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FACULTY OF PHARMACY Drug

UNIVERSITY OF SANTO TOMAS - Any substance that brings about a change


in biologic function through chemical actions
PHARMACOLOGY
Receptor
General Principles of Pharmacology
- Specific molecule in the biologic system that
PHARMACOLOGY plays a regulatory role
- Body of knowledge concerned with the action The Nature of Drugs
of chemicals on biologic systems, especially by
binding to regulatory molecules (receptors) and
activating or inhibiting normal body processes

- Inorganic ions, nonpeptide organic molecules,


small peptides and proteins, nucleic acids,
lipids, and carbohydrates
- Found in plants or animals, many are partially or
completely synthetic
 Hormones
 Xenobiotics

Physical Nature of Drugs


Medical Pharmacology
- Solid
- Area of pharmacology concerned with the use
- Liquid
of chemicals in the prevention, diagnosis,and
- Gas
treatment of disease, especially in humans
- Drugs are given at a site distant from the
Toxicology intended site of action

- Area of pharmacology concerned with the Drug Size and Molecular Weight (MW)
undesirable effects of chemicals on biologic
- Vary in size
systems
 MW 7 (lithium)
Pharmacogenomics  MW 50,000 (thrombolytic agents)
- Majority have MW between 100 and 1000
- Finds the exact mechanism of action of drugs
- 100 MW
- Identifies the receptors
 For selective binding

- 1000 MW
For traversing to different barriers of - Strongest
the body - Irreversible
- >1000 MW
ELECTROSTATIC BONDS
 Cannot move within the body
 Given directly at the site of action - More common
- Weaker
Drug Shape
- Eg, between cation and an anion GENERAL
- Chirality PRINCIPLES OF
 Stereoisomerism
HYDROPHOBIC BONDS
 Exist as enantiomeric pairs
o Carvedilol - Weakest
 (S)(-) isomer, potent beta receptor - Highly lipid soluble drugs
blocker
 (R)(+) isomer weak beta receptor Drug - Body Interactions
blocker
- PHARMACODYNAMICS
o Ketamine
- PHARMAKOKINETICS
 (+) more potent anesthetic and less
toxic than the (-) PHARMACODYNAMIC PRINCIPLES
 Racemic mixture
- Drug (D) + receptor-effector (R) → drug-
receptor-effector complex → effect
- D + R → drug-receptor complex → effector
Lock and key mechanism
molecule → effect
- D + R → D-R complex → activation of coupling
molecule → effector molecule → effect
- Inhibition of metabolism of endogenous
activator → increased activator action on an
effector molecule → increased effect

PHARMACODYNAMICS

- Constitutive activity
 Some of the receptor pool must exist in
Ra form
 May produce same physiologic effect as
agonist-induced activity
 Occurs in the absence of the agonist
- Agonist-binds to and activate the receptor
Drug Receptor Bonds  Full agonist
o Activates receptor-effector
- Chemical forces or bonds through which the
system to the maximum
drug interacts with the receptors
extent (Ra-D pool){activated
- Weaker bonds are more selective bonds
form}
Drug Receptor Bonds  Partial agonist
o Binds to the same receptors
COVALENT BONDS and activate them in the
same way but do not evoke - A model of drug-receptor interaction. The
as great a response receptor is able to assume two conformations.
- Allosteric modulators In the Ri conformation, it is inactive and
 Binds to a site on the receptor produces no effect, even when combined with a
molecule separate from the agonist drug molecule. In the Ra conformation, the
binding site receptor can activate downstream mechanisms
 Modifies receptor activity without that produce a small observable effect, even in
blocking agonist activity the absence of drug (constitutive activity). In
 May increase or decrease response to the absence of drugs, the two isoforms are in
agonist equilibrium, and the Ri form is favored.
 Noncompetitive Conventional full agonist drugs have a much
- Inverse agonist higher affinity for the Ra conformation, and
 Drug has a stronger affinity for the Ri mass action thus favors the formation of the
pool (nonfunctional form) Ra–D complex with a much larger observed
 Reduces constitutive activity effect. Partial agonists have an intermediate
 Results in effects that are opposite of affinity for both Ri and Ra forms. Conventional
the effects produced by conventional antagonists, according to this hypothesis, have
agonists equal affinity for both receptor forms and
- Antagonist maintain the same level of constitutive activity.
 Binds to a receptor, compete with Inverse agonists, on the other hand, have a
and prevent binding by other much higher affinity for the Ri form, reduce
molecules constitutive activity, and may produce a
contrasting physiologic result.

PHARMACOKINETICS

- Prodrug
 Inactive precursor
 Must be administered and
converted to the active drug by
biologic process inside the body
 Absorption
 Distribution
 Metabolism
 Elimination

The Movement of Drugs in the Body

- To reach its receptors and bring about biologic


effect
 A drug molecule (eg, sedative) must
travel from the site of administration
(eg, gastrointestinal tract) to the site
of action (eg, brain)
A. PERMEATION
- Movement of drug molecules into and within 5. EXOCYTOSIS
the biologic environment - Reverse process
1. AQUEOUS DIFFUSION - Expulsion of membrane-encapsulated
- Movement of molecules through the watery material from the cell
extracellular and intracellular spaces  Neurotransmitters
- Membranes of capillaries with small water-
filled pores
- Passive process
- Governed by Fick’s law
2. LIPID DIFFUSION
- Movement of molecules through membranes
and other lipid structures
- Most important factor for drug permeation
- Large lipid barriers that separate the
compartments of the body
- Passive process Mechanisms of drug permeation. Drugs may diffuse
- Governed by Fick’s law passively through aqueous channels in the intercellular
3. TRANSPORT BY SPECIAL CARRIERS junctions (eg, tight junctions, A), or through lipid cell
- Drugs transported across barriers by membranes (B). Drugs with the appropriate
mechanisms that carry similar endogenous characteristics may be transported by carriers into or
substances out of cells (C). Very impermeant drugs may also bind to
 Amino acid, peptides, glucose cell surface receptors (dark binding sites), be engulfed
- Capacity limited by the cell membrane (endocytosis), and then released
- Not governed by Fick’s law inside the cell or expelled via the membrane-limited
vesicles out of the cell into the extracellular space
ACTIVE TRANSPORT
(exocytosis, D).
- Needs energy
B. FICK’S LAW OF DIFFUSION
- Against a concentration gradient
- Predicts the movement of molecules across
FACILITATED DIFFUSION a barrier
- Drug absorption is faster in organs with larger
- No energy required surface areas (eg, small intestine) than from
- Downhill organs with smaller absorbing areas (eg,
4. ENDOCYTOSIS stomach)
- Binding to specialized components (receptors) - Fick’s Law of Diffusion
on cell membranes
- Internalization by infolding of the area of the
membrane and contents of the vesicle are
subsequently released into the cytoplasm
- Permits very large or very lipid-insoluble
chemicals to enter the cell - Drug absorption is faster from organs with thin
 B 12 with intrinsic factor membrane barriers (eg, lungs) than those with
 Iron with transferrin thick barriers (eg, skin)
THE HENDERSON-HASSELBACH EQUATION - Weak acids dissociate to its charged, polar form
in alkaline urine and cannot readily diffuse back
from the renal tubule back to the blood
(protonated) - Large number of drugs are weak bases with
amine containing molecules
log ___________ = pka - pH - Nitrogen of a neutral amine has 3 atoms
associated with it plus a pair of unshared
(unprotonated)
electrons
- Protonated means associated with a proton
(a hydrogen ion)
C. WATER AND LIPID SOLUBILITY OF DRUGS
3. Ionization of Weak Acids and Weak Bases

WEAK BASE

- Neutral molecule that can form a cation


(+ charged) by combining with a proton
(hydrogen ion)
- Ionized, more polar, more water soluble
when they are protonated

WEAK ACID

- Neutral molecule that can reversibly dissociate


into an anion (- charged) and a proton
( hydrogen ion)
- Not ionized, less polar, less water soluble when
they are protonated

The Henderson-Hasselbach Equation

- Clinically important when it is necessary to


estimate or alter the partition of drugs between
compartments of different pH
- When a patient takes an overdose of a weak
acid drug, excretion maybe accelerated by
alkalinizing the urine

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