Dr. Baltazar's Introduction to Pharmacology

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Pharmacology: Study of drugs.Pharmacology: Study of drugs.SUBSPECIALTIES:SUBSPECIALTIES:

Pharmacognosy: Science of drug sources (plants, animals,Pharmacognosy: Science of drug sources (plants, animals,minerals, synthetic) with their physical and chemicalminerals, synthetic) with their physical and chemicalproperties.properties.

Pharmacodynamics: Drug action, sites of action, therapeuticPharmacodynamics: Drug action, sites of action, therapeuticas well as side effects which come hand-in-hand withas well as side effects which come hand-in-hand withtherapeutic effects.therapeutic effects.

Pharmacokinetics: Fate of the drug from the time the drug isPharmacokinetics: Fate of the drug from the time the drug istaken in until it is excreted. This includes: time of taken in until it is excreted. This includes: time of administration (routes with available dosage forms),administration (routes with available dosage forms),absorption, distribution, metabolism, redistribution,absorption, distribution, metabolism, redistribution,excretion.excretion.


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SUBSPECIALTIESSUBSPECIALTIESPharmacotherapeutics: Drug application in the managementPharmacotherapeutics: Drug application in the managementof various diseases. Treatment is included here. Drugs areof various diseases. Treatment is included here. Drugs areprescribed to relieve, cure, prevent, diagnose diseases, andprescribed to relieve, cure, prevent, diagnose diseases, andto replace or supplement. Drug use (RDU) is governed by:to replace or supplement. Drug use (RDU) is governed by: S safetyS safety A affordability A affordability N needN need E effectivenessE effectiveness

Posology: Dosages of drugs. How much? Therapeutic dosePosology: Dosages of drugs. How much? Therapeutic dose(minimum, average, maximum)(minimum, average, maximum)


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ADVERSE DRUG REACTION ADVERSE DRUG REACTION

Allergy: Antigen-antibody reaction; not dose-related. Allergy: Antigen-antibody reaction; not dose-related.

Toxic effect: Dose-related.Toxic effect: Dose-related.

Side effect: Dose-related; minimum, average, maximum.Side effect: Dose-related; minimum, average, maximum.

Teratogenic effectTeratogenic effect

Genetic defect: Enzyme deficiency.Genetic defect: Enzyme deficiency.


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PHARMACOKINETICSPHARMACOKINETICS

Biologic response is related to DRUG CONCENTRATIONBiologic response is related to DRUG CONCENTRATIONat SITE OF ACTIONat SITE OF ACTION related to the DOSErelated to the DOSE fractionfractionthat reaches the site is dependent on:that reaches the site is dependent on:

Route of administrationRoute of administration Dosage formsDosage forms

Physiologic factors influencing drug concentration:Physiologic factors influencing drug concentration:1.1. Absorption: Drug ability to enter the blood stream. Absorption: Drug ability to enter the blood stream.2.2. Distribution: Drug movement to various sites.Distribution: Drug movement to various sites.

3.3. Biotransformation/metabolism: Alteration of chemicalBiotransformation/metabolism: Alteration of chemicalstructure of drug.structure of drug.

4.4. Excretion: Ability of living system to remove a drug andExcretion: Ability of living system to remove a drug andits biotransformation products (metabolites) from theits biotransformation products (metabolites) from theinternal environment.internal environment.


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DOSE-RESPONSE RELATIONSHIPDOSE-RESPONSE RELATIONSHIP

DOSE:DOSE:Dosage formsDosage formsRoute of administrationRoute of administration

DRUG CONCENTRATION (binding sites):DRUG CONCENTRATION (binding sites): Absorption AbsorptionDistributionDistributionBiotransformationBiotransformation

ExcretionExcretion

RESPONSERESPONSE


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Dose Response CurvesDose Response Curves

Quantal dose response curveQuantal dose response curve All or none response to a drug and relates to the frequency with All or none response to a drug and relates to the frequency with

which a specified dose of a drug produces a specific response in awhich a specified dose of a drug produces a specific response in apopulation.population.

Graded dose response curveGraded dose response curve

As the dose is increased, the effect will also increase. As the dose is increased, the effect will also increase. At a certain dose, the resulting effect will reach a max (ceiling At a certain dose, the resulting effect will reach a max (ceiling

effect).effect).

No. of pxresponding

Min. dose for response (mg/kg)

Drug A Drug

BDrugEffect

Dose

D150mg

D2100mg

Cumulative Graph of the FrequencyDistribution Curve


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BIOTRANSFORMATION

DOSE BLOODACTIVE

SITERESPONSE

EXCRETION

OTHER TISSUES

ABSORPTION DISTRIBUTION

PHARMACOKINETICS PHARMACODYNAMICS

DOSE-RESPONSE RELATIONSHIP

CONCENTRATION-RESPONSERELATIONSHIP


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GOALS IN PHARMACOKINETICSGOALS IN PHARMACOKINETICS

Minimize ineffective concentration of drug.Minimize ineffective concentration of drug.Maximize therapeutic concentration.Maximize therapeutic concentration.

Avoid toxic concentration. Avoid toxic concentration.

Drug-plasmaconc.

TIME

TOXIC RANGE

THERAPEUTIC RANGE

INEFFECTIVE RANGE


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ABSORPTION ABSORPTION

The process by which a drug enters the bloodstream withoutThe process by which a drug enters the bloodstream withoutbeing chemically altered.being chemically altered.

Factors which influence the rate of absorption:Factors which influence the rate of absorption: Types of transportTypes of transport Physico-chemical properties of drugs (lipid solubility, ionization)Physico-chemical properties of drugs (lipid solubility, ionization) Protein bindingProtein binding RoutesRoutes Dosage formsDosage forms Circulation at sites of absorptionCirculation at sites of absorption Drug concentrationDrug concentration


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TYPES OF TRANSPORTTYPES OF TRANSPORT

PASSIVEPASSIVE FiltrationFiltration

Compounds cross membranes by hydrodynamic flow.Compounds cross membranes by hydrodynamic flow.Water flows through membrane pores carrying with it any soluteWater flows through membrane pores carrying with it any solutemolecules whose dimensions are less than those of the pores.molecules whose dimensions are less than those of the pores.When hydrostatic or osmotic pressure exists across membranes,When hydrostatic or osmotic pressure exists across membranes,solutes with molecular weights greater than 100-200 dont passsolutes with molecular weights greater than 100-200 dont passthrough.through.Filtration is the predominant process by which drugs cross mostFiltration is the predominant process by which drugs cross most

capillary endothelial membranes.capillary endothelial membranes. Simple diffusionSimple diffusion

SPECIALIZED TRANSPORT: Involves membraneSPECIALIZED TRANSPORT: Involves membraneassociated protein carrier for drugs.associated protein carrier for drugs.


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SIMPLE DIFFUSIONSIMPLE DIFFUSION

The rate of drug transfer is directly proportional to their The rate of drug transfer is directly proportional to their concentration gradient across the membrane. Speed of concentration gradient across the membrane. Speed of passage is determined by lipid solubility (lipid to water passage is determined by lipid solubility (lipid to water partition coefficient).partition coefficient).The higher the lipid to water partition coefficient, the greater The higher the lipid to water partition coefficient, the greater is the rate of transfer across membranes.is the rate of transfer across membranes.Non-ionized drugsNon-ionized drug s have greater rate of transfer thanhave greater rate of transfer than ionizedionizeddrugsdrug s ..Proportion of a drug is the non-ionized form depends onProportion of a drug is the non-ionized form depends onDISSOCIATIONDISSOCIATION constant of the drug and onconstant of the drug and on pH of thepH of themediummedium shown byshown by Henderson-Hasselbalch equationHenderson-Hasselbalch eq uation ..


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Henderson-Hasselbalch EquationHenderson-Hasselbalch Equation

concentration of non-ionized acidconcentration of non-ionized acidpKpKAA = pH + log= pH + log

concentration of ionized acidconcentration of ionized acid

WEAK ACID OR ACIDIC DRUGWEAK ACID OR ACIDIC DRUG

concentration of ionized baseconcentration of ionized base

pKpKAA = pH + log= pH + logconcentration of non-ionized baseconcentration of non-ionized base

BASIC DRUGBASIC DRUG


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SPECIALIZED TRANSPORTSPECIALIZED TRANSPORT

ACTIVE TRANSPORT ACTIVE TRANSPORT Solute crosses the membrane against a concentration gradient.Solute crosses the membrane against a concentration gradient. Transport mechanism becomes saturated at high soluteTransport mechanism becomes saturated at high solute

concentration showing a transport maximum.concentration showing a transport maximum.

Process is selective for certain ionic or structural configurations.Process is selective for certain ionic or structural configurations. If 2 compounds are transported, 1 will competitively inhibit theIf 2 compounds are transported, 1 will competitively inhibit the

transport of the other.transport of the other. Transport process can be inhibited non-competitively byTransport process can be inhibited non-competitively by

substances which interfere with cell metabolismsubstances which interfere with cell metabolism

FACILITATED DIFFUSIONFACILITATED DIFFUSION Solute is not transferred against a concentration gradient.Solute is not transferred against a concentration gradient.

PINOCYTOSISPINOCYTOSIS


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SPECIALIZED TRANSPORTSPECIALIZED TRANSPORT

PINOCYTOSISPINOCYTOSIS A specialized transport of large molecules and proteins (greater A specialized transport of large molecules and proteins (greater

than 1,000 daltons).than 1,000 daltons). In this complex process, the cell invaginates a small portion of In this complex process, the cell invaginates a small portion of

the cellular membranes and engulfs a droplet of extracellular fluidthe cellular membranes and engulfs a droplet of extracellular fluidcontaining the compound.containing the compound.

SITES WHEREIN CARRIER MEDIATED DRUG TRANSPORTSITES WHEREIN CARRIER MEDIATED DRUG TRANSPORTOCCUR:OCCUR:

1.1.

Renal tubuleRenal tubule

2.2. Biliary tractBiliary tract3.3. Blood-brain barrier Blood-brain barrier 4.4. GITGIT


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METHODS FOR DELAYINGMETHODS FOR DELAYING ABSORPTION ABSORPTION

Use of vasoconstrictorsUse of vasoconstrictors Adrenaline with local anesthetics By delaying absorption, it will reduce Adrenaline with local anesthetics By delaying absorption, it will reduce

systemic toxicity and prolongs the anesthetic effect of the drug.systemic toxicity and prolongs the anesthetic effect of the drug.Use of an insoluble slow-release form (poorly soluble salt, ester, or Use of an insoluble slow-release form (poorly soluble salt, ester, or complex) Procaine Penicillincomplex) Procaine PenicillinEsterification of steroid hormones (Testosterone propionate,Esterification of steroid hormones (Testosterone propionate,Fluphenazine decanoate)Fluphenazine decanoate)Subc. implantation of solid pelletsSubc. implantation of solid pellets Estradiol Its rate of absorption is proportional to the surface area of theEstradiol Its rate of absorption is proportional to the surface area of the

implant.implant.

Physical characteristics of a preparation may also be changed byPhysical characteristics of a preparation may also be changed bycombination (Insulin Zinc suspension ).combination (Insulin Zinc suspension ). Insulin fine amorphous suspension rapidly absorbed.Insulin fine amorphous suspension rapidly absorbed. Zinc suspension of large crystals which are slowly absorbed.Zinc suspension of large crystals which are slowly absorbed. Mixture of the 2 will produce immediate, sustained effect.Mixture of the 2 will produce immediate, sustained effect.


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DRUG DISTRIBUTIONDRUG DISTRIBUTION

I.I. BODY FLUID COMPARTMENTSBODY FLUID COMPARTMENTSa.a. Extracellular (plasma): 4.5% of body weightExtracellular (plasma): 4.5% of body weightb.b. Interstitial: 16%Interstitial: 16%c.c. Lymph: 1-2%Lymph: 1-2%d.d. Intracelular: 30-40%Intracelular: 30-40%e.e. Transcellular: 2.5% - includes CSF, intraocular,Transcellular: 2.5% - includes CSF, intraocular,

peritoneal, pleural, synovial and digestive secretions.peritoneal, pleural, synovial and digestive secretions.To enter the transcellular compartment from theTo enter the transcellular compartment from theextracellular compartment, a drug must cross aextracellular compartment, a drug must cross acellular cellular barrier barrier ..


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DRUG DISTRIBUTIONDRUG DISTRIBUTIONII.II. BLOOD-BRAIN BARRIERBLOOD-BRAIN BARRIER

Brain is inaccessible to many systemically acting drugs. DisruptionBrain is inaccessible to many systemically acting drugs. Disruptionof this barrier can occur in the of this barrier can occur in the

a.a. Presence of inflammationPresence of inflammationb.b. Peptides (bradykinins, enkephalins) increase BBB permeability byPeptides (bradykinins, enkephalins) increase BBB permeability by

increasing pinocytosis.increasing pinocytosis.c.c. Extreme stress renders the barrier permeable to drugsExtreme stress renders the barrier permeable to drugs

(pyridostigmine a cholinesterase inhibitor).(pyridostigmine a cholinesterase inhibitor).d.d. Tertiary ammonium compounds traverses through BBB.Tertiary ammonium compounds traverses through BBB.e.e. Lipid soluble drugs traverses through barriers.Lipid soluble drugs traverses through barriers.

f.f. Lipid insoluble drugs are mainly confined to plasma and interstitialLipid insoluble drugs are mainly confined to plasma and interstitialfluids.fluids.

III.III. PLACENTAL BARRIER:PLACENTAL BARRIER: Lipid soluble drugs pass through this barrier.Lipid soluble drugs pass through this barrier.


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PROTEIN BINDINGPROTEIN BINDING

Plasma albumin binds many acidic drugs. Basic drugs mayPlasma albumin binds many acidic drugs. Basic drugs maybe bound bybe bound by B-globulinB-globulin andand acid glycoproteinacid g lycoprotein ..

PLASMA

PBD Storage depotFree drug(unbound,

active) Absorption

BiotransformationDistribution

Elimination / Excretion


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DRUG DISTRIBUTIONDRUG DISTRIBUTION

BRAIN moreaccumulation of drugs

PLASMA

REDISTRIBUTED

LESSTISSUES LESS ADIPOSE

TISSUES


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BIOAVAILABILITYBIOAVAILABILITY

It is the fraction of administered drug that gains access toIt is the fraction of administered drug that gains access tothe systemic circulation in a chemically unchanged form.the systemic circulation in a chemically unchanged form.

Ex.: If 300 mg of a drug is taken orally and 150 mg of thisEx.: If 300 mg of a drug is taken orally and 150 mg of thisdrug is absorbed unchanged, then the bioavailability of thedrug is absorbed unchanged, then the bioavailability of thedrug is 50%.drug is 50%.

Factors that influence bioavailability:Factors that influence bioavailability: First pass hepatic metabolism or biotransformation: DrugsFirst pass hepatic metabolism or biotransformation: Drugs

undergoing metabolism has low or decreased bioavailability.undergoing metabolism has low or decreased bioavailability. Drug absorption: Decreased absorptionDrug absorption: Decreased absorption low bioavailability.low bioavailability.


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THERAPEUTIC INDEXTHERAPEUTIC INDEX

It is the ratio of the dose that produces toxicity to the doseIt is the ratio of the dose that produces toxicity to the dosethat produces a clinically desired effective response.that produces a clinically desired effective response.This is a measure of drugs safety since a large valueThis is a measure of drugs safety since a large value

indicates that there is a wide margin between doses that areindicates that there is a wide margin between doses that areeffective and doses that are toxic.effective and doses that are toxic.

Therapeutic Index =Therapeutic Index = Toxic dose (LD)Toxic dose ( LD)

Effective dose (ED)Effective dose (ED)


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KINETICSKINETICSIt is the study of the rates of reaction.It is the study of the rates of reaction.

In general, drug absorption, distribution, eliminationIn general, drug absorption, distribution, elimination(biotransformation and excretion) processes follow 1(biotransformation and excretion) processes follow 1 stst order kinetics.order kinetics.

1.1. First-order kinetics The process is one in which aFirst-order kinetics The process is one in which a

constant fraction or % of a drug is handled per unit of time.constant fraction or % of a drug is handled per unit of time. After any route of administration except IV, drug After any route of administration except IV, drugabsorption follows 1absorption follows 1 stst order kinetics (constant fraction of order kinetics (constant fraction of the drug is absorbed).the drug is absorbed).

2.2. Zero-order kinetics A constant amount of the drug isZero-order kinetics A constant amount of the drug ishandled per unit of time.handled per unit of time. After IV administration, the absorption of the drug follows After IV administration, the absorption of the drug followszero-order kinetics.zero-order kinetics.


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GENETIC DEFECTS WHICH MODIFY DRUGGENETIC DEFECTS WHICH MODIFY DRUGBIOTRANSFORMATIONBIOTRANSFORMATION

G6PD deficiencyG6PD deficiency ASA, acetophenetidin, PAS,ASA, acetophenetidin, PAS,nitrofurans, quinidine,nitrofurans, quinidine,sulfonamides, primaquinesulfonamides, primaquine

Acute hemolyticAcute hemolyticanemiaanemia

GlucoronylGlucoronyl

transferasetransferasedeficiencydeficiency

Acetophenetidin, chloral hydrate,Acetophenetidin, chloral hydrate,

codeine, morphine, nicotinic acid,codeine, morphine, nicotinic acid,probenicidprobenicid

ExaggeratedExaggerated

drug toxicitydrug toxicity

ALA synthetaseALA synthetasestimulationstimulation

Barbiturates, chloroquine,Barbiturates, chloroquine,estrogen, sulfonamidesestrogen, sulfonamides

AcuteAcuteintermittentintermittentporphyriaporphyria

Pseudo-Pseudo-cholinesterasecholinesterasedeficiencydeficiency

SuccinylcholineSuccinylcholine ProlongedProlongedapneaapnea

AcetylaseAcetylasedeficiencydeficiency

INHINH PeripheralPeripheralneuropathyneuropathy


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FACTORS AFFECTING DRUG DOSAGEFACTORS AFFECTING DRUG DOSAGE

Age, body weight Age, body weightPregnancy and lactationPregnancy and lactationPathologic states kidney and liver diseasePathologic states kidney and liver diseaseGenetic defectGenetic defectDrug interaction: Enzyme induction or stimulation, enzymeDrug interaction: Enzyme induction or stimulation, enzymeinhibition, protein binding, synergism, antagonism.inhibition, protein binding, synergism, antagonism.Individual biologic variationIndividual biologic variation Tolerance tachyphylactic effect; true tolerance andTolerance tachyphylactic effect; true tolerance and

pseudotolerance.pseudotolerance. IdiosyncrasyIdiosyncrasy Cumulative effectCumulative effect HypersensitivityHypersensitivity

Time of administrationTime of administration


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DOSE COMPUTATIONDOSE COMPUTATION(PEDIATRIC DOSE - < 12)(PEDIATRIC DOSE - < 12)

Clarks RuleClarks Rule Dose =Dose = weight in poundsweig ht in pounds X adult doseX adult dose

150 pounds150 pounds

Freids RuleFreids Rule Dose =Dose = age in monthsag e in months X ADX AD

150 mos.150 mos.

Youngs RuleYoungs Rule Dose =Dose = age in yearsag e in years X ADX AD

age in years + 12age in years + 12Cowlings RuleCowlings Rule Dose =Dose = age in years on next b-dayag e in years on next b-day X ADX AD

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Dr. Baltazar's Introduction to Pharmacology

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