Principles of Pharmacology

Mary Jane Bergado Flores

 Pharmacology
• the study of the effects of drugs on the
nervous system and behavior
Definition of terms
1. Drugs – exogenous chemical not necessary
for cellular functioning that significantly alters
the functions of certain cells
2. Exogenous – produced outside the body
3. Psychoactive drugs – alter behavior and
states of consciousness
 Definition of Terms
• Drug effects – noticeable physiological
and behavioral changes
Example: less pain
• Sites of action – locations where drug
molecules bind with cells of the body
– after attaching to specialized receptors they
alter the activity of the neurons
 Pharmacokinetics
How the drugs are
1. Absorbed
2.Distributed within the body – in the blood and
CNS
3.Metabolized – deactivated by enzymes in the
liver
4.Excreted – by the kidneys

- Drug molecules are absorbed into the body

based on how they are administered
 Administration of Drugs
1. Intravenous (IV) injection – into the vein;
fastest route to the brain
2. Intraperitoneal (IP) injection – into the
abdominal wall
- peritoneal cavity – space around the
abdominal organs
3. Intramuscular (IM) injection – into muscles;
capillaries in muscles
4. Subcutaneous (SC) injection – under the
skin
 Administration of Drugs
5. Intracerebral administration – direct to the
brain
6. Intracerebroventricular (ICV) – into the
cerebral ventricles
7. Oral
8. Sublingual – under the tongue
9. Inhalation – through smoking
10.Topical administration –on the skin
11. Insufflation (“snorting”) – through the nose
Concentration of cocaine in blood plasma
with different administration
 Drug Entry to the Brain
- Effects of drugs only when they reach their
sites of action
- Sites of action (receptors) are found in cells
of the CNS

- Lipid solubility – or ability of fat-based

molecules to pass through cell membranes
- determines how fast drugs reach action sites
 Metabolism and Excretion
Example:
heroin – more lipid soluble than morphine
therefore rapid effects than morphine; more
intense “rush”
- Enzymes that deactivate the drugs are found
in liver and blood;
- Brain has enzymes that can deactivate some
drugs
- heroin – more lipid soluble than morphine
therefore rapid effects than morphine; more
intense “rush”
 Drug Effectiveness
1. Sites of Action – where in the body
2. Affinity of drug with its site of action

Affinity – readiness to bind with other

molecules

High affinity – effective even with low doses

Low affinity – needs high doses for effect
Dose-response curve – no more effect after
maximum effects achieved
 Drug Effectiveness
✓ Most drugs have
more than one effect
- therapeutic or toxic
- hence dosage is
determined
✓ Therapeutic index –
margin of safety
- ratio of therapeutic
vs toxic effects
- the higher the better
 Effects of Repeated Use
✓ Tolerance – effects diminish over time
✓ Sensitization – drug becomes more
effective the more it is administered
✓ Withdrawal symptoms
- indication of physical dependence on the
drug
- leads to compulsive drug taking
 Placebo Effects
✓ Placebo – an inactive substance
✓ Placebo effect – person’s expectations
produce physiological and behavioral
changes
Sensitization – drug becomes more effective
the more it is administered
✓ Withdrawal symptoms
- indication of physical dependence on the
drug
- leads to compulsive drug taking
 Drugs in Action Sites

✓ Two categories of drugs according to

effects on synaptic transmission
a) Antagonists – block or inhibit
postsynaptic effects
b) Agonists – facilitate them
 Drugs in Action Sites

Agonist Effects
1. Drug serves as precursor (e.g. L-DOPA-
dopamine)
2. Drug stimulates release of NT
3. Drug stimulates postsynaptic receptors
4. Drug blocks autoreceptors; increases
synthesis/release of NT
5. Drug blocks reuptake
6. Drug inactivates acetylcholinesterase
 Drugs in Action Sites

Antagonist Effects
1. Drug prevents storage of NT in vesicles
2. Drug inhibits release of NT
3. Drug blocks postsynaptic receptors
4. Drug stimulates autreceptors; inhibits
synthesis/release of NT
5. Drug inactivates synthetic enzyme; inhibits
synthesis of NT
 Effects on Production of NTs

NTs
1. Synthesized by presynaptic neurons –
mostly precursors – drugs mimic this
* useful when there’s lack of NTs – agonist
function of drugs
* Eg. Parkinson’s disease
2. Drugs deactivate enzymes that facilitate
synthesis of NTs
* antagonist function
Effects on Storage and Release of NTs

1. Vesicle transporters – pump molecules of

the NT into the cell
* some drugs block and inactivate vesicle
transporters
2. Terminal membrane transporters – move
molecules from synapse into the
presynaptic cell
* Some drugs prevent the release on NTs from
terminal button
 Effects on Receptors

Dependent on
1. Where receptor is located
* presynaptic
* postsynaptic
- Direct agonist
- Direct antagonist – receptor blockers
2. What its normal effects are
3. Whether drug activates the receptor or
blocks its actions
 Effects on Reuptake and
Deactivation of NTs

1. Attach to terminal membrane transporter

molecules and inactivate them to block
reuptake
2. Bind with enzymes to prevent them from
deactivating NTs
 Effects on Reuptake and
Deactivation of NTs

1. Attach to terminal membrane

transporter molecules and
inactivate them to block reuptake
(agonist)
2. Bind with enzymes to prevent them
from deactivating NTs (antagonist)
 NTs and Neuromodulators

In the brain, most synaptic communication is

performed by 2 amino acid NTs:
1. Glutamate (excitatory)
2. GABA (inhibitory)

In spinal cord and lower brain stem

Glycine (inhibitory)
 NTs and Neuromodulators

All other NTs have modulating effects

instead of information-transmitting effects
- they tend to activate or inhibit entire
circuits of neurons involved in behavior and
mental processes

Some drugs selectively affect neurons that

secrete particular NTs, they have specific
effects on behavior
 Amino Acid as Neurotransmitters

At least 8 amino acids also serve as NTs

1. Glutamate
- main excitatory NT in the brain and spinal
cord
- synthesized by precursor (glutamine) by
an enzyme (glutaminase)
- 4 major glutamate receptors are NMDA,
AMPA, and kainate receptors; and
metabotropic glutamate receptor
 Glutamate Receptors cont’d.

• NMDA and AMPA receptors play important

roles in learning and memory
• Chemicals called NMDA, AMPA, and
kainate are direct agonists for glutamate
receptors
• Alcohol – is an antagonist
• The NMDA channel is a voltage- and NT
dependent ion channel. Glycine has to be
present, magnesium absent, and calcium
present to depolarize
 Glutamate Receptors cont’d.

• The drug PCP (phencyclidine) – binds to the

PCP site deep within the ion channel
• PCP is an indirect antagonist; it blocks
calcium ions from passing through the ion
channel
• Ketamine (drug) has the same effect
• Both PCP and ketamine are originally
anesthetic drugs but discontinued use due
to hallucinatory effects
Glutamate Reuptake and Deactivation

• Deactivated by glutamine synthase enzyme

• If glutamate is not deactivated it keeps
stimulating
• Too much glutamate stimulation can
damage neurons, the brain in stroke and
amyotrophic lateral sclerosis (ALS)
• Riluzole (Rilutek) – reduces glutamate
signaling; used to treat ALS
 GABA

• Produced by …