Pharmacology L-2

A F m Nazmus Sadat
 Agonist
An agonist is a term used to describe a type of
ligand or drug that binds and alters the activity
of a receptor.
antagonists, a type of receptor ligand which also
bind a receptor but which do not alter the
activity of the receptor.
Receptor: is a protein molecule, embedded in
either the plasma membrane or cytoplasm of
a cell, to which a mobile signaling (or "signal")
molecule may attach.
Ligand:
A molecule which binds to a receptor is called a ligand.
It may be,
Peptide (eg. neurotransitter), a hormone, a
pharmaceutical drug, a toxin,
when such binding occurs, the receptor goes into a
conformational change which ordinarily initiates a
cellular response.
However, some ligands merely block receptors without
inducing any response (e.g. antagonists).
Ligand-induced changes in receptors result in
physiological changes which constitute the biological
activity of the ligands.
Agonists versus antagonists
Not every ligand that binds to a receptor also
activates the receptor. The following classes of
ligands exist:
• (Full) agonists are able to activate the receptor
and result in a maximal biological response.
Most natural ligands are full agonists.
• Partial agonists do not activate receptors
thoroughly, causing responses which are partial
compared to those of full agonists.
• Antagonists bind to receptors but do not activate
them. This results in receptor blockage,
inhibiting the binding of other agonists.
• Inverse agonists reduce the activity of receptors
by inhibiting their constitutive activity.
 Examples of agonist
• Full agonists bind (have affinity for) and activate a
receptor, displaying full efficacy at that receptor. One
example of a drug that acts as a full agonist is
isoproterenol which mimics the action of adrenaline at
β adrenoreceptors. Another example is morphine,
which mimics the actions of endorphins at μ-opioid
receptors throughout the central nervous system.
• Partial agonist: (such as buspirone, aripiprazole,
buprenorphine, or norclozapine) also bind and activate
a given receptor, but have only partial efficacy at the
receptor relative to a full agonist.
• An inverse agonist is an agent which binds to the
same receptor binding-site as an agonist for that
receptor and reverses constitutive activity of receptors.
Inverse agonists exert the opposite pharmacological
effect of a receptor agonist.
 Examples of agonist… Cont.
• A co-agonist works with other co-agonists to produce
the desired effect together. NMDA receptor activation
requires the binding of both of its glutamate and
glycine co-agonists. An antagonist blocks a receptor
from activation by agonists.
• A selective agonist is selective for one certain type of
receptor. It can additionally be of any of the
aforementioned types.
• A physiological agonist is a substance that creates
the same bodily responses, but does not bind to the
same receptor.
• Receptors can be activated or inactivated either by
endogenous (such as hormones and
neurotransmitters) or exogenous (such as drugs)
agonists and antagonists, resulting in stimulating or
inhibiting a biological response.
 Types of receptor
Depending on their functions and ligands, several types of
receptors may be identified:
- Some receptor proteins are peripheral membrane proteins.
- Many hormone and neurotransmitter receptors are
transmembrane proteins: transmembrane receptors are
embedded in the phospholipid bilayer of cell membranes, that
allow the activation of signal transduction pathways in response
to the activation by the binding molecule, or ligand.
– Metabotropic receptors are coupled to G proteins and affect the cell
indirectly through enzymes which control ion channels.
– Ionotropic receptors contain a central pore which functions as a ligand-
gated ion channel.
- Another major class of receptors are intracellular proteins such
as those for steroid and intracrine peptide hormone receptors.
These receptors often can enter the cell nucleus and modulate
gene expression in response to the activation by the ligand.
Potency of Agonist
The potency of an agonist is usually defined by
its EC50 value.
This can be calculated for a given agonist by
determining the concentration of agonist
needed to elicit half of the maximum biological
response of the agonist.
Importance:- Elucidating an EC50 value is useful
for comparing the potency of drugs with similar
efficacies producing physiologically similar
effects. The lower the EC50, the greater the
potency of the agonist the lower the
concentration of drug that is required to elicit
the maximum biological response.
Therapeutic index
When a drug is used therapeutically, it is important to
understand the margin of safety that exists between
the dose needed for the desired effect and the dose
that produces unwanted and possibly dangerous side
effects.
This relationship, termed the therapeutic index, is
defined as the ratio LD50:ED50.
In general, the narrower this margin, the more likely it is
that the drug will produce unwanted effects. The
therapeutic index has many limitations, notably the
fact that LD50 cannot be measured in humans and,
when measured in animals, is a poor guide to the
likelihood of unwanted effects in humans.
Nevertheless, the therapeutic index emphasizes the
importance of the margin of safety, as distinct from the
potency, in determining the usefulness of a drug.
Receptor antagonist
A receptor antagonist is a type of receptor
ligand or drug that does not provoke a
biological response itself upon binding to a
receptor, but blocks or dampens agonist-
mediated responses.
In pharmacology, antagonists have affinity
but no efficacy for their cognate receptors
and binding will disrupt the interaction and
inhibit the function of an agonist or
inverse agonist at receptors.
Antagonists mediate their effects by binding to
the active site sites on receptors or they may
interact at unique binding sites not normally
involved in the biological regulation of the
receptor's activity.
Antagonist activity may be reversible or
irreversible depending on the longevity of the
antagonist–receptor complex which in turn
depends on the nature of antagonist receptor
binding.
The majority of drug antagonists achieve their
potency by competing with endogenous ligands
or substrates at structurally defined binding
sites on receptors.
Competitive antagonist:
reversibly bind to receptors at the same binding site (active site)
as the endogenous ligand or agonist, but without activating the
receptor.
Agonists and antagonists "compete" for the same binding site on
the receptor. Once bound, an antagonist will block agonist
binding.
The level of activity of the receptor will be determined by the
relative affinity of each molecule for the site and their relative
concentrations.
High concentrations of a competitive agonist will increase the
proportion of receptors which the agonist occupies, higher
concentrations of the antagonist will be required to obtain the
same degree of binding site occupancy.
The interleukin-1 receptor antagonist, IL-1Ra is an example of a
competitive antagonist. The effects of a competitive antagonist
may be overcome by increasing the concentration of agonist.
Often (though not always) these antagonists possess a very
similar chemical structure to that of the agonist.
Non-competitive antagonists
Non-competitive antagonists are also known as allosteric
antagonists. These antagonists bind to a distinctly separate
binding site from the agonist, exerting their action to that
receptor via the other binding site.
Cyclothiazide has been shown to act as a reversible non-
competitive antagonist of mGluR1 receptor. Thus, they do not
compete with agonists for binding.
The bound antagonists may result in a decreased affinity of an
agonist for that receptor, or alternatively may prevent
conformational changes in the receptor required for receptor
activation after the agonist binds.
No amount of agonist can completely overcome the inhibition
once it has been established. In functional assays of non-
competitive antagonists, depression of the maximal response of
agonist dose-response curves, and in some cases, rightward
shifts, is produced. The rightward shift will occur as a result of a
receptor reserve and inhibition of the agonist response will only
occur when this reserve is depleted.
Uncompetitive antagonists
Uncompetitive antagonists differ from non-competitive
antagonists in that they require receptor activation by
an agonist before they can bind to a separate
allosteric binding site.
This type of antagonism produces a kinetic profile in
which "the same amount of antagonist blocks higher
concentrations of agonist better than lower
concentrations of agonist".
Memantine, used in the treatment of Alzheimer's disease
, is an uncompetitive antagonist of the NMDA receptor
.
Partial agonists and inverse agonists
Partial agonists are defined as drugs which, at a given receptor,
might differ in the amplitude of the functional response that they
elicit after maximal receptor occupancy.
Although they are agonists, partial agonists can act as a
competitive antagonist if co-administered with a full agonist, as
it competes with the full agonist for receptor occupancy and
producing a net decrease in the receptor activation observed
with the full agonist alone.
Clinically, their usefulness is derived from their ability to enhance
deficient systems while simultaneously blocking excessive
activity. Exposing a receptor to a high level of a partial agonist
will ensure that it has a constant, weak level of activity, whether
its normal agonist is present at high or low levels. In addition, it
has been suggested that partial agonism prevents the adaptive
regulatory mechanisms that frequently develop after repeated
exposure to potent full agonists or antagonists.
Buprenorphine, a partial agonist of the μ-opioid receptor, binds
with weak morphine-like activity and is used clinically as an
analgesic in pain management and in reversing morphine
addiction as an alternative to methodone in the treatment of
drug addiction.
Inverse Agonist
An inverse agonist can have effects similar to an
antagonist, but causes a distinct set of downstream
biological responses.
Constitutively active receptors which exhibit intrinsic or
basal activity can have inverse agonists, which not
only block the effects of binding agonists like a
classical antagonist, but inhibit the basal activity of
the receptor. Drugs previously classified as
antagonists are now beginning to be reclassified as
inverse agonists because of the discovery of
constitutive active receptors.
Antihistamines, originally classified as antagonists of
histamine H1 receptors have been reclassified as
inverse agonists.
Reversibility
Many antagonists are reversible antagonists that, like most
agonists, will bind and unbind a receptor at rates determined by
receptor-ligand kinetics.
Irreversible antagonists covalently bind to the receptor target and
generally cannot be removed; inactivating the receptor for the
duration of the antagonist effects is determined by the rate of
receptor turnover, the rate of synthesis of new receptors.
Phenoxybenzamine is an example of an irreversible alpha blocker
—it permanently binds to α adrenergic receptors, preventing
adrenaline and noradrenaline from binding.
Inactivation of receptors normally results in a depression of the
maximal response of agonist dose-response curves and a right
shift in the curve occurs where there is a receptor reserve
similar to non-competitive antagonists. A washout step in the
assay will usually distinguish between non-competitive and
irreversible antagonist drugs as effects of non-competitive
antagonists are reversible and activity of agonist will be
restored.
 Efficacy & Affinity
Efficacy is the capacity to produce a desired size of an effect
under ideal or optimal conditions.
In pharmacology, intrinsic activity or efficacy refers to the ability of
a drug-receptor complex to produce a functional response.
Efficacy must be distinguished from the affinity, which is a
measure of the ability of the drug to bind to its molecular target,
and the EC50, which is a measure of the potency of the drug.
High efficacy agonists can produce the maximal response of the
receptor system while occupying a relatively low proportion of
the receptors in that system. While Agonists of lower efficacy
are not as efficient at producing a response from the drug-
bound receptor
• agonist: affinity and high efficacy
• antagonist : affinity without efficacy
• partial agonist: affinity and low efficacy, in a system with a small
number of receptors
 EC50
The term half maximal effective concentration (EC50) refers to
the concentration of a drug or antibody which induces a
response halfway between the baseline and maximum. It is
commonly used as a measure of drug potency.
The EC50 of a graded dose response curve therefore represents
the concentration of a compound where 50% of its maximal
effect is observed. The EC50 of a quantal dose response curve
represents the concentration of a compound where 50% of the
population exhibit a response.
It is also related to IC50 which is a measure of a compound's
inhibition (50% inhibition). For competition binding assays and
functional antagonist assays IC50 is the most common
summary measure of the dose-response curve. For
agonist/stimulator assays the most common summary measure
is the EC50.
Concentration measures typically follow a Sigmoidal curve,
increasing rapidly over a relatively small change in
concentration. The point at which the effectiveness slows with
increasing concentration is the IC50. This can be determined
mathematically by derivation of the best-fit line.
Antagonists will block the binding of an agonist at a receptor
molecule, inhibiting the signal produced by a receptor-agonist
coupling.
 Side effect
Side effect can mean:
• Adverse drug reaction, an unintended
consequence specifically arising from drug
therapy
• Therapeutic effect, an unintended but desirable
consequence of any kind of medical treatment
• Adverse effect (medicine), an unintended, and
undesirable, consequence of any kind of
medical treatment
An adverse drug reaction (abbreviated ADR) or
adverse drug event (abbreviated ADE) is an
expression that describes the unwanted,
negative consequences associated with the
use of given medications.
An ADR is a particular type of adverse effect. The
meaning of this expression differs from the
meaning of "side effect", as this last expression
might also imply that the effects can be
beneficial. The study of ADRs is the concern of
the field known as pharmacovigilance.
Classification
ADRs may be classified by e.g. cause and severity.
Cause
• Type A: Augmented pharmacologic effects
• Type B: Bizarre effects (or idiosyncratic)
• Type C: Chronic effects
• Type D: Delayed effects
• Type E: End-of-treatment effects
• Type F: Failure of therapy
Types A and B were proposed in the 1970s, and the
other types were proposed subsequently when the
first two proved insufficient to classify ADRs.
Seriousness and Severity
The American Food and Drug Administration defines
a serious adverse event as one when the patient
outcome is:
• Death
• Life-Threatening
• Hospitalization (initial or prolonged)
• Disability - significant, persistent, or permanent
change, impairment, damage or disruption in the
patient's body function/structure, physical activities
or quality of life.
• Congenital Anomaly - or - Requires Intervention
to Prevent Permanent Impairment or Damage
Severity is a point on an arbitrary scale of
intensity of the adverse event in question.
The terms "severe" and "serious" when
applied to adverse events are technically
very different. They are easily confused but
can not be used interchangeably, require
care in usage.
A headache is severe, if it causes intense
pain. There are scales like "visual analog
scale" that help us assess the severity. A
headache, on the other hand, can hardly
ever be serious, unless it also satisfies the
criteria for seriousness, listed above.
Overall Drug Risk
While no official scale exists yet to communicate
overall drug risk, the iGuard Drug Risk Rating
System is a five color rating scale similar to the
Homeland Security Advisory System:
• Red (High Risk)
• Orange (Elevated Risk)
• Yellow (Guarded Risk)
• Blue (General Risk)
• Green (Low Risk)
 Location
• Adverse effects may be local, i.e. limited to a
certain location, or systemic, where a
medication has caused adverse effects
throughout the systemic circulation.
• For instance, some ocular antihypertensives
cause systemic effects, although they are
administered locally as eye drops, since a
fraction escapes to the systemic circulation.
Mechanisms
• As research better explains the
biochemistry of drug use, less ADRs are
Type B and more are Type A. Common
mechanisms are:
• Abnormal pharmacokinetics due to
– genetic factors
– co morbid disease states
• Synergistic effects between either
– a drug and a disease
– two drugs
Abnormal pharmacokinetics
Co morbid disease states: Various diseases,
especially those that cause renal or hepatic
insufficiency, may alter drug metabolism.
Resources are available that report changes
in a drug's metabolism due to disease states.
Genetic factors: Abnormal drug metabolism
may be due to inherited factors of either
Phase I oxidation or Phase II conjugation.
Pharmacogenomics is the study of the
inherited basis for abnormal drug reactions.
Phase I reactions: Inheriting abnormal alleles of
cytochrome P450 can alter drug metabolism.
Inheriting abnormal butyrylcholinesterase (
pseudocholinesterase) may affect metabolism
of drugs such as succinylcholine.
Phase II reactions: Inheriting abnormal N-
acetyltransferase which conjugated some drugs
to facilitate excretion may affect the metabolism
of drugs such as isoniazid, hydralazine, and
procainamide.
Inheriting abnormal thiopurine S-
methyltransferase may affect the metabolism of
the thiopurine drugs mercaptopurine and
azathioprine.
Interactions with other drugs: The risk of
drug interactions is increased with polypharmacy.

Protein binding: These interactions are usually

transient and mild until a new steady state is
achieved. These are mainly for drugs without
much first-pass liver metabolism. The principal
plasma proteins for drug binding are:
– albumin
– α1-acid glycoprotein
– lipoproteins
 Synergistic effects
Synergy (from the Greek syn-ergo, συνεργός
meaning working together) is the term used to
describe a situation where the final outcome of
a system is greater than the sum of its parts.
The opposite of synergy is antagonism, the
phenomenon where two agents in combination
have an overall effect that is less than that
predicted from their individual effects.
Synergy can also mean:
A mutually advantageous conjunction where
the whole is greater than the sum of the
parts.
A dynamic state in which combined action is
favored over the sum of individual component
actions.
Behavior of whole systems unpredicted by the
behavior of their parts taken separately. More
accurately known as emergent behavior.
The cooperative action of two or more stimuli or
drugs.
Drug synergism occurs when drugs can interact in ways
that enhance or magnify one or more effects, or side
effects, of those drugs.
This is sometimes exploited in combination preparations,
such as codeine mixed with acetaminophen or
ibuprofen to enhance the action of codeine as a pain
reliever. This is often seen with recreational drugs,
where 5-HTP (5-Hydroxytryptophan) , a serotonin
precursor often used as an antidepressant, is often
used prior to, during, and shortly after recreational use
of MDMA (3,4-methylenedioxy-N-methylamphetamine)
as it allegedly increases the "high" and decreases the
"comedown" stages of MDMA use (although most
anecdotal evidence has pointed to 5-HTP moderately
muting the effect of MDMA). Other examples include
the use of cannabis with LSD, where the active
chemicals in cannabis enhance the hallucinatory
experience of LSD-use.
 Nice to read
(5-Hydroxytryptophan or 5-HTP is a naturally-occurring
amino acid, a precursor to the neurotransmitter serotonin
and an intermediate in tryptophan metabolism. It is
marketed in the United States and other countries as a
dietary supplement for use as an antidepressant,
appetite suppressant, and sleep aid.
MDMA (3,4-methylenedioxy-N-methylamphetamine),
most commonly known today by the street name
Ecstasy (often abbreviated E, X, or XTC), is a
semisynthetic member of the amphetamine class of
psychoactive drugs, a subclass of the phenethylamines.
[3] MDMA also falls under many other broad categories
of substances, including stimulants, psychedelics, and
the empathogenic-entactogens. )
An example of negative effects of synergy is
if more than one depressant drug is used
that affects the central nervous system
(CNS), for example alcohol and Valium.
The combination can cause a greater
reaction than simply the sum of the
individual effects of each drug if they were
used separately. In this particular case, the
most serious consequence of drug synergy
is exaggerated respiratory depression,
which can be fatal if left untreated.
 Toxicity
Toxicity is the degree to which a substance is able to
damage an exposed organism. Toxicity can refer to
the effect on a whole organism, such as a human,
bacterium, or plant, as well as the effect on a
substructure of the organism, such as a cell
(cytotoxicity) or an organ (organotoxicity) such as the
liver (hepatotoxicity).
A central concept of toxicology is that effects are dose-
dependent; even water can lead to water intoxication
when taken in large enough doses, whereas for even
a very toxic substance such as snake venom there is
a dose below which there is no detectable toxic effect.
 Types of toxicity
There are generally three types of toxic entities;
chemical, biological, and physical.

Chemicals include inorganic substances such as

lead, hydrofluoric acid, and chlorine gas,
organic compounds such as methyl alcohol,
most medications, and poisons from living
things.
Biological toxic entities include those bacteria
and viruses that are able to induce disease in
living organisms.
Biological toxicity can be complicated to measure
because the "threshold dose" may be a single
organism. Theoretically one virus, bacterium or
worm can reproduce to cause a serious
infection.
However, in a host with an intact immune system
the inherent toxicity of the organism is balanced
by the host's ability to fight back; the effective
toxicity is then a combination of both parts of
the relationship. A similar situation is also
present with other types of toxic agents.
Physically toxic entities include things not usually
thought of under the heading of "toxic" by many
people: direct blows, concussion, sound and vibration,
heat and cold, non-ionizing electromagnetic radiation
such as infrared and visible light, and ionizing radiation
such as X-rays and alpha, beta, and gamma radiation.
Acute Toxicity
Acute toxicity looks at lethal effects following oral,
dermal or inhalation exposure. It is broken into
five categories of severity where Category 1
requires the least amount of exposure to be
lethal and Category 5 requires the most
exposure to the be lethal.
Oral Toxic Category
a. Category 1: LD50 ≤ 5 mg/kg of bodyweight
b. Category 2: LD50 ≤ 50 mg/kg of bodyweight
c. Category 3: LD50 ≤ 300 mg/kg of bodyweight
d. Category 4: LD50 ≤ 2000 mg/kg of bodyweight
e. Category 5: LD50 ≤ 5000 mg/kg of bodyweight
*substances beyond category 5 are not
defined, though they cannot legally be defined
as orally toxic.
2. Dermal
a. Category 1: LD50 ≤ 50 mg/kg of bodyweight
b. Category 2: LD50 ≤ 200 mg/kg of bodyweight
c. Category 3: LD50 ≤ 1,000 mg/kg of bodyweight
d. Category 4: LD50 ≤ 2,000 mg/kg of bodyweight
e. Category 5: LD50 ≤ 5,000 mg/kg of bodyweight
*substances beyond category 5 are not
defined, though they cannot legally be defined
as dermally toxic.
3. Inhalation – Gases
a. Category 1: LC50 ≤ 100 ppmV
b. Category 2: LC50 ≤ 500 ppmV
c. Category 3: LC50 ≤ 2,500 ppmV
d. Category 4: LC50 ≤ 20,000 ppmV
e. Category 5: not defined though is
expected to have an equivalent of
category 5 oral and dermal
4. Inhalation – Vapours
a. Category 1: LC50 ≤ 0.5 mg/l
b. Category 2: LD50 ≤ 2.0 mg/l
c. Category 3: LD50 ≤ 10 mg/l
d. Category 4: LD50 ≤ 20 mg/l
e. Category 5: not defined though is
expected to have an equivalent of
category 5 oral and dermal
5. Inhalation – Dust and Mists
• Category 1: LC50 ≤ 0.05 mg/l
• Category 2: LD50 ≤ 0.5 mg/l
• Category 3: LD50 ≤ 1.0 mg/l
• Category 4: LD50 ≤ 5 mg/l
• Category 5: not defined though is
expected to have an equivalent of
category 5 oral and dermal
 Teratogenicity
The term teratology generally refers to disfiguring
birth defects or malformations.
Another term for this is dysmorphology, meaning "the
study of abnormal form."
Etymology
• As early as the 17th century, Teratology referred to a discourse
on prodigies and marvels, of anything so extraordinary as to
seem abnormal.
• In 19th century, it acquired a meaning closer related to
biological deformities, mostly in the field of botany. Currently, its
most instrumental meaning is that of the medical study of
teratogenesis, congenital malformations or grossly deformed
individuals. Monster is a pejorative term for a grossly deformed
individual, although it is interesting to note that, etymologically,
this word is related to demonstration, and used to simply mean
something worth looking at, for being unusual, without
necessarily being pejorative.
• Teratology as a medical term was popularized in the 1960s by
Dr. David W. Smith of the University of Washington Medical
School, one of the researchers who became known in 1973 for
the discovery of Fetal alcohol syndrome. With greater
understanding of the origins of birth defects, the field of
teratology now overlaps with other fields of basic science,
including developmental biology, embryology, and genetics.
 Teratogenesis
• Birth defects are known to occur in 3-5% of all
newborns. They are the leading cause of infant
mortality in the United States, accounting for more
than 20% of all infant deaths. Seven to ten percent of
all children will require extensive medical care to
diagnose or treat a birth defect. And although
significant progress has been made in identifying
etiologic causes of some birth defects, approximately
65% have no known or identifiable cause.
• It was previously believed that the mammalian embryo
developed in the impervious uterus of the mother,
protected from all extrinsic factors. However, after the
thalidomide disaster of the 1960s, it became apparent
and more accepted that the developing embryo could
be highly vulnerable to certain environmental agents
that have negligible or non-toxic effects to adult
individuals.
 Wilson's 6 principles
Along with this new awareness of the in utero vulnerability of the
developing mammalian embryo came the development and
refinement of The Six Principles of Teratology which are still
applied today. These principles of teratology were put forth by
Jim Wilson in 1959 and in his monograph Environment and
Birth Defects. These principles guide the study and
understanding of teratogenic agents and their effects on
developing organisms:
1. Susceptibility to teratogenesis depends on the genotype of the
conceptus and the manner in which this interacts with
adverse environmental factors.
2. Susceptibility to teratogenesis varies with the developmental
stage at the time of exposure to an adverse influence. There
are critical periods of susceptibility to agents and organ
systems affected by these agents.
3. Teratogenic agents act in specific ways on developing cells and
tissues to initiate sequences of abnormal developmental
events.
4. The access of adverse influences to developing tissues
depends on the nature of the influence. Several factors
affect the ability of a teratogen to contact a developing
conceptus, such as the nature of the agent itself, route
and degree of maternal exposure, rate of placental
transfer and systemic absorption, and composition of the
maternal and embryonic/fetal genotypes.
5. There are four manifestations of deviant development
(Death, Malformation, Growth Retardation and Functional
Defect).
6. Manifestations of deviant development increase in
frequency and degree as dosage increases from the No
Observable Adverse Effect Level (NOAEL) to a dose
producing 100% Lethality (LD100).
Studies designed to test the teratogenic potential of environmental
agents use animal model systems (e.g., rat, mouse, rabbit, dog,
and monkey). Early teratologists exposed pregnant animals to
environmental agents and observed the fetuses for gross
visceral and skeletal abnormalities. While this is still part of the
teratological evaluation procedures today, the field of
Teratology is moving to a more molecular level, seeking the
mechanism(s) of action by which these agents act.
Genetically modified mice are commonly used for this purpose.
In addition, pregnancy registries are large, prospective studies
that monitor exposures women receive during their pregnancies
and record the outcome of their births. These studies provide
information about possible risks of medications or other
exposures in human pregnancies.
Understanding how a teratogen causes its effect is not only
important in preventing congenital abnormalities but also has
the potential for developing new therapeutic drugs safe for use
with pregnant women.
 Teratogenic agents
A wide range of different chemicals and environmental
factors are suspected or are known to be teratogenic
in humans and in animals. A selected few include:
• Ionizing radiation: atomic weapons, radioiodine,
radiation therapy
• Infections: cytomegalovirus, herpes virus,
parvovirus B-19, rubella virus (German measles),
syphilis, toxoplasmosis,
Venezuelan equine encephalitis virus
• Metabolic imbalance: alcoholism, endemic cretinism,
diabetes, folic acid deficiency, hyperthermia,
phenylketonuria, rheumatic disease and
congenital heart block, virilizing tumors
• Drugs and environmental chemicals:
13-cis-retinoic acid, isotretinoin (Accutane),
temazepam (Restoril; Normisson), nitrazepam
(Mogadon), nimetazepam (Ermin), aminopterin,
androgenic hormones, busulfan, captopril,
enalapril, chlorobiphenyls (PCBs), Dioxin,
coumarin, cyclophosphamide, diethylstilbestrol,
diphenylhydantoin (Phenytoin, Dilantin,
Epanutin), ethanol, ethidium bromide, etretinate
, hexachlorophene, lithium, methimazole,
organic mercury, penicillamine, tetracyclines,
thalidomide, trimethadione, uranium,
methoxyethyl ethers and valproic acid.
• The status of some of the above substances (e.g.
diphenylhydantoin) is subject to debate, and many
other compounds are under varying degrees of
suspicion. These include Agent Orange, nicotine,
aspirin and other NSAIDs. Other compounds are
known as severe teratogens based on veterinary work
and animal studies, but aren't listed above because
they have not been studied in humans, e.g.
cyclopamine. Teratogenic effects also help to
determine the pregnancy category assigned by
regulatory authorities; in the United States, a
pregnancy category of X, D, or C may be assigned if
teratogenic effects (or other risks in pregnancy) are
documented or cannot be excluded.
• Isotretinoin (13-cis-retinoic-acid; brand name
Accutane), which is often used to treat severe
acne, is such a strong teratogen that just a
single dose taken by a pregnant woman may
result in serious birth defects. Because of this
effect, most countries have systems in place to
ensure that it is not given to pregnant women,
and that the patient is aware of how important it
is to prevent pregnancy during and at least one
month after treatment. Medical guidelines also
suggest that pregnant women should limit
vitamin A intake to about 700 ug/day, as it has
teratogenic potential when consumed in
excess.
 Teratogenic outcomes
• Exposure to teratogens can result in a
wide range of structural abnormalities
such as cleft lip, cleft palate, dysmelia,
anencephaly, ventricular septal defect. In
most cases, specific agents produce a
specific teratogenic response.
• Cleft lip (cheiloschisis) and cleft palate
(palatoschisis), which can also occur together
as cleft lip and palate are variations of a
type of clefting congenital deformity caused
by abnormal facial development during
gestation. This type of deformity is
sometimes referred to as a cleft. A cleft is a
sub-division in the body's natural structure,
regularly formed before birth. A cleft lip or
palate can be successfully treated with
surgery soon after birth. Cleft lips or palates
occur in somewhere between one in 600-800
births.
• The term harelip is no longer used to
describe the condition as it is considered
offensive.
Anencephaly is a cephalic disorder that results
from a neural tube defect that occurs when
the cephalic (head) end of the neural tube
fails to close, usually between the 23rd and
26th day of pregnancy, resulting in the
absence of a major portion of the brain, skull,
and scalp. Children with this disorder are
born without a forebrain, the largest part of
the brain consisting mainly of the
cerebral hemispheres (which include the
isocortex, which is responsible for higher
level cognition, i.e., thinking). The remaining
brain tissue is often exposed - not covered by
bone or skin.
There is no cure or standard treatment for
anencephaly and the prognosis for affected
individuals is poor. Most anencephalic babies
do not survive birth, accounting for 55% of
non-aborted cases. If the infant is not stillborn
, then he or she will usually die within a few
hours or days after birth from
cardiorespiratory arrest.
 drug interaction
• A drug interaction is a situation in which a substance affects the
activity of a drug, i.e. the effects are increased or decreased, or they
produce a new effect that neither produces on its own. Typically,
interaction between drugs come to mind (drug-drug interaction).
However, interactions may also exist between drugs & foods (drug-
food interactions), as well as drugs & herbs (drug-herb interactions).
• Generally speaking, drug interactions are to be avoided, due to the
possibility of poor or unexpected outcomes. However, drug
interactions have been deliberately used, such as co-administering
probenecid with penicillin prior to mass production of penicillin.
Because penicillin was difficult to manufacture, it was worthwhile to
find a way to reduce the amount required. Probenecid retards the
excretion of penicillin, so a dose of penicillin persists longer when
taken with it, and it allowed patients to take less penicillin over a
course of therapy.
• A contemporary example of a drug interaction used as an advantage is the
co-administration of carbidopa with levodopa (available as
Carbidopa/levodopa). Levodopa is used in the management of
Parkinson's disease and must reach the brain in an un-metabolized state to
be beneficial. When given by itself, levodopa is metabolized in the
peripheral tissues outside the brain, which decreases the effectiveness of
the drug and increases the risk of adverse effects. However, since
carbidopa inhibits the peripheral metabolism of levodopa, the co-
administration of carbidopa with levodopa allows more levodopa to reach
the brain un-metabolized and also reduces the risk of side effects.
• Drug interactions may be the result of various processes. These processes
may include alterations in the pharmacokinetics of the drug, such as
alterations in the Absorption, Distribution, Metabolism, and Excretion (
ADME) of a drug. Alternatively, drug interactions may be the result of the
pharmacodynamic properties of the drug, e.g. the co-administration of a
receptor antagonist and an agonist for the same receptor.
• Metabolic drug interactions
• Many drug interactions are due to alterations in drug metabolism.[1] Further, human
drug-metabolizing enzymes are typically activated through engagement of
nuclear receptors.[1]
• One notable system involved in metabolic drug interactions is the enzyme system
comprising the cytochrome P450 oxidases. This system may be affected by either
enzyme induction or enzyme inhibition, as discussed in the examples below.
• Enzyme induction - drug A induces the body to produce more of an enzyme which
metabolises drug B. This reduces the effective concentration of drug B, which may
lead to loss of effectiveness of drug B. Drug A effectiveness is not altered.
• Enzyme inhibition - drug A inhibits the production of the enzyme metabolising drug B,
thus an elevation of drug B occurs possibly leading to an overdose.
• Bioavailability - drug A influences the absorption of drug B.
• The examples described above may have different outcomes depending on the
nature of the drugs. For example, if Drug B is a prodrug, then enzyme activation is
required for the drug to reach its active form. Hence, enzyme induction by Drug A
would increase the effectiveness of the drug B by increasing its metabolism to its
active form. Enzyme inhibition by Drug A would decrease the effectiveness of Drug B.
• Additionally, Drug A and Drug B may affect each other's metabolism.
• Drug tolerance occurs when a subject's
reaction to a psychoactive drug (such as a
painkiller or intoxicant) decreases so that larger
doses are required to achieve the same effect.
Drug tolerance can involve both
psychological drug tolerance and physiological
factors.
• Tachyphylaxis is a medical term referring to the
rapid development of drug tolerance.
• A psychoactive drug or psychotropic substance is a chemical substance that acts
primarily upon the central nervous system where it alters brain function, resulting in
temporary changes in perception, mood, consciousness and behaviour. These drugs
may be used recreationally to purposefully alter one's consciousness, as entheogens
for ritual or spiritual purposes, as a tool for studying or augmenting the mind, or
therapeutically as medication.
• Because psychoactive substances bring about subjective changes in consciousness
and mood that the user may find pleasant (e.g. euphoria) or advantageous (e.g.
increased alertness), many psychoactive substances are abused, that is, used
excessively, despite risks or negative consequences. With sustained use of some
substances, physical dependence may develop, making the cycle of abuse even
more difficult to interrupt. Drug rehabilitation can involve a combination of
psychotherapy, support groups and even other psychoactive substances to break the
cycle of dependency.
• In part because of this potential for abuse and dependency, the ethics of drug use are
the subject of a continuing philosophical debate. Many governments worldwide have
placed restrictions on drug production and sales in an attempt to decrease drug
abuse.
• Uses of psychoactive substances
• Psychoactive substances are used by humans for a number of different purposes. These uses vary widely between cultures. Some substances may have controlled or illegal uses while others may have shamanic purposes, and still
others are used medicinally. Other examples would be social drinking or sleep aids. Caffeine is the world's most widely consumed psychoactive substance, but unlike many others, it is legal and unregulated in nearly all jurisdictions. In
North America, 90% of adults consume caffeine daily.[6]
• [edit] Anesthesia
– Main article: Anesthesia
• General anesthetics are a class of psychoactive drug used on patients to block pain and other sensations. Most anesthetics induce unconsciousness, which allows patients to undergo medical procedures like surgery without physical
pain or emotional trauma.[7] To induce unconsciousness, anesthetics affect the GABA and NMDA systems. For example, halothane is a GABA agonist,[8] and ketamine is an NMDA receptor antagonist.[9]
• [edit] Painkillers
– Main article: Analgesics
• Aspirin
• Psychoactive drugs are often prescribed to manage pain. As the subjective experience of pain is regulated by endorphins, neurochemicals that are endogenous opioids, pain can be managed using psychoactives that operate on this
neurotransmitter system. This class of drugs includes narcotics, like morphine and codeine,[10] and also NSAIDs (which don't affect endorphins) such as aspirin and ibuprofen.
• [edit] Psychiatric medications
– Main article: Psychiatric medications
•
• Zoloft, an antidepressant (and anti-anxiety) medication
• Psychiatric medications are prescribed for the management of mental and emotional disorders. There are 6 major classes of psychiatric medications:
• Antidepressants, which are used to treat disparate disorders such as clinical depression, dysthymia, anxiety, eating disorders and borderline personality disorder.[11]
• Stimulants, which are used to treat disorders such as attention deficit disorder and narcolepsy and to suppress the appetite.
• Antipsychotics, which are used to treat psychoses, schizophrenia and mania.
• Mood stabilizers, which are used to treat bipolar disorder and schizoaffective disorder.
• Anxiolytics, which are used to treat anxiety disorders.
• Depressants, which are used as hypnotics, sedatives, and anesthetics.
• [edit] Recreational drugs
– Main article: Recreational drug use
• Many psychoactive substances are used for their mood and perception altering effects, including those with accepted uses in medicine and psychiatry. Classes of drugs frequently used recreationally include:
• Stimulants, which elevate the central nervous system. These are used recreationally for their euphoric effects.
• Hallucinogens (psychedelics, dissociatives and deliriants), which induce perceptual and cognitive distortions.
• Hypnotics, which are used recreationally because they induce inebriation.
• Analgesics, which are used recreationally because of their euphoric effects.
• Inhalants, in the forms of gas aerosols, or solvents, which are inhaled as a vapor because of their stupefying effects. Many inhalants also fall into the above categories (such as Nitrous Oxide which is also an anelgesic)
• Examples include caffeine, alcohol, cocaine, LSD, and cannabis.[12]
• In some sub-cultures, drug usage is seen as a status symbol. Recreational drugs are seen as status symbols at events such as at nightclubs and parties.[13] This is true of many cultures throughout history; drugs have been viewed as
status symbols since ancient times. For example, in ancient Egypt, gods were commonly pictured holding hallucinogenic plants.[14]
• Because there is controversy about regulation of recreational drugs, there is an ongoing debate about drug prohibition. Critics of prohibition believe that regulation of recreational drug use is a violation of personal autonomy and freedom.
[15] In the United States, critics have noted that prohibition or regulation of recreational and spiritual drug use might be unconstitutional.[16]
• [edit] Ritual and spiritual use
•
• Timothy Leary was a leading proponent of spiritual hallucinogen use.
– Main article: Entheogens
• Certain psychoactives, particularly hallucinogens, have been used for religious purposes since prehistoric times. Native Americans have used mescaline-containing peyote cacti for religious ceremonies for as long as 5700 years.[17] The
muscimol-containing Amanita muscaria mushroom was used for ritual purposes throughout prehistoric Europe.[18] Various other hallucinogens, including jimsonweed, psilocybin mushrooms, and cannabis have been used in religious
ceremonies for centuries.[19]
• The use of entheogens for religious purposes resurfaced in the West during the counterculture movements of the 1960s and 70s. Under the leadership of Timothy Leary, new religious movements began to use LSD and other
hallucinogens as sacraments.[20] In the United States, the use of peyote for ritual purposes is protected only for members of the Native American Church, which is allowed to cultivate and distribute peyote. However, the genuine
religious use of Peyote, regardless of one's personal ancestry, is protected in Colorado, Arizona, New Mexico, Nevada, and Oregon.[21]
• [edit]
• Administration
• For a substance to be psychoactive, it must cross the
blood-brain barrier so it can affect neurochemical function.
Psychoactive drugs are administered in several different ways. In
medicine, most psychiatric drugs, such as fluoxetine, quetiapine,
and lorazepam are ingested orally in tablet or capsule form.
However, certain medical psychoactives are administered via
inhalation, injection, or rectal suppository/enema. Recreational
drugs can be administered in several additional ways that are not
common in medicine. Certain drugs, such as alcohol and caffeine,
are ingested in beverage form; nicotine and cannabis are often
smoked; peyote and psilocybin mushrooms are ingested in
botanical form or dried; and certain crystalline drugs such as
cocaine and methamphetamines are often insufflated. The efficiency
of each method of administration varies from drug to drug.[22]
• Administration
• For a substance to be psychoactive, it must cross the
blood-brain barrier so it can affect neurochemical function.
Psychoactive drugs are administered in several different ways. In
medicine, most psychiatric drugs, such as fluoxetine, quetiapine,
and lorazepam are ingested orally in tablet or capsule form.
However, certain medical psychoactives are administered via
inhalation, injection, or rectal suppository/enema. Recreational
drugs can be administered in several additional ways that are not
common in medicine. Certain drugs, such as alcohol and caffeine,
are ingested in beverage form; nicotine and cannabis are often
smoked; peyote and psilocybin mushrooms are ingested in
botanical form or dried; and certain crystalline drugs such as
cocaine and methamphetamines are often insufflated. The efficiency
of each method of administration varies from drug to drug.[22]
• [edit] Effects
• Illustration of the major elements of neurotransmission. Depending on its method of action, a
psychoactive substance may block the receptors on the post-synaptic neuron (dendrite), or block
reuptake or affect neurotransmitter synthesis in the pre-synaptic neuron (axon).
– Main article: Neuropsychopharmacology
• Psychoactive drugs operate by temporarily affecting a person's neurochemistry, which in turn
causes changes in a person's mood, cognition, perception and behavior. There are many ways in
which psychoactive drugs can affect the brain. Each drug has a specific action on one or more
neurotransmitter or neuroreceptor in the brain.
• Drugs that increase activity in particular neurotransmitter systems are called agonists. They act
by increasing the synthesis of one or more neurotransmitters or reducing its reuptake from the
synapses. Drugs that reduce neurotransmitter activity are called antagonists, and operate by
interfering with synthesis or blocking postsynaptic receptors so that neurotransmitters cannot
bind to them.[23]
• Exposure to a psychoactive substance can cause changes in the structure and functioning of
neurons, as the nervous system tries to re-establish the homeostasis disrupted by the presence
of the drug. Exposure to antagonists for a particular neurotransmitter increases the number of
receptors for that neurotransmitter, and the receptors themselves become more sensitive. This is
called sensitization. Conversely, overstimulation of receptors for a particular neurotransmitter
causes a decrease in both number and sensitivity of these receptors, a process called
desensitization or tolerance. Sensitization and desensitization are more likely to occur with long-
term exposure, although they may occur after only a single exposure. These processes are
thought to underlie addiction.[24]