Download INTRODUCTION TO SCIENTIFIC RESEARCH

General Principles of Pharmacology
Targets for drug action
* A drug is a chemical that affects physiological
function in specific way
* Most drugs are effective because they bind to
particular target protein including receptors
TYPES OF RECEPTORS
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TYPES OF RECEPTORS
1- Channel-linked receptors
- coupled directly to an ion channel such
acetylcholine, GABA & Glutamate receptors
2- G-protein-Coupled receptors
- it produces second massenger as well as opening
channel
-stimulated by adrenergic drugs, muscarinic &
hormones
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Continue TYPES OF RECEPTORS
3- Kinase-linked receptors
- insulin & growth hormone receptors
- this type also linked to guanylate cyclase
*** ALL PREVIOUS TYPES OF RECEPTORS ARE MEMBRANE BOUND
4- Receptors that regulate gene
transcription
* They are soluble receptor usualy inside the
cell (cytosol or intranuclear protein)
* Steroid , thyroid, retinoic acid & vit D
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Drug Specificity
* Drug binds only to certain targets
* Individual targets recognise only
certain class of drug
* There rae no drugs completely specific
in action
* Increase the dose will affect other
targets in cell
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Binding of Drugs to Receptors
* Binding of drugs to receptors obeys the
law of mass action (the rate of chemical reaction is
proportional to the product concentrations of reactants)
*At equilibrium, receptor occupancy is
related to drug concentration
* The higher the affinity of drug for receptor,
the lower the concentration needed for
occupancy
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Agonist & antagonist
* drug acting on receptor may be agonist or antagonist
A- Agonist initiates changes in cell function
* Full agonist: has high efficacy
* Partial agonist
- it produces submaximal effects
- it has intermediate efficacy
What is is the efficacy ?
It is the ability of drug to initiate biochemical changes
leads to the effect of drug
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Antagonist
* it binds with receptor without initiating
biochemical changes
* it has zero efficacy
* it binds with any state of receptor (active &
inactive)
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Types Drug Antagonist
A- Chemical antagonist
B- Pharmacokinetic antagonist
* one drug affecting other drug via:
- Absorption
- Metabolism
- Excretion
C- Competitive antagonism
* Reversible & * Irreversible
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Continue Types Drug Antagonist
D- Non-Competitive antagonism
- interrupts receptor-effector linkage
- e.g. calcium channel blocker prevents the effects
epinephrine on the heart and blood vessels
E- Physiological antagonism
- Two drugs producing opposite effects
- Omeprazole blocks histamine in gastric acid secretion
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Desensitization and Tachyphylaxis
* They are synonymous which describe RAPID loss in the
effect of drug despite an
increase in the dose of drug
* Due to depletion of endogenous neurotransmitters
TOLERANCE
* It is a decrease in effects of drug as a result of repeated use
of drug
* It take few days or weeks to develop
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Mechanism of Tolerance,
Tachyphylaxis & desensitisation etc..
1- Change in Receptors
- (agonist failure to induce biochemical changes)
2- Loss of Receptors
3- Exhaustion of mediators (depletion)
4- increased metabolic degradation
5- Physiological adaptation (kidney &
antihypertensive)
6- Active extrusion of drug from cells
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DOSE RESPONSE RELATIONSHIP
It is a relationship between the drug amount
(concentration) and pharmacological effects
• Types of responses
a- Graded response
- response increases by increase the dose
b- All or none response such as
anti-convulsant.
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Therapeutic index
* it is a measure of drug safety
* How to calculate ?
- LD50/ED50
Potency of drug
* It is the minimum dose required to cause
maximum response
* Potency of drug is not important clinically
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HOW DRUGS MEDIATE
THEIR ACTIONS ?
* Via interacting with its target(s) leading to:
1- activation or blocking of receptors
2- block endogenous mediators (counterfeit)
3-open or close ionic channels (Benzodiazepine
&L.A. )
4- compete with uptake system (carrier)
- imipramine, cocaine, proton pump inhibitor, digoxin,
probenecid
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Continue HOW DRUGS MEDIATE THEIR ACTIONS ?
5- Enzymes (dihydrofolate reductase targeted by
methotrexate & trimethoprim, cyclooxygenase, xanthine
oxidase, MAO, Dopa decarboxylase, ACE etc…..)
6- Other targets such as
* Immunophilins in lymphocyte targeted by
immunosuppresants such as Cyclosporin & Tacrolimus
* Tubulin of phagocytes and other cells including
cancerous cells
- Targeted by Colchicine, Vincristine & Taxol
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Continue HOW DRUGS MEDIATE THEIR ACTIONS ?
7- Physical means
- Osmotic diuretics
- inhalational anesthesia
8- Chelating agent
* reacts with DNA or ions
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Examples on the mechanisms of drugs action
1- activation of muscarinic receptor in the
heart(M2)
* ACTIVATE Gi-protein which lead to decrease in Camp
* This leads to decrease in calcium influx
* This causeS bradycardia
2- Activation of muscarinic receptor in
smooth muscle (M3)
* This leads to activate Gs-protein leads which leads to increase
calcium influx which causes contraction
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Examples on the mechanisms of drugs action
3- activation of alpha-1 receptor in the blood
vessels
* ACTIVATE Gi-protein which lead to increase in IP3(Inositol
triphosphate VIA activation of G-protein
* This leads to an
vasoconstriction
increase in calcium influx and
4- Activation of beta-1 receptor in heart
* This leads to activate Gs-protein leads which leads to activate
adenylate cyclase which causes phosphorylation of calcium
channel
* calcium influx which causes contraction(Tachycardia &
increase in the force of cardiac muscle contraction (+ve inotropic
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Examples on the mechanisms of drugs action
5- Activation of beta-2 receptor in smooth
muscle
* This causes to activate Gs-protein and to activate adenylate
cyclase
•CAMPactives protein kinase which leads to series of
phosphorylation of various protein
•phosphorylation either activates or inhibits target enzyme or
channel
* in smoth muscle , CAMP dependent protein kinase
phosphoryate myosin-light chain kinase which required for
contraction (relaxation occurred)
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Classification of adverse effects
1- TYPE A
- It is dose related
- It depends on therapeutic index
2- Type B
- Non-dose related
- immunological reactions
- Pharmacogenetic
3- Long-Term effects
- Adaptive changes
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Classification of adverse effects
- Rebound Phenomena
- It depends on therapeutic index
4- Delayed effects
- Non-dose related
- Carcingenesis
- impair fertility
- Teratogenicity
- drug in breast milk
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Pharmacokinetic of drugs
1- ABSORPTION OF DRUG
- From the site of administration
2- Distribution
- To reach the site of action
3- metabolism
- to inactivate or activate
4- Excretion
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ROUTE OF DRUG ADMINISTRATION
1- Oral administration (P.O.)
2- Subcutaneous (S.C.)
3- Intradermal
4- Intramuscular (I.M.)
5- Intravenous (I.V.)
6- Sublingual
7- Rectal
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ROUTE OF DRUG ADMINISTRATION
8- Intrathecal & epidural
9- Inhalation
10- Topical
* skin
* eye
* mucous membrane
-nasal, vaginal, oropharynx
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Pharmacokinetics
Disposition of Drugs
Time Course of Drug Action
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Major Topics
•
•
•
•
•
•
Passage of drugs across membranes
Absorption of drugs
Distribution of drugs
Metabolism of drugs
Excretion of drugs
Pharmacokinetic models
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Passage of drugs across
membranes
• Structure of the plasma membrane
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Mechanisms of transport
• Passive diffusion: passage of drugs through
the lipid surface (major mechanism of drug
absorption)
– Lipid-soluble drugs
– Small water-soluble drugs
– Noncharged form of weak electrolytes
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Membrane permeability versus
lipid (olive oil):water partition
coefficient
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Weak electrolytes and membrane
permeability
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Mechanisms of transport (2)
• Filtration: bulk flow of water-soluble drugs
through pores (glomerular, capillary)
– Glomerulus: 80Å pores
– Capillary endothelium: gap junctions
– Blood brain barrier: 8Å passageways
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Mechanisms of transport (3)
• Facilitated diffusion: carrier-mediated, ATP
not required (e.g., glucose)
• Active transport: carrier-mediated, ATP
required (e.g., Na+, K+, Ca++)
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Mechanisms of transport (4)
• Endocytosis and exocytosis: (e.g., for very
large compounds)
Receptor
Dynamin
Clathrin
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Absorption of drugs
• From gastrointestinal tract: lipid-soluble, nonionized
forms of drugs are absorbed better than water-soluble,
ionized forms of drugs
– environmental pH important in absorption
– acidic drugs (aspirin) absorbed better theoretically in
stomach (pH 1-2), basic drugs (codeine) absorbed better in
intestine (pH 7-8)
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Henderson-Hasselbach equation
base
pH - pKa = log
acid
For an acidic drug: acid = HA; base = AFor a basic drug: acid = BH+; base = B
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Theoretical absorption of aspirin
and codeine for dental pain
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Unique characteristics of the oral
route
• Influences of gastric emptying, mucosal
surface area, and drug inactivation
important for oral route
• Small intestine usually most important
because of large surface area (folds of
Kerckring, villi, microvilli)
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• Clinical advantages
– Safest route
– Cheapest route
– Best patient acceptance
• Disadvantages
– Delayed effect
– Patient cooperation required
– Unique problems with GI toxicity
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Absorption of drugs (2)
• From oral, sublingual, or rectal mucosa:
passive diffusion.
– May bypass first-pass inactivation
• From the lungs: passive diffusion
– rapid absorption, dependent on particle size (6
µm cutoff)
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Absorption of drugs (3)
• From injection sites: subcutaneous tissues,
muscle or fat, absorbed by diffusion and
affected by blood flow
• From miscellaneous sites: skin, spinal canal,
tooth pulp
• Intravenous, intraarterial injection avoids
absorption
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Bioavailability
• Clinical pharmacology of differential
absorption
• Related terms
– biologic equivalence
– chemical equivalence
– therapeutic equivalence
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Distribution
• Absorbed drugs leave capillary wall quickly
and freely (via filtration and diffusion) to
enter interstitial fluid; blood flow being
important in the regional distribution of
drugs
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• Binding to plasma proteins (mostly to albumin and,
for basic drugs, a1-acid glycoprotein)
– major distribution site
– highest drug concentrations usually found in blood; serve
as drug depots, thus prolonging half-life of drugs
– pharmacologic effects and toxic manifestations affected
by hypoalbuminemia and copresence of other drugs also
bound effectively to albumin
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• Central nervous system: permeable to lipidsoluble drugs only; limited permeability to
water-soluble drugs when inflamed
• Placental transfer: limited by blood flow,
not by a "barrier"
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• Fat tissue: depot for thiopental and
chlorinated hydrocarbon insecticides (e.g.,
DDT)
• Sites for metabolism and excretion: liver,
kidney, intestine, lungs
• Redistribution: especially important for IV
injection of lipophilic drugs
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Redistribution of thiopental after
intravenous injection
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Metabolism
• General considerations - drug metabolism
(biotransformation) usually results in more watersoluble, more polar metabolites, thus facilitating
their excretion by reducing renal tubular
reabsorption
• drug metabolism does not always result in
detoxification and inactivation of drugs, although
these usually occur
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Chemical reactions
• Phase I
–
–
–
–
–
microsomal oxidation (important)
nonmicrosomal oxidation (e.g., alcohol)
reduction
hydrolysis
dehalogenation
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Microsomal enzyme oxidation
system
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• Role of cytochrome P450 system
– CYP3A4
– CYP2D6
– CYP2C
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CYP1A2
CYP2E1
CYP3A
CYP2D6
CYP2C
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Chemical reactions (2)
• Phase II (conjugation)
–
–
–
–
–
–
glucuronidation (microsomal, important)
acetylation
amino acid synthesis
methylation
sulfate addition
others (e.g., glutathione addition)
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Factors affecting drug
metabolism
• reversible binding to plasma proteins
• localization of drugs (e.g., fat)
• hepatic blood flow
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Factors affecting drug
metabolism (2)
• pathology-, age-, or genetics-related deficiency or
alteration in drug metabolizing enzyme (e.g.,
pseudocholinesterase deficiency and
succinylcholine)
• inhibition of drug metabolizing enzyme (e.g., by
erythromycin)
• induction of drug metabolizing enzyme (e.g., by
phenobarbital)
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Excretion
• Renal excretion
– involves glomerular filtration and tubular
reabsorption and secretion
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– excretion increased by decreasing tubular
reabsorption, thus basic drugs are excreted
better in acidic urine, acidic drugs better in
alkaline urine
– clinical application—aspirin and barbiturate
poisonings are treated by alkalization of
patients’ urine by giving sodium bicarbonate
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• phase II reactions (conjugation) increases
tubular secretion and prevents reabsorption
(exception: methylation)
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• Others
–
–
–
–
–
–
Bile
Lung
Feces
Saliva (pp. 24-25, Table 2-1)
Sweat
Milk
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Time Course of Drug Action
• General rules
• Compartment models
– Single-compartment
– Multiple-compartment
• Exceptions to general rules
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General rules
• Plasma concentration related to degree of
receptor binding, thus magnitude of drug
effect
• Disposition processes usually first order
• Elimination usually slower process than
absorption or distribution
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• First-order process:
– dC/dT = k•C (constant fraction)
• Zero-order process:
– dC/dT = k (constant amount)
• Capacity limited process:
– low C, first-order; high C, zero-order
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Single-compartment model
ka
Absorption
Vd
Body
ke
Elimination
C = D/Vd or Vd = D/C
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Single compartment model: no
absorption, first-order elimination
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• Clearance (CL): the measurement of blood
cleared of the drug by elimination per unit
time (as in units of mL/sec). It and the
volume of distribution (Vd) create the
dependent variable T1/2. They are related by
the following formula:
T1/2 = 0.693Vd/CL
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With renal excretion
C•Cl = U•V
Where C = plasma concentration,
Cl = clearance, U = urinary
concentration, and V = urinary
volume
Cl = U•V/C
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• Drug disappearance
– usually follows first-order kinetics (exponential decay),
with a constant fraction (not amount) of drug being
eliminated per unit of time
– the process is independent of the kind and amount of
drug
– half-life (T1/2), not dose, is the primary factor in
prolonging drug effects
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Overriding importance of halflife on duration of drug effect
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Drug accumulation with repeated
dosing
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Multicompartment models
• combine kinetics of redistribution and
elimination
• provide best description of drugs with high
lipid
solubility
and
drugs
given
intravenously
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Two-compartment model
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ORAL ADMINISTRATION
1- PROS
• Convenient
• Safe ?
• Economical (does not need sterilization)
2- CONS
• Requires patient compliance
• Drugs irritant to stomach
• Drugs not stable in GIT
• Drugs extensively metabolize by the liver
• Drugs NOT absorb from GIT
• Leads to food drug interaction
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INTRAVENOUS ADMINISTRATION
1- PROS
• Rapid action
• Delivered the desired amount
• irritant drug can be given only I.V. but NOT S.C.
2- CONS
• Increase the risk of adverse effects
• Must inject slowly in order to minimize the
effects of drug on the heart
• It needs constant monitoring the reponse of
patient
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SUBCUTANEOUS ADMINISTRATION
1- PROS
• It provides sustain effects because of slow absorption
• Addition of vasoconstrictor decreases further the rate
of absorption from the site of injection
• It is suitable for insoluble drugs such as pellets
and suspension
2- CONS
• can not inject large volume
• can not inject irritant drug
• repeated injection leads to necrosis (atrophy of skin)
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INTRAMUSCULAR ADMINISTRATION
1- PROS
• Suitable for oily vehicle and irritant drug
• The rate of absorption is very high because of high
blood flow in the muscle
2- CONS
• It is not recommended in patient taking Anticoagulant
• Increase CPK
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PULMONARY ADMINISTRATION
1- PROS
• Rapid absorption
• Local administration into the lung is beneficial in
bronchial asthma
•Avoid hepatic effects
•Can absorb fine droplets (aerosol), prticle size,
gaseous and volatile drugs
2- CONS
• Difficult to regulate & administered the dose
• some drugs cause lung irritation
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TOPICAL ADMINISTRATION
1- Mucous membrane
• Rapid absorption such as local anesthetic & ADH
2- Skin
• Lipophilic drugs absorb rapidly from skin such as
nitroglycerin skin batch, scopolamine batch
• Inflammed, burned, abraded skin absorb drug faster
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TOPICAL ADMINISTRATION
3- Ophthalmic absorption
• it is used for local effectss
• systemic absorption occurs through
NASOLACRIMAL CANAL such as β-adrenergic
blockers eye drops
•Ointment and suspension minimized systemic
absorption
•Ocular insert provides continous delivery of drug with
minimum systemic absorption
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SUBLINGUAL ADMINISTRATION
• Excellent absorption for non-ionized drug Example
Nitroglycerin, apomorphine (Uprima)
• It has high absorption rate close to intravenous
injection
• Avoid hepatic first pass metabolism
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RECTAL ABSORPTION
• It is used when oral route is warranted such as
vomiting or coma
• It has erratic, irregular and incomplete absorption
(50%)
• It goes in partial hepatic first pass metabolism
•Some drugs may cause rectal irritation
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DRUGS DISTRIBUTION
Factors influence drug distribution
1- Permeability of drug to biological membranes
•Blood brain barrier
•Testicular barrier
•Placental barrier
- LIPID SOLUBLE DRUGS
-They have large Vd (volume of distribution)
2- Extent of plasma protein
- Highly protein bound stay in circulation & also have large Vd
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DRUGS DISTRIBUTION
Factors influence drug distribution
-Drugs with large Vd have the following properties
•High protein binding
•High lipid solubility
•High affinity to other tissues such as bone & liver
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DRUGS DISTRIBUTION
Factors influence drug distribution
3- Availability of transport mechanism
- passive diffusion: The drug must be in unionized form
- Active transport: require ATP
- Facilitative diffusion: it requires carrier but without energy
such vit B12, glucose and amino acid
- ion pair transport: the ionic compound combines reversibly
with endogenous compound such as MUCIN in GIT
4- Regional pH
- breast milk more acidic than blood: Weak base drugs
accumulate in breast milk
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DRUGS DISTRIBUTION
Factors influence drug distribution
4- Rate of blood flow to tissues
- Skeletal muscles have high blood flow
5- Regional pH
- breast milk more acidic than blood: Weak base drugs
accumulate in breast milk
6- Tissues mass
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DRUG METABOLISM
OBJECTIVES OF METABOLISM
1- To make the drug more water soluble in order
to facilitate its excretion
2- To activate or inactivate the drug
* Some drugs become highly toxic or
carcinogenic
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Factors influence Metabolism
1- Drugs
- inducer: rifampicin, dilantin, barbiturate
- inhibitors: cimetidine, macrolide & antifungal drugs
2- Liver diseases
3- Diet
- grape fruit, vitamins deficeincy such vit B6 is cofactor for
decarboxylation
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Types of reactions in metabolism
* Phase-I reaction
- consist of oxidation (dealkylation & deamination) ,
reduction or hydrolysis
- the product is reactive such as hydroxyl
-Some time highly toxic
- the product ready to enter other phase of metabolism
* Phase-II
- Normally results to inactive compound
- involve conjugation of glucuronyl, sulfate Play a role
in enterohepatic cycle
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EXCRETION OF DRUGS
1- TYPES OF EXCRETION
• Renal excretion
• Biliary excretion
• Pulmonary excretion
• Excretion via other body fluids
- Saliva
-Breast milk
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RENAL EXCRETION OF DRUGS
Some drugs mainly excreted via
kidney such as metformin & sotalol
etc…
•Factors influence renal excretion
•GFR
• Interference with renal active transport of drug such
as probenecid
• Altering passive diffusion by change PH, lipid
solubility
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RENAL EXCRETION OF DRUGS
•Altering passive diffusion by change PH
-
When pH of urine acidic, weak base drug will
not be reabsorb from renal tubule
-When pH of urine alkaline, weak acid drugs
will not reabsorb from renal tubule
•Lipid water solubility
- Highly lipid soluble drug stay in circulation for longer time
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BILIARY EXCRETION &
ENTEROHEPATIC CYCLE OF DRUGS
Liver cells transfer various drug from plasma to bile by
• Transport system similar to renal tubule
• conjugates drugs and concentrate these drugs in bile
and the delivered into the intestine
• Some conjugate drugs which is delivered into the
intestine hydrolyzed to unconjugated drug (free drug)
• The free drug reabsorb back into circulation
• This called enterhepatic cycle.
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BILIARY EXCRETION &
ENTEROHEPATIC CYCLE OF DRUGS
• This creates a reservoir of recirculating drugs which
represent around 20% of total drug in the body
• This cycle maintains drug blood levels leading to
prolongs the drug action
• Examples of drugs go through enterohepatic cycle:
- Digoxin
- morphine
- steroids including sex hormones
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PULMONARY EXCRETION OF DRUGS
Pulmonary excretion does not require
metabolism
• Factors
influence pulmonary excretion
1- Rate of respiration
2- Cardiac output
3- solubility of gas in blood
- High blood solubility decreases gases loss from lung
- In contrast less blood soluble, leads to faster loss of gas via
lung such nitrous oxide
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Excretion of drugs via other body fluids
1- Sweat
- Drugs or its metabolite may be responsible for
induction of dermatitis or other skin reactions
2- Saliva
- change in taste or induction metallic taste
3- Milk
- The PH of milk is 6.5, therefore the weak base drugs
will concentrate in milk
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Thank you
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