derived from the greek word for drug a science that studies drug effects within a living system,...
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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?
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A drug is defined as any substance; chemical agent; used in the
• Diagnosis• Cure• Treatment• prevention of a disease or condition
Drug
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Chemical NameGeneric NameTrade Name
Drug Names
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Describes its molecular structure and distinguishes it from other drugs
Chemical Name
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Determined by the pharmaceutical company along with a special organization known as the U.S. Adopted Names Council (USAN)
Generic name
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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
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The particular spelling of a brand name drug is proposed by a manufacturer for one of several reasons.
How is the Trade Name Chosen?
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Azmacort- treats asthma
Rythmol- treats cardiac arrhythmias
1. To indicate the disease process being treated
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Pseudoephedrine to Sudefed
Haloperidol to Haldol
Ciprofloxacin to Cipro
2. To simplify the generic name
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Slow-K slow release potassium supplement
3. To indicate the duration
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Or legend drugs Means in order to obtain drug, you
must have a legal prescription
Prescription Drugs
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Or Over-the-Counter (OTC) drugs Drug that may be purchased
without a prescription
Non-Prescription Drugs
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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
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Routes of drug administration
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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
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The main routes of drug entry into the body may be divided into two classes:
◦Enteral◦Parenteral
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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
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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
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Disadvantages
◦inconvenient◦small doses◦unpleasant taste of some drugs
Sublingual/Buccal
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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
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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
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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
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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)
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First-pass Effect
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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.
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RECTAL ADMINISTRATION:
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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
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◦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
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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
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Intramuscular
1. very rapid absorption of drugs in aqueous solution 2. Slow release preparations Disadvantages
pain at injection sites for certain drugs
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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
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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
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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
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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.
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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-
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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
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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
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LIPID BILAYER
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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
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DIFFUSION THROUGH MEMBRANES
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KLECOP, Niani 44
MOVEMENT OF SUBSTANCES ACROSS CELL MEMBRANES
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1) Passive diffusion2) Carrier- mediated transport a) Facilitated diffusion
b) Active transport3) PINOCYTOSIS
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MECHANISMs OF DRUG ABSORPTION
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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.
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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
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2) CARRIER MEDIATED TRANSPORT MECHANISM
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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.
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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.
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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
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3) Pinocytosis
This process is important in the absorption of oil soluble vitamins & in the uptake of nutrients.
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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
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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.
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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
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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
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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
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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
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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
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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.
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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.
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Bioavailability the proportion of the drug in a
dosage form available to the body
i.v injection gives 100% bioavailability.
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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
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Seru
m
Con
cen
trati
on
Time
Injected Dose
Oral Dose
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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
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DEFINITION OF PHARMACOKINETICS AND PHARMACODYNAMICS
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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
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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
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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
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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
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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
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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.
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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
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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
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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.
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LONGITUDNAL SECTION OF KIDNEY
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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
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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
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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
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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
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How Drugs Act: Pharmacodynamics
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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.
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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
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Majority of drugs interact with target biomolecules: Usually a Protein
ENZYMES
ION CHANNELS
TRANSPORTERS RECEPTORS
Targets of drug action
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I- Ion Channels
DirectPhysical blocking
of channel local anesthetic & amiloride
ModulatorBind to the channel
protein itselfCa channel blockers
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II- Enzymes
ChE inhibitors
α-Methyl dopa
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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)
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III- Carrier Molecules What is carrier molecule? Carrier protein molecules function to
transport ions & small organic molecules (too polar to penetrate) across cell membranes.
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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.
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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.
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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
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IV- Receptors
There are FOUR types of receptors, classified according to their molecular structure and the nature of
the receptor-effector linkage
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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
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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
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nAch receptor: pentamer protein (α2βγδ),
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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
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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
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2nd Messenger
Adenylate cyclase Phospholipase C
cAMP
Activation of protein Kinase C
DAG IP3
Regulation of free Ca in the cell
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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)
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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)
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Drug (D) + Receptor (R) K1 K2
DR complex
Pharmacologic Response
Drug-Receptor Interactions
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Lock and key theory
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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
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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
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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
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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)
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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
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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
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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.
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Potency Amount of the drug necessary to produce
certain magnitude of the effect e.g. 50% of the max. effect (EC50)
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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
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Dose-Effect Curves
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A) Additive: 1+1= 2
B) Synergism: 1+1= 4
C) Potentiation: 1+0= 2
Enhancement of drug effects
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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
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Therapeutic Index
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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
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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
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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
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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)
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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)
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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)
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MCQs
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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
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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
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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
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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
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Majority of drugs interact with target biomolecules: Usually a Protein
ENZYMES ION CHANNELS TRANSPORTERS RECEPTORS
Targets of drug action
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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
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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
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•are translocated across membrane•binding to specific transporters (carriers) –,Pump the metabolites/ions In the direction of concentration gradient or against it
Transporters
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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
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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
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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
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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
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Receptors regulating gene expression Intracellular- cytoplasmic or nuclear Ex:All
steroid hormones,thyroxine, Vit A
TRANSCRIPTION RECEPTORS
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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
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Drug+receptor drug-receptor complex effect
Lock and key theory
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Affinity: Ability of a substrate to bind with receptor
Intrinsic activity (IA): Capacity to induce functional change in the receptor
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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.
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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)
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Desenstization or down-regulation Supersenstivity or up-regulation
Receptor regulation
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A) Additive: 1+1= 2
B) Synergism: 1+1= 4
C) Potentiation: 1+0= 2
Enhancement of drug effects
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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
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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
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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
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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
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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
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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
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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.
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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
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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
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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
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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.
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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).
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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
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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
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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.)
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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.
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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.