General Principles in Pharmacology

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General Principlesin Pharmacology

• Ma. Victoria M. Villarica M.D.

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Basic Principles

• Pharmacology study of substances that interact
  with living systems to produce an effect
• Pharmacotherapeutics drugs used in the
• diagnosis, treatment and prevention of
  diseases
• Toxicology toxic effects of drugs
• Pharmacognosy drugs in their unaltered state

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Pharmacogenetics

• Pharmacoeconomics
• Drug substance that brings about change through
  its chemical action
• Physical properties of a drug
• a. physical nature of a drug
• b. drug size
• c. chemical forces covalent, electrostatic,
  hydrophobic

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Basic Pharmacologic concepts

• Pharmacokinetics body ? drug
• - drug-concentration relationship
• 4 processes
• A. absorption rate ? circulating fluids
• factors drug solubility, drug
  concentration, local conditions, blood flow,
  surface area

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Routes of drug administration

• a. enteral oral , rectal
• b. parenteral IV, IM, SC, intraperitoneal,
  intrathecal, intraarterial, inhalational, otic,
  optic
• c. topical
• B. distribution site of administration ?site
  of action
• factors size of the organ, blood flow,
  solubility, binding

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Permeation how a drug transverses the plasma
membrane

• Passive diffusion, active transport, facilitated
  diffusion, pinocytosis
• C. metabolism biotransformation liver
• 2 phases
• 1. phase I introduce or expose a functional
  group
• e.g. dealkylation, oxidation, reduction,
• hydrolysis, deamination, cytochrome p450

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2. Phase II formation of covalent linkage

• between the functional group on the
• parent compound cytosol
• e.g. glucoronidation, sulfation, acetylation
• Factors
• Inducer
• Inhibitor
• D. excretion elimination kidneys
• Factors

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2 Basic Parameters of Pharmacokinetics

• 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

• capacity-limited elimination varies, depending
  upon concentration of the drug that is achieved
  saturable dose/concentration dependent
• e.g. phenytoin, ethanol, aspirin
• rate of elimination Vmax x C
• Km x C
• Vmax maximum elimination capacity
• Km drug conc. at w/c rate of elimination
  is 50 of Vmax
• pseudo-zero order kinetics elimination is
  independent of concentration

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b. Flow dependent elimination dependent on the
rate of delivery of the drug to the organ

• high extraction drugs
• first order kinetics a constant fraction of
  drug 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 ½) time required to change the
  amount of drug by ½
• t ½ 0.7 x Vd
• Cl
• Drug accumulation drug interval is shorter than
  4 t ½ , accumulation is detectable
• Accumulation factor 1/ 1 fraction
• remaining before next
  dose

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Bioavailability fraction of unchanged drug
reaching the circulation extent of absorption
varies

• first pass elimination
• ER C liver
• Q (hepatic blood flow)
• Steady state achieved when rate of elimination
  rate of administration
• rate in rate out
• Area under the curve (AUC) 1st order
  elimination time concentration profile after a
  dose 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 peak high pts. of
  fluctuations (toxic effects)
• troughs low pts. of fluctuations (lack drug
  of effects)

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2. Pharmacodynamics drug ?body

• Receptors
• inert binding site binds with a drug w/out
  initiating events leading to any of the drugs
  effects buffers concentration gradient that
  drives diffusion
• active site recognition site

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Principles

1. Concentration effect curve response 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 in response can be
   achieved
2. Receptor-effector coupling transduction process
   that occurs between occupancy of the receptors
   and drug response

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Spare receptor

• Receptor antagonists prevent agonist from
  binding and activating receptors
• 2 classes
• a. competitive antagonist
• b. irreversible antagonist unavailable
• chemical antagonist protamine and warfarin or
  heparin
• Physiologic antagonist steroids and insulin
• Receptor agonist full agonist and partial
  agonist

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Signaling mechanism and drug action

1. Intracellular receptors for lipid soluble agents
   NO, hormones, corticosteroids, sex hormones,
   vit D, thyroid hormone
2. Ligand regulated transmembrane enzymes insulin,
   growth factor
3. Cytokine receptor JAK enzyme, STAT growth
   hormone, erythropoietin, interferon
4. Ligand-gated channels ACTH, GABA
5. G-proteins and 2nd messengers cAMP, Ca, cGMP

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Relation between drug dose and clinical response

• A. Graded dose response
• pharmacologic potency EC50 and
• ED50
• maximal efficacy extent or degree of
• an effect that can be achieved by the
• patient
• B. Quantal dose effect responsemargin of safety
  indicates variability of responsiveness ED50,
  LD50, TD50, TI TD50
• ED50

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Variations in drug responsiveness

• - mechanisms involve alteration in concentration
  of a drug and changes in the receptor
• Hyporeactive
• Hyperreactive
• Tolerance - ? responsiveness due to continued
  drug administration
• Tachyphylaxis rapid, diminishing responsiveness

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Basic and Clinical Evaluation of a New Drug

• 1st step discovery of a potential molecule
  (chemical modification, random screening of
  natural products, rational drug design,
  biotechnology and cloning)
• 2nd step drug screening ? LEAD compound
• 3rd step preclinical and toxicity testing
  limitations
• (acute and chronic toxicity, teratogenicity,
  carcinogenicity, mutagenicity, investigative
  toxicology)
• 4th step evaluation in humans factors

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Phases of clinical trial

• Phase 1 25-50 healthy volunteers
• Phase 2 10-200 patients with target disease
• Phase 3 larger 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