Upload
roxanne-barranda
View
224
Download
0
Embed Size (px)
Citation preview
8/12/2019 General Principles (Pharma)
1/22
General Principlesin
Pharmacology
Ma. Victoria M. Villarica M.D.
8/12/2019 General Principles (Pharma)
2/22
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
8/12/2019 General Principles (Pharma)
3/22
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
8/12/2019 General Principles (Pharma)
4/22
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
8/12/2019 General Principles (Pharma)
5/22
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
8/12/2019 General Principles (Pharma)
6/22
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
8/12/2019 General Principles (Pharma)
7/22
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
8/12/2019 General Principles (Pharma)
8/22
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
8/12/2019 General Principles (Pharma)
9/22
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
8/12/2019 General Principles (Pharma)
10/22
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
8/12/2019 General Principles (Pharma)
11/22
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
8/12/2019 General Principles (Pharma)
12/22
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
8/12/2019 General Principles (Pharma)
13/22
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)
8/12/2019 General Principles (Pharma)
14/22
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
8/12/2019 General Principles (Pharma)
15/22
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
8/12/2019 General Principles (Pharma)
16/22
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
8/12/2019 General Principles (Pharma)
17/22
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
8/12/2019 General Principles (Pharma)
18/22
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
8/12/2019 General Principles (Pharma)
19/22
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
8/12/2019 General Principles (Pharma)
20/22
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
8/12/2019 General Principles (Pharma)
21/22
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.)
8/12/2019 General Principles (Pharma)
22/22
Maraming Salamat