Title: General Principles in Pharmacology
1General Principlesin Pharmacology
- Ma. Victoria M. Villarica M.D.
2Basic 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
4Basic 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
5Routes 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
6Permeation 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
72. 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
82 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
9Clearance
- 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
10b. 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
11Other 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
12Bioavailability 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
13Minimum 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)
142. 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
15Principles
- 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 - Receptor-effector coupling transduction process
that occurs between occupancy of the receptors
and drug response
16Spare 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
17Signaling mechanism and drug action
- Intracellular receptors for lipid soluble agents
NO, hormones, corticosteroids, sex hormones,
vit D, thyroid hormone - Ligand regulated transmembrane enzymes insulin,
growth factor - Cytokine receptor JAK enzyme, STAT growth
hormone, erythropoietin, interferon - Ligand-gated channels ACTH, GABA
- G-proteins and 2nd messengers cAMP, Ca, cGMP
18Relation 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
-
19Variations 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
20Basic 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
-
21Phases 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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