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1
INTRODUCING
PHARMACOKINETICS ANDPHARMACODYNAMICS
Kinanti Narulita DPharmacology Department
FACULTY OF MEDICINE – UNISSULA
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LEARNING OUTCOMES
Define and discuss pharmacokinetic factorsDiscuss the factors that affect absorption,
distribution, metabolism and excretion-howthey affect drug therapyDefine and discuss pharmacodynamicmechanisms of drug actionsApply pharmacokinetic andpharmacodynamic concepts to patientscenarios.
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PHARMACOKINETIC
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PHARMACOKINETICS :CONSIDERING SUCH TERMS AS
Route Absorption
DistributionProtein BindingHepatic Metabolism
Metabolic productsRenal ExcretionHalf-life
Toxicity
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Route : oral, parenteral, inhalation, rectal,transdermal, injection.
Absorption entry into body-acidity and solubility.
First-pass-metabolic change due to liver enzymes :patients with liver disease poor metabolism toxicity.Distribution extent of protein binding important as
only free (unbound) drug can have effect. Penicillin ishighly protein bound. Two drug co-administered,degree of protein binding can be altered, displaced?Toxicity?Excretion removal or clearance of drug from body.Half-life how long does it take the plasmaconcentration of drugs to go down to 50%.Toxicity consider the pharmacological routes toadverse drug effects.
5
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PHARMACOKINETIC
Pharmacokinetics is what the body does tothe drugs (THE BODIES RESPONSE TOMEDICATION) , pharmacokinetics refers to thehandling of a drug within the body.For almost all drugs the magnitude ofpharmacological effect depends on itsconcentration at its site of action.To achieve the pharmacological responsedesired, the drug must first be in an availableand suitable form and then administrated by an
appropriate route. 6
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DistributionMetabolism
Excretion
Absorption
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Absorption
Route
EnteralParenteral
IVTopical
transdermal inhalationoral sublingual
Distribution
Systemic circulation
Absorption Absorption
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ABSORPTION
Process of drug movement from theadministration site to the systemic circulation.The amount and rate of absorption are determinedby several factors :
Drug characteristics that affect absorption /physical nature of the dosage form : molecularweight, ionization, solubility, & formulation
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Disintegration and dissolution of the releaseddrug into the correct part of the GI tract is
required for the drug to be absorbed. Drugs inliquid dose form require no disintigration andoften dissolution are already accomplished andtherefore absorb more rapidly with faster effects.
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ABSORPTION
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Food effect on some drugs affects thebioavailability.
GI motility effects the thorough mixing in the GItract which increases the efficacy in which thedrug makes contact with surfaces that areavailable to engage absorption.
Drug absorption is mainly in the upper smallintestine that is facilitated by the large surfacearea of villi and the rich blood supply.
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ABSORPTION
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ABSORPTION
KEYNOTE Factors affecting drugabsorption related to patients :
Route of administrationGastric or intestinal pHContents / composition of GI tract
Presence or absence of food in thestomachMesenteric blood flow
Concurrent administration with other drugs
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BIOAVAILABILITY
“Bioavailability is the proportion of the administereddose that reaches the systemic circulation. ” = refersto the amount and the rate of appearance of thedrug in the blood after administration in its initial
dose form.Orally administered drug bioavailability is directlyrelated to the individual solubility in body fluids.
Poor solubility = low bioavailability
To become affective i.e. produce a therapeuticeffect, a drug must reach an adequate concentrationin the blood. Drugs administered by the IV route arebioavailable in 100% of cases as it is administered
directly into the blood.
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BIOAVAILABILITY
Some drugs with the same active principle, made bydifferent manufacturers may differ in thebioavailability, dependant on the degree of
compression or nature of excipients (addedsubstances), that may affect the disintigration anddissolution of the drug.Drugs licensed for use in the UK (including parallel
imports) the manufacturing processes are controlledto ensure bioavailability across drug production isconsistent.Brand vs generic prescribing . Bioequivalenceshould be similar with a few exceptions.
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Time to Peak Concentration
010
20
30
40
50
6070
80
90
100
0 5 10 20 30 60 120 180
minutes
c o n c e n
t r a
t i o n
IV
Oral
Rectal
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EFFECT OF FOOD ON THEABSORPTION OF DRUGSBioavailability of some drugs is affected by thepresence of food. E.g : penicillin, erythromycin,rifampicin, thyroxine.Some drugs are taken before meals to allowtime for drug to act before food is taken.Gastric irritation can be caused by drugs takenon an empty stomach.
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FIRST PASS EFFECT
Drugs that are absorbed via the GIT arecirculated to the liver first via
the hepatic portal veinLiver then acts as a filterOnly part of the drug is
circulated systemicallyThe combination of
processes is termed
the ‘First Pass’ effect
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All drugs taken orally that are absorbed pass bythe hepatic portal vein. This is a defencemechanism to detoxify substances coming into
the body.The liver protects the body from systemicallycirculating toxins that are absorbed via the GIT by
filtering drugs through a range of detoxificationmechanisms seeking for natural toxins. As a result only part of the administered drugreaches the systemic circulation via the hepaticartery.
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FIRST PASS EFFECT
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Distribution
Factors affecting
Absorption Metabolism
Low albumin Problems with:Heart
CirculationDiabetes
Bound drugs are pharmacologically inactive because the drug-
protein complex is unable to cross cell membranes.
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Membrane permeabilitycross membranes to site of action
Plasma protein bindingbound drugs do not cross membranesmalnutrition = albumin = free drug
Lipophilicity of druglipophilic drugs accumulate in adipose tissue
Volume of distribution
DISTRIBUTION
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Low Affinity, high capacity binding Proteins : Albumin (e.g. phenytoin) 1-acid glycoprotein (cationic lidocaine)Lipoproteins
Specific binding Proteins (high affinity lowcapacity) : cortisol binding globulin, thyroidbinding globulin
PLASMA PROTEINS
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Protein Berat Molekul
(Da)Konsentrasi
(g/L)Obat yangmengikat
Albumin 65,000 3.5 –5.0 Acid drugs (large variety ofdrug)
α1 - acidglycoprotein
44,000 0.04 – 0.1 Basic drug : propranolol,imipramine and lidocaine.
Globulins : corticosteroids.
Lipoproteins 200,000 – 3,400,000 .003-.007 Basic lipophilic drug :chlorpromazine
α1 globulin
α2 globulin
59000
13400
.015-.06 Steroid, thyroxine,Cynocobalamine,
Vit. A,D,E,K
IKATAN OBAT – PROTEINPLASMA
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PENYAKIT DANPROTEIN BINDING
Protein Binding (Ikatan Obat – Protein) Menurun Pada Kondisi :
PENYAKIT LIVER PENYAKIT RENAL
DapsoneDiazepamMorphinePhenytoinPrednisoloneQuinidineTolbutamideTriamterene
Barbiturates SalicylatesCardiac Glycosides SulfonamidesChlordiazepoxide TriamtereneClofibrateDiazepamDiazoxideFurosemideMorphinePhenylbutazone
Phenytoin
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Beberapa obat mampuberikatan dgn HAS lebih satubinding site :- Flucoxacillin, flurbiprofen,
ketoprofen, tamoxifen dandicoumarol berikatan dgn2 binding site
- Indomethacin berikatan
dengan 3 binding site. AAG mempunyai kapasitasterbatas. AAG hanyamempunyai binding site 1untuk lidocaine.
Site 1
Site 2
Site 3
site4
DRUG BINDING SITEON HSA
Warferinbinding
site
Diazapambinding
site
Digitoxinbinding site
Tamoxifenbinding site
HSA
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METABOLISM
Drugs are metabolised in the liver, lungs, kidneys,blood and intestines.In order for drugs to pass across the lipid cellmembrane they must be lipophilic. Lipophilic
means fat soluble. Hydrophilic means watersoluble.The higher the solubility in lipids compared towater, the more rapid the tissue entry.
Metabolic rate determines the duration of theaction of the drugs.The primary metabolic site is the liver. If enzymefunction is inadequate the metabolic effect can becompromised and cause toxicity.
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Eg : liver disease, very young and very old whohave diminished hepatic microsomal enzymeactivity.
Body works to convert drugs to less active formsand increase water solubility (hydrophilic thanlipophilic) to enhance elimination / excretion.
The speed with which a drug is metabolised willdetermine the duration of the action of the drug.This in turn will determine how often the drug isadministered.
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METABOLISM
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Cytochrome P450 systemLocated within the endoplasmic reticulumof hepatocytesThrough electron transport chain, a drugbound to the CYP450 system undergoesoxidation or reduction
Enzyme inductionDrug interactions
PHASE 1 REACTIONS
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HydrolysisOxidation
ReductionDemethylationMethylation
Alcohol dehydrogenase metabolism
PHASE 1 REACTIONS
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Polar group is conjugated to the drugResults in increased polarity of the drug
Types of reactionsGlycine conjugationGlucuronide conjugation
Sulfate conjugation
PHASE 2 REACTIONS
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Pulmonary = expired in the airBile = excreted in feces
enterohepatic circulationRenal
glomerular filtration
tubular reabsorptiontubular secretion
EXCRETION / EXCRETION
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EXCRETION / EXCRETION
Drugs are primarily excreted by the kidneysIn order for drugs to be excreted they need to
become hydrophilicExcretion of drugs can be affected by theurinary pH
How the drug is excreted can influenceprescribing decisionsThe excretion rate varies from hours to weeksand on the condition of the kidneys
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Aging patient with reduced renal capacitymore prone to build up (toxicity) of drugs
excreted renally, more of problem with drugsnarrow therapeutic range e. g digoxin. somebeta blockers (celiprolol, sotaolol) etc.Excretion and prescribing influence. Egampicillin is excreted in high concentrationsin bile, so is a good chioce for biliary tractinfection.
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EXCRETION / EXCRETION
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When lipid soluble drugs pass through thekidneys they are re-absorbed in the distal
tubule and return to the plasma. In order tobe excreted they need to become morehydrophilic. This occurs in the Bowman’s capsule, converted to less active metabolitesmore easily excreted.
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EXCRETION / EXCRETION
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Steady State : the amount of drugadministered is equal to the amount of drug
eliminated within one dosing interval resultingin a plateau or constant serum drug level.Drugs with short half-life reach steady state
rapidly; drugs with long half-life take days toweeks to reach steady state.
EXCRETION / EXCRETION
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HALF LIFE OF DRUGS
Drug excretion is commonly expressed in termsof half life (t1/2)This is the time required for the concentration of
the drug in the plasma to decrease by one-halfof it’s initial valueDrug half life is variable and can be long or shortSubsequent doses are given to raise theconcentration levels to a peakIn theory, the optimal dosage interval betweendrug administration is equal to the half-life ofthe drug
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Eg. half life of drugs – aspirin 6 hours,metronidazole 9 hours, digoxin 36 hours.Half-life is affected by :
Short half life : extensive tissue uptake, rapidmetabolism, rapid excretion.Long half life : extensive protein binding, slow
metabolism, poor excretion.Concentration falls after metabolism andexcretion. If dose interval is too long, effect is notachieved, too short an interval leads to toxicity.
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HALF LIFE OF DRUGS
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LOADING DOSES
Are used when the medical conditiondemands high concentrations very quickly
This is achieved by an initial dose that istwice the maintenance doseExample :
Acute infections : use stat dose ofantibiotic, 2 times the next dose.Digoxin loading dose.
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Loading dosesallow rapidachievement of
therapeutic serumlevelsSame loading doseused regardless ofmetabolism /eliminationdysfunction
0
5
10
15
20
25
30
35
40
w/ bolus
w/o
bolus
LOADING DOSES
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Renal Disease : same hepatic metabolism,same / increased volume of distribution andprolonged elimination dosing intervalHepatic Disease : same renal elimination,same / increased volume of distribution, slowerrate of enzyme metabolism dosage,
dosing intervalCystic Fibrosis Patients : increasedmetabolism / elimination, and larger volume ofdistribution dosage, dosage interval
SPECIAL PATIENTPOPULATIONS
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PHARMACODYNAMIC
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PHARMACODYNAMICS
Pharmacodynamics : study of the biochemicaland physiologic processes underlying drug action
what the drug does to the body or mode of
action of drugs in the body , ideally including howdrugs exert their effect at a general , cellular levelor the molecular mechanism by which the drugacts.
Mechanism of drug action Drug-receptor interaction
EfficacySafety profile
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Understanding the pharmacodynamics ofdrugs will enable you to predict drug
interactions and toxicities.The pharmacology of a drug is not alwaysknown-but where it is, it would be nice if youhad a handle on how the drugs you will beprescribing exert their effect
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PHARMACODYNAMICS
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ReceptorsReceptors-agonist, partialagonist and antagonist
Ion channels
Ion channels-gating ofintracellular ionsEnzymes
Enzymes-drugs act to inhibit or
potentiateCarrier molecules
Carrier molecules-allowmolecules not lipid soluble to
cross cell membrane
CONSIDERING
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CONSIDERING
ChemotherapyChemotherapeutic agents
Drug tolerance / dependenceEffects of pathological state and biologicalvariability
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TYPES OF RECEPTORS
G-protein-couple receptors. G protein receptorswork in seconds, e.g. muscarinic ACh receptors,adrenoceptors, histamine receptors. Proteins or
glycoproteins :Present on cell surface, on an organelle within thecell, or in the cytoplasmFinite number of receptors in a given cell
Kinase linked receptors. Kinase (enzyme) linkedreceptors can take hours, e.g. Insulin, Growth factor.Nuclear intracellullar receptors, e.g. steroid, thyroidhormone.
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Action occurs when drug binds to receptor andthis action may be :
Ion channel is opened or closedSecond messenger is activated :
cAMP, cGMP, Ca ++, inositol phosphates,etc.Initiates a series of chemical reactions
Normal cellular function is physically inhibitedCellular function is “turned on”
DRUG RECEPTORS
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AffinityRefers to the strength of binding between adrug and receptorNumber of occupied receptors is a functionof a balance between bound and free drug
DRUG RECEPTORS
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RECEPTORSReceptors are a target molecule thata drug molecule has to combine withto produce a specific effectReceptors must be compatible –like 2pieces of a jigsaw e.g.neurotransmission
Main types of action at receptor :
Receptor agonistsReceptor antagonists
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AGONISTDrugs which alter the physiology of a cell by
binding to plasma membrane or intracellularreceptors.Full agonist is isoproterenol , which mimicsthe action of adrenaline at β -adrenoreceptors . Morphine , which mimicsthe actions of endorphins at μ -opioidreceptors throughout the CNS.
DRUG RECEPTORS
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PARTIAL AGONIST A drug which does not produce maximaleffect even when all of the receptors areoccupied. E.g : Clomiphene & Tamoxifen
partial agonist at estrogen receptor.
Buprenorphine partial agonist at μ -opioid receptors throughout the CNS.
DRUG RECEPTORS
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ANTAGONISTSInhibit or block responses caused by
agonists. Physiological antagonist =opposing physiological actions , but actat different receptors. They are sometimescalled blockers ; examples include : α -blockers, β -blockers, CCB .
DRUG RECEPTORS
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COMPETITIVE ANTAGONISTCompetes with an agonist for receptors. Highdoses of an agonist can generally overcomeantagonist.Naloxone is used to reverse opioid overdose caused by heroin / morphine .
Flumazenil vs benzodiazepines.Competitive antagonists combine with thesame receptor as an endogenous agonist(e.g . ranitidine at histamine H2-receptors ).
DRUG RECEPTORS
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NONCOMPETITIVE ANTAGONISTBinds to a site other than the agonist-bindingdomain. Induces a conformation change in the
receptor such that the agonist no longer“recognizes” the agonist binding site. High dosesof an agonist do not overcome the antagonist inthis situation.
Histamine ↓ arterial pressure through vaso-dilatation at the H1 receptor, while adrenaline ↑ arterial pressure through vasoconstrictionmediated by α -adrenergic receptor activation.
DRUG RECEPTORS
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IRREVERSIBLE ANTAGONISTBind permanently to the receptor binding site
by forming a covalent bond to the active site/ just by binding so tightly, therefore they cannot be overcome with agonis.Irreversible enzyme inhibitors that actsimilarly are clinically used and include drugssuch aspirin, omeprazol and monoamineoxidase inhibitors .
DRUG RECEPTORS
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Drugs act to affect cellular gating mechanismin cell wall. Ligand-gated ion channels work inmilliseconds e.g GABA benzodiazepines,Nicotinic Ach.Some ion channels are gated by receptor(open only when receptor is occupied by an
agonist) while other are voltage-gated-drugasaffect the permage or flow of for example,potassioum, sodium or calcium in and out ofthe cell.
ION CHANNELS
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Drugs acting at ion channels include :Benzodiazepines that act at GABA
(gamma amino butyric acid receptor)chloride channel return over excitablereceptor to constitutive (normal) level ofactivationCalcium channel blockers prevent diffusionof calcium through cell membraneNicorandil acts at potassium channels
ION CHANNELS
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Another examples of this drugs :Loop diuretics which inhibit sodium,
potassium and chlorine passage in the lopof Henle Another example omeprazole inhibitsproton pump in the gastric mucosaTricyclics inhibit noradrenaline uptake
ION CHANNELS
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Carrier molecules allow transport of smallorganic molecules that are too polar – notsufficiently lipid soluble to penetrate cellmembranes on their own. Drugs act oncarrier transporters which allow molecules
eg. glucose and amino acids.
CARRIER MOLECULES
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ENZYME INHIBITORS
An enzyme is a protein that can promote oraccelerate a biochemical reaction with asubstrateWhen the enzyme mistakes the drug for asubstrate, a drug-enzyme interaction occursThis interaction could increase or decreasethe rate of the biochemical reaction
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Many drugs target enzymes acting as falsesubstrates to competitively inhibit eitherreversibly e.g.neostigmine or irreversibly e.g
AspirinSimvastatin inhibits HMG CoA REDUCTASE
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ENZYME INHIBITORS
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CHEMOTHERAPEUTIC
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CHEMOTHERAPEUTICAGENTS
Cytotoxic drugs act by interfering with cellgrowth and division at different stages of the
cycle Anti-infective drugs
CHEMOTHERAPEUTIC
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Examples :Folic acid is required for DNA synthesis.Methotrexate inhibits the formation of folicacid.Penicillins and cephalosporins inhibitsynthesis of bacterial cell walls.
Nyastatin acts by increasing the permeabilityof of cell membranes of invading organisms.Erythromycin inhibits bacterial protein
synthesis.67
CHEMOTHERAPEUTICAGENTS
Bacterial Cell
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Cell wall
Cell membraneDNA
C l a
s s
1 r e
a c t i o
n s
C l a
s s
2 r e
a c t i o
n s
C l a
s s 3
r e a c t i o
n s
Glucose Precursormolecules
Aminoacids
Nucleotides
ProteinsRNA
DNA
Metabolism of bacterial cell
CHEMOTHERAPEUTIC
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Chemotherapy-exploiting the differencesbetween host and bacteria.
Class 1 reactions are not good targets forchemotherapy no marked difference in theway humans and bacteria obtain energy fromglucose.Class 2 are better targets as some pathwaysconverting precursor molecules to aminoacids occur in bacteria but not in human.
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CHEMOTHERAPEUTICAGENTS
CHEMOTHERAPEUTIC
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E.g. man cannot manufacture own folate(needed for DNA synthesis) and needs totake from diet. Bacteria make their own folateand cannot transport into cell fromenvironment.Class 3 reactions are excellent target for
chemotherapy because every cell makes itsown macromolecules, e.g. needed formanufacture of bacterial cell wall, differentfrom human cells. 70
CHEMOTHERAPEUTICAGENTS
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DEFINITIONS
EFFICACYDegree to which a drug is able to producethe desired response
POTENCY Amount of drug required to produce 50% ofthe maximal response the drug is capableof inducingUsed to compare compounds withinclasses of drugs
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EFFECTIVE CONCENTRATION 50% (ED 50 )Concentration of the drug which induces a specifiedclinical effect in 50% of subjects.
LETHAL DOSE 50% (LD 50 )
Concentration of the drug which induces death in50% of subjects.
THERAPEUTIC INDEXMeasure of the safety of a drug.Calculation : LD 50 /ED 50
MARGIN OF SAFETYMargin between the therapeutic and lethal doses of adrug .
DEFINITIONS
DOSE RESPONSE
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DOSE-RESPONSERELATIONSHIP
Drug induced responses are not an “all ornone” phenomenon.
Increase in dose may :Increase therapeutic responseIncrease risk of toxicity
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PHYSIOLOGICAL
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PHYSIOLOGICALVARIABILITY
Reduced hepatic blood flowRenal disease
Potential to reduce the elimination of drugsif eliminated largely by the kidneys. Thiscould lengthen the half life of drugs if the
metabolites are pharmacologically active.Dosage adjustments are required
PHYSIOLOGICAL
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PHYSIOLOGICALVARIABILITY
Allergy Allergy incidence is increasing with multiple
drug therapy. Penicillin groups mostcommonly involved.Initial reaction is the formation ofantibodies. Subsequent exposure causeschemicals to be releases e.g. histaminethat causes the allergic response
Decreased plasma proteins
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REMEMBERNo drug produces
a single effect!!!