Transcript Pharmacology for the Health Sciences

Pharmacology for the Health Sciences
Lecture 2a
Dr. Steven I. Dworkin
Lecture 1
Review
Dr. Steven I. Dworkin
Drug Effects Are Determined By
• (1) how much of the drug reaches its target sites, where it
has biological action
• (2) how quickly it reaches those sites
Dr. Steven I. Dworkin
Pharmacokinetic Factors Determine
Bioavailability
• Method of administration
• The route of administration is significant because it determines
both onset and duration of drug action. The method of administration influences absorption of the drug because it deter-mines
the area of the absorbing surface, the number of cell layers the
drug must pass through, and the extent of first-pass metabolism
– Rate of absorption and distribution
– Binding at inactive sites,
– Biotransformation
– Excretion.
• These factors interact, so that as a drug is being absorbed and distributed throughout the body to act at target sites, some of its molecules
are simultaneously being bound to inactive sites, while others are
metabolized and excreted.
Dr. Steven I. Dworkin
Absorption
• Absorption is dependent on administration method and the solubility
and ionization of the drug.
• Addition Considerations and Influences
– Individual differences in age, sex, and body size, which contribute
to the concentration of the drug.
– Lipid solubility- drugs are not ionized and readily pass through
fatty membranes at a rate dependent on the concentration gradient.
• Drugs that are weak acids tend to remain unionized (lipid
soluble) in acidic body fluids like stomach juices; they are
more readily absorbed there than in the more alkaline intestinal
fluid, where ionization of weak acids increases and absorptibon
is reduced.
• Drugs that are weak bases are more ionized in the acidic
stomach fluid, so they are absorbed less readily there than from
the more basic intestine, where ionization is reduced and the
drugs become more lipid soluble.
Dr. Steven I. Dworkin
Degradation and Elimination
•
•
•
In addition to the absorption and distribution of a drug in the body, the rate of
degradation and elimination is equally important in determining
bioavailability.
Drugs are most often biotransformed by liver enzymes (e.g., cytochrome
P450) that produce products for excretion that are inactive and more water
soluble.
– Phase I metabolism involves oxidation, reduction, or hydrolysis and
produces an ionized metabolite that may be inactive, equally active, or
more active than the parent drug.
– Phase II metabolism involves the conjugation of the drug with a simple
molecule provided by the body, such as glucuronide or sulfate.
• Products of phase II metabolism are always inactive and more water
soluble.
The kidney is most often responsible for filtration of metabolites from the
blood before excretion with the urine. Alternatively, the metabolites maybe
excreted into bile and eliminated with the feces.
Dr. Steven I. Dworkin
Psychopharmacology
•
Several factors that influence drug metabolism and elimination are significant to
psychopharmacologists because they are responsible for many drug interactions and also
explain why some individuals respond differently to drugs.
– 1. Liver enzymes can be induced (increased) by some class-es of drugs given
repeatedly. More enzyme means more-efficient metabolism, which reduces blood
levels of drug and reduces the intensity and/or duration of its effects.
– 2. Some drugs directly impair liver enzyme action, so any drug normally
metabolized by that enzyme will remain in the body for longer periods of time,
producing pro-longed drug effects.
– 3. The limited number of enzymes also means that if two drugs share a metabolic
system, then the two will compete for biotransformation, causing elevated blood
levels of one or the other or both drugs.
– 4. Individuals who are very sensitive or very resistant to drug effects may differ
genetically in the efficiency of the metabolic enzymes. Rapid metabolizers will
appear to be less responsive to the drug, while slow metabolizers may show greater
response, increased side effects, or toxicity.
– 5. In addition to genetic differences, differences in age, sex, nutrition, and organ
(e.g., kidney and liver) function also are responsible for varying rates of
biotransformation.
Dr. Steven I. Dworkin
Pharmacology for the Health Sciences
Lecture 2
Pharmacodynamics: Drug-Receptor
Interactions
Dr. Steven I. Dworkin
Pharmacodynamics
– The study of the physiological and biochemical
interaction of drug molecules with the target tissue that
is responsible for the ultimate drug effects.
– Drugs can be classified into a wide variety of
categories (see next slide).
– Many of the drugs we are concerned with affect cell
function in target tissue by acting on receptors.
– Knowing which receptors a drug acts on and where the
receptors are located is crucial to understanding what
actions and side effects will be produced.
Dr. Steven I. Dworkin
Dr. Steven I. Dworkin
Receptors
– Large protein molecules located either on the surface of or within cells,
Initial sites of action of a biologically active agent including
• Neurotransmitters, hormones, or drugs (all referred to as ligands).
– A ligand is any molecule that binds to a receptor with some
selectivity. Because most drugs do not readily pass into neurons,
neuropharmacology is most often interested in receptors found
on the outside of cells that relay information through the
membrane to affect intracellular processes (see next slide).
– There are many possible intracellular changes that a ligand can
produce depends upon whether the receptor is coupled to an ion
channel (ionotropic receptor) or to a G protein (metabotropic
receptor).
– The essence of neuropharmacology is to identify drugs that can
act at neurotransmitter receptors that either enhance or reduce the
normal functioning of the cell..
Dr. Steven I. Dworkin
Most drugs and neurotransmitters remain outside the cell and bind
to receptors on the exterior cell surface. When these receptors are
activated,they initiate changes in an effector,which causes
intracellular changes, such as movement of ions or changes in
enzyme activity
Dr. Steven I. Dworkin
Structure and function of ionotropic receptors
Dr. Steven I. Dworkin
Functions of metabotropic receptors
Dr. Steven I. Dworkin
Receptors
• A second type of receptor is found within the target cell
– In the cytoplasm (as for the glucocorticoids)
– In the nucleus (e.g., sex steroid receptors).
• Most of the hormones that act on the brain to influence neural
events utilize this type of receptor.
» Hormonal binding to intracellular receptors alters cell
function by triggering changes in the expression of
the genetic material within the nucleus, producing
differences in protein synthesis.
» Sex hormones act in this way to facilitate mating
behavior and other activities related to reproduction.
Dr. Steven I. Dworkin
Many hormones are capable of entering the cell before acting
on an intracellular receptor that changes the expression of
specific genes within the nucleus.The altered protein synthesis
in turn leads to changes in cell function.
Dr. Steven I. Dworkin
Extracellular and intracellular receptors
have several common features
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•
The ability to recognize specific molecular shapes is one very important
characteristic.
– Only a limited group of neurochemicals or drugs can bind to a particular
receptor protein to initiate a cellular response.
• These neurochemicals are called agonists.
– Molecules that have the best chemical "fit" (have the highest
affinity) attach most readily to the receptor.
– Ligand maybe recognized by a receptor (attach to the receptor) without
initiating a biological action.
• Such ligands are considered to have low efficacy.
• These molecules are called antagonists because not only do they
produce no cellular effect after binding, but by binding to the receptor
they prevent an "active" ligand from binding and "block" the receptor
from interacting with high efficacy ligands.
A second significant feature of receptors is that the binding or attachment of
the specific ligand is usually temporary.
– Most ligands dissociates (i.e., separates) from the receptor.
Dr. Steven I. Dworkin
Extracellular and intracellular receptors
have several common features
•
Third, ligands binding to the receptor produce a physical change in the threedimensional shape of the protein,
– Initiating a series of intracellular events that ultimately generates a
biobehavioral effect.
– How much intracellular activity occurs depends on the number of
interactions with the receptor as well as the ability of the ligand to alter the
shape of the receptor, which reflects its efficacy.
– Fourth, although we tend to think about receptors as a permanent
characteristic of cells, these proteins in fact have a life cycle just as other
cell proteins do
– Both increased and decreased concentrations of ligands can modified both
the number (long-term regulation) and in sensitivity (more rapid
regulation via second messengers) of receptors.
• Long-term regulation, called up-regulation when receptor numbers
increase or down-regulation when receptors are reduced in number,
reflects compensatory changes following prolonged absence of receptor agonists or chronic activation of the receptor, respectively
Dr. Steven I. Dworkin
Dr. Steven I. Dworkin
Dose-response Curves
•
The dose-response curve
– Used to evaluate receptor activity is which describes the amount of
biological or behavioral effect (response) for a given drug concentration
(dose).
– When plotted on semilog scale, the curve takes on a classic S-shape.
– At low doses, the drug-induced effect is slight, because very few receptors
are occupied.
• The threshold dose is the smallest dose that produces a measurable
effect.
– As the dose of the drug is increased, more receptors are activated and a
greater biological response occurs.
• The ED50 (50% effective dose) is the dose that produces half the
maximal effect.
• The maximum response occurs at a dose at which we assume the
receptors are fully occupied (ED 100).
Dr. Steven I. Dworkin