PRINCIPLES OF PHARMACOLOGY
The same drug can have multiple actions and effects -> multiple ways of producing molecular
1. Acts at neurotransmitter binding sites
2. Modifies gating mechanism inside channel
3. Direct interaction with channel protein
4. Stimulates G shich is linked to adenylyl cyclase
1. Alters lipid composition
2. Interacts with polar heads of phospholipids
3. Disturbs the relationship of protein in membrane
Neurotransmitte Acute cellular Chronic cellular Behavioral effects
r effects effects
Glutamate Receptor antagonism Memory loss
and reduces release
Up-regulation of Rebound hyper
receptors and excitability of the
rebound increase in abstinence syndrome
Extreme hyper Brain damage
massive Ca influx
GABA Acutely enhances Sedative effects:
GABA-induced Cl - anxiety reduction,
influx to sedation,
memory impairment Neuroadaptive Tolerance and signs
decrease in GABA of hyper excitability
function without during withdrawal
change in receptor (seizures, tremors)
Dopamine Acute increase in Reinforcement
Chronic effects show Negative effect as a
reduced firing rate, sign of withdrawal
Opioids Acute increase in Reinforcement
Site of drug action is not always the site of drug effect
E.g.: miosis and mydriasis are controlled by different mechanisms
Opiates/opioids acute action pupil constriction
- Atropine, a competitive antagonist for the muscarinic acetylcholine receptor, produces
mydriasis because the pupils are no longer capable of constriction and dilation results.
- Miosis induced by central (ciliary ganglion) stimulation of parasympathetic input to the
iris sphincter muscle, resulting in constriction of the pupil.
Similar drug effects can be initiated by different drugs/actions
- Nicotinic receptors are found in VTA neurons when nicotine binds, I causes dopamine
release, that is critical for drug reinforcement
o Nicotine binds predominantly to nicotinic acetylcholine receptors (nACh)
o Release of dopamine in the nucleus accumbens (whih is linked to reward)
- Opioids inhibit GABA neurons -> then they stop inhibiting other neurons, leading to more
firing and dopamine release. Determinants of drug action
1. Chemical structure of a drug & dose
2. Where the drug acts (target sites)
3. How much drug is free to bind to target sites to elicit drug action (at the same time, the
drug is being collected by nonspecific binding, reducing the amount available in the
blood to get to the target sites) Bioavailability. Collectively, these factors constitute the
pharmacokinetic component of drug action.
4. In addition to bioavailability, the drug effect experienced will also depend on I) how
quickly the drug reaches its target sites, and II) for how long it is available at the target
Pharmacokinetic factors that determine bioavailability of drugs
(1) Drug administration – oral, intravenous, intraperitoneal, subcutaneous, intramuscular,
inhalation determines how quickly and how completely the drug is absorbed into the
(2) Absorption and distribution – membranes of oral cavity, gastrointestinal tract,
peritoneum, skin, muscles, lungs because a drug rarely acts where it initially contacts
the body, it must pass through a variety of cell membranes and enter the blood plasma
(3) Binding – while in the blood, a drug may also bind (depot binding) to plasma proteins or
may be stores temporarily in bone or fat, where is inactive.
(4) Inactivation – liver occurs primarily as a result of metabolic processes in the liver.
(5) Excretion – intestines, kidneys, lungs, sweat glands, etc.
Drug absorption and distribution
Two major categories of administration methods:
a. Enteral methods – use the gastrointestinal tract; agents are generally slow in onset and
produce highly variable blood levels of drug.
b. Parenteral methods – include those that do not use the alimentary canal, such as
injection, pulmonary, and topic administration. Routes of administration – how much drug reaches its site of action and how quickly the drug
effect occurs. It depends on:
- Area of absorbing surface
- Number of cell layers between site of administration and blood
- Amount of drug destroyed by first-pass liver metabolism
- Extent of binding to food or inert complexes
- Drug concentration
Oral administration (PO) – most popular route, the drug must be resistant to destruction by
stomach acid and enzymes (for this reason insulin cannot be administered orally). Oral
administration produces drug plasma levels that are more irregular and unpredictable and rise
more slowly than those produced by other methods of administration.
Rectal administration – requires the placement of a drug-filled suppository in the rectum.
Intravenous (IV) – most rapid and accurate method, however, the quick onset of drug effect is
also a potential hazard. The drug reaches the brain almost instantly, toxic reactions are
common, risk of infections.
Intramuscular (IM) – advantage of slower, more even absorption over a period of time.
Intraperitoneal (IP) – is rarely used with humans, but is the most common route of
administration for small laboratory animals. It produces rapid effects, but not as rapid as those
produced by IV injection.
Subcutaneous (SC) – absorption rate is dependent on blood flow to the site, but is usually fairly
slow and steady.
Inhalation – absorption is very rapid because the area of the pulmonary absorbing surfaces is
large and rich with capillaries. The effect on the brain I very rapid because blood from the
capillaries of the lungs travels only a short distance back to the heart before it is pumped quickly
to the brain via the carotid artery.
Topical – provides local drug effects. Intranasal administration can also have systemic effects.
Special injection methods must be used for some drugs that act on nerve cells, because a
cellular barrier, the blood-brain barrier, prevents or slows passage of these drugs from the blood
into neural tissue. E.g. epidural.
- In animal experiences, a microsyringe or a cannula enables precise drug injection into
discrete areas of brain tissue (intracranial IC), or into the cerebrospinal fluid-filled
chambers, the ventricles (intracerebroventricular ICV).
Drug dose is expressed in mg of drug/kg of body weight.
- More kg = larger volume of body fluids = require more drug
- In females, ratio of adipose tissue to body water is greater, so at equivalent dose and kg,
drug concentration is higher in females. Drug transport across membranes
The molecular characteristics of the cell membrane prevent most molecules from passing
through unless they are soluble in fat.
Lipid soluble drugs
Move through cell membranes by passive diffusion, and the movement across the membranes
is always in a direction from higher to lower concentration. The larger the concentration gradient
the more rapid is the diffusion.
Partition ratio = concentration of drug in oil / in water. The characteristic that determines
oil/water solubility is the extent of ionization of the molecule.
Extent of ionization of a drug depends on the electron attraction and repulsion of the various
atoms that make up the molecule.
Drugs that are unionized have very little electrostatic charges. This allows them to freely
mix with lipid layers that are non polar. These drugs have high partition ratio.
o Unionized drugs = lipid soluble drugs
Drugs that are ionized are bound to water molecules by electrostatic attraction and do
not readily move from the aqueous to the lipid components of membranes. These drugs
have low partition ratio.
o Ionized drugs = lipid insoluble drugs ionization depends on the acidity and the
alkalinity of the fluid in which the drug is dissolved.
o pKa of a drug = extent of ionization of a drug (pH of the aqueous solution in
which that drug would be 50% ionized and 50% unionized)
o drugs that are weak acids become more ionized in alkaline environments (less
lipid soluble) and become less ionized in acidic environments (therefore more
Rate of passive diffusion is modulated by:
1. Concentration gradient
2. Blood flow to the absorbing area if it is very quick, the concentration will be very high all
the time; however, if it is slower, the drug will not be removed quickly and the passive
diffusion will be slower as well.
Effect of ionization on drug absorption
a. In stomach acid (pH 2.0) aspirin molecules tend to remain in the non-ionized form
promotes the passage of the drug through the cell walls to the blood (pH 7.4)
b. Once they reach the blood, they ionize (more alkaline environment) and are trapped in
the blood to be circulated throughout the body. Drug binding
2. Silent receptors (depot binding) albumin, muscles, bone, fat
a. Drug binding occurs at inactive sites, where no measurable biological effect is
initiated. Any drug molecules tied up in these depots cannot reach active sites,
nor can they be metabolized by the liver. However, the drug binding is reversible,
so the drug remains bound only until the blood level drops, causing it to unbind
gradually and circulate in the plasm.
Receptors – two general locations
I) Embedded in cell membrane – receptors found on the outside of cells that relay
information through the membrane to affect intracellular processes.
II) In the cytoplasm or in the nucleus – alters cell function by triggering changes in
expression of genetic material within the nucleus, producing differences in protein
Common features of receptors
- Ligands = biologically active agents that bind to receptors
- Ligand affinity = molecules that have the best chemical “fit”, i.e., the highest affinity,
attach most readily to the receptor.
- Ligand efficacy = alteration of the 3D structure of the receptor and initiation of
intracellular changes; if a ligand is recognized by a receptor but it does not initiate a
biological action, it is considered to have low efficacy.
- Ligand binding and dissociation = is temporary. When the ligand dissociates from the
receptor, it has opportunities to attach once again.
- Receptor antagonists = not only do they produce no cellular effect after binding, but by
binding to the recepto