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General Principles in Pharmacology

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Title: General Principles in Pharmacology


1
General Principlesin Pharmacology
  • Ma. Victoria M. Villarica M.D.

2
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

3
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

4
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

5
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

6
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

7
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

8
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

9
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

10
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

11
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

12
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

13
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)

14
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

15
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

16
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

17
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

18
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

19
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

20
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

21
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.)

22
  • Maraming Salamat
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