General Principlesin

Pharmacology

Ma. Victoria M. Villarica M.D.

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

• 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

Basic Pharmacologic concepts:

1. Pharmacokinetics – body → drug

- “ drug-concentration” relationship

4 processes:

A. absorption – rate → circulating fluids

factors: drug solubility, drug concentration, local conditions, blood flow, surface area

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

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

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

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

Clearance:a. 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

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

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

•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

•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)

2. Pharmacodynamics – drug →body

• Receptors

inert binding site – binds with a drug w/out initiating events leading to any of the drug’s effects; buffers concentration gradient that drives diffusion

active site – recognition site

Principles:

a. 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

b. Receptor-effector coupling – transduction process that occurs between occupancy of the receptors and drug response

• 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

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, GABA5. G-proteins and 2nd messengers – cAMP, Ca,

cGMP

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 patientB. Quantal dose effect responsemargin of safety;

indicates variability of responsiveness; ED50, LD50, TD50, TI = TD50

ED50

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

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

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.)

Maraming Salamat