance
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
slide79

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

KLECOP, Nipani

metabolism excretion kinetics
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 leads

to toxic reactions

E = Vmax x C

km + C

slide81

Therapeutic success of a rapidly & completely absorbed drug.

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.

Plasma

Drug

Conc.

Minimum effective conc.

Therapeutic failure of a slowly absorbed drug.

Subtherapeutic level

Time

l oading dose
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
  • 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
slide84

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.

half life t 1 2
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
  • 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
importance of steady state ss
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:
    • drug accumulates and plateaus at a particular level
    • rate of accumulation determined by half life
    • reach steady state in about five times the elimination half-life

Dosing and Steady State

slide91

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.

principles of drug action
Principles of drug action

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

  • STIMULATION
  • DEPRESSION
  • REPLACEMENT
  • CYTOTOXIC ACTION
targets of drug action
Targets of drug action

Majority of drugs interact with target biomolecules: Usually a Protein

  • ENZYMES
  • ION CHANNELS
  • TRANSPORTERS
  • RECEPTORS
i ion channels
I- Ion Channels

Direct

Physical blocking

of channel

local anesthetic & amiloride

Modulator

Bind to the channel

protein itself

Ca channel blockers

ii enzymes
II- Enzymes

ChE inhibitors

α-Methyl dopa

ii enzymes cont
II- Enzymes (cont.)
  • Drug acts as
    • Substrate leading to reversible OR irreversible inhibition of enzyme
      • reversible inhibition of cholinesterase by neostigmine
      • Irreversible inhibition of cyclo-oxygenase by aspirin
    • True/False substrate
      • L-DOPAconverted into dopamine
      • α-methyldopa converted into α-methylnorepinephrine (false transmitter)
iii carrier molecules
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 molecules1

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
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.
slide100

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 receptors1
IV- Receptors

There are FOUR types of receptors, classified according to

their molecular structure and the nature of

the receptor-effector linkage

receptor structure
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
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 muscle

δ-aminobuteric acid (GABA) receptors in the brain

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

Class 2: G-protein-Coupled (Metabotropic) Receptors
slide108

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

  • Ion chanels: Na+ / H+ exchange
  • Enzyms: GiInhib. Adenylylcyclase

Gs Stimul. Adenylylcyclase

GqStimul. Phospholipase C

  • One ligand can bind to more than one type of G-proteins coupled receptors second messenger pathways
slide110

2nd Messenger

Phospholipase C

Adenylate cyclase

IP3

cAMP

DAG

Activation of protein

Kinase C

Regulation

of free Ca in the cell

enzyme linked receptors
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,
    • Guanylatecyclase-coupled receptors for atrial natriuretic peptide (ANP)
class 4 gene transcription regulating receptor
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 receptor interactions
Drug-Receptor Interactions

Drug (D) + Receptor (R)

K1 K2

DR complex

Pharmacologic Response

slide116
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
Affinity & Efficacy

Key & Lock theory

Affinity

DR complex

Drug

Receptor

Efficacy

Affinityis the tendency of drug to combine with its receptor

Efficacy is the ability of a drug to initiate a cellular effect

Biological response

according to efficacy the drug may be
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
slide119

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
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
drug effectiveness
Drug Effectiveness
  • 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)
dose response curves
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
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 = 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
enhancement of drug effects
Enhancement of drug effects
  • A) Additive: 1+1= 2
  • B) Synergism: 1+1= 4
  • C) Potentiation: 1+0= 2
therapeutic index
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
targets for drug action
Targets for drug action

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)
adverse effects of drugs
Adverse effects of drugs
  • 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.
desensitization and tachyphylaxis
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
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 desensitization1
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 desensitization2
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)
slide144
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

slide145
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

slide146
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

principles of drug action1
Principles of drug action

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

  • STIMULATION
  • DEPRESSION
  • REPLACEMENT
  • CYTOTOXIC ACTION
targets of drug action1
Targets of drug action

Majority of drugs interact with target biomolecules: Usually a Protein

  • ENZYMES
  • ION CHANNELS
  • TRANSPORTERS
  • RECEPTORS
enzymes drug targets
Enzymes – drug targets
  • 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
ion channnels
Ion Channnels
  • 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
transporters
Transporters

are translocated across membrane

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

receptors
Receptors
  • 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
g protein coupled receptor
G-Protein coupled receptor
  • 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
slide154

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

  • Ion chanels: Na+ / H+ exchange
  • Enzyms: GiInhib. Adenylylcyclase

Gs Stimul. Adenylylcyclase

GqStimul. Phospholipase C

  • One ligand can bind to more than one type of G-proteins coupled receptors second messenger pathways
enzyme linked receptors1
ENZYME LINKED RECEPTORS
  • Receptors intracellular domain is either protein kinase or guanylcyclase 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
transcription receptors
TRANSCRIPTION RECEPTORS
  • Receptors regulating gene expression
  • Intracellular- cytoplasmic or nuclear Ex:All steroid hormones,thyroxine, Vit A
functions of receptors
FUNCTIONS OF 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
slide159

Affinity: Ability of a substrate to bind with receptor

  • Intrinsic activity (IA): Capacity to induce functional change in the receptor
slide160

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.
slide163

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)
receptor regulation
Receptor regulation
  • Desenstization or down-regulation
  • Supersenstivity or up-regulation
enhancement of drug effects1
Enhancement of drug effects
  • A) Additive: 1+1= 2
  • B) Synergism: 1+1= 4
  • C) Potentiation: 1+0= 2
adverse effects of drugs1
Adverse effects of drugs
  • 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.
desensitization and tachyphylaxis1
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
slide169
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

slide170
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
Apparent Volume of Distribution

Vd = Amount of drug inthe 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 distribution water body compartments
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)

slide173

Plasma

Compartment

Extracellular

Compartment

Intracellular

Compartment

Drug has large Mol. Wt.

OR

Bind extensively to pp

Vd = 4L

6% of BW

e.g. Heparin

Drug has low Mol. Wt.

Hydrophilic

Distributed in plasma &

Interstitial fluid

Vd = 14L

21% of BW

e.g. Aminoglycosides

Drug has low Mol. Wt.

Hydrophobic

Distributed in three comp.

Accumulated in fat

Pass BBB

Vd= 42L

60% of BW

e.g. Ethanol

plasma protein binding
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
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

176

Displacement of Class-I Drug

alter plasma binding of drugs
Alter plasma binding of drugs

1000 molecules

900

999

% bound

1

100

molecules free

100-fold increase in free pharmacologically

active concentration at site of action.

EffectiveTOXIC

slide178
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

Slit junctions

Brain capillary

Glial cell

Tight junctions

Endothelial cells

barriers to drug distribution
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
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.

Metabolism

slide181
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
Reactions of Drug Metabolism

Phase I

Phase II

Conversion of

Lipophyllic molecules

Into

more polar molecules

by

oxidation, reduction and hydrolysis

reactions

Conjugation with certain substrate

↑↓or unchanged

Pharmacological

Activity

Inactive compounds

phase i biotransformation
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
phase i biotransformation cont
Phase I Biotransformation (cont.)
  • 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 ii biotransformation
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
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.