Ethiopan Pharmacology 2015

PHARMACOLOGY
Prepared by ;
weku bedada (PhD Candidate)
Tusday ,May12,2015 Designed by YAYA 1

Pharmacology
 From pharmakon: ‘drug ’ and -logia: ‘the study of’
 The study of the interactions that occur between a living
organism and chemicals that affect normal or abnormal
biochemical function. Such interactions are explained by
the two major principles; the pharmacokinetics and the
pharmacodynamics.
 Pharmacokinetics studies the effects of biological
systems on the drugs and pharmacodynamics studies the
effects of the drugs on biological systems.
 A drug may be broadly defined as any chemical agent
that affects biological system. If the chemical has
medicinal properties, it is considered pharmaceutical.
 The most important properties of an ideal drug are:
effectiveness and safety. 2Tusday ,May12,2015 Designed by YAYA

Body-drug interactions
3Tusday ,May12,2015 Designed by YAYA

Rudolf Buchheim
• Rudolf Buchheim (1820–1879) was a
German pharmacologist .
• He created the first pharmacological institute University
of Dorpat at 1845.
• In 1867 he became professor of pharmacology
and toxicology at the University of Giessen.
• Buchheim is remembered for his pioneer work in
experimental pharmacology. He introduced
the bioassay to pharmacology, and created a
methodology for determining the quantitative and
medical aspects of chemical substances.
• A well-known student of his was chemist Oswald
Schmiedeberg (1838–1921), who was to become the
"founder of modern pharmacology".

Branches of Pharmacology
• Clinical pharmacology: application of pharmacological
principles and methods in the medical clinic and towards
patient care and outcomes
• Toxicology: Study of harmful or toxic effects of drugs
(including those beneficial in lower doses).
• Pharmacogenetics: Clinical testing of genetic variation
that gives rise to differing response to drugs
• Pharmacogenomics: Application of genomic technologies
to new drug discovery and further characterization of
older drugs
• Pharmacoepidemiology: Study of effects of drugs in large
numbers of people
• Pharmacognosy: deals with the composition, use, and
development of natural medicinal substances.

Sources of Drugs
• Drugs are derived from a wide variety of different
sources, including plants, minerals, animals, synthetic
and DNA sources.
• Plants e.g Quinidine from cinchona bark, digoxin from
foxglove plant and morphine from opium poppy plant.
• Minerals e.g . Milk of magnesia (Mg) , Zinc oxide (Zn)
• Animals: insulin from pancreas of the cow or pig
• Synthetic: Acetylsalicylic acid(Aspirin) Meperidine,
Diphenoxylate, Co-Trimoxazole.
• Recombinant DNA: Hepatitis B vaccine, insulin and the
growth hormone.

Discovery
Phase I
Preclinical
Phase II
Phase III
Approval
Post marketing surveillance
6 years 6 years 2 years
Preclinical Clinical Approval
Drug development - success rate by stageDrug development - success rate by stage
Safety and dosage (20-80 healthy volunteers)
Efficacy and side effects (100-300 patient volunteers)
Adverse reactions (1000-5000 patients)
Laboratory and animal testing
Target validation and lead discovery
(250 lead compounds)
(5 drug candidates)
(1 drug)
(>104
compounds)
5-10 years
Cost >$800m
Success
1 in 5,000

Drug names
• Most drugs have three names; brand name, generic
name and chemical name.
• Chemical name: derived using rules established by
the International Union of Pure and Applied
Chemistry (IUPAC). These rules allow scientists all over
the world to name structures the same way so that any
other scientist will know what structure is being
referred to based on the name.
• Since chemical names are usually long and complicated,
the drugs are given a standard, shorter generic name.
• E.g. 7-chloro-1,3-dihydro-1- methyl-5-phenyl-2H-1,4-
benzodiazepin-2-one for Diazepam ; N-acetyl-para-
aminophenol for Acetaminophen

Drug names…
• Brand names: trade name, properietry name
• Brand name is chosen by the company that makes it.
The name is often chosen to be memorable for
advertising, or to be easier to say or spell than some
long generic name.
• The brand name is usually written most clearly on any
packaging. However, you will always see the generic
name written somewhere on the packet (often in small
print).
• The original manufacturer of a drug receives a patent on
the drug and is the only manufacturer who can produce
and sell the drug during this patent period.
• E.g Valium for Diazepam,Bactrim for co-trimoxazole,
Losec for co-trimoxazole 9Tusday ,May12,2015 Designed by YAYA

Drug names…
• Generic names: official/non-proprietry names.
When patent protection expires on a drug, a
bioequivalent version may be sold as a "generic" version
of the brand name drug, typically at a significant discount
below the brand name. Generic drugs are cheaper
because the manufacturers have not had the expenses of
developing and marketing a new drug.
• Generic drugs are copies of brand-name drugs that have
exactly the same dosage, intended use, effects, side
effects, route of administration, risks, safety, and
strength as the original drug.
• Sometimes, generic versions of a drug have different
colors, flavors, or combinations of inactive ingredients
than the original medications. 10Tusday ,May12,2015 Designed by YAYA

Pharmacokinetics and Pharmacodynamics

Pharmacokinetics
• “What the body does to the drug” .
• The clinical application of is termed as Clinical
Pharmacokinetics
• Clinical pharmacokinetics attempts to provide both a
quantitative relationship between dose and effect and a
framework within which to interpret measurements of
concentrations of drugs in biological fluids for the benefit
of the patient
Liberation
Absorption
Distribution
Metabolism
Excretion

Pharmacokinetics

Absorption from the GIT
• Absorption from the GI tract is governed by factors such
as surface area, blood flow to the site of absorption, the
physical state of the drug, its water solubility, and the
drug's concentration at the site of absorption.
• Since most drug absorption from the GI tract occurs by
passive diffusion, absorption is favored when the drug is
in the nonionized and more lipophilic form.
• Drugs that are weak acids would be better absorbed
from the stomach (pH 1 to 2) than from the upper
intestine (pH 3 to 6), and vice versa for weak bases.
• Drugs that are destroyed by gastric secretions or that
cause gastric irritation sometimes are administered in
dosage forms with an enteric coating that prevents
dissolution in the acidic gastric contents.

Absorption from the GIT…
• The stomach has small surface area; by contrast, the villi
of the upper intestine provide an extremely large surface
area (approximately 200 m2
). Accordingly, the rate of
absorption of a drug from the intestine will be greater
than that from the stomach even if the drug is
predominantly ionized in the intestine and largely
nonionized in the stomach.
• Hence, any factor that accelerates gastric emptying will
be likely to increase the rate of drug absorption, whereas
any factor that delays gastric emptying is expected to
have the opposite effect, regardless of the characteristics
of the drug.

Routes of absorption
• Enteral routes: Oral, Sublingual, Buccal and Rectal.
• Pareneteral:Intravenous, Intramuscular, Subcutaneous,
Intra-arterial, Intradermal,Intraperitoneal etc
• Pulmonary (Metered Dose Inhaler,Dry Powder Inhaler,
Nebulizer
• Topical: Percutaneous, Ocular, Nasal,vaginal

Routes of Drug Administration

Oral Route Advantages:
Convenient, cheapest, easy to use
Safe and acceptable.
 Disadvantages:
Less bioavailability (first pass effect: hepatic
metabolism of drug when absorbed and delivered
through portal blood ).
Some drug is destroyed by gastric juices e.g. adrenaline,
insulin, oxytocin
Slow; not preferred during emergency.
Might cause gastric irritation
Might be objectionable in taste.
It might cause discoloration of teeth e.g. iron causes
staining, tetracyclines. 18Tusday ,May12,2015 Designed by YAYA

Sublingual Route
 Involves tablets placed under the tongue or between
cheeks or Gingiva. The drug should be lipid soluble and
small.
 Advantages:
Rapid absorption.
Less first pass effect: Venous drainage from the mouth
is to the superior vena cava, bypassing the portal
circulation.
Spitting out of the drug removes its effect
 Disadvantages:
 Inconvenient; Person may swallow the drug.
 Irritation of the mucous membrane might occur
 Might be unpleasant in taste.
Examples: nitroglycerin, oxytocin, nifedipine. 19Tusday ,May12,2015 Designed by YAYA

Rectal Route
 Local or systemic actions after absorption.
 Advantages:
Preferred in unconscious or uncooperative patients.
Avoids nausea or vomiting
Less first pass effect; the rectum's venous drainage is
two thirds systemic (middle and inferior rectal vein) and
one third portal (superior rectal vein). Additionally,
CYP3A4, is not present in high amount the lower
intestine in contrast to the upper intestine.
 Disadvantages:
Generally not acceptable by the patients.
Have 50% first pass metabolism.
Examples: glycerin, Bisacodyl , Indomethacin
Retention enema is diagnostic and is used for finding
the pathology of lower intestines. 20Tusday ,May12,2015 Designed by YAYA

Parenteral

Route…
• Intravenous: drug delivery is controlled and achieved
with an accuracy and immediacy not possible by any
other procedure. Also, certain irritating solutions can be
given only in this manner because the drug, if injected
slowly, is greatly diluted by the blood. Drugs in an oily
vehicle must not be given by this route.
• Subcutaneous: involves administration into the
subcutaneous tissue, a layer of fat located directly below
the dermis and epidermis, collectively referred to as
the cutis.
• Viscous formulations are not generally administered
subcutaneously. Typical sites of SC injection include the
arms, legs and abdomen.

Parenteral…
• IM: involves administration into a muscle, usually the
gluteal (buttocks), vastus lateralis (lateral thigh) or
deltoid (upper arm) muscles. The musculature resides
below the subcutaneous tissue (which itself lies beneath
the epidermis and the dermis).
• The volume of injection is small, usually 1–3 ml or up to
10 ml in divided doses.
• Absorption may be modulated to some extent by local
heating, massage, or exercise.
• Faulty injection technique may lead to local muscle
damage.

Parenteral…
• Intradermal /Intracutaneous: made into the outer layer
of skin (dermis) and produce local effects.
• Used mainly for local anesthesia and sensitivity tests,
such as allergy panels and tuberculin tests.
• Intrasynovial/Intra-articular : are used for the relief of
joint pain or the local application of medication.
• Intrathecal: has also been referred to as intraspinal,
subdural, subarachnoid, or lumbar injection.
• Permits direct administration of medication into the
subarachnoid space of the spinal cord.
• Intra-arterial: injected into an accessible artery.
• This route requires specialist training to administer
therapeutic agents as if the artery is missed, possible
damage to adjacent nerves may result.

Advantage : Parenteral
• Fast: 15–30 seconds for IV, 3–5 minutes for IM and SC
• Essential for drugs that offer poor bioavailability or those
that are rapidly degraded within the gastrointestinal tract
(e.g. insulin and other peptides).
• For unconscious or uncooperative or for patients with
nausea and vomiting (and additionally dysphagia).
• Local effects may be achieved using parenteral
formulations, e.g. local anaesthesia.
• Parenteral formulations provide a means by which
serious imbalances in electrolytes may be corrected
(using infusion solutions).
• Total parenteral nutrition offers a means by which
nutrition may be provided using specially formulated
solutions that are infused into the patient.

Disadvantage : Parenteral
• The manufacturing process is more complicated. Need
for strict asepsis
• Skill of administration is required to ensure that the
dosage form is administered by the correct route.
• Parenteral formulations are associated with pain on
administration. If not done properly, potentially fatal
air boluses (bubbles) can occur.
• It is difficult to reverse the effects of drugs that have
been administered parenterally, even immediately after
administration.
• If needles are shared, there is risk of HIV and other
infectious diseases.

Inhalation Route
 Gaseous and volatile agents and aerosols
 Rapid onset of action due to rapid access to circulation
 large surface area
 High blood flow
 Advantages
Fastest method, 7-10 seconds
Users can titrate the amount of drug they are receiving
 Disadvantages
Most addictive route since it hits the brain so quickly
Particles larger than 20 micron and the particles impact
in the mouth and throat. Smaller than 0.5 micron and
they aren't retained.

Transport System
• Passive diffusion: Drugs diffuse across a cell membrane
from a region of high concentration (eg, GI fluids) to one
of low concentration (eg, blood). Diffusion rate is directly
proportional to the gradient but also depends on the
molecule's lipid solubility, size, degree of ionization, and
the area of absorptive surface.
• Facilitated diffusion is a process of passive transport
aided by integral membrane proteins.
• Active transport is the movement of a substance against
its concentration gradient. Active transport uses energy,
unlike passive transport, which does not use any type of
energy.

The Movement of Drugs Across Cell Barriers
Mechanism
Direction Energy required Carrier Saturable
Passive diffusion Along gradient No No No
Facilitated diffusion Along gradient No Yes Yes
Active transport Against gradient Yes Yes Yes

Bioavailability: The fraction of the dose (F) that is
absorbed and escapes any first-pass elimination.

Plasma drug concentration
• t max. The time of peak plasma concentration, t max,
corresponds to the time required to reach maximum drug
concentration after drug administration.
• C max. The peak plasma drug concentration, C max, represents
the maximum plasma drug concentration obtained after
oral administration of drug.
• AUC. The area under the plasma level–time curve, AUC, is
a measurement of the extent of drug bioavailability. The
AUC reflects the total amount of active drug that reaches
the systemic circulation.
• Css. Drugs are administered in such a way as to maintain
a steady state of a drug in the body ,i.e., just enough drug
is given in each dose to replace the drug eliminated since
the preceding dose. Thus, calculation of the appropriate31Tusday ,May12,2015 Designed by YAYA

Plasma drug concentration…
• It takes approximately three to five half-lives to reach
steady-state concentrations during continuous dosing. In
three half-lives, serum concentrations are at
approximately 90% of their ultimate steady-state values.
• Therapeutic effects are delayed for drugs with longer
t1/2. To reduce the onset time of the drug—a loading
(priming) or initial dose of drug is given. The main
objective of the loading dose is to achieve desired plasma
concentrations, as quickly as possible.
• Elimination Half-Life(t1/2): the time required for drug
blood levels to be reduced by 50%
• Clearance: may be defined as the volume of fluid cleared
of drug from the body per unit of time. The units for
clearance are mL/min or L/hr.

Plasma drug concentration
Single dose Multiple dose

Distribution
• After a drug is absorbed into the bloodstream, it rapidly
circulates through the body.
• Once absorbed, most drugs do not spread evenly
throughout the body. Drugs that dissolve in water
(water-soluble drugs), such as atenolol , tend to stay
within the blood and the fluid that surrounds cells
(interstitial space). Drugs that dissolve in fat , such as the
anesthetic drug halothane, tend to concentrate in fatty
tissues.
• Some drugs leave the bloodstream very slowly, because
they bind tightly to proteins circulating in the blood.
Others quickly leave the bloodstream and enter other
tissues, because they are less tightly bound to blood
proteins.

Distribution…
• The protein-bound part is generally inactive. As unbound
drug is distributed to tissues and its level in the
bloodstream decreases, blood proteins gradually release
the drug bound to them.
• A highly plasma protein bound drug (e.g., ibuprofen) will
have a small Vd while a drug with high tissue protein
binding (digoxin) will have a large Vd.
• In plasma, acidic drugs tend to bind mainly to albumin
while basic compounds have greater affinity towards
alpha acid glycoproteins.
• Due to the limitation in both the number and the type of
binding sites 1) binding may be saturable and, 2) drugs
may compete with one another for binding to the same
site.

Volume of distribution(Vd)
• It is defined as the hypothetical volume of plasma in
which the drug is dissolved. Vd is an indicative of the
extent of distribution of a drug.
• The volume of distribution is more properly termed
the apparent volume of distribution as it does not
correlate to any actual body volume.
• It is obvious that Vd has no physiological meaning.
Nevertheless, it is a very useful pharmacokinetic
parameter. The larger the Vd, the greater is the extent of
the distribution.
• Vd= total amount of drug adminstered
drug blood plasma concentration
• The units for Volume of Distribution are typically
reported in (ml or liter)/kg body weight

Distribution…
Vd % Body Weight Extent of Distribution
5 7 Only in plasma
5-20 7-28 In extracellular fluids
20-40 28-60 In total body fluids.
>40 >56 In deep tissues; bound to
peripheral tissues

Metabolism

Biotransformation (Metabolism)
 Many pharmaceuticals are lipophilic, which enables the
drug to pass across cell membranes. Unfortunately, the
same chemical property that enhances bioavailability of
drugs may also make renal excretion difficult.
 Metabolism often converts lipophilic compounds into
more readily excreted hydrophilic products. The rate of
metabolism determines the duration and intensity of a
drug's action.
 Although the liver is quantitatively the most important
organ in metabolizing drugs, every tissue in the body is
capable of drug metabolism to some degree- skin, lungs,
GIT, and kidneys.
 Biotransformation reactions are classically divided into
two main types: (phase I) and conjugation (phase II). 39Tusday ,May12,2015 Designed by YAYA

Metabolism…
 Phase I reactions (also termed nonsynthetic reactions)
may occur by oxidation, reduction, hydrolysis. These
reactions typically involve a cytochrome P450 (often
abbreviated CYP), NADPH and oxygen.
 Results in drug inactivation (most of drugs), conversion of
inactive drug into active metabolite, conversion of active
drug into active metabolite, conversion to toxic
metabolite.
 Phase II (Synthetic) reactions: Functional group formed
by phase I is masked by natural conjugates such as
glucuronic acid, glutathione, sulphate, acetic acid, glycine
or methyl group.
 Sites on drugs where conjugation reactions occur include
-COOH,-OH), NH2, and -SH groups.

CYP (Cytochrome P450 ) Families
• Multiple CYP gene families have been identified in
humans, and the categories are based upon protein
sequence homology
• Most of the enzymes are in CYP 1, 2, & 3 families .
• Frequently, two or more enzymes can catalyze the same
type of oxidation, indicating redundant and broad
substrate specificity.
• CYP3A4 is very common to the metabolism of many
drugs; its presence in the GI tract is responsible for poor
oral availability of many drugs.
• Percentage of drugs metabolized by CYP3A4-5:33%,
CYP2D6:23%, CYP2C9:14%, CYP1A2:14%, CYP2C19:11%.

Factors affecting drug metabolism
• Enzymes induction (phenobarbitone, phenytoin) and
enzyme inhibition (Cimetidine, erythromycin). This is
very important in predicting drug-drug interactions
• Genetics variation: Isoniazid(Slow/fast acetylators).
There will be high adverse effects in slow acetylators
• Nutrition state: low protein diet can decrease glycine.
• Overdose:acetaminophen overdose causes
hepatotoxicty
• Age: children (immature enzyme), elders (organ
degeneration)
• Gender: Diazepam metabolism is faster in women while
propranolol metabolism is faster in men.
• Disease state: kidney and liver failure
• Route of Administration: First pass hepatic effect in oral
routes of administration

Excretion
 Drugs are eliminated from the body either unchanged by
the process of excretion or converted to metabolites.
 Renal excretion provides the most common mechanism
of drug excretion; this form of excretion relies on the
hydrophilic character of a drug or metabolite.
 It is the result of three processes: Filtration, active
tubular secretion and passive re-absorption.
 Most drugs cab be effectively filtered by Kidney.
 Penicillin is an example of a drug that is eliminated
largely by active transport in the proximal tubule.
 Drugs that are converted to polar metabolites by liver
will not be passively reabsorbed through tubules and
thus excreted through urine.

Excretion…
 Drug reabsorption in the tubule can be enhanced or
inhibited by chemical adjustment of the urinary pH. E.g.
Aspirin overdose is treated by administering sodium
bicarbonate to alkalinize the urine.
 Substances excreted in the feces are principally
unabsorbed orally ingested drugs or drug metabolites
excreted either in the bile or secreted directly into the
intestinal tract and not reabsorbed. Excretion of drugs in
breast milk is important not because of the amounts
eliminated, but because the excreted drugs are potential
sources of unwanted pharmacological effects in the
nursing infant. Excretion from the lung is important
mainly for the elimination of anesthetic gases.

Pharmacodynamics
• Pharmacodynamics is used to describe the effects of a
drug on the body. It is often summarized as the study of
what a drug does to the body.
• Understanding Pharmacodynamics can provide the basis
for the rational therapeutic use of a drug and the design
of new and superior therapeutic agents.
• Mechanism of action: the molecular interactions by
which pharmacologic agents exert their effects.
• The majority of drugs:
₋ mimic or inhibit normal physiological/biochemical
processes/ pathological processes
₋ inhibit vital processes of parasites and microbes.
• The desired activity of a drug is mainly due to
interaction with receptors.

Effects of drugs
• Therapeutic effect: desirable and beneficial effects of
drugs.
• Adverse effect : harmful and undesired effect of drugs.
– An adverse effect may be termed a "side effect",
when judged to be secondary to a main or
therapeutic effect, and may result from an
unsuitable or incorrect dosage or procedure, which
could be due to medical error.
– Adverse effects may cause medical complications of
a disease or procedure and negatively affect its
prognosis.
– They may also lead to non-adherence with a
treatment regimen.

Drug-Receptor Interaction
• Therapeutic and toxic effects of drugs result from their
interactions with molecules in the patient. Most drugs
act by associating with specific macromolecules in ways
that alter the macromolecules' biochemical or
biophysical activities.
• The component of a cell or organism that interacts with
a drug and initiates the chain of events leading to the
drug's observed effects is called receptor.
• Receptors largely determine the quantitative relations
between dose or concentration of drug and
pharmacologic effects. The receptor's affinity for binding
a drug determines the concentration of drug required to
form a significant number of drug-receptor complexes,
and the total number of receptors may limit the maximal
effect a drug may produce. 47Tusday ,May12,2015 Designed by YAYA

Receptor Theory
• Receptor occupancy model: based on mass-action
kinetics and attempts to link the action of a drug to the
proportion of receptors occupied by that drug at
equilibrium.
• In particular, the magnitude of the response is directly
proportional to the amount of drug bound, and the
maximum response would be elicited once all receptors
were occupied at equilibrium
• Two-state receptor theory:describe the interaction
between a ligand and its receptor, but also the active
receptor (R*
). It proposes that ligand binding results in a
change in receptor state from an inactive to an active
state based on the receptor's conformation. A receptor
in its active state will ultimately elicit its biological
response. 48Tusday ,May12,2015 Designed by YAYA

Drug-Receptor Interaction…
• Receptors include receptors on the cell surface and
within the cell, as well as enzymes and other
components that generate, amplify, coordinate, and
terminate postreceptor signaling by chemical second
messengers in the cytoplasm.
• Two major categories of receptors: Ligand gated
(ionotropic) and G-protein coupled (metabotropic).
• Ligand-Gated Channels :regulate the flow of ions
through plasma membrane channels.
• G-protein Coupled Receptors: act through increasing
the intracellular concentrations of second messengers
such as cyclic adenosine-3',5'-monophosphate (cAMP),
calcium ion, or the phosphoinositides.

NE signal Transduction

Drug-Receptor Interaction…
• Receptors are responsible for selectivity of drug action.
Changes in the chemical structure of a drug can
dramatically increase or decrease a new drug's affinities
for different classes of receptors, with resulting
alterations in therapeutic and toxic effects.
• Receptors mediate the actions of both pharmacologic
agonists and antagonists.
• Agonists activate the receptor to signal as a direct result
of binding to it.
• Antagonists bind to receptors but do not activate
generation of a signal; consequently, they interfere with
the ability of an agonist to activate the receptor.

Drug-receptor interaction…
• “Spare” receptors: receptors are said to be "spare" for a
given pharmacologic response if it is possible to elicit a
maximal biologic response at a concentration of agonist
that does not result in occupancy of the full complement
of available receptors.
• Experimentally, spare receptors may be demonstrated
by using irreversible antagonists to prevent binding of
agonist to a proportion of available receptors and
showing that high concentrations of agonist can still
produce an undiminished maximal response.
• “Orphan" receptors: receptors for which ligands are
presently unknown; useful targets for the development
of new drugs.

Drug-Receptor interaction…
• Many receptors for drugs can be modeled as having two
conformational states that are in reversible equilibrium
with one another. These two states are called the active
state and the inactive state.
• Many drugs function as ligands for such receptors and
affect the probability that the receptor exists
preferentially in one conformation or the other. The
pharmacologic properties of drugs are often based on
their effects on the state of their cognate receptors.
• A drug that, upon binding to its receptor, favors the
active receptor conformation is called an agonist; a drug
that prevents activation of the receptor by agonist is
referred to as an antagonist.

• Affinity: a measure of the ability of the drug to bind to its
molecular target
• Intrinsic activity : refers to the ability of a drug-receptor
complex to produce a functional response. It is used to
distinguish the relative extent of pharmacologic response
between different drug molecules that bind to the same
receptor.
• Efficacy :Efficacy can be thought of as the state at which
receptor-mediated signaling is maximal and, therefore,
additional drug will produce no additional response.
• Potency: The potency of a drug is the concentration of
drug needed to obtain a specific pharmacologic effect,
such as the EC50 . More potent drug is the one that
requires lower dose to cause same effect

Drug-Receptor interaction…
• Chronic administration of a drug (e.g. organic nitrates)
causes a down-regulation or desensitization of
receptors, which results in the rapid development of
complete tolerance, a process known as tachyphylaxis.
• To avoid tachyphylaxis, it is necessary to interrupt
therapy.

SEMILOG DOSE-RESPONSE CURVE
EFFECT
POTENCY
EFFICACY
ED50
Maximal Effect
Log [Dose]

Dose-Response Relationships

• Therapeutic Index: In animal studies, the therapeutic
index is defined as the ratio of the TD50 to ED50.
• Thus if TD50 = 500 mg and ED50 = 5 mg, the drug is 100-
fold more selective for the desired response and the
therapeutic index is 100. The therapeutic index in
humans is never known with great precision.

Dose-Response Curve
• The pharmacodynamics of a drug can be quantified by
the relationship between the dose (concentration) of the
drug and the organism's (patient's) response to that
drug.
• One might intuitively expect the dose–response
relationship to be related closely to the drug–receptor
binding relationship, and this turns out to be the case for
many drug–receptor combinations.
• Thus, a useful assumption at this stage of discussion is
that the response to a drug is proportional to the
concentration of receptors that are bound (occupied) by
the drug.

Dose-Response Curve…
• The hyperbolic shape of the curve becomes sigmoid
when plotted semi-logarithmically. Dose–response
curves presented in this way are sigmoidal in shape and
have three basic properties: threshold, slope, and
maximal asymptote. These parameters characterize
and quantitate the activity of the drug.

Dose-Response…
• Graded Responses: is the situation in which a single
animal (or patient) gives graded responses to graded
doses; that is,as the dose is increased, the response
increases. With graded responses, one can obtain a
complete dose–response curve in a single animal.
• Quantal dose-response: determining the dose of drug
required to produce a specified magnitude of effect in a
large number of individual patients or experimental
animals and plotting the cumulative frequency
distribution of responders versus the log dose. The
specified quantal effect may be chosen on the basis of
clinical relevance (e.g., relief of headache/death). It
may also be used to generate information regarding the
margin of safety of a drug (e.g. Therapeutic index). 61Tusday ,May12,2015 Designed by YAYA

Quantal

Drug receptor interaction…
• Four types of related responses may occur at receptor:
• Agonist: a drug molecule that interacts with the receptor
and elicits a maximal pharmacologic response.
• Partial agonist: a drug that elicits a partial (below
maximal) response. Partial agonists produce a lower
response, at full receptor occupancy, than do full
agonists.
• Antagonist: an agent that elicits no response from the
receptor, but inhibits the receptor interaction of a
second agent. The primary action of antagonists is to
prevent agonists (other drugs or endogenous regulatory
molecules) from activating receptors.
• “Inverse agonists“: reduce receptor activity below basal
levels.

Pharmacodynamic Drug-Drug Interactions
• A drug–drug interaction occurs when one drug interacts
with or interferes with the action of another drug.
• Drug–drug interactions can produce effects that are
additive, synergistic,or antagonistic.
• An additive drug reaction occurs when the combined
effect of two drugs is equal to the sum of each drug
given alone. E.g. heparin and alcohol
• Drug synergism occurs when drugs interact with each
other and produce an effect that is greater than the sum
of their separate actions. E.g Diazepam and alcohol.
• An antagonistic drug reaction occurs when one drug
interferes with the action of another, causing
neutralization or a decrease in effect of other drug.

Pharmacological Antagonists
• Can be competitive (reversible or irreversible) or non-
competitive
• The effect of a reversible antagonist can be overcome by
more drug (agonist).
• The effect of irreversible antagonists cannot be overcome
by more drug (agonist). The antagonist bind to the
receptor in an irreversible fashion, by forming a covalent
bond with the receptor.
• In case of non-competitive(e.g. benzodiazepines), the
antagonist drug binds allosterically to the receptor at
different site from that of active site; but lead in to
conformational change of the active.
• The primary action of antagonists is to prevent agonists
from activating receptors.

Pharmacological Antagonism

Non-receptor antagonism
• Not all of the mechanisms of antagonism involve
interactions of drugs or endogenous ligands at a single
type of receptor, and some types of antagonism do not
involve a receptor at all.
• Chemical antagonism: protamine can be used clinically
to counteract the effects of heparin, an anticoagulant; in
this case, one drug acts as a chemical antagonist of the
other.
• Physiologic antagonism: physiologic antagonism
between endogenous regulatory pathways mediated by
different receptors. For example, histamine lead to
increased bronchoconstriction ,an effect that is
physiologically opposed by adrenaline. Histamine and
adrenaline act on quite distinct receptor systems.

Adverse effects
• The transfer of drugs across the placenta is of critical
importance because drugs may cause
anomalies(teratogenicity) in the developing fetus.
• FDA has a categorized drug from "Category A" (safest) to
"Category X" (known danger) based on their risk to fetus.
• A: Adequate and well-controlled studies in pregnant
women have not shown an increased risk of fetal
abnormalities.
• B: Animal studies have revealed no evidence of harm to
the fetus; however, there are no adequate and well-
controlled studies in pregnant women, or animal studies
have shown an adverse effect, but adequate and well-
controlled studies in pregnant women have failed to
demonstrate a risk to the fetus. 69Tusday ,May12,2015 Designed by YAYA

Pregnancy category…
• C: Animal studies have shown an adverse effect, and
there are no adequate and well-controlled studies in
pregnant women, or no animal studies have been
conducted, and there are no adequate and well-
controlled studies in pregnant women.
• D: Adequate well-controlled or observational studies in
pregnant women have demonstrated a risk to the fetus.
However, the benefits of therapy may outweigh the
potential risk.
• X: Adequate well-controlled or observational studies in
animals or pregnant women have demonstrated positive
evidence of fetal abnormalities. The use of the product is
contraindicated in women who are or who may become
pregnant. 70Tusday ,May12,2015 Designed by YAYA

Hypersensitivity/ allergic reaction
• The presence of an antigen stimulates the antigen-
antibody response that in turn prompts the body to
produce antibodies.
• Some allergic reactions occur within minutes (even
seconds) after the drug is given; others may be delayed
for hours or days.
• Anaphylactic shock is an extremely serious allergic drug
reaction that usually occurs shortly after the
administration of a drug to which the individual is
sensitive.
• Symptoms include itching, various types of skin rashes,
and hives (urticaria),difficulty breathing, wheezing,
cyanosis, a sudden loss of consciousness, and swelling of
the eyes, lips, or tongue.

Other common adverse effects
• Carcinogenicity: the ability or tendency to produce
cancer
• Mutagenicity: the capacity to induce mutations
• Genotoxicity describes deleterious action on a cell's
genetic material affecting its integrity.
• Idiosyncrasy: unusual or abnormal reaction to a drug. For
example, a patient may be given a drug to help him or
her sleep (e.g., a hypnotic). Instead of falling asleep, the
patient remains wide awake and shows signs of
nervousness or excitement. This is not to be mistaken
with idiopathic which implies that the cause is not
known.

Pharmacology of peripheral
nervous system

Autonomic Nervous System(ANS)
• The autonomic nervous system, also called the visceral,
vegetative, or involuntary nervous system, is distributed
widely throughout the body and regulates autonomic
functions that occur without conscious control.
• The autonomic nervous system consists of two large
divisions: (1) the sympathetic or thoracolumbar outflow
and (2) the parasympathetic or craniosacral outflow.
• The neurotransmitter of all preganglionic autonomic
fibers, most postganglionic parasympathetic fibers, and a
few postganglionic sympathetic fibers is acetylcholine.
• The adrenergic fibers comprise the majority of the
postganglionic sympathetic fibers; here the primary
transmitter is norepinephrine (NE, noradrenaline)..
• The terms cholinergic and adrenergic describe neurons
that liberate ACh or norepinephrine, respectively. 76Tusday ,May12,2015 Designed by YAYA

ANS…
• In most instances, the sympathetic and parasympathetic
neurotransmitters can be viewed as physiological or
functional antagonists. If one neurotransmitter inhibits a
certain function, the other usually augments that
function.
• Most viscera are innervated by both divisions of the
autonomic nervous system, and the level of activity at
any moment represents the integration of influences of
the two components.
• Actions on male sexual organs are complementary and
are integrated to promote sexual function.
• The control of peripheral vascular resistance is primarily,
but not exclusively, due to sympathetic control of
arteriolar resistance.

ANS …
• The sympathoadrenal system can discharge as a unit,
particularly during rage and fright.
• HR is accelerated; BP rises; blood flow is shifted from the
skin and splanchnic region to the skeletal muscles; blood
glucose rises; the bronchioles and pupils dilate; and the
organism is better prepared for "fight or flight.”
• The parasympathetic system is organized mainly for
discrete and localized discharge.
• Concerned primarily with conservation of energy and
maintenance of organ function during periods of minimal
activity.
• Slows the HR, lowers the BP, stimulates gastrointestinal
movements and secretions, aids absorption of nutrients,
protects the retina from excessive light, and empties the
urinary bladder and rectum. 78Tusday ,May12,2015 Designed by YAYA

Eye

Cardiovascular system

Lung and GIT

Urinary & Reproductive System

Liver

Neurotransmission
• The terms cholinergic and adrenergic were proposed
originally by Dale to describe neurons that liberate
ACh or norepinephrine, respectively.
• Nerve impulses elicit responses in smooth, cardiac,
and skeletal muscles, exocrine glands, and
postsynaptic neurons by liberating specific chemical
neurotransmitters.
• A neurotransmitter is a substance released
synaptically by one neuron onto another cell (neuron
or neuroeffector) to produce some response -
localized effect as opposed to systemic (hormone).

Cholinergic Transmission
• Acetylcholine is synthesized in the nerve
terminal from acetyl-CoA (produced in
mitochondria) and choline (transported
across the cell membrane) by the enzyme
choline acetyltransferase (ChAT).
• Release of transmitter stores from vesicles
in the nerve ending requires the entry of
calcium.
• Acts on Nicotnic (Nn, Nm) and Muscarnic
(M1-M5)
• The action of acetylcholine in the synapse
is normally terminated by metabolism to
acetate and choline by the
enzyme acetylcholinesterase in the
synaptic cleft.

Adrenergic Transmission
• Norepinephrine is synthesized
from amino acid tyrosine
through the action of tyrosine
hydroxylase, dopa
decarboxylase and Dopamine β-
hydroxylase.
• Acts on α( 1,2) and β(1-3)
receptors
• NE that has been released is
taken up by the selective NE
transporter (NET);which is then
concentrated in vesicles by
vesicular monoamine
transporter (VMAT).
• MAO and COMT also involve in
termination of NE activity.

Directly acting : Choline esters
• Acetylcholine: actions are diffuse, and hydrolysis is
rapid. Available as an ophthalmic surgical aid for the
rapid production of miosis.
• Methacholine differs from ACh chiefly in its greater
duration and selectivity for cardiac muscarnic receptors.
It may be used for diagnosis of bronchial hyperreactivity.
• Bethanechol (methyl analog of carbachol): has mainly
muscarinic actions, with prominent effects on motility of
the GI tract and urinary bladder. It is completely
resistant to hydrolysis by cholinesterases.
• Carbachol: Almost completely resistant to hydrolysis by
cholinesterases. Carbachol retains substantial nicotinic
activity, particularly on autonomic ganglia.

Directly acting : Natural alkaloids
• Muscarine was first isolated from Amanita muscaria in
1869. It was the first muscarnic agonist ever studied and
causes profound activation of the peripheral cholinergic
nervous system that may end in convulsions and death.
• Pilocarpine, from the genus Pilocarpus, has a dominant
muscarinic action; present clinical use is restricted
largely to the employment of pilocarpine as a sialagogue
(treatment of xerostomia) and miotic agent.
• Major contraindications include asthma, coronary
insufficiency, and acid-peptic disease.
• Adverse effects: salivation, sweating, abdominal cramps,
a sensation of tightness in the urinary bladder, difficulty
in visual accommodation.

Indirect-Acting Cholinergic Drugs
• Classified as reversible and irreversible.
• Mechanism: prevention of hydrolysis of ACh by AChE at
sites of cholinergic transmission.
1.Reversible agents
• Edrophonium, neostigmine, pyridostigmine, and
physostigmine (Physostigma venenosum, calabar bean)
• Physostigmine is absorbed readily from the GI tract,
subcutaneous tissues, and mucous membranes.
Neostigmine and pyridostigmine are absorbed poorly
after oral administration.
• Used to diagnose and treat myasthenia gravis,
(weakness and marked fatigability of skeletal muscle),
and for reversal of non-depolarizing neuromuscular
blockers.

Reversible…
• Physostigmine, also called eserine, is an alkaloid
obtained from the Calabar or ordeal bean, the dried, ripe
seed of Physostigma venenosum, a perennial plant
found in tropical West Africa.
• The Calabar bean once was used by native tribes of West
Africa as an "ordeal poison" in trials for witchcraft. A
pure alkaloid was isolated by Jobst and Hesse in 1864
and named physostigmine.
• After basic research elucidated the chemical basis of the
activity of physostigmine, scientists began systematic
investigations of a series of substituted aromatic esters
of alkyl carbamic acids. Neostigmine was introduced into
therapeutics in 1931 for its stimulant action on the GI
tract and subsequently was reported to be effective in
the symptomatic treatment of myasthenia gravis. 90Tusday ,May12,2015 Designed by YAYA

Indirect-Acting Cholinergic Drugs….
• The similarity between the symptoms of myasthenia
gravis and curare poisoning in animals suggested to Jolly
that physostigmine, an agent known to antagonize
curare, might be of therapeutic value. Forty years
elapsed before his suggestion was given systematic trial.
• The edrophonium test for evaluation of possible
myasthenia gravis is performed by rapid IV injection of 2
mg of edrophonium chloride, followed 45 seconds later
by an additional 8 mg if the first dose is without effect; a
positive response consists of brief improvement in
strength.
• Excessive dose of anti-ChE results in a cholinergic crisis.

Indirect-Acting Cholinergic Drugs….
2. Irreversible
 Highly lipid soluble
 Organophosphate insecticides (malathion, parathion) or
nerve gases (sarin, tabun)
 Pralidoxime is used as antidote for irreversible
cholinesterase inhibitors.
 Certain phosphorylated AChEs can undergo a fairly rapid
process of "aging," so that within the course of minutes
or hours they become completely resistant to the
reactivators.

Muscarnic receptor antagonists
• Muscarinic receptor antagonists prevent the effects of
ACh by blocking its binding to muscarinic cholinergic
receptors at neuroeffector sites on smooth muscle,
cardiac muscle, and gland cells; in peripheral ganglia;
and in the CNS.
• The actions of most clinically available muscarinic
receptor antagonists differ only quantitatively from
those of atropine, considered as the prototype of the
group.
1. Natural alkaloids: atropine, scopolamine
2.Synthetic: Cyclopentolate , tropicamide, ipratropium,
pirenzepine, Benztropine, Trihexyphenidyl .

Atropine
• Atropine and scopolamine are alkaloids of the
belladonna (Solanaceae) plants.
• Compete with ACh and other muscarinic agonists for a
common binding site on the muscarinic receptor.
• Because atropine has limited CNS effects, it is preferred
to scopolamine for most purposes.
• Dilate the pupil (mydriasis) and paralyze
accommodation (cycloplegia). The wide pupillary
dilation results in photophobia; the lens is fixed for far
vision, near objects are blurred, and objects may appear
smaller than they are.
• The dominant effect on heart is tachycardia.
• Cause bronchodilation and inhibit secretions of the
nose, mouth, pharynx, and bronchi.

Atropine
•  secretion, tone and motility of GI and urinary tract.
• Dose-Response ladder: salivary and bronchial secretion
and sweating  mydriasis & cycloplegia, HR 
micturition and tone and motility of the gut 
gastric motility and particularly secretion.
• Absorbed rapidly from the GIT. Systemic absorption of
inhaled or orally ingested quaternary muscarinic
receptor antagonists is minimal.
• Atropine has a half-life of ~4 hours; hepatic metabolism
accounts for the elimination of about half of a dose; the
remainder is excreted unchanged in the urine.

Atropine
Therapeutic uses
• Symptomatic relief of acute rhinitis and treatment of
airway disease
• Urinary urgency, PUD and Spasm
• Examination of the eye and breaking of adhesions
between the iris and the lens.
• Anticholinesterases Poisoning.
Adverse effects
• Tachycardia
• Dry mouth
• Blurred vision
• Constipation
• Urinary retention 96Tusday ,May12,2015 Designed by YAYA

Neuromuscular blockers(NMBs)
• Curare has been used for centuries by the Indians along
the Amazon and Orinoco Rivers for immobilizing and
paralyzing wild animals used for food; death results from
paralysis of skeletal muscles.
• A localized paralytic action of curare was first described
by Claude Bernard in the 1850s. Griffith and Johnson
reported the first trial of curare for promoting muscular
relaxation in general anesthesia in 1942.
• Gallamine is one of a series of synthetic substitutes for
curare described by Bovet and coworkers in 1949.
• Classified as Non-depolarizing and Depolarizing.
• Currently, only a single depolarizing agent is in clinical
use, whereas many non-depolarizing agents are
available.

Non-depolarizing
• Tubocurarine, pancuronium, atracurium, vecuronium
• Combine with the NM receptor at the NMJ and thereby
competitively block the binding of ACh.
• Small, rapidly moving muscles such as those of the eyes,
jaw, and larynx relax before those of the limbs and
trunk. Ultimately, the intercostal muscles and finally the
diaphragm are paralyzed, and respiration then ceases.
• Recovery of muscles usually occurs in the reverse order
to that of their paralysis, and thus the diaphragm
ordinarily is the first muscle to regain function
• Devoid of central effects following ordinary clinical
doses because of their inability to penetrate the blood-
brain barrier.

Non-depolarizing…
• Tubocurarine might produce partial blockade probably at
autonomic ganglia and at the adrenal medulla, which
results in a fall in blood pressure and tachycardia.
• Anti-ChE agents can be used in the treatment of
overdosage with competitive blocking agents. Atropine is
used concomitantly to prevent stimulation of muscarinic
receptors and thereby to avoid slowing of the heart rate.
• The anti-ChE agents, however, are synergistic with the
depolarizing blocking agents, particularly in their initial
phase of action.
• Therapeutic use : an adjuvant in surgical anesthesia to
obtain relaxation of skeletal muscle, particularly of the
abdominal wall, to facilitate operative manipulations.
• Use: prolonged apnea, CV collapse, anaphylaxis

Depolarizing blockers: Succinylcholine
• Their initial action is to depolarize the membrane by
opening channels in the same manner as ACh.
• However, they persist for longer durations at the
neuromuscular junction primarily because of their
resistance to acetylcholinesterase.
• In such cases, the depolarizing agents produce initially
the characteristic fasciculations and potentiation of the
maximal twitch, followed by the rapid onset of
neuromuscular block; termed a dual mechanism.
• No longer indicated for children 8 years of age and
younger unless emergency intubation is necessary.

Adrenergic neurotransmission

Adrenergic Neurotransmission
• The ultimate response of a target organ to
sympathomimetic amines is dictated not only by the
direct effects of the agents, but also by the reflex
homeostatic adjustments of the organism.
• A rise in arterial BP caused by stimulation of α-receptors
elicits compensatory reflexes that are mediated by the
carotid-aortic baroreceptor system. As a result,
sympathetic tone is diminished and vagal tone is
enhanced.
• Conversely, when there is a fall in mean BP at the
mechano-receptors of the carotid sinus and aortic arch,
the baroreceptor reflex works to restore pressure by
reducing vagal outflow and increasing sympathetic
outflow to the heart and vessels.

Adrenergic Agonists
 Direct-acting agonists: act directly by binding to the
adrenergic receptors
 A feature of direct-acting sympathomimetic drugs is that
their responses are not reduced by prior treatment with
reserpine or guanethidine.
 Indirect-acting agonists: cause the release of NE from
intra-neuronal storage vesicles by the virtue of being
taken up by the pre-synaptic adrenergic neurons (e.g.,
amphetamine, tyramine)
 Mixed-action agonists: acts by directly activating
receptors and also enhancing release of
neurotransmitter from storage vesicles; is not a substrate
for COMT or MAO , can cross BBB. e.g. Ephedrine

Direct acting: α-agonists
 Selective α1: Phenylephrine, xylometazoline
 Selective α 2: Clonidine, Methyl Dopa
 Non-selective: Dopamine
 Pharmacologic effects of α-agonists
• Decrease NE release (α2)
• Elevate blood pressure (α1)
• Vasoconstriction of the URT lowers congestion(α1).
• leads to Mydriasis without loss of accommodation (α1).
• Inhibits Insulin release (α1)
• Increases contraction of pregnant human uterus (α1)
α-Methyldopa, an inhibitor of aromatic L-amino acid
decarboxylase and successively decarboxylated and
hydroxylated in its side chain to form the putative "false
neurotransmitter"α-methylnorepinephrine which is α2-106Tusday ,May12,2015 Designed by YAYA

Direct acting : β-agonists
 Selective β2:Salbutamol, Salmeterol ,Ritodrine
 Selective β1: Dobutamine
 Non-selective: Dopamine, Isopreternol
 Pharmacologic effects of β-agonists
• Increase HR, Contractility, conduction velocity(β1)
• Relaxation of bronchiolar smooth muscle and
bronchodilation(β2)
• Causes contraction of ciliary muscles (β2)
• Inhibits uterine tone and contractions (β2)
• Renin release from juxtaglomerular area(that results in
production of Angiotensin I, and then Angiotensin II.
Angiotensin II is potent vasoconstrictor and also causes
Na and water retention through Aldosterone) (β1).

Therapeutic uses adrenergic agonists
• α-agonists: eye disorder, nasal congestion, epistaxis,
anaphylactic shock, cardiac arrest, hypotension (α1
agonists), hypertension(α2 agonists)
• β-agonists: Bronchial asthma and delay delivery in
premature labor (β2 agonists), heart failure (β1
agonists)
Adverse effects of adrenergic agonists
• Anxiety, restlessness and tremors, tachycardia,
palpitation, angina and arrhythmia
• Eye irritation
• Gangrene (vasoconstriction)

Mixed Agonist: Ephedrine
• Chemically related to EP and stimulates release of NE
• It is not a substrate for COMT or MAO & hence has
long duration of action
• It activates β2 as well as α- and β1-aderenergic receptors
• It is used to treat mild cases of asthma
• It crosses BBB giving rise to CNS stimulant action
• It is now replaced by more selective β2 agonists

Adrenergic antagonists
 Direct acting
• α- blockers: prazosin,phentolamine
• β-blockers: metoprolol, proporanolol
• Mixed-blocker: labetalol,carvedilol
 Indirect acting
• Storage depleters: Reserpine, Guanethedine

Alpha-Adrenergic Blockers
 Non-selective:
• Phenoxybenzamine(irreversible)
• Phentolamine (Reversible)
 Selective
• Selective α1-blockers: Prazosin, Doxazosin
• Selectivity for α1A blocker:Tamsulosin
• Selective α2-blocker: Yohimbine
 Selectivity for α1A may favor blockade of receptors in
prostate.
 Therapeutic uses: Hypertension, Pheochromocytoma,
Benign prostatic Hyperplasia(BPH)
 Adverse Effects: First dose phenomenon, postural
hypotension, Reflex Tachycardia, Headache, and nasal
stuffiness 111Tusday ,May12,2015 Designed by YAYA

Beta-Adrenergic Receptors Blockers
 Selective β1
-blocker: Atenolol, metoprolol
 Selective β2
- blocker: butoxamine
 Non-selective β blocker: Propranolol, Timolol
 Mixed α & β- blocker: labetalol, Carvedilol
 Therapeutic uses: CVS diseases, Thyrotoxicosis ,
Pheochromocytoma
 Adverse effects: Bradycardia, bronchospasm, Masking
symptoms of hypoglycemia, lipid disturbance,
hypotension.

Indirect adrenergic antagonists
• Guanethidine: is transported across the sympathetic
nerve membrane by uptake. Once guanethidine has
entered the nerve, it is concentrated in transmitter
vesicles, where it replaces norepinephrine. However,
such agents can transiently stimulate the release of
norepinephrine because of their capacity to displace the
amine from storage sites.
• Reserpine: block the vesicular monoamine transporter
(VMAT 2) and produces a slow, prolonged depletion of
the adrenergic transmitter from adrenergic storage
vesicles, where it is largely metabolized by
intraneuronal MAO.

CNS pharmacology
Werku bedada

I. Sedative-Hypnotics
• An effective sedative (anxiolytic) agent should reduce
anxiety and exert a calming effect.
• The degree of central nervous system depression caused
by a sedative should be the minimum consistent with
therapeutic efficacy.
• A hypnotic drug should produce drowsiness and
encourage the onset and maintenance of a state of
sleep.
• Hypnotic effects involve more pronounced depression of
the central nervous system than sedation, and this can
be achieved with many drugs in this class simply by
increasing the dose.

Anxiolytics /Sedative-Hypnotics
1. Benzodiazepines
2. Barbiturates
3. BZ1 selective agonist: Zolpidem (anxiolytics)
4. 5-HT1A agonist: Buspirone (anxiolytics)

Benzodiazepines
 Alprazolam(12-15hrs) and chlordiazepoxide (15–40
hrs), clonazepam(23-28hrs) and diazepam ( 20–80hrs).
 Mechanism: increase in the frequency of chloride
channel-opening by promoting the binding of GABA to
the GABAA receptors.
 Sedatives, Hypnotics, Anxiolytics, Anticonvulsants,
anesthetics and skeletal Muscle relaxants.
 Decrease time to sleep onset and waking during the
night
 Cross the placental barrier and are secreted into breast
milk. Metabolized extensively by cytochrome P450
enzymes; have many active metabolites.

Benzodiazepines…
 Adverse Reactions: motor incoordination, amnesia,
tolerance and mild dependence,
 The criminal use of benzodiazepines in cases of "date
rape" is based on their dose-dependent amnestic
effects (flunitrazepam).
 Antidote: Flumazenil binds with high affinity to specific
sites on the GABAA receptor, where it competitively
antagonizes the binding and allosteric effects of
benzodiazepines and other ligands. It is given
intravenously.
 Use: anxiety, insomnia, epilepsy, anesthesia, spasticity

Barbiturates
 Phenobarbitone, pentobarbitone , thiopental.
 Were used extensively as sedative-hypnotic drugs; they
have been replaced largely by the much safer
benzodiazepines.
 Mechanism: increase the duration of the GABA-gated
chloride channel openings. At high concentrations, the
barbiturates may also be GABA-mimetic, directly
activating chloride channels.
 Can produce all degrees of depression of the CNS.
 Adverse effects: Oliguria or anuria, Strong physical
dependence and depression of the medullary centers.
 DDIs: Potent induction of liver enzymes.
 Use: Anxiety, Insomnia, Anesthesia, Epilepsy

GABA receptors
• GABA receptors are divided into two types:
I. GABA- A
II. GABA- B.
– GABA- A receptors open chloride channels and are antagonized by
picrotoxin and bicuculline, which both cause generalized
convulsions.
– GABA- B receptors, which can be selectively activated by the
antispastic drug baclofen,are coupled to G proteins that either
inhibit calcium channels or activate potassium channels.
• Inmost regions of the brain, IPSPs have a fast and slow component
mediated by GABA-A and GABA-B receptors, respectively.
• Immunohistochemical studies indicate that a large majority of the
localcircuit neurons synthesize GABA.
• A special class of local circuit neuron localized in the dorsal hornof
the spinal cord also synthesizes GABA.
• These neurons form axoaxonic synapses with primarysensory nerve
terminals and are responsible for presynaptic inhibition.

II. Antidepressants
 Depression is characterized by feelings of intense
sadness and despair, mental slowing and loss of
concentration, pessimistic worry, lack of pleasure, self-
deprecation, and variable agitation or hostility.
 Evidence implicates alterations in NE , Serotonin (5-HT)
and Dopamine ( DA).
 As many as 10% -15% of individuals with severe
depression, and up to 25% of those with bipolar disorder,
display suicidal behavior at some time.
 Lifetime risk for major depression is considerably higher,
at 5% to 10%, and approximately twice the risk in women
than in men.
 Drugs: TCA (amytriptiline, Imipramine),SSRIs (Fluoxetine,
Fluvoxamine), MOIs (Phenelzine, Selegiline) .

Tricyclic Antidepressants (TCAs)
• Characteristic three ring nucleus
• Mechanism: inhibit SERT and NET thus increasing the level of
5-HT and NE respectively.
• Most are incompletely absorbed
• High protein binding, high lipid solubility
• All are metabolized in liver, High first pass effect. Drugs that
inhibit CYP2D6, such as SSRIs, may increase plasma exposures
of TCAs
• “Therapeutic lag" lasting 3-4 weeks before a measurable
therapeutic response becomes evident. This challenge is
compounded by the early emergence of side effects.
• SEs:anticholinergic Ses (↓M), Orthostatic hypotension (↓α1),
Sedation(↓H1) and weight gain, Cardiac toxicity, Sexual
dysfunction.

Selective Serotonin Reuptake Inhibitors
 Mechanism:↓ reuptake of 5-HT.
 Better safety profile.
 Fluoxetine is the prototype drug in the family
 Fairly well absorbed and distributed
 t1/2 : 16-24 hrs ; norfluoxetine has t1/2:8 days
 Drug interaction: Serotonin Syndrome (hyperthermia,
muscle rigidity, rapid changes in mental status and vital
signs) if taken with MAO-Is.
 Inhibitors of CYP3A4 and CYP2D6
 Adverse effects: nausea, vomiting and delayed or
impaired orgasm, insomnia, agitation.
 Paroxetine is associated with an increased risk of
congenital cardiac malformations.

III. Mood stabilizers
 Used in bipolar disorder/manic-depressive disorder
 Characterized by substantial mood fluctuations, a cycling between very low and very high moods.
 Mania is characterized by excessive physical activity, rapidly changing ideas, and impulsive behavior.
 Can have additional disorders (psychosis, anxiety).
 A deficiency of monoaminergic
transmission in the CNS might
cause depression, whereas an
excess may result in mania.
 Drugs: Lithium, Valproate,
Carbamazepine, aripiprazole
 Combination therapy often
required

Lithium Carbonate
• Cornerstone for the treatment and prophylaxis of mania.
• Mechanism: develops a relatively small gradient across
biological membranes and therefore cannot maintain
membrane potentials (inhibit release of NE and DA).
• Complete absorption occurs in about 8 hours, with peak
plasma concentrations occurring 2 to 4 hours after an
oral dose. Distribute in total body water like Na. Excreted
through kidney. Optimal Serum levels:0.5 and 1.0 mEq/L.
• Li+
competes with Na+
for reabsorption, and Li+
retention
can be increased by Na+
loss related to diuretic use, or
febrile, diarrheal, or other GI illness.
• SEs: tremor, convulsions, nephrotoxicity,
hypothyroidism, arrhythmias, coma and death
• Pregnancy category D: tricuspid valve malformation.

Pharmacology of SchizophreniaPharmacology of Schizophrenia

Schizophrenia
 A symptom of mental illnesses characterized by a
distorted or non-existent sense of reality.
 Schizophrenia is a neurodevelopmental disorder with
complex genetics and incompletely understood
pathophysiology. Certain environmental exposures
confer an increased risk of developing schizophrenia,
including fetal second-trimester viral and nutritional
insults, birth complications, and substance abuse in the
late teen or early adult years.
 Positive symptoms : Hallucinations, delusions,
disorganized speech and agitated behavior.
 Negative symptoms :apathy, avolition, alogia,cognitive
deficits: deficits in working memory, processing speed,
social cognition, and problem solving

Neurotransmitter changes
 Dopamine theory : drugs that increase DA activity, such
as levodopa (a precursor), amphetamines (releasers of
DA), and apomorphine (a direct DA receptor agonist)
aggravate schizophrenia. DA receptor density has been
found postmortem to be increased in the brains of
schizophrenics who have not been treated with
antipsychotic drugs
 Serotonin theory : atypical antipsychotic drugs have
much less effect on D2 receptors and yet are effective in
schizophrenia.
 Glutamate theory: antagonists of the NMDA receptor
such as phencyclidine, when administered to
nonpsychotic subjects, produce much more
"schizophrenia-like" symptoms than do DA agonists.

Dopamine
tract
Innervation Function D-antagonist effects
Mesolimbic Limbic areas
Arousal, memory,
motivation
Psychosis relief
Mesocortical Cortex
Cognition,
communication, social
functions, stress
response
Psychosis relief
Nigro-striatal Striatum
Extrapyramidal system,
movement
coordination
Movement disorders
Tubero-
infundibular
Pituitary gland Prolactin regulation Hyperprolactinemia
Dopamine pathways

I. Typical Antipsychotics
 Mechanism: D2 receptors antagonism
 High potency (e.g. Haloperidol, Fluphenazine) and low potency(e.g.
Chlorpromazine, Thioridazine).
 The high potency antipsychotics have fewer autonomic effects but greater
extrapyramidal effects due to excessive D2 blockade.
 Low-potency have high affinities for H1(sedation), M (anticholinergiceffects), and α 1(hypotension) receptors.
 Generally more effective against positive than the
negative symptoms. Choice usually based on tolerability of side effects
 4-6wk until full response ;70-80% of patients respond.
 t1/2 of most antipsychotics is long (15-30 hours)
 Metabolized by liver and excreted in the urine.

Typical antipsychotics…
 Adverse effects
• Parkinson-like symptoms(catalepsy)
• Acute dystonia: sustained muscular contraction
• Akathisia : continuous motor restlessness
• Tardive dyskinesia: involuntary movements in
face/tongue and limbs months or years later.
• Neuroleptic malignant syndrome: characterized by
hyperthermia, severe muscular rigidity, autonomic
instability, changing levels of consciousness.
• Gynecomastia, galactorrhea
• Anticholinergic side-effects, orthostatic hypotension,
sedation, weight gain.
• QTc prolongation (e.g., thioridazine)

MANAGEMENT OF EPS
• Dystonia and parkinsonism: anticholinergic &
antiparkinsonian drugs
• Neuroleptic malignant syndrome: muscle relaxants,
DA agonists, supportive therapy
• Akathisia: benzodiazepines, β-blockers
• Tardive dyskinesia: increase neuroleptic dose; switch
to Clozapine

II. Atypical Antipsychotics
• Clozapine, Olanzapine, Risperidone, Aripiprazole
• Mechanism: D2 and 5-HT2 in cortical and limbic areas
• The newest, aripiprazole, appears to be a partial agonist
of D2 receptors.
• Effective against positive and negative symptoms.
• Clinically effective doses of atypical agents show
markedly reduced EPS risk (or nearly absent in the case
of quetiapine and clozapine) compared to typical
antipsychotic agents.
• There has been increased concern over metabolic
effects: weight gain, hypertriglyceridemia, and new-
onset type 2 DM, and diabetic ketoacidosis
• Risk of agranulocytosis with clozapine requires continual
monitoring. 134Tusday ,May12,2015 Designed by YAYA

Antiparkinson’s Drugs

Parkinson’s Disease
 First described by James Parkinson in 1817 as paralysis
agitans, or the "shaking palsy.
 Arvid Carlsson, Eric Kandel, and Paul Greengard won
the Nobel Prize in Physiology and Medicine in 2000 for
work with the neurotransmitter dopamine and its
effects in Parkinson's disease.
 Symptoms
– Bradykinesia
– Rigidity
– Tremor
– Postural instability
136
James Parkinson(1755-1824)
Tusday ,May12,2015 Designed by YAYA

Pathophysiology
• The pathological hallmark of PD is a loss of the
pigmented, dopaminergic neurons of the substantia
nigra pars compacta, with the appearance of
intracellular inclusions known as Lewy bodies.
• The D1 and D2 proteins are abundant in the striatum and
are the most important receptor sites with regard to the
causes and treatment of PD.
• Most symptoms do not appear until striatal DA levels
decline by at least 70-80%
• Without treatment, PD progresses over 5 to 10 years to
a rigid, akinetic state in which patients are incapable of
caring for themselves.

Pharmacologic Agents
 Dopaminergic agents
1. Dopamine precursor: L-DOPA
2. D2 agonists: bromocriptine ,pramipexole
3. MAOI: selegiline
4. COMTI: tolcapone, entacapone
 Glutamate antagonist: amantadine
 Antimuscarnics : Trihexyphenidyl, Benztropine

Levodopa Levodopa
Dopamine
Selegiline
Tolcapone Bromocriptine
Pramipexole
D2-receptors
(-)
(+)
Dopaminergic Drugs
MAO-B
COMT
(-)

1. Levodopa
• A prodrug that is converted to dopamine by DOPA
decarboxylase and can cross the blood-brain barrier.
• When administered orally, levodopa is absorbed rapidly
from the small intestine. Concentrations of the drug in
plasma usually peak between 0.5 and 2 hours after an
oral dose. The half-life in plasma is 1-3 hrs.
• To assure that adequate concentrations of levodopa
reach the CNS, and to reduce peripheral toxicity, L-dopa
is administered with Carbidopa, and Benserazide a
decarboxylase inhibitor that do not cross the BBB.
• Adverse effects:“On/off" effect, Motor
complications ,Nausea, Hallucinations and confusion.

2. Dopamine Agonists
 Durations of action (8-24 hrs) substantially longer than
that of levodopa and are useful in the management of
dose-related fluctuations in motor state.
 Two types: older ergot derivatives(Bromocriptine) and
newer non-ergot derivatives (Pramipexole).
 Bromocriptine is also used for treatment of
hyperprolactinemia. Initial treatment with
bromocriptine may cause profound hypotension, so they
should be initiated at low dosage.
 Pramipexole can be initiated more quickly, achieving
therapeutically useful doses in a week or less. Generally
cause less GIT disturbance than do the ergot derivatives.

• Benefit parkinsonism by blocking ACh receptors in the CNS, thereby partially redressing
the imbalance created by decreased dopaminergic activity.
• Also produce modest improvement in tremor, rigidity, hypersalivation, muscular stiffness
and leg cramp, but little in bradykinesia, which is the most disabling symptom of
Parkinson’s disease.
 Adverse effects: xerostomia, blurred vision, constipation,
urine retention, Tachycardia, confusion.
3. Antimuscarnics

Anti-seizure drugs

Epilepsy
• Electrophysiological analyses of individual neurons
during a seizure demonstrate that the neurons undergo
depolarization and fire action potentials at high
frequencies.
• Pharmacological studies disclosed that antagonists of
the GABA or agonists of glutamate trigger seizures.
• Drug mechanism: Na+
channels, GABA-mediated
inhibition, T current Ca2+
channel
• Classified into partial (simple/complex) seizures and
generalized (absence, myoclonic, and tonic-clonic)
seizures. A simple partial seizure is associated with
preservation of consciousness.
• Therapy is symptomatic. Available drugs inhibit seizures,
but neither effective prophylaxis nor cure is available.144Tusday ,May12,2015 Designed by YAYA

Classes of Anti-epileptic drugs
Older drugs
• Phenytoin
• Carbamazepine
• Ethosuximide
• Valproic Acid
• Phenobarbital
• Diazepam
Newer drugs
• Lamotrigine
• Topiramate
• Gabapentin
• Tiagabine
• Vigabatrin

Phenytoin
• Effective against all types of seizures, except absence.
• Mechanism: Na+
channels inactivation.
• Control of seizures generally is obtained with
concentrations above 10 µg/ml, while toxic effects
develop at concentrations around 20 µg/ml.
• The low aqueous solubility of phenytoin hindered its
intravenous use and led to production of
fosphenytoin, a water-soluble prodrug.
 Plasma half-life ranges 6-24 hrs at plasma
concentrations . Metabolized by CYPs.
 Adverse effects : Hypersensitivity, Cardiac
arrhythmias, gingival hyperplasia, osteomalacia, and
megaloblastic anemia,hirsutism
 Pregnancy category D 146Tusday ,May12,2015 Designed by YAYA

Carbamazepine
• Useful in all seizures except absence.
• Produce therapeutic responses in manic-depressive
patients. Further, it has antidiuretic effects.
• Mechanism: Na+
channels inactivation.
• Absorbed slowly and erratically. Peak concentrations
usually are observed 4-8 hours after PO; distributes
rapidly into all tissues
• Hepatic CYP3A4 is primarily responsible for
biotransformation of Carbamazepine.
• Acute intoxication with Carbamazepine can result in
stupor or coma, hyperirritability, convulsions, and
respiratory depression.
• A late complication is retention of water

Valproic acid
• Absence, myoclonic, partial, and tonic-clonic seizures.
• Mechanism: Na+
channels inactivation, T-current Ca2+
inactiation, GABA actiation.
• Absorbed rapidly and completely after oral
administration. Peak concentration in 1 to 4 hrs. The t1/2
is approximately 15 hrs; hepatic metabolism.
• The most common side effects are anorexia, nausea, and
vomiting in ~16% of patients. Effects on the CNS include
sedation, ataxia, and tremor.
• Rash, alopecia, and stimulation of appetite have been
observed occasionally and weight gain has been seen
with chronic valproic acid treatment in some patients.
• Elevation of hepatic transaminases in plasma is observed
in up to 40% of patients. 148Tusday ,May12,2015 Designed by YAYA

Ethosuximide
• Primary agent for the treatment of absence seizures.
• Inhibits Ca2+
currents (T currents) in thalamic neurons
• Absorption is complete, with peak conc in 3 hours. The
t1/2 averages 40- 50 hrs.
• Approximately 25% of the drug is excreted unchanged in
the urine.
• The most common dose-related side effects are
gastrointestinal complaints (nausea, vomiting, and
anorexia) and CNS effects (drowsiness, lethargy,
euphoria, dizziness, headache, and hiccough).

Benzodiazepines
• Clonazepam and clorazepate have been approved for
the long-term treatment of certain types of seizures.
• Diazepam and lorazepam have well-defined roles in the
management of status epilepticus.
• The antiseizure actions of the benzodiazepines, as well
as other effects that occur at non-sedating doses, result
in large part from their ability to enhance GABA-
mediated synaptic inhibition.
• Clonazepam is useful in the therapy of absence seizures
as well as myoclonic seizures in children.

Barbiturates
• Most barbiturates have antiseizure properties. However,
only some of these agents, such as Phenobarbital, exert
maximal antiseizure action at doses below those
required for hypnosis, which determines their clinical
utility as antiseizure agents.
• Phenobarbital is an effective agent for generalized tonic-
clonic and partial seizures. Its efficacy, low toxicity, and
low cost make it important for these types of epilepsy.
• Its sedative effects and its tendency to disturb behavior
in children have reduced its use as a primary agent

Newer anti-seizure drugs
• Gabapentin: GABA agonist.
• Tiagabine: inhibits the GABA transporter, GAT-1.
• Vigabatrin:irreversible inhibitor GABA-transaminase
• Lamotrigine: inactivation of Na+
channels; inhibition
glutamate relaese.
• Topiramate: inactivation of Na+
channel; activation
K+
current, enhancing GABA; inhibits glutamate
activity.

Status epilepticus …
• Status epilepticus is a neurological emergency. Mortality
for adults approximates 20%.
• Critical to the management is a clear plan, prompt
treatment with effective drugs in adequate doses, and
attention to hypoventilation and hypotension.
• Four IV treatments: diazepam followed by phenytoin;
lorazepam; Phenobarbital; and phenytoin alone .
• Success rates ranged from 44% to 65%, but lorazepam
alone was significantly better than phenytoin alone.
• No significant differences with respect to recurrences or
adverse reactions.
•

Anti-Seizure Therapy and Pregnancy
• Infants of epileptic mothers are at 2x risk of major congenital
malformations (heart defects, neural tube defects) than
offspring of non-epileptic mothers (4-8% vs. 2- 4%).
• The failure rate of oral contraceptives is in women receiving
antiseizure drugs is high compared to non-epileptic women
(3.1/100 years vs. 0.7/100 years).
• Phenytoin, carbamazepine, valproate, and phenobarbital all
have been associated with teratogenic effects.
• Newer antiseizure drugs have teratogenic effects in animals
but whether such effects occur in humans is yet uncertain.

Anesthetics & Central Muscle
Relaxants

Anesthetics
• Surgery is generally painful, it must thus be preceded by
the administration of anesthetics. Anesthetics block the
perception of pain.
• Anesthetic agents are categorized in to general and
local.
• Given and monitored by doctors (anesthesiologists),
nurse and anesthesia practitioners (anesthetists).
• The practice of anesthesia also includes controlling
breathing and monitoring body's vital functions.
• In modern practice, different drugs (anesthetics,
analgesics, muscle relaxants, amnesiatic, anxiolytics,
etc.) are used to achieve balanced anesthesia.
• Stages of anesthesia: analgesia, excitement, surgical
anesthesia and medullary depression. 156Tusday ,May12,2015 Designed by YAYA

General anesthetics
• Drugs that induce general anesthesia, a global but
reversible depression of CNS function resulting in the
loss of response to and perception of all external stimuli.
• They also suppress normal homeostatic reflexes.
Besides, they have low therapeutic indices.
• Classified as inhaled and injectable.
 Inhaled: Nitrous oxide, halothane, enflurane
 Injectable: ketamine ,propofol ,thiopental
• Generally act by enhancing GABA activity.
• Adverse effects: Myocardial depression, Malignant
hyperthermia(MH)
• MH: uncontrolled increase in skeletal muscle oxidative
metabolism, overwhelms capacity to supply oxygen,
eventually leading to circulatory collapse.

Adjunctive agents
 It is mandatory to use combinations of anesthetics,
analgesics, muscle relaxants, and other drugs to come
up with balanced anesthesia.
 Balanced anesthesia allows us to minimize patient risk
and maximize patient comfort and safety.
 Adjunctive agents include:
• Sedative-hypnotics ( calming and amnesiatic )
• Opioids (analgesics)
• Neuromuscular blocking agents (muscle relaxants)
• Anticholinergic (antispasmodic & antisecretory)

Local Anesthetics
• Bind reversibly to a specific receptor site within the pore
of the Na+
channels in nerves and block ion movement
through this pore.
• In clinical practice, a vasoconstrictor, usually
epinephrine, is often added to local anesthetics.
• Classified in to two as ester type (procine, tetracaine)
and amide type ( lidocaine, bupivacaine).
• Hypersensitivity occurs more frequently with ester type.
Amides produces faster, more intense, longer lasting,
and more extensive anesthesia than does an equal
concentration of esters.
• The side effects of amides include drowsiness, tinnitus,
dizziness, and twitching.

Centrally acting muscle relaxants
 Include Diazepam, Baclofen and Dantrolene
 Used to treat spasm and spasticity. Common causes are
epilepsy, trauma, stroke etc.
 Baclofen is a GABAB agonist that suppresses
hyperactive reflexes
 Dantrolene depresses excitation-contraction
coupling in skeletal muscle by binding to the ryanodine
receptor, and thus decreasing intracellular calcium
concentration. It is the only specific and effective
treatment for malignant hyperthermia, a rare, life-
threatening disorder triggered by general anesthesia.

Analgesics
1.Opioid analgesics
2.NSAIDS
3. Others

Pain
 Unpleasant physical or emotional experience, associated
with actual or potential tissue damage.
 Intact neural pathways (nociceptive pain) or damage to
neural structures(neuropathic pain).
 Endogenous Opioids:enkephalin, dynorphins, endorphins
 Exogenous Opioids: obtained from the juice of the opium
poppy, Papaver somniferum.
 Opioid receptors: µ, δ and k.
 Analgesics: Opioid analgesics ,NSAIDs
 Opioids are classified as:
Agonist: Morphine, Codeine, Methadone, Fentanyl,
Meperidine
 Antagonist: Naloxone, Naltrexone

Opium Poppy-Papaver somniferum

1. Morphine
• Continuous dull pain is relieved more effectively than
sharp intermittent pain.
• Depress the cough reflex at least in part by a direct effect
on a cough center in the medulla.
• Provoke histamine release which causes hypotension.
• Erratic oral availability; thus given parentrally.
• The half-life is about 2 hours; eliminated by GF, primarily
as morphine-3-glucuronide.
• Adverse effects: Nausea, Vomiting, constipation,
hypotension, sedation, respiratory depression, miosis,
tolerance, dependence.
• Therapeutic use: Relief of pain ,Diarrhea, Cough
•

Others
2. Tramadol: A synthetic codeine analog that is a
weak( 1/6000 that of morphine) µ-opioid
receptor agonist.
• Part of its analgesic effect is produced by
inhibition of uptake of norepinephrine and
serotonin.
• Used in the treatment of mild-to-moderate pain.
• Can cause seizures.
3. Naloxone: Reverses all of the effects of morphine.
Onset 3-5 min; duration is 30-45 minutes.
Naltrexone is used orally and has long duration
of activity (24hrs)
4. Dextromorphan: relatively devoid of analgesic action. It
is effective antitussive drug.
5. Loperamide, Diphenoxylate: Peripheral opioid

Non-Steroidal Anti-inflammatory Drugs(NSAIDS)
• Inflammatory mediators (e.g. prostaglandins, serotonin,
Leukotriens etc.) released from non-neuronal cells
during tissue injury increase the sensitivity of nociceptors
and potentiate pain perception.
• The principal therapeutic effects of NSAIDs derive from
their ability to inhibit prostaglandin production through
inhibition of cyclo-oxygenases ( COX-1 and COX-2).
• Classified into TWO categories:
1.Non-selective COX inhibitors: Aspirin, Paracetamol
Ibuprofen, indomethacin, Diclofenac, Dipyrone
2.Selective COX-2 inhibitors: celecoxib, rofecoxib.

NSAIDs…
• Effective only against low to moderate pain
• Generally are well absorbed orally.
• Distributed widely throughout the body and readily
penetrate arthritic joints, yielding adequate synovial fluid
concentrations (i.e., ibuprofen, indomethacin).
• Most NSAIDs achieve sufficient concentrations in the CNS
to have a central analgesic effect.
• Hepatic biotransformation and renal excretion are the
principal route of elimination.

Aspirin(Acetylsalicylic Acid)
• Mechanism: Irreversibly inhibits both COX-1 and COX-2
• Reduces the risk of serious vascular events in high-risk
patients (e.g. Myocardial infarction) by 20-25%.
• Rapidly and completely absorbed from the GIT, with peak
concentrations occurring within 1-4 hrs.
• Extensively protein-bound (95% to 99%).
• Anti-inflammatory, analgesic, antipyretic and anti-platelet
• Adverse effects: Hypersensitivity ,CV risks, GIT, Salicylism
(ringing in the ears, nausea, and vomiting), Respiratory
failure, Reye’s syndrome (when used in viral illnesses).
• Reye's syndrome: Potentially fatal disease that has
numerous detrimental effects to brain and liver, as well
as causing hypoglycemia. The classic features are a rash,
vomiting, and liver damage.

Paracetamol(Acetaminophen)
• Chronic use of >2 g/day is associated with
hepatotoxicity. Kidney damage has been reported.
• Rash and other allergic reactions occur occasionally.
• Acetaminophen, at therapeutic doses, is oxidized only to
a small fraction to form traces of the highly reactive
metabolite, N-acetyl-p-benzoquinone imine (NAPQI).
• Glucuronic acid (60%), sulfuric acid ( 35%), cysteine
( 3%). CYP induction (heavy alcohol consumption) or GSH
depletion(fasting or malnutrition) increase the
susceptibility to hepatic injury.
• Antidote: N- acetylcysteine-both repletes GSH stores
and may conjugate directly with NAPQI by serving as a
GSH substitute.

Acetaminophen metabolism

Pharmacology of GIT

Peptic Ulcer Disease
• Erosion of the mucous membrane that lines the upper
digestive tract (gastric ulcer, duodenal ulcer).
• Imbalance between mucosal defense factors
(somatostatin, bicarbonate, mucus, prostaglandin) and
injurious factors (gastrin, HCl and pepsin) due to mainly
of Helicobacter pylori (≈80%),non-steroidal anti-
inflammatory drugs (NSAIDs), ethanol, cigarette & stress.
• H. pylori is a spiral-shaped, pH-sensitive, gram-negative,
microaerophilic bacterium that resides between the
mucus layer and surface epithelial cells in the stomach,
or any location where gastric-type epithelium is found.
• H. pylori produces large amounts of urease, which
hydrolyzes urea in the gastric juice and converts it to
ammonia and carbon dioxide.

Physiology of acid secretion
• ACh, histamine, and gastrin all increase acid secretion
through their specific receptors (M3, H2, and CCK2
receptors, respectively) on parietal cells.
• In parietal cells, the cAMP and the Ca2+
-dependent
pathways activate H+
,K+
-ATPase, which exchanges H+
and
K+
ions across the parietal cell membrane.
• Drugs:
1. Antisecretory: proton-pump inhibitors(PPIs), histamine
receptor blockers(H2-blockers)
2. Mucosal protective: Misoprostol, Sucralfate, Bismuth
3. Antacids
4. Antibacterials

PPIs
• Includes omeprazole, esomeprazole, lansoprazole
• Mechanism: irreversibly inactivate H+
/K+
ATPase. Acid
secretion resumes only after new pump molecules are
synthesized(24-48hrs).
• Diminish the daily production of acid by 80% to 95%.
• All PPIs have equivalent efficacy at comparable doses.
• Plasma half-life -0.5-2 hrs.
• Adverse effects : Nausea, Diarrhea, abdominal pain,
constipation, flatulence. Subacute myopathy, arthralgias,
headaches, and skin rashes also have been reported.
• Use: PUD, Gastro-esophageal reflux disease(GERD),
Zollinger-Ellison syndrome (ZES)

H2 Receptor Antagonist
• Includes cimetidine, ranitidine, famotidine
• Mechanism: Inhibit acid production by reversibly
competing with H2 receptors on the parietal cells.
• Suppress 24-hr gastric acid secretion by about 70%,
predominantly inhibit basal acid secretion.
• Long-term use of cimetidine at high doses can cause
galactorrhea in women and gynecomastia, reduced
sperm count, and impotence in men.
• Adverse effects: Diarrhea, headache, drowsiness,
fatigue, muscular pain, and constipation.
• Cimetidine inhibits cytochrome enzymes .
• Use: PUD, GERD.

Mucosal Protectives
• Misoprostol: analog of prostaglandin E1
• The usual recommended dose is 200 µg four times a day.
A single dose inhibits acid production within 30 minutes.
• Can cause diarrhea and abdominal pain. It is
contraindicated during pregnancy.
• FDA approved to prevent NSAID-induced mucosal injury.
• Sucralfate: at pH <4, it undergoes extensive cross-linking
to produce a viscous, sticky polymer that adheres to
epithelial cells and ulcer craters for up to 6 hours.
• Should be taken on empty stomach 1 hour before meals.
• The most common side effect is constipation.
• Bismuth subsalicylate: bind to the base of the ulcer,
promote mucin and bicarbonate production, and have
significant antibacterial effects. 176Tusday ,May12,2015 Designed by YAYA

Antacids
• Magnesium and Aluminum salts e.g. Mg(OH)2, Al(OH)3
• Combinations of Mg2+
(rapidly acting, diarrhea) and Al3+
(slowly acting, constipation) hydroxides provide a
relatively balanced and sustained neutralizing capacity.
• Antacids are given orally 1-3 hrs after meals and at
bedtime. Cleared from the empty stomach in ≈ 30 min.
• With renal insufficiency, Al3+
can contribute to
osteoporosis, encephalopathy, and proximal myopathy.
• By altering pH and through chelation, antacids may
affect the absorption of a number of drugs (e.g.
ketoconazole, allopurinol). Such problems can be
avoided by taking antacids 2 hrs before or after
ingestion of other drugs.

Antibacterials
• Includes amoxicillin, tetracycline, clarithromycin, and
metronidazole. Single-antibiotic regimens are ineffective.
• Eradicating H.pylori infection is a current standard care.
• Triple therapy : Omeprazole 2X/d + Clarithromycin 500
mg plus metronidazole 500 mg/Amoxicillin 1g 2X/d
(tetracycline 500 mg can be substituted for amoxicillin or
metronidazole)
• Quadruple therapy: Omeprazole 2X/d + Metronidazole
500 mg 3X/d plus Bismuth Subsalicylate 525 mg +
Tetracycline 500 mg 4X/d OR Famotidine 2X/d plus
Bismuth subsalicylate 525 mg + Metronidazole 250 mg +
Tetracycline 500 mg 4X/d.
• 10-14 days regimen is better.

Antiflatulent
• "Gas" is a common but relatively vague GI complaint,
used in reference not only to flatulence and eructation,
but also bloating or fullness.
• Simethicone: a mixture of siloxane polymers stabilized
with silicon dioxide.
• It is an inert, nontoxic insoluble liquid. Because of its
ability to collapse bubbles by forming a thin layer on their
surface, it is an effective antifoaming agent.
• Available either by itself or in combination with other OTC
medications including antacids and digestants.

Laxatives
• water accounts for 70-85% of total stool weight.
• Net stool fluid content reflects a balance between
luminal ingestion and secretion of water and electrolytes
and absorption along the length of the GIT.
• About 8-9L of fluid enter the Small intestine daily. The
colon extracts most of the remaining fluid, leaving about
100 ml of fecal water daily.
• With decreased motility and excess fluid removal, feces
can become inspissated and impacted, leading to
constipation. On the other hand, when the capacity of
the colon to absorb fluid is exceeded, diarrhea will occur.
• Constipation is treated by laxatives/purgatives, whereas
diarrhea is treated with antidiarrheal agents.

Laxatives
• Classified in as bulk-forming, stimulant, osmotic, and
surfactant based on their actions.
• Bulk-forming: Bran, methylcellulose
• Stimulant: Bisacodyl, cascara, Castor Oil
• Osmotic: MgSO4, Lactulose, Polyethylene Glycol
• Surfactant: Docusate sodium,Mineral oil.

Diarrhea
• Diarrhea (Greek and Latin: dia, through, and rheein, to
flow or run); “Too rapid evacuation of too fluid stools.“
• Diarrhea can be caused by increased osmotic load within
the intestine; excessive secretion of electrolytes and
water into the intestinal lumen; exudation of protein and
fluid from the mucosa; and altered intestinal motility
resulting in rapid transit.
• In severe cases, dehydration and electrolyte imbalances
are the principal risk, particularly in infants, children, and
frail elderly patients.
• Oral rehydration therapy is a cornerstone for patients
with acute illnesses resulting in significant diarrhea.

Antidiarrheal agents
 Nonspecific antidiarrheal agents: provide symptomatic
relief in mild cases of acute diarrhea.
• Opioids: diphenoxylate and loperamide.
• Clays such as kaolin and attapulgite bind water avidly
and also may bind enterotoxins.
• Bile Acid Sequestrants: Cholestyramine, colestipol;
effectively bind bile acids and some bacterial toxins.
 Specific Antidiarrheal agents: infectious diarrhea
• Antimicrobials

Ethiopan Pharmacology 2015

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