general principles (pharma)

8/12/2019 General Principles (Pharma)

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General Principlesin

Pharmacology

Ma. Victoria M. Villarica M.D.


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Basic Principles:

Pharmacologystudy of substances thatinteract with living systems to produce aneffect

Pharmacotherapeuticsdrugs used in thediagnosis, treatment and prevention ofdiseases

Toxicologytoxic effects of drugs

Pharmacognosydrugs in their unalteredstate


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Pharmacogenetics

Pharmacoeconomics Drugsubstance that brings about change

through its chemical action

Physical properties of a drug:

a. physical nature of a drug

b. drug size

c. chemical forcescovalent, electrostatic,

hydrophobic


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Basic Pharmacologic concepts:

1. Pharmacokineticsbody drug

- drug-concentration relationship

4 processes:A. absorptionrate circulating fluids

factors: drug solubility, drug concentration,

local conditions, blood flow, surface area


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Routes of drug administration:

a. enteraloral , rectal

b. parenteralIV, IM, SC, intraperitoneal,intrathecal, intraarterial, inhalational, otic,optic

c. topical

B. distributionsite of administration site ofaction

factors: size of the organ, blood flow, solubility,binding


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Permeationhow a drug transverses the

plasma membrane

Passive diffusion, active transport, facilitated

diffusion, pinocytosis

C. metabolismbiotransformation; liver

2 phases:

1. phase Iintroduce or expose a functional

groupe.g. dealkylation, oxidation, reduction,

hydrolysis, deamination, cytochrome p450


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2. Phase IIformation of covalent linkage

between the functional group on the

parent compound; cytosol

e.g. glucoronidation, sulfation, acetylation

FactorsInducer

Inhibitor

D. excretionelimination; kidneys

Factors


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2 Basic Parameters of Pharmacokinetics

1. Volume of distribution (Vd)amount of

apparent space in the body able to contain a

drug

Vd = amt of drug in body / concentration (C)

2. Clearance (Cl)ability of the body to

eliminate a drug

Cl = rate of elimination / C


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Clearance:

a. capacity-limited eliminationvaries, dependingupon concentration of the drug that is achieved;

saturable; dose/concentration dependente.g. phenytoin, ethanol, aspirin

rate of elimination = Vmax x C

Km x C

Vmaxmaximum elimination capacity

Kmdrug conc. at w/c rate of elimination is 50% ofVmax

pseudo-zero order kinetics elimination isindependent of concentration


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b. Flow dependent eliminationdependent on

the rate of delivery of the drug to the organ

high extraction drugs

first order kinetics a constant fraction ofdrug is eliminated/unit of time; not saturated

zero-order kinetics a constant amount of

drug is eliminated/unit of time; saturable


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Other parameters:

Half-life (t )time required to change the

amount of drug by

t = 0.7 x Vd

Cl

Drug accumulationdrug interval is shorter

than 4 t , accumulation is detectable

Accumulation factor = 1/ 1fraction

remaining before next dose


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Bioavailabilityfraction of unchanged drug reaching

the circulation; extent of absorption varies

first pass elimination

ER = C liver

Q (hepatic blood flow)

Steady stateachieved when rate ofelimination = rate of administration

rate in = rate out

Area under the curve (AUC)1

st

orderelimination; time concentration profile after adose; C is constant


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Minimum effective concentration Loading dose = Vd x desired plasma conc.

bioavailability

- initial dose that is given

Maintenance dose =

Cl x desired plasma conc.

bioavailability Therapeutic index (TI)dose to produce

desired effect

Intermittent dose: peakhigh pts. offluctuations (toxic effects)

troughslow pts. of fluctuations (lack drug ofeffects)


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2. Pharmacodynamicsdrug body

Receptors

inert binding sitebinds with a drug w/out

initiating events leading to any of the drugs

effects; buffers concentration gradient that

drives diffusion

active siterecognition site


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Principles:

a. Concentration effect curveresponse to low

dose increases in direct proportion to dose;

however, as dose increases, the response

increment diminishes that finally, doses may

be reached at w/c no further increase inresponse can be achieved

b. Receptor-effector couplingtransduction

process that occurs between occupancy ofthe receptors and drug response


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Spare receptor

Receptor antagonistsprevent agonist from

binding and activating receptors

2 classes:

a. competitive antagonist

b. irreversible antagonistunavailable

chemical antagonistprotamine and warfarin or

heparin

Physiologic antagoniststeroids and insulin Receptor agonistfull agonist and partial agonist


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Signaling mechanism and drug action

1. Intracellular receptors for lipid soluble agentsNO,hormones, corticosteroids, sex hormones, vit D,thyroid hormone

2. Ligand regulated transmembrane enzymesinsulin, growth factor

3. Cytokine receptorJAK enzyme, STAT; growthhormone, erythropoietin, interferon

4. Ligand-gated channelsACTH, GABA5. G-proteins and 2ndmessengerscAMP, Ca, cGMP


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Relation between drug dose and clinical response

A. Graded dose responsepharmacologic potencyEC50 and

ED50

maximal efficacyextent or degree of

an effect that can be achieved by thepatient

B. Quantal dose effect responsemargin of safety;indicates variability of responsiveness; ED50, LD50,

TD50, TI = TD50ED50


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Variations in drug responsiveness:

- mechanisms involve alteration in

concentration of a drug and changes in thereceptor

Hyporeactive

Hyperreactive

Tolerance - responsiveness due to

continued drug administration

Tachyphylaxisrapid, diminishingresponsiveness


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Basic and Clinical Evaluation of a New Drug

1st stepdiscovery of a potential molecule(chemical modification, random screening of naturalproducts, rational drug design, biotechnology andcloning)

2ndstepdrug screening LEAD compound 3rdsteppreclinical and toxicity testing; limitations

(acute and chronic toxicity, teratogenicity,carcinogenicity, mutagenicity, investigative

toxicology) 4thstepevaluation in humans ; factors


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Phases of clinical trial:

Phase 125-50 healthy volunteers

Phase 210-200 patients with target disease

Phase 3larger population; difficult phase;NDA is submitted and approval takes place 3

yrs or more

Phase 4 post-marketing surveillance;

apply for a patent (20 yrs.)


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Maraming Salamat

general principles (pharma)

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