PHARMACOLOGY
Lyceum Northwestern University
COLLEGE OF MEDICINE
INTRODUCTION TO PHARMACOLOGY:
The Nature of Drugs
Dr. Perfecto Soriano
Pharmacology can be defined as the study of
substances that interact with living systems through
chemical processes, especially by binding to regulatory
molecules and activating or inhibiting normal body
processes.
Medical Pharmacology is often defined as the science
of substances used to prevent, diagnose, and treat
disease.
Toxicology is the branch of pharmacology that deals
with the undesirable effects of chemicals on living
systems, from individual cells to humans to complex
ecosystems.
FIGURE 1–1 Major areas of study in pharmacology. The
actions of chemicals can be divided into two large
domains. The first (left side) is that of medical
pharmacology and toxicology, which is aimed at
understanding the actions of drugs as chemicals on
individual organisms, especially humans and domestic
animals. Both beneficial and toxic effects are included.
Pharmacokinetics deals with the absorption,
distribution, and elimination of drugs.
Pharmacodynamics concerns the actions of the
chemical on the organism. The second domain (right
side) is that of environmental toxicology, which is
concerned with the effects of chemicals on all
organisms and their survival in groups and as species.
➢ THE HISTORY OF PHARMACOLOGY
Materia Medica—the science of drug preparation and
the medical uses of drugs—began to develop as the
precursor to pharmacology.
François Magendie and his student Claude Bernard
- began to develop the methods of experimental
physiology and pharmacology in the late 18th and early
19th centuries.
Advances in chemistry and the further development of
physiology in the 18th, 19th, and early 20th centuries
laid the foundation needed for understanding how
drugs work at the organ and tissue levels.
Controlled clinical trial, were reintroduced into
medicine—only about 60 years ago—did it become
possible to accurately evaluate therapeutic claims.
Around the same time information accumulated about
drug action and the biologic substrate of that action,
the drug receptor. Studies of the local molecular
environment of receptors have shown that receptors
and effectors do not function in isolation; they are
strongly influenced by other receptors and by
companion regulatory proteins.
Pharmacogenomics—the relation of the individual’s
genetic makeup to his or her response to specific
drugs—is close to becoming an important part of
therapeutics.
Discovery that small segments of RNA can interfere with
protein synthesis with extreme selectivity has led to
investigation of small interfering RNAs (siRNAs) and
micro-RNAs (miRNAs) as therapeutic agents.
Similarly, short nucleotide chains called antisense
oligonucleotides (ANOs), synthesized to be
complementary to natural RNA or DNA, can interfere
with the readout of genes and the transcription of RNA.
These intracellular targets may provide the next major
wave of advances in therapeutics.
Two general principles that the student should
remember:
(1) That all substances can under certain circumstances
be toxic, and the chemicals in botanicals (herbs and
plant extracts, “nutraceuticals”) are no different from
chemicals in manufactured
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drugs except for the much greater proportion of
impurities in botanicals;
(2) That all dietary supplements and all therapies
promoted as health enhancing should meet the same
standards of efficacy and safety as conventional drugs
and medical therapies.
*There should be no artificial separation between
scientific medicine and “alternative” or
“complementary” medicine. Ideally, all nutritional and
botanical substances should be tested by the same
randomized controlled trials (RCTs) as synthetic
compounds.
➢ GENERAL PRINCIPLES OF PHARMACOLOGY
THE NATURE OF DRUGS
Drug may be defined as any substance that brings about
a change in biologic function through its chemical
actions.
In most cases, the drug molecule interacts as an agonist
(activator) or antagonist (inhibitor) with a specific
molecule in the biologic system that plays a regulatory
role. This target molecule is called a receptor.
In a very small number of cases, drugs known as
chemical antagonists may interact directly with other
drugs, whereas a few drugs (osmotic agents) interact
almost exclusively with water molecules.
Drugs may be synthesized within the body (eg,
hormones) or may be chemicals not synthesized in the
body (ie, xenobiotics, from the Greek xenos, meaning
“stranger”).
Poisons are drugs that have almost exclusively harmful
effects.
Paracelsus (1493–1541) famously stated that “the dose
makes the poison,” meaning that any substance can be
harmful if taken in the wrong dosage.
Toxins are usually defined as poisons of biologic origin,
ie, synthesized by plants or animals, in contrast to
inorganic poisons such as lead and arsenic.
PHARMACOLOGY
✓ The Physical Nature of Drugs
Drugs may be solid at room temperature (eg, aspirin,
atropine), liquid (eg, nicotine, ethanol), or gaseous (eg,
nitrous oxide). These factors often determine the best
route of administration.
✓ Drug Size
The molecular size of drugs varies from very small
(lithium ion, MW 7) to very large (eg, alteplase [t-PA],
a protein of MW 59,050). However, most drugs have
molecular weights between 100 and 1000.
To have a good “fit” to only one type of receptor, a drug
molecule must be sufficiently unique in shape, charge,
and other properties, to prevent its binding to other
receptors.
To achieve such selective binding, it appears that a
molecule should in most cases be at least 100 MW
units in size.
Drugs much larger than MW 1000 do not diffuse
readily between compartments of the body.
✓ Drug Reactivity & Drug-Receptor Bonds
Drugs interact with receptors by means of chemical
forces or bonds. These are of three major types:
covalent, electrostatic, and hydrophobic.
Covalent bonds are very strong and in many cases
not reversible under biologic conditions.
Ex: covalent bond formed between the acetyl
group of acetylsalicylic acid (aspirin) and
cyclooxygenase, its enzyme target in platelets, is not
readily broken
Electrostatic bonding is much more common than
covalent bonding in drug-receptor interactions but are
much weaker than covalent bonds. They vary from
relatively strong linkages between permanently charged
ionic molecules to weaker hydrogen bonds and very
weak induced dipole interactions such as van der Waals
forces.
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Hydrophobic bonds are usually quite weak and are
probably important in the interactions of highly lipid-
soluble drugs with the lipids of cell membranes and
perhaps in the interaction of drugs with the internal
walls of receptor “pockets.”

Note: Drugs that bind through weak bonds to their

receptors are generally more selective than drugs that
bind by means of very strong bonds. This is because
weak bonds require a very precise fit of the drug to its
receptor if an interaction is to occur.

✓ Drug Shape
The shape of a drug molecule must be such as to permit
binding to its receptor site via the bonds. Optimally, the
drug’s shape is complementary to that of the receptor
site in the same way that a key is complementary to a
lock.

The phenomenon of chirality (stereoisomerism) is so

common in biology that more than half of all useful
drugs are chiral molecules; that is, they can exist as
enantiomeric pairs.

Note: Enzymes are usually stereoselective, one drug

enantiomer is often more susceptible than the other to
drug metabolizing enzymes. As a result, the duration of
action of one enantiomer may be quite different from
that of the other. Similarly, drug transporters may be
stereoselective.

✓ Rational Drug Design

Rational design of drugs implies the ability to

predict the appropriate molecular structure of a
drug on the basis of information about its biologic
receptor.
A few drugs now in use were developed through
molecular design based on knowledge of the three
dimensional structure of the receptor site.

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Lyceum Northwestern University
COLLEGE OF MEDICINE

PRINCIPLES OF PHARMACOKINETICS
AND DRUG METABOLISM
Dr. Perfecto Soriano

➢ PHARMACOKINETICS
– refers on how the BODY acts on the DRUGS.
- The qualitative study of drug movement in,
through and out of the body.
Explanation:
- Intensity of effect is related to concentration of
- PK involves Absorption, Distribution,
the drug at the site of action. (Depend on its
Metabolism and Elimination (ADME), while PD
pharmacokinetic properties).
involves Efficacy and Toxicity.
• Pharmacokinetic properties of particular
- Process starts with PK which includes: Drug
drug is important to determine: dose, Drug concentration in blood and Drug
1. Route of administration concentration at target site but half way
2. Dose through the 3rd process PD also starts and
3. Onset of action continues with the Effect and Body’s Clinical
4. Peak Response
5. Action time
6. Frequency of dosing ➢ PHARMACOKINETIC PROCESS

➢ CLINICAL PHARMACOKINETICS
- Study of time course of a drugs movement
through the body
- Understanding of what the body does to or
with the drug.
-Application of Therapeutic Drug Monitoring
(TDM) and individualization of drug therapy
• TDM – branch of clinical pharmacology
that specializes in the measurement of
medication concentrations in the blood. ➢ DRUG TRANSPORTATION: Biological Membrane

➢ PHARMACODYNAMICS
- What the DRUGS do to the body.
- Drug concentration at the site of action or in
plasma is related to the magnitude of effect.

➢ PHARMACOKINETICS (PK) AND

PHARMACODYNAMICS (PD) RELATIONSHIP

- Bilayer of phospholipid and cholesterol

molecule = 100 Armstrong thickness
- EXTRINSIC AND INTRINSIC PROTEINS are
embedded in the membrane.

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Lyceum Northwestern University
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- GLYCOPROTEIN – on the surface. The drug which are UNIONIZED, LOW
- This proteins varies from cell to cell POLARITY AND HIGHER SOLUBILITY are
- Paracellular spaces and channels are also EASY to permeate membrane
present The drug which are IONIZED, HIGH
- Drug molecules can cross cell membrane by: POLARITY AND LOWER SOLUBILITY are
• Passive Transport DIFFICULT to permeate membrane
• Carrier – mediated (protein-mediated)
o Facilitated transport ➢ pH EFFECT
o Active transport - Most drugs are weak acids or weak bases
-Primary -The ionization of drugs may markedly reduce
-Secondary their ability to permeate membrane
- The degree of ionization of drugs is
determined by surrounding pH and their pKa
* pKa- index to express acidity of weak acids;
the smaller pKa value the stronger the acid is.

➢ HENDERSON-HASSELBALCH EQUATION
[𝑨 −]
𝒑𝑯 = 𝒑𝑲𝒂 + 𝒍𝒐𝒈
[𝑯𝑨]

pKa = negative logarithm of acid dissociation

constant
➢ PASSIVE TRANSPORT (Downhill movement) [A-] = ionized drug
- Most important transport mechanism for [HA] = unionized drug
most drugs.
-Majority of drugs diffuses across the ➢ IMPLICATION (Important)
membrane in the direction of concentration • Acidic drugs reabsorbed are largerly
gradient unionized in the stomach and absorbed
- No Active role of the membrane faster; while basic drugs are absorbed
-Proportional to lipid: water partition coefficient faster in the small intestines
-Lipid soluble drugs diffuse by dissolving in the • Ion trappinig
lipoidal matrix of the membrane • ACIDIC DRUGS are excreted faster in
- Characteristic: ALKALINE URINE.
• Not requiring energy
• BASIC DRUGS are excreted faster in
• Having no saturation ACIDIC URINE.
• Having no carriers
• Not resting competitive inhibition
- Affecting factors: ➢ FILTRATION
• Size of the molecules
• Lipid solubility
• Polarity
• Degree of ionization
• pH of the environment (fluid of body,
cell, blood, urine)
-REMEMBER:

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- Passage of drugs through aqueous pores in
membrane or through paracellular spaces
- Lipid insoluble drugs can cross if the molecular
size is small
-Majority of intestinal mucosa and RBC have
small pores and drugs cannot cross
-CAPILLARIES have large paracellular spaces and
most drugs can be filter through this
PHARMACOLOGY
• Carrying the substrate to the other side
of the membrane
• Dissociates
• Return back to its original position
-Move substrate of SINGLE CLASS (unipoters)
down a concentration gradient
- No energy dependent transport in the
direction of electrochemical gradient
-Similar to entry of glucose into the muscle
(GLUT 4)

➢ CARRIER-MEDIATED TRANSPORT
- Involves specific membrane transport ➢ ACTIVE TRANSPORT
proteins (transmembrane protein) known as - Energy dependent
drug transporter or carriers which is specific for - Can move solutes against concentration
the substrate: Physiological important ions, gradient
nutrients, metabolites, transmitters • Primary active transporter – generate
- They also translocate xenobiotics including energy THEMSELVEs (ex: ATP
drug metabolites
hydrolysis)
-Drug molecules:
• Secondary active transporter – utilize
1. Bind to the transporter
energy stored in voltage and ion
2. Translocated across membrane
gradients generated by primary active
3. Released on the other side of the
transporter (ex: NA/K ATPase)
membrane
- Symporters (co-transporter)
-Specific, saturable and inhibitable
- Antiporters (exchangers)
- Depending on energy requirement can be
either facilitative (passive) or active transport

➢ FACILITATIVE TRANSPORTER
-Higher to Lower concentration
- Transmembrane protein bind with their
substrate transiently (temporary)
- Conformational changes:

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➢ MAJOR DRUG TRANSPORTERS
1. ATP- BINDING CASSETTE (ABC)
TRANSPORTER SUPER FAMILY
- Primary active transport
• P- glycoprotein
- Intestinal mucosa, renal
tubules and blood brain barrier
-Mediated only EFFLUX OF
SOLUTE from cytoplasm
detoxification
PHARMACOLOGY
4. ANTIPORT/EXCHANGE TRANSPORT
- moving in opposite direction
-mediates efflux of drug and metabolite
-ex: Na+Cl dependent neurotransmitter
➢ ENDOCYTOSIS
- Very little importance to drug translocation
- Large protein molecules and metabolic waste
-Either phagocytosis, pinocytosis or receptor-
mediated endocytosis.
➢ PINOCYTOSIS
- It involves the invagination of a part of the cell
membrane and trapping within the cell of a
small vesicle containing extracellular
constituents.
- The vesicle contents can be released within
the cell or extruded from the other side of the
cell.

2. SOLUTE-CARRIER (SLC) TRANSPORTER

- Secondary active transport
- Energy to pump one solute derived from
downhill movement of another solute
(mostly Na)
• Organic Anion Transporting - It is important for the transport of some
Polypeptides (OATPs) MACROMOLECULES (ex: INSULIN through BBB)
- Central transporters in
disposition of drugs and other THE PROCESS OF PHARMACOKENETICS
xenibiotics (ADME)
- mediate wide variety of
endogenous substrate
• Organic Cation Transporters (OCTs)
- have specificity for a large
number of cationic substrate
that are both endogenous and
exogenous
- Both transporters are expressed in
LIVER and RENAL TUBULES, for
metabolism and excretion of drugs
3. SYMPORT/CO-TRANSPORT
- Concentration gradient is such that
both solute move in the same direction

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Lyceum Northwestern University
COLLEGE OF MEDICINE
I. ABSORPTION OF DRUGS • For Abraded Skin- Tannic acid
(can cause: Hepatic necrosis)
➢ Absorption – is the transfer of a drug from its - Cornea is permeable to lipid soluble
site of administration to the blood stream drug
- Most of the drugs are absorbed by the way of - Mucus membranes of mouth, rectum,
passive transport and vagina are permeable to lipophilic
-Intravenous (IV) administration has NO drugs
ABSORPTION
- Fraction of administered dose and rate of b. SUBCUTANEOUS AND
absorption are important INTRAMUSCULAR ROUTE
- Drugs directly reach vicinity of
➢ Factors affecting absorption: capillaries (passes capillary endothelium
• Drug properties – aqueous solubility, and reach circulation)
concentration, lipid solubility, molecular -Passes through the large paracellular
weight amd polarity pores
• Blood flow (vascularity) to the - Faster and more predictable than oral
absorption site administration
- Exercise and heat – increase
• Total surface area available for
absorption
absorption surface
-Adrenaline – decrease absorption
• Affinity with special tissue
• ROUTE OF ADMINSTRATION IS c. ORAL ROUTE
IMPORTANT! - Physical properties: physical state
(solid or liquid), lipid or water solubility
- Dosage Forms:
• Particle size
• Disintegration time and
dissolution rate
• Formulation
-Physiological factors:
• Ionization, pH effect
• Presence of food
• Presence of other agents
➢ ROUTE OF ADMINISTRATION:
➢ ORAL ADMINISTRATION: 1ST PASS
a. TOPICAL ROUTE METABOLISM
- Depends on lipid solubility – only lipid • Before the drugs reaches systemic
soluble drugs will penetrate intact skin (only circulation, the drug can be
few drugs are used therapeutically) metabolized in the liver. As a result, the
-Examples: concentration of drug in the systemic
• GTN, Hyosine,Nicotine, circulation will be REDUCED.
Testosterone and Estradiol
• Organophosphorous d. BUCCAL AND RECTAL
compounds – can cause - bypasses the liver
systemic toxicity if ingested

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e. INTRAVENOUS ROUTE
- has no absorption phase
➢ ACCORDING TO THE RATE OF ABSORPTION:
(Fastest to slowest)
1. Inhalation
2. Sublingual
3. Rectal
4. Intramuscular
5. Subcutaneous
6. Oral
7. Topical or Transdermal
- Example: Nitroglycerine
• IV – immediate
• Sublingual – 1-3 minutes
• Per rectal – 40-60 minutes
➢ BIOAVAILABLITY
- refers to the RATE AND EXTENT OF
ABSORPTION of a drug from dosage form as
determined by its concentration-time curve in
blood or by its excretion in urine
- It is the measure (fraction) of a drug that
reaches the systemic circulation in
unchanged form
- Useful to compare two different drugs or
different dosage forms of same drugs
- It is a concept for ORAL ADMISTRATION
-BIOAVALABILITY of drug administration
IV is 100% but unpredictable after oral
ingestion because:
• The drug may be incompletely
absorbed
• The absorbed drug may undergo
first pass metabolism in the
PHARMACOLOGY
intestinal wall and/or liver or
excreted in bile
➢ BIOAVAILABILTY AREA UNDER CURVE (AUC)
- is used to calculate the bioavailability of
a drug
- The area under the plasma drug
concentration-time curve (AUC) reflects
the actual body exposure to drug after
administration of a dose of the drug and
is expressed in mg*h/L
- This area under the curve is
dependent on the rate of elimination of
the drug from the body and the dose
administered.
➢ ROUTE OF ADMISNISTRATION DETERMINES
BIOAVAILABILITY
- For drugs taken by routes other than
the IV route, the extent of absorption
and the bioavailability must be
understood in order to determine what
dose will induce the desired therapeutic
effect.
- Its will also explain why the same dose
may cause a therapeutic effect by one
route but toxic or no effect by another.
➢ BIOEQUIVALENCE
- Therapeutic agent that has the same
pharmacologic potency and
bioavailability as another drug at the
same dose
- containing the same active ingredient
are bioequivalent if their rates and
extents of absorption (bioavailability) is
the same.
- Drugs may
have the same
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bioavailability but they may not be
bioequivalent = have the same
pharmacologic effect
II. DISTRIBUTION OF DRUGS
➢ Distribution – it is the passage of drug
from the circulation to the tissue and its
site of action
-The extent of distribution of drug depends
on its: solubility, ionization at physiological
pH (dependent on pKa), extent of binding
to plasma and tissue proteins and
differences in regional blood flow, disease
like CHF, uremia, and cirrhosis.
-Movement of Drug – until equilibrium
between unbound drug in plasma and
tissue fluids.
➢ VOLUME OF DISTRIBUTION (Vd)
• Apparent Volume of Distribution
- The volume that would accommodate
all the drugs in the body, if the
concentration was the same as in plasma
-Expressed as in Liters
• Drug may distribute into any of all the
following compartments:
-Plasma
-Interstitial fluid
-Intracellular fluid
• Total Body Fluid = approximately 42 liters
PHARMACOLOGY
➢ FACTORS INFLUENCING Vd
• Lipid solubility (Lipid: water partition
coefficient)
• pKa of the drug
• Affinity for different tissues
• Blood flow-brain vs fat
• Disease states
• Plasma protein binding
➢ REDISTRIBUTION
- Highly lipid soluble drugs get distributed to:
• High perfusion low capacity – brain, heart
and kidney
• Low perfusion high capacity – muscle and
fats
- When plasma concentration of drugs falls,
drug is withdrawn from this site prolonging the
action of this drug
-Greater the lipid solubility, the faster is its
redistribution (Thiopentene Na)
-Shorter acting drug can be prolonged by
administering slowing and continuously –low
perfusion high capacity tissues
➢ BRAIN AND CSF PENETRATION
• Blood-Brain-Barrier (BBB)
- includes capillary endothelial cells
(which have tight junctions and large
intracellular pores) and an investment
of glial tissue, over the capillaries
- Similar barrier is located in the
choroid plexus
• BBB is lipoidal and limits entry of non-
lipid soluble drugs (Amikacin,
Gentamicin, Neostigmine, etc.)
- REMEMBER: Only lipid soluble
unionized drug penetrate and have
action on the CNS
• Efflux carriers like P-glycoprotein
present in brain capillary endothelial
cell (also in intestinal mucosal, renal
tubular, hepatic canalicular, placental
and testicular
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COLLEGE OF MEDICINE
cells)extrude drugs that enter brain by • High degree of protein binding makes the
other processes drug long acting, because bound
- Inflammation of meninges of the fraction is not available for metabolism,
brain INCREASES PERMEABLITY of BBB unless it is actively excreted by liver or
• Dopamine does not enter brain, but its kidney tubules
precursor Levodopa does • Generally expressed plasma
concentrations of the drug refer to
➢ PLACENTAL BARRIER bound as well as free drugs
-Placental membrane are lipoidal and allows • In hypoalbuminemia, binding may be
free passage of lipophilic drugs, while reduced and high concentration of free
restricting lipophobic drugs
drugs may be attained (Phenytoin)
- Only lipid soluble drugs can penetrate and
limitation of hydrophobic drugs
➢ TISSUE STORAGE
- But higher concentration of lipophobic drugs
- Drugs may also accumulate in specific
in the maternal tissues gains access to the fetus.
organs or get bound to specific tissue
- Beside this:
constituent
-It’s an incomplete barrier – some influx
Organ Drugs
transporter operate (Thalidommide)
Heart and Digoxin
• Placental efflux – P-glycoprotein serves
skeletal muscle
a limiting factor Liver Digoxin, Chloroquine,
• Influx transporter Tetracyclin
Kidney Digoxin, Chloroquine
➢ PLASMA PROTEIN BINDING (PBB) Thyroid gland Iodine
- Most drugs possess physiocochemical affinity Brain Chlorpromazine, Isoniazid,
for plasma proteins. Acetazolamide
- ACIDIC DRUGS BIND TO PLASMA ALBUMIN Retina Chloroquine
and BASIC DRUGS BIND TO ALPHA 1- Iris Ephedrine, Atrophine
GLYCOPROTEIN Bones and teeth Tetracyclines, Heavy
-Extent of binding depends on the individual Metals
Adipose tissue Thiopental, Ether,
compound. Increasing concentration of drug
Minocycline, DDT
can progressively saturate the binding sites.
-The CLINICAL IMPLICATIONS of PBB are:
III. METABOLISM OF THE DRUG:
• Highly PPB drugs are largely restricted to
BIOTRANSFORMATION
the vascular compartment and tend to
have lower Vd
➢ Biotransformation –
• The PBB fraction is not available for action
chemical alteration of
• There is equilibrium between PBB fraction the drug in the body
of drug and free molecules of drug. -Aim: To convert non-
• The drugs with high physicochemical polar lipid soluble
affinity for plasma proteins (Aspirins, compounds to polar
sulfonamides, chloramphenicol) can lipid insoluble
replace the other drugs compounds to avoid
(Acenocoumarol, warfarin) or reabsorption in renal
endogenous compounds (bilirubin) with tubules.
lower affinity - Most
hydrophilic

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drugs are less biotransformed and
excreated unchanged (Streptomycin,
Neostigmine and Pancuronium)
- Biotransformation is required for
protection of body from toxi
metabolites.
➢ RESULT OF BIOTRANSFORMATION:
• Activation – few drugs are
administered in inactive form
(prodrug) and needs to be activated to
form active metabolite
- Stability, good bioavailability, less
side effect or toxicity, desired
pharmacokinetic properties
• Inactive drug (prodrug) to
active/enhanced activity
-Levodopa-dopamine
- Prednisome to Prednisolone
- Enapril to Enalprilat
• Inactivation – active drug and its
metabolite to inactive metabolites
• Usually most drugs (Ibuprofen,
Paracetamol, Chloramphenicol,
Propanolol, Lidocaine)
• Active drug to active product
- Phenacetin to Acetaminophen or
Paracetamol
-Morphine to Morphine-6 –glucuronide,
digitoxin to digoxin
• No toxic or less toxic drug to toxic
metabolites (Isoniazid to acetyl
isoniazid)
- Mutagenecity
-Teratogenicity
-Carcinogenicity
-Hepatotoxicity
➢BIOTRANSFORMATION: CLASSIFICATION OR
PHASES
❖ Phase I (Non-synthetic/functional/ catabolic) –
metabolite maybe active or inactive
- Functional group is generated, more
chemically reactive
PHARMACOLOGY
❖ Phase II (Synthetic/Conjugation, anabolic) –
result in inactive products/metabolites
-(Morphine to Morphine-6 –glucuronide and
active sulfate metabolite of Minoxil are
exceptions)
- Both phases decrease lipid solubility, thus
increasing renal elimination
-Mostly occurs in liver, although some are
metabolized in plasma, lung and gut.
PHASE I- OXIDATION
-Most important drug metabolizing reaction-
addition of oxygen (negative) charge radical or
removal of hydrogen (positive) charged radical.
-Insertion of Oxygen – short lived highly reactive
quinone/epoxide/superoxide
- Various oxidation reaction- are oxygenation or
hydroxylation of C, N or S atoms; N or O-
dealkylation, Oxidative deamination
-Examples: Barbiturates, Phenothiazines,
Paracetamol and Steroids
- Involve Cytochrome P-450 monooxygenases
(CYP), NADPH and Oxygen
-More than 100 CYP P-450 isoenzymes are
identified and grouped into more than 20 families
(1, 2, 3…)
- Sub-families are identified as A, B, C…
-In human, only 3 isoenzyme families are
important – CYP1, CYP2, CYP3
-CYP 3A4/5 carry out biotransformation of
largest number (30-50%) of drugs. In addition to
liver, this isoforms are expressed in intestine
(responsible for 1st pass metabolism at this site),
and kidneys too.
- Inhibition of CYP3A4 by erythromycin,
clarithromycin, ketoconazole, itraconazole,
verapamil, ditiazem, and
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constituents of grape fruit juice is responsible for
untoward interaction with terfenadine and
astemizole
- Inducers of CYP3A4 are rifampicin, phenytoin,
carbamazepine, Phenobarbital
➢ NONMICROSOMAL ENZYME OXIDATION
- Some drugs are oxidized by non-microsomal
enzymes (mitochondrial and cytoplasmic:
• Alcohol – dehydrogenase
• Adrenaline –MAO and COMt
• Mercaptopurine – Xantine Oxidase
PHASE I – REDUCTION
-This reaction is opposite of oxidation and
involves CYP 450 enzyme working in the
opposite direction
-Examples: chloralhydrate,
chloramphenicol,levodopa,halothane and
warfarin
Dopa decarboxylase
Levodopa Dopamine
PHASE I – HYDROLYSIS
-This cleavage of drug molecule by uptake of a
molecule of water with the help of enzymes like
esterases, amidases, peptidases
- Examples: Amides and polypeptides are
hydrolyzed by amidases and peptidases
-Choline esters, procaine, lidocaine,
procainamides, aspirin, carbamazepine-epoxide,
pethidine, oxytocin
-Hydrolysis occurs in liver, intestines, plasma and
other tissues
PHASE I – CYCLIZATION
- Formation of ring structure from straight chain
compound
- e.g. Proguanil
PHASE I – DECYCLIZATION
- Opening up a ring structure of the cyclic
molecule
-e.g. Phenytoin, Barbiturates
PHASE II METABOLISM
PHARMACOLOGY
• Conjugation of the drug or its phase I
metabolite with an endogenous substrate-
polar highly ionized organic acid to be excreted
in urine or bile – high energy requirement
• Glucoronide conjugation - most synthetic
reaction
• Compounds with hydroxyl or carboxylic acid
group are easli conjugated with glucoronic acid
(derived from glucose) by enzyme UDP-
glucuronyl transferase
- Examples: chloramphenicol, aspirin,
morphine, metronidazole, bilirubin, thyroxine
• Drugs glucuromides, excreted in the bile can be
hydrolyzed in the gut by bacteria, producing
beta-glucoronidase-liberated drug is
reabsorbed and undergoes the same fate-
Enterohepatic recirculation (e.g.
Chloramphenicol, Phenolpthlein, Oral
Contraceptives) and prolongs their action
• Acetylation: compounds having amino or
hydrazine residues are conjugated with the
help of acetyl CoA
-e.g. sulfonamides, Isoniazid, Hydralazine,
Clonazepam, Procainamide.
• Genetic Polymorphism (slow and fast
acetylators
• Sulfate conjugation: the phenolic compounds
and steroids are sulfated by sulfokinases
-e.g. Chloramphenicol, adrenal and sex steroids
• Methylation: the amines and phenols can be
methylated. Methionine and cysteine acts as
methyl donor
-examples: adrenaline, histamine, nicotinic acid,
methyldopa, captopril, mercaptopurine
• Ribonucleoside/nucleotide synthesis:
activation of many purine and pyrimidine
antimetabolites used in cancer chemotherphy.
• Sulfate Conjugation: Phenolic and steroid
compounds-sulfated by sulfottransferase
(SULTs)
• Glycine Conjugation: Salicylates and other
drugs having carboxylic acid-conjugated with
glycine
- Not a major pathway
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• Glutathione Conjugation: Inactivates highly
reactive quinines or epoxides intermediates –
Paracetamol
-When glutathione falls short (toxicity) toxic
products formed causing tissue damage
-Minor Pathway
➢ FACTORS AFFECTING BIOTRANSFORMATION
• Concurrent use of drug: induction and inhibition
• Genetic polymorphism
• Pollutant exposure from environment or
industry
• Pathological status
• Age
➢ METABOLIC ENZYMES
• Drug metabolizing enzyme is divided into 2
types:
-Microsomal Enzymes
-Non-microsomal Enzymes
• Both of this is deficit in newborn-susceptible to
manydrugs (chloramphenicol, opiods)
-Develop in 1st month partially and completely
in 3 months
• Amount and kind – genetically controlled,
altered by environmental factiors
-Drug response variation
➢ USE OF ENZYME INDUCTION
• Congenital non-hemolytic jaundice (deficient
glucuronidation of bilirubin)
- Phenobarbital hastens the clearance of
jaundice
• Cushing Syndrome – phenytoin enhances
degradation of adrenal steroids
• Chronic poisoning – faster metabolism of poison
• Liver disease
➢ ENZYME INHIBITION OF DRUG METABOLISM
• One drug can inhibit metabolism of other if
utilizes same enzyme or co-factors
• However, not common because different drugs
are substrate of different CYPs (100
isoenzymes of CYP – 450 alone)
PHARMACOLOGY
• A drug mau inhibit one isoenzyme while being
substrate of other isoenzyme – quinidine
-Quinidine is metabolized by CYP3A4 but
inhibits CYP2D6
• Some enzyme inhibitors- allopurinol,
erythromycin, verapamil, diltiazem,
omeprazole, metronidazole, ciprofloxacin and
sulfonamides
➢ HOFFMAN ELIMINATION
- Inactivation of drug in body fluids by spontaneous
molecular rearrangement without use if any
enzyme
IV. EXCRETION OF DRUG
➢Excretion is a transport procedure which the
prototype drug (parent drug) or other
metabolic products are excreted through
excretion organ or secretion organ
- Hydrophilic compounds can easily be
excreted
➢ROUTES OF DRUG EXCRETION
• Kidney
• Biliary excretion
• Sweat and saliva
• Milk
• Pulmonary
➢ HEPATIC EXCRETION
• Drugs can be excreted in bile especially when
they are conjugated with glucuronic acid
• Drug is absorbed, glucuronidated or sulfated in
the liver and excreted through the bile,
glucuronic acid/sulfate is cleaved off by bacteria
in the GIT, drug is reabsorbed (steroid
hormones, rifampicin,amoxicillin,
contraceptives
• Anthraquinone, heavy metal – directly excreted
in the colon
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COLLEGE OF MEDICINE
➢ RENAL EXCRETION: URINE
• Most important channel for excretion of drugs
• It eliminates water soluble substances
• Amount of drug or its metabolite depends on:
-Glomerular Filtration (GFR)
-Tubular Reabsorption (TR)
- Tubular Secretion (TS)
-Net Renal Excretion = (GFR + TS)-TR
➢ GLOMERULAR FILTRATION (GFR)
-Normal GFR – 120ml/min
-Glomerular capillaries have pores larger than
usual
-The kidney is responsible for excreting of all
water soluble substances
-All nonprotein bound drugs (lipid soluble or
insoluble) presented to the glomerulus are
filtered
- Glomerular Filtration of drugs depends on
their plasma protein binding and renal blood
flow-protein bound drugs are not filtered
-Renal failure and elderly
➢ TUBULAR REABSORPTION
• Passive diffusion depends on
- Lipid solubility
– 99% of lipid soluble GF gets
reabsorbed
- Non-lipid soluble are unable to do so
- Ionization of drug at existing pH
- Highly ionized drugs are not absorbed
• Depends on pH of urine, ionization, etc
• Lipid insoluble ionized drug excreated as it
is aminoglycosides (amikin, gentamicin,
tobramycin)
• Changes in urinary ph can change the
excretion pattern of drugs
-weak bases ionized more or less
reabsorbed in acidic urine
-weak acids ionized more or less reabsorbed
in alkaline urine
• Utilized clinically in salicylate and barbiturate
poisoning – alkalinized urine (drugs with pKa:
5-8)
• Acidified urine- atrophine and morphine etc
PHARMACOLOGY
➢ TUBULAR SECRETION
• Certain cations and anions
• Epithelium of the proximal tubules into
tubulkar fluid via special consuming
transport system
• Energy dependent active transport- reduce
free concentration of drugs- further, more
secretion (protein binding is facilitated for
excretion of some drugs)
-OAT – organic acid transport
-OCT – organic base transport
-P-glycoprotein
• Limited capacity
• Competitive inhibition can occur
• Bidirectional transport –blood vs tubular
fluid
• Utilized clinically – penicillin vs probenecid,
probenecid vs uric acid (salicylate)
• Quinidine decreases renal and biliary
clearance of digoxin by inhibiting efflux
carrier P-gp
• If renal clearance is greater than
120ml/min – TS is assumed to occur
• It reduces the amount of free form of drug
• PPB drugs gets dissociates to get
eliminated via this route
• OAT: penicillin, probenecid, urinc acid,
salicylates, indomethacin, methotrexate,
glucuronides, etc
• OCT: thiazide, amiloride, triametene,
furosemide, quinine, choline, cimetidine
• Both transporters are bidirectional – blood
vs tubular fluid
• Not well developed at birth-prolong action
of drugs (penicillin, cephalosporin)
• Gets matured in infancy
• Progressively declines after the age of 50
years and almost lowers of most drugs
after 75 years old
➢ PULMONARY EXCRETION
- Gases and volatile drugs or particulate matter-
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COLLEGE OF MEDICINE
irrespective of lipid solubility
-Alveolar transfer of gas –partial pressure in blood
-example: General anesthesia, paraldehyde,
alcohol
➢SALIVA AND SWEAT EXCRETION
-minor importance for drug excretion
-example: lithium, potassium iodide, rifampicin
and heavy metals
➢MILK EXCRETION
- Most of drug enter – breast milk by passive
diffusion
-Lipid soluble and PBB drugs do it better
-% of drug reaching infant is very less – majority
of drugs can be given to lactating mothers
without ill effect
-But lactating mother should be prescribed with
drugs with caution
-Contraindicated drugs: amiodarone,
anthraquinone, chloramphenicol, ciprofloxacin,
cyclosporine, indomethacin, methotrexate,
tetracycline
- Special precaution: ampicilin, aspirin, losartan,
metoclopramide, sulfonamide
➢ KINETICS OF ELIMINATION
➢Pharmacokinetic Parameters
• Bioavailabilty (F): fraction of administered drug
that reaches systemic circulation in unchanged
form
- F= amt. of drug that enters the systemic
circulation (AUC) dose administered
• Volume of Distribution (V): volume that
accommodate all the drugs in body; if
concentration throughout was the same as in
plasma
- V= dose administered/plasma drug
concentration
• Clearance (CL): volume of plasma containing
the amount of drug that is removed from the
body in unit time
PHARMACOLOGY
- CL= Rate of elimination/C
-Example: if a drug has 20 mcg/min and RoE is
100mcg/min
-CL = 100/20 5ml/min
➢ FIRST ORDER KINETICS (EXPONENTIAL)
• Rate of elimination is directly
proportional to drug concentration
• CL remaining constant
• Constant fraction of drug is eliminated
per unit time
➢ ZERO ORDER KINETICS (LINEAR); FEW DRUGS
• The rate of elimination remains constant
irrespective of drug concentration
• CL decreases with increase in
concentration
• Constant fraction of drug is eliminated
per unit time
• Alcohol, theophyline, tolbutamide, etc.
➢PLASMA HALF LIFE
- Defined as time required for plasma
concentration to be reduced to half (50%) of its
original value – 2 phase: rapid declining
Mathematically: t 1/2= 0.693/k
• t1/2=In2/k
• Ln2=natural logarithm of 2(0.693)
• K=elimination rate constant = CL/V
• t1/2= 0.693xV/CL
• Complete drug elimination can occur in
4-5 half life
➢STEADY-STATE PLASMA CONCENTRATION
• Steady-state Plasma Concentration (Cpss)
- Repeated drug
administration at
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Lyceum Northwestern University
COLLEGE OF MEDICINE
relatively short interval of time
-Input drug balance = clearance
- Cpss= dose rate/CL
- From this equation, it is clear that the dose rate
can be calculated if CL and Target Cpss of drug is
unknown
- Earlier equation is valid for drug route
administration where the bioavailability (F) is
100% but where if falls short the equation turns
to be
- Dose rate= (target Cpss xCL)/F
- Both these equations stands valid for the drugs
following 1st order kinetics
➢MICHELIS MENTEN KINETICS
• Elimination changes from 1st order to zero
order kinetics over therapeutic range
• This signifies that till the saturation level of
drug, Cpss is related to dose rate
• But it turns out proportion beyond it
-Rate of drug elimination = (Vmax) (C)/Km+C
-Km = plasma conc. At whihch elimination rate is
half maximal
-C=plasma concentration of drug
-Vmax=maximum rate of drug elimination
➢PLATEAU PRINCIPLE OF DRUG ACCUMULATION
• Repeated Dosing
- When constant dose of drug is repeated
before the expiry of 4 half life- the higher peak
concentration is achieved after certain interval,
because some remnant drugs will be present in
the body
-subsequent plasma concentration becomes
constant and forms a plateau and fluctuates
around desired therapeutic level of drug
-Desired therapeutic level reaches 4-5 half lives
PHARMACOLOGY
-Balances between doses administered and
dose interval
➢LOADING DOSE
• Single or few quickly repeated dose to attain
concentration rapidly
-Loading dose = (target Cp x V)/F
• So loading dose is governed by V not CL or half-
life of drug
➢MAINTENANCE DOSE
• The amount of drug given to maintain the
steady state plasma concentration (Cpps) of
drug at regular interval so as to balance the
elimination
-Dose rate = (target Cpss x CL)/F
• So it is dependent on CL or half-life of drug
➢THERAPEUTIC DRUG MONITORING (TDM)
• Cpss of a drug depends on its F, V and
clearance – each of this parameters varies
from patient to patient
• Measurement of plasma concentration of drug
after initial drug administration (based on
average patient) can give all this parameters of
an individual
• This helps for the subsequent quantification of
drug dose regimen
➢USE OF TDM
• Low safety margin – digoxin, anticonvulsants,
antiarrhythmics, theophylline,
aminoglycosides, lithium, TCA
• Potentially toxic drugs
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Lyceum Northwestern University
COLLEGE OF MEDICINE
DRUG EVALUATION AND REGULATION
Dr. Perfecto Soriano
New drugs are discovered or developed through:
-identification of new drug target
-rational design of a new molecule
-screening for biological activity of large numbers of
natural products
-chemical modification of a known active molecule
Drug screening
-done to define pharmacologic profile (activity and
selectivity of the drug)
-desired result of screening is called a lead compound
Preclinical safety toxicity testing
“All drugs are toxic in some individuals at some dose”
Preclinical toxicity testing includes most or all these
procedures:
Goals of preclinical toxicity is to:
-identify potential human toxicities
-design tests to further define the toxic mechanisms
- predicting the most relevant toxicities to be monitored
in clinical trials
No-effect dose- MAXIMUM dose at which a specific
toxic effect is NOT seen
Minimum lethal dose - the SMALLEST dose that is
observed to KILL any experimental animal
PHARMACOLOGY
Median lethal dose (LD50) - the dose that KILLS aprox
50% of the animals
These doses are used to calculate the initial dose to be
tried in humans
(Usually taken as one hundredth to one tenth of the
NO-EFFECT DOSE in animals)
Limitations of preclinical testing
-toxicity testing is time consuming and expensive
-large numbers of animals may be needed to obtain
valid data
-toxic data from animals to humans are unpredicted
-adverse effects are unlikely to be seen in preclinical
testing
Evaluation in humans
Confounding factors in clinical trials
A)the variable natural history of most diseases
-many diseases disappear spontaneously
Crossover design - alternating periods of administration
of test drug, placebo,standard treatment
- way to minimize errors
B) The presence of other diseases and risk factors
-Can be minimized by crossover technique and proper
selection and assignment of patient to a group
C) Subject and observer bias and other factors
Single blind design- minimize subjective bias, px doesn't
know if he/she is in taking placebo
Double blind design- minimize observer bias, px and
personnel doesn't know the medication being used. A
third party holds the code identifying the medication
Clinical trials
Phase 1
-The effects of the drug as a function of dosage are
established (20-100 healthy px) (if drug is expected to
have toxic effect should be
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COLLEGE OF MEDICINE
done in px with the disease ex. Cancer aids px)
- nonblind or open, blinded and placebo controlled Adverse drug reactions
- harmful unintended response
-Done to determine the probable limits of the safe - Fourth leading cause of death (higher than
clinical dosage range pulmonary disease,AIDS,accidents and mobile
accidents)
Phase 2
-To determine the efficacy (proof of concept), and the Orphan drugs
doses to be used in any follow on trials (100-200 px with -drugs for rare diseases
the target disease)
-highest rate of failure
- single-blind design

Phase 3
-Certain toxic effects caused by immunologic processes
may first appear
- done to thousands of px
-phase 1 2 3 minimize errors caused by placebo effect
-double blind and cross over technique

Phase 4
- Monitoring the safety of the new drug under
actual conditions
- Has no fixed duration
- Low incidence drug effects are not generally
seen before phase 4

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Lyceum Northwestern University
COLLEGE OF MEDICINE
3. Nucleic acids
DRUG-RECEPTOR INTERACTION and
4. Polysaccharides
PHARMACODYNAMIC PRINCIPLES
Interaction
Dr. H.H. Maramba
DRUG MOLECULE (D)
OBJECTIVES
▪ Agonist (activator) (A)
▪ Drug-Receptor Interaction ▪ Antagonist (inhibitor)
▪ Agonists & Antagonists
▪ Graded Dose-Response TARGET MOLECULE
▪ Potency and Efficacy
▪ Quantal Dose-Effect ▪ Receptor (R)

Drug AFFINITY

Any substance that bring about a change in biologic

function through its chemical actions at the molecular
level
D + R = DR complex→ Effect
Pharmacodynamics
Receptor Principles
Actions of the drug on the body “what the drug does to
the body” 1. Receptor largely determine the quantitative
relations between dose or concentration of the
drug
✓ “the receptor’s affinity for binding a
drug determines the concentration of a
drug required to form a significant
amount of drug-receptor complexes”
2. Receptors are responsible for selectivity of drug
action
✓ “the molecular size, shape, and
electrical charge of a drug determine
whether it will bind to a particular
receptor among a wide array of
receptor/binding sites available at the
action site”
Drug Molecule (D) 3. Receptors mediate actions of pharmacologic
1. Appropriate size agonists and antagonists
2. Electric charge ✓ “the receptors mediate the action of
3. Shape the agonist (or antagonist) by producing
4. Anatomic composition an activated or inactivated response”
Michaelis - Menten Principle
Drug Receptor
➢ the amount of an enzyme is kept constant and
▪ A macromolecular component of the cell with the concentration of its substrate is gradually
which a drug (molecule ligand) interacts to increased, the reaction velocity will increase
produce a response until it reaches a maximum…
▪ Usually a protein molecule
Molecules capable of serving as drug receptors are: 1.
Enzymes
2. Membrane proteins

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Lyceum Northwestern University
COLLEGE OF MEDICINE
decreasing response
An activated receptor-effector
system is Ra
AGONISTS
1. Full agonists
2. Partial agonist
3. Inverse agonist

Full agonist
✓ Agonist drugs that bind to receptor sites and
activate the receptor effector system to the
maximum extent
Partial agonist
➢ Agonist drugs that bind to the same receptor
site, activates the receptor-effector system in
the same way but do not evoke maximum
response
Inverse agonist
➢ An agonist with a high affinity for the Ri form of
the receptor and stabilizes most of these
receptors preventing them from conversion to
their active form

DRUG-RECEPTOR INTERACTIONS
Agonistic (A)
➢ activate the agonist binding site
Antagonistic (B)
➢ Compete with the agonist
Allosteric Activator (C)
➢ Act at a separate site and increasing response
Allosteric Inhibitor (D)
➢ Act at a
separate site
a
n
d

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Lyceum Northwestern University
COLLEGE OF MEDICINE
ANTAGONIST (ED50) to produce an effect (50% of that drug’s
maximal effect)
1. Interacts with the receptor but does not change the
receptor
2. Blocks the action of other drug molecules
3. Effect is only observed in the presence of an agonist
4. Have Affinity but no Efficacy
Types of Antagonism
1. Competitive antagonism
2. Irreversible antagonism

Competitive antagonism
▪ These drugs bind to the receptor sites but
generally does not stimulate a response but
prevents the binding of the agonists to the
same receptor sites.
o High concentrations of the agonist drug
can overcome the effect of a
competitive antagonist
Irreversible antagonism
▪ These drugs usually bind to the receptor sites in
an irreversible manner.
o A high concentration of the agonist
drug cannot completely reverse the
antagonistic drug’s effect
➢ Potency of a drug depends on the affinity of
receptors for binding the drug and in part on
the efficiency with which drug-receptor
interaction is coupled to response.
 Affnity is the propensity of the drug to
bind to a recptor.
2. Efficacy
➢ Maximal effect of a drug which can be achieved
with highest therapeutic doses
➢ Maximum effect (Emax)

RELATION BETWEEN DRUG DOSE AND CLINICAL

RESPONSE
Dose and Response in patients
▪ Graded dose-response relations
▪ Shape of dose-response curves
▪ Quantal dose-effect curves
GRADED DOSE-RESPONSE RELATIONSHIP
1. Potency
➢ Ability of the drug molecules to reach the
receptors and bind to these receptors
➢ Refers to the concentration (EC50) or dose

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Lyceum Northwestern University
COLLEGE OF MEDICINE
responses include: relief of headache for an
antimigraine drug, increase in heart rate of at
least 20 bpm for a cardiac stimulant, or 10
mmHg fall in diastolic blood pressure for an
antihypert
ensive.

In Graded Dose-Response Curves (relationship), data is

obtained individually from a few study participants.
QUANTAL DOSE-EFFECT RELATIONSHIP
▪ Therapeutic index employs the use of the
quantal dose-effect curves
o Quantal Response = all or none
response
o The therapeutic index of a drug is the
ratio of the dose that produces toxicity
to the dose that produces a clinically
desired or effective response in a
population of individuals.
Therapeutic index

▪ TD50 is the dose of drug that causes a toxic

response in 50% of the population
▪ ED50 is the dose of drug that is therapeutically
effective in 50% of the population.
▪ Both ED50 and TD50 are calculated from
quantal dose response curves (QDRC), which
represent the frequency with which each dose
of drug elicits the desired response or toxic
effect in the population
Characteristics of QDRC
▪ Dose of drug in plasma is plotted in the
horizontal axis while the percentage of
individuals (animals or humans) that responds
or shows a toxic effect is represented in the
vertical axis.
▪ These curves measure all or none (positive or
negative) responses. Some examples of positive

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Lyceum Northwestern University
COLLEGE OF MEDICINE
6. Affinity Propensity of a drug to bind with a
receptor site
7. Michaelis-Menten The magnitude of a response
is attributed to the amount of available
receptors sites and the quantity of drug
molecules
8. Agonist Activates the receptor by binding at the
drug binding site
9. Antagonist Competes with the agonist for the
same binding site
10. Drug-Receptor Complex Product of a drug-
receptor coupling

Examples of drugs with Narrow TI

▪ Warfarin
▪ Lithium
▪ Digoxin
▪ Phenytoin
▪ Gentamycin
▪ Amphotericin B
▪ 5-fluorouracil
▪ AZT (zidovudine)

POP QUIZ
1. Receptor A macromolecule that binds with a
cell or ligand to produce a response
2. Allosteric Activator Binds to the receptor at a
separate site and increases the response
produced
3. Drug Substance that brings about a change in
biologic function through its chemical actions at
the molecular level
4. Quantal Relationship All-or-none response
5. Pharmacodynamics Actions of the drug on the
body

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Lyceum Northwestern University
COLLEGE OF MEDICINE
central nervous system through the cranial nerves
AUTONOMIC PHARMACOLOGY (especially the 3rd , 7th , 9th , and 10th ) and the third and
Dr. Perfecto Soriano fourth sacral spinal roots- “cranio-sacral”

Somatic Nervous System

➢ No ganglia present
➢ Largely non-autonomic
➢ Skeletal muscle is innervated by somatic
nerve nerves; controlling voluntary
actions
Autonomic Nervous System
➢ Has ganglia
➢ Largely autonomous (independent)
➢ Its activities are not under direct
conscious control

o Most of the sympathetic preganglionic fibers

terminate in ganglia located in the
paravertebral chains that lie on either side of
the spinal column.

o From the ganglia, postganglionic sympathetic

fibers run to the tissues innervated.

o The majority of parasympathetic preganglionic

fibers terminate on ganglion cells distributed
diffusely or in networks in the walls of the
innervated organs.
Enteric Nervous System

➢ a semiautonomous part of the ANS located in o Some preganglionic parasympathetic fibers

the GIT which specific function for the control terminate in parasympathetic ganglia located
of this organ system. outside the organs innervated.

• Consists of the myenteric o Because of the location of the ganglia, the

plexus (plexus of Auerbach) and preganglionic sympathetic fibers are short and
the submucous plexus (plexus the postganglionic fibers are long.
of Meissner)- they send sensory o Parasympathetic system: preganglionic fibers
input to the parasympathetic are longer and postganglionic fibers are short
and sympathetic nervous
systems and receive motor
output from them

The sympathetic preganglionic fibers leave the central

nervous system through the thoracic and lumbar spinal
nerves- "thoracolumbar system.”

The parasympathetic preganglionic fibers leave the

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Lyceum Northwestern University
COLLEGE OF MEDICINE
• Synthesized in the nerve terminal from
acetyl CoA (produced in mitochondria)
and choline (transported across the cell
membrane) by enzyme choline
acetyltransferase

• The rate-limiting step is probably the

transport of choline into the nerve
terminal - inhibited by hemicholinium

• Acetylcholine is actively transported into

its vesicles for storage by the vesicle-
associated transporter (VAT)- inhibited
by vesamicol

2. Release of acetylcholine

• Release of transmitter stores from

vesicles in the nerve endings requires the
Neurotransmitter Aspects of the ANS entry of calcium through calcium
Transmitter channels and triggering of an interaction
between SNARE(soluble N-
• Transmitter crosses the cleft by diffusion and
ethylmaleimide-sensitive-factor
activates or inhibits the postsynaptic cell by
attachment protein receptor) proteins.
binding to a specialized receptor molecule.
• SNARE proteins include v-SNARES
• Acetylcholine ( Ach)
associated with vesicles (VAMPs-
• Norepinephrine ( NE)
vesicle-associated membrane proteins:
• Dopamine
synaptobrevin, synaptotagmin) and t-
• The synthesis, storage, release, receptor
SNARE proteins associated with the
interactions, and termination of action of the
nerve terminal membrane (SNAPS,
neurotransmitters all contribute to the action of
synaptosome-associated proteins:
autonomic drugs
SNAP25, syntaxin and others)

Cholinergic Transmission • This interaction results in docking of the

vesicle to the terminal membrane and,
• Acetylcholine (Ach) is the primary transmitter in
with influx of calcium, fusion of the
all autonomic ganglia and at the synapses
membrane of the vesicles with the
between parasympathetic postganglionic
nerve ending membranes, the opening
neurons and their effector cells (cholinergic
of a pore to the extracellular space, and
fibers)
the release of stored transmitter.
• It is the primary transmitter at the somatic
• Botulinum toxins enzymatically alter
(voluntary) skeletal muscle neuromuscular
synaptobrevin or one of the other
junction.
docking or fusion protein to prevent the
1. Synthesis and storage

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Lyceum Northwestern University
COLLEGE OF MEDICINE
release process
3. Termination of action of acetylcholine
• The action of acetylcholine in the synapse is
normally terminated by metabolism to
acetate and choline by the enzyme
acetylcholinesterase in the synaptic cleft.
• The product are not excreted but are
recycled in the body
• Inhibition ofacetylcholinesterase is an
important therapeutic (and potentially
toxic) effect of several drugs.
4. Drug effects on synthesis, storage, release and
termination of action of acetylcholine
• Synthesis- hemicholinium
• Storage- vesamicol
• Release- botulinum toxin
PHARMACOLOGY
ADRENERGIC TRANSMISSION
Norepinephrine (NE) is the primary transmitter at the
sympathetic postganglionic neuron- effector cell
synapses in most tissues except sympathetic fibers to
thermoregulatory (eccrine) sweat gland and vasodilator
sympathetic fibers in skeletal muscle (adrenergic fibers)
Dopamine may be a vasodilator transmitter in renal
blood vessels but NE is the vasoconstrictor of these
vessels
1. Synthesis and storage
• The synthesis of dopamine and NE requires
several steps:
• After transport across the cell membrane,
tyrosine is hydroxylated by tyrosine hydroxylase
to DOPA (dihydrophenylalanine),
decarboxylated to dopamine; and (inside the
vesicle) hydroxylated to NE
• Tyrosine hydroxylase is inhibited by metyrosine
• NE and dopamine are transported into the
vesicles and stored there
• Monoamine oxidase (MAO) is present on
mitochondria in the adrenergic nerve ending
and inactivates a portion of the dopamine and
NE in the cytoplasm
• MAO inhibitors may increase the stores of these
transmitters and other amines in the nerve
endings
• Vesicular transporter can be inhibited by
reserpine- resulting in depletion of transmitter
stores.
2. Release and termination of action
• Dopamine and NE are released from their nerve
endings by the same calcium-dependent
mechanism responsible for acetylcholine
release
• Metabolism is not responsible for termination
of action of catecholamine transmitters-
dopamine and NE
• Diffusion and reuptake (norepinephrine
transporter, NET or dopamine transporter, DAT)
reduce their
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 PHARMACOLOGY
Lyceum Northwestern University
COLLEGE OF MEDICINE
concentration in the synaptic cleft and stop
their action.
• Outside the cleft, these transmitters can be
metabolized- by MAO and catechol-O-
methyltransferase (COMT)- and the product of
these enzymatic reactions are excreted
• Determination of metanephrine,
normetanephrine,3-methoxy-4-
hydroxymandelic acid (VMA) and other
metabolites provides a measure of the total
body production of catecholamines
• Inhibition of MAO increases stores of
catecholamines and has both therapeutic and
toxic potentials

3. Drugs effects on adrenergic transmission

• Block NE synthesis- metyrosine

• Catecholamine storage- reserpine

• Catecholamine release- guanethidine

• Promote catecholamine release- amphetamine-

like agents

COTRANSMITTERS

• ATP
• Enkephalins
• Vasoactive intestinal peptide
• Neuropeptide Y
• Substance P
• Neurotensin
• Somatostatin
• The main role in autonomic function appears to
involve modulation of synaptic transmission
• The same substance function as primary
transmitters in other synapses

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 PHARMACOLOGY
Lyceum Northwestern University
COLLEGE OF MEDICINE

CHOLINERGIC RECEPTORS

Acetylcholine receptor subtypes :

1. muscarinic
2. nicotinic

The term cholinoceptor denotes receptors (both

muscarinic and nicotinic) that respond to acetylcholine.

ADRENERGIC RECEPTORS

The term adrenoceptor is widely used to describe

receptors that respond to catecholamines such as
norepinephrine.

The adrenoceptors can be subdivided into (α-

adrenoceptor and β-adrenoceptor types on the basis of
both agonist and antagonist selectivity.

AUTONOMIC RECEPTORS

Cholinoceptors
Adrenoceptors
Dopamine receptors

DOPAMINE RECEPTORS

Describe receptors that respond to dopamine.

DA receptors: mesenterium, renal, cardiovascular

system, brain

Presynaptic regulation

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 PHARMACOLOGY
Lyceum Northwestern University
COLLEGE OF MEDICINE

Functional Organization of Autonomic Activity

(Function of receptors)

A basic understanding of the interactions of autonomic

nerves with each other and with their effector organs is
essential for an appreciation of the actions of
autonomic drugs, especially because of the significant
"reflex" effects that may be evoked by these agents.

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 PHARMACOLOGY
Lyceum Northwestern University
COLLEGE OF MEDICINE

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Lyceum Northwestern University
COLLEGE OF MEDICINE
Central Integration
• At the highest level--midbrain and medulla—
the two divisions of the autonomic nervous
system and the endocrine system are integrated
with each other, with sensory input, and with
information from higher central nervous system
centers.
• These interactions are such that the
parasympathetic system a trophotropic one (ie,
leading to growth) and the sympathetic system
an ergotropic one (ie, leading to energy
expenditure) that was activated for "fight or
flight."
• Sympathetic system is most active when the
body needs to react to changes in the internal
or external environment
• During rage or fright the sympathetic system
can discharge as a unit--affecting multiorgan
systems.
At a more subtle level of interactions in the brain stem,
medulla, and spinal cord, there are important
cooperative interactions between the parasympathetic
and sympathetic systems.
PHARMACOLOGY
For some organs, sensory fibers associated with the
parasympathetic system exert reflex control over motor
outflow in the sympathetic system.
Thus, the sensory carotid sinus baroreceptor fibers in
the glossopharyngeal nerve have a major influence on
sympathetic outflow from the vasomotor center.
Similarly, parasympathetic sensory fibers in the wall of
the urinary bladder significantly influence sympathetic
inhibitory outflow to that organ.
Within the enteric nervous system, sensory fibers from
the wall of the gut synapse on both preganglionic and
postganglionic motor cells that control intestinal
smooth muscle and secretory cells.
Integration of Cardiovascular Function
• Autonomic reflexes are particularly important in
understanding cardiovascular responses to
autonomic drugs.
• Autonomic and hormonal control of
cardiovascular function.
• The sympathetic nervous system directly
influences four major variables: peripheral
vascular resistance, heart rate, force, and
venous tone. It also directly modulates renin
production.
• The parasympathetic nervous system directly
influences heart rate.
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 PHARMACOLOGY
Lyceum Northwestern University
COLLEGE OF MEDICINE

Pharmacologic Modification of Autonomic Function

• Because transmission involves different

mechanisms in different segments of the
autonomic nervous system, some drugs
produce highly specific effects while others are
much less selective in their actions.

The way on effects of autonomic drugs

1) Direct effect on receptor

• agonist：receptor →→ activation, similar to

transmitter
Presynaptic & Postsynaptic Regulation
• antagonist：receptor →→blockade
• Up- and down-regulation are known to occur in
2) To influence transmitter
response to decreased or increased activation,
respectively, of the receptors. • act on the transmitter biochemical synthesis
• Up- regulation : receptor number increase • act on the transmitter metabolism (enzymatic
inactivation of transmitter)
An extreme form of up-regulation occurs after
• act on the transmitterrelease
denervation of some tissues, resulting in
• act on the transmitter storage
"denervation supersensitivity" of the tissue to
activators of that receptor type

• down-regulation : receptor number decrease

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 PHARMACOLOGY
Lyceum Northwestern University
COLLEGE OF MEDICINE
NEUROTRANSMITTERS AND NEURORECEPTORS
CHOLINERGIC AGONISTS  Acetylcholine andnorepinephrine
Dr. Perfecto Soriano  All preganglionic neurons are cholinergic
 Parasympathetic postganglionic neurons are
CHOLINORECEPTOR – ACTIVATING (CHOLINERGIC cholinergic
AGONIST) AND CHOLINESTERASE – INHIBITING DRUGS
 Sympathetic postganglionic neurons are
adrenergic except sympathetic innervating
PARASYMPATHETIC DIVISION sweat glands, blood vessels in skeletal
muscle, and piloerection muscles, which are
 Preganglionic cell bodies in nuclei of brainstem or cholinergic
lateral parts of spinal cord gray matter from S2
– S4
o Preganglionic axons from brain pass to PARASYMPATHETIC NERVOUS SYSTEM
ganglia through cranial nerves RECEPTORS: CHOLINERGIC RECEPTORS
o Preganglionic axons from sacral region
pass through pelvic nerves to ganglia 1. MUSCARINIC RECEPTORS
 Preganglionic axons to terminal ganglia within - Associated with parasympathetic
wall of or near organ innervated functions and are located at the ends of
postganglionic neurons in peripheral
SITES OF CHOLINERGIC ACTIVTIY tissues (effectors, eg. Internal organs,
 Preganglionic synapses of both sympathetic and smooth muscle) innervated by the
parasympathetic ganglia parasympathetic system
 Parasympathetic postganglionic neuroeffector - Stimulation of the muscarinic receptors
junctions may result in either excitation or
 All somatic motor end plates on skeletalmuscles inhibition, depending on the organ
involved
A membrane protein: upon stimulation by
neurotransmitter, it causes the opening of ion channels
indirectly, through a second messenger. For this reason,
the action of a muscarinic synapse is relatively slow

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 PHARMACOLOGY
Lyceum Northwestern University
COLLEGE OF MEDICINE
MUSCARINIC RECEPTORS AND ITS LOCATION
 M1 receptor – nerve endings
 M2 receptor – heart and some nerve endings
 M3 receptor – effector cells, smooth muscle,
glands and endothelium
 M4 & M5 – CNS

MUSCARINIC ACTION
 Eye (miosis and set lens for near vision)
 Smooth muscle, exocrine glands
o Bronchoconstriction, ↑secretion, ↑
GI motility
o ↑ urination
 Heart & vascular beds (vagal stimulation
o ↓SA & AV conduction velocity
o ↓ force of atrial contraction DIRECT ACTING CHOLINERGIC AGONIST
o ↓ vascular resistance – due
to activation of receptors on CHOLINE ESTERS
endothelium
  ABSORPTION: polarity dependent (poor for
EDRF (endothelium Ach, quaternary ammonium), intravenous,
derived relaxation factor) subcutaneous and intramuscular for local
o Effects modified by reflexes effects (Ach)
 METABOLISM: highly dependent on the
2. NICOTINIC RECEPTORS susceptibility to acetylcholinesterase (AChE)
- Located in the autonomic ganglia of
both the sympathetic and
parasympathetic systems and the nerve
endings of the somatic motor system PROPERTIES OF CHOLINE ESTERS
(eg. motor nerves and skeletal muscle)
- Stimulation results in  Table 7 – 2 (page 100)
muscle contraction
- A channel protein that, upon binding by
acetylcholine, opens to allow diffusion
of cations
- NN – autonomic ganglia (NN)
- NMJ (NM) – muscle contraction 
paralysis

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 PHARMACOLOGY
Lyceum Northwestern University
COLLEGE OF MEDICINE
PHARMACOLOGIC EFFECTS MODES OF ACTION
 EYES  Direct acting cholinergics are lipid insoluble
o Contraction of ciliary muscle and  Do not readily enter the CNS so effects are
smooth muscle of the iris sphincter peripheral
(miosis) – aqueous humor outflow,  Resistant to metabolism by acetylcholinesterase
drainage of the anterior chamber (except for Acetylcholine chloride)
 Effects are longer acting than with acetylcholine
 CARDIOVASCULAR
(endogenous neurotransmitter)
o Bradycardia (possibly preceded by
 Widespread systemic effects when they
tachycardia)
combine with muscarinic receptors in cardiac
o Vasodilation (all vascular beds including
muscle, smooth muscle, exocrine glands and
pulmonary and coronary – M3) and
the eye
hypotension
o Reduction of the contraction strength
ADVERSE EFFECTS
(atrial and ventricular cells, IK+, Ica2+,
 Major contraindications:
diastolic depolarization, NO –
o Asthma  Bronchoconstrictor
inhibitable ATP?), negative inotropic &
actioncould precipitate an asthmatic attack
chronotropic effect (inhibition of
o Hyperthyroidism  Hyperthyroid
adrenergic activation), variable BP
patients may develop atrial fibrillation
effects
o Coronary insufficiency  Hypotension
induced by these agents can severely
 GI
reduce coronary blood flow, especially
o Increases in tone, amplitude of
if it is already compromised
contractions, and peristaltic activity of
o Acid – peptic disease  The gastric
the stomach and intestines
acid secretion produced by the choline
o Enhances secretory activity of the
esters can aggravate the symptoms of
salivary glands and GIT
acid – peptic disease
 URINARY BLADDER
POSSIBLE SIDE EFFECTS
o Increase ureteral peristalsis
 Sweating (very common)
o Contract the detrusor muscle of the
 Abdominal cramps
urinary bladder
 Sensation of tightness in the urinary bladder
o Increase the maximal voluntary voiding
pressure  Difficulty in visual accommodation for far vision
o Decrease the capacity of the bladder  Headache
o Relaxation of the sphincter  Salivation

 OTHER EFFECTS *Antidote – ATROPINE

o Increased secretion from all glands that
receive parasympathetic innervations *Epinephrine may be used to overcome severe
(salivary, lacrimal, tracheobronchial – cardiovascular or bronchoconstrictor responses.
increased respiratory secretion,
digestive and exocrine sweat glands)
o Increased tone and contractility of
bronchial smooth
muscle: BRONCHOCONSTRICTION

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Lyceum Northwestern University
COLLEGE OF MEDICINE
1. ACETYLCHOLINE
 Quaternary ammonium ester that is rapidly
hydrolyzed by acetylcholinesterase and plasma
cholinesterase
 Therapeutic uses:
- Used as a MIOTIC in cataract surgery
FIGURE 7 -2 (pg. 99)
 Molecular structures of four choline esters.
 Acetylcholine and methacholine are acetic acid
esters of choline and B-methylcholine,
respectively.
 Carbachol and bethanechol are carbamic acid
esters of the same alcohols.
FIGURE 7 – 3 (pg. 100)
 Structures of some cholinomimetic alkaloids
2. METHACHOLINE
 Chemistry
o Differs chemically from acetylcholine by
the addition of a methyl group to the B
position of a choline. As a result:
• Hydrolyzed only
acetylcholinesterase  has
a longer duration of action
than acetyl choline
• It becomes virtually a pure
muscarinic – acting agent
PHARMACOLOGY
 Pharmacologic effects
o Similar to acetylcholine
 Methacholine choride
o acetyl-b-methylcholine chloride
o PROVOCHOLINE
o May be administered for diagnosis of
bronchial hyperreactivity and asthmatic
conditions
3. CARBACHOL
 Has a carbamic acid – ester link, which is not
readily susceptible to hydrolysis by
cholinesterases
 Has all the pharmacologic properties of
acetylcholine. It exerts both nicotinic and
muscarinic effects.
 Used ophthalmically as a miotic agent
4. BETHANECHOL
 Structural features of both methacholine and
carbachol.
 Resistant to hydrolysis by cholinesterases
 Mainly muscarinic in action
 Used therapeutically for abdominal distention,
esophageal reflux, and urinary bladder
distention
 Alternative to pilocarpine to promote salivation
– Xerostomia (dryness of the mouth)
 Sjogren syndrome (immunologic disorder with
destruction of the exocrine glands) leading to
mucosal dryness
 Should be administerd ONLY by the oral or Q S
route for systemic effects
 Also used locally in the eye
by
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 PHARMACOLOGY
Lyceum Northwestern University
COLLEGE OF MEDICINE
1. PILOCARPINE OTHER TERTIARY AMINES

 Isolated from Pilocarpus jaborandi, P.  NICOTINE

Microphyllus o A liquid, sufficiently lipid – soluble to be
 Plant family: Rutaceae (citrusfamily) absorbed across the skin
 Common name: Jaborandi (means slobber o Used as gum or transdermal patch
mouth plant in Tupi language) o Duration of action: 4 – 6 hours
 Origin: lowland wet forests of Tropical America, o Toxic effect associated with smoking
West Indies o Acute toxicity:
 Ethnomedical uses: members of the Tupiculture • Central stimulant actions
in Brazil chew leaves to induce salivation and 
sweating coma, respiratory arrest
 Chemical class: tertiary amine alkaloid • Skeletal muscle endplate
 MOA: cholinergic receptor agonist with strong depolarization blockade 
postganglionic (muscarinic receptor) depolarization blockade and
stimulation and mild ganglionic (nicotinic respiratory paralysis
receptor) stimulation • Hypertension and cardiac
 Muscarinic receptor stimulation effects: arrhythmias
o Salivation • Fatal dose: 40 mg or 1 drop of
o Intestinal motility pure liquid
o Pupil constriction o Treatment:
• Symptom directed
THERAPEUTIC USES
 Topical agent on eyes – constricts pupils  SUCCINYLCHOLINE
o Treats open – angle glaucoma by o N – receptor, moderately selective for
reducing intraocularpressure neuromuscular endplate (NM)
 Oral administration treats dry mouth o NM relaxation
(xerostomia) o Highly polar, IV administration
 Also used to reduce side effects of morphine o Duration of action: 5 to 10 minutes
treatment, including: o Treatment:
o Dry mouth • Symptom directed
o Constipation • Muscarinic excess resulting
o Urinary retention from parasympathetic
 Overdose may cause cardiovascular collapse ganglion stimulation can be
 Antedote is atropine (conversely, pilocarpine si controlled by atropine
sometimes used as an antedote in cases of • Central stimulation is usually
atropine poisoning) treated with anticonvulsants
o Chronic toxicity:
• Cardiovascular diseases

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 PHARMACOLOGY
Lyceum Northwestern University
COLLEGE OF MEDICINE
o Diarrhea
o Hypotension
2. MUSCARINE
o Bradycardia
 Compound isolated from various species of
o Bronchospasm
fungi:
o Amanita muscaria
o Amanita phalloides – Amanita phalloides: inhibits mRNAsynthesis – 24 h
deadly nightcap symptom free period followed by liver and kidney
o Amanita spp. malfunction, death within 4 to 7 days
o Inocybe spp.  Oxotremorine effects: neurobiological
o Clitocybe spp. research
 Antedote: 1 – 2 mg of atropine IM every 30
 Common name: amanita, fly agaric
mins
 Origin: Siberia, North America
 Habit: mushroom with red, orange, yellow 3. ARECOLINE
or cream colored cap with white spots.  From Areca catechu
Grows on forestfloor.  Plant family: Arecaceae (palmfamily)
 Common name: betelnut, betel, areca nut
 Ethnomedical/cultural uses:  Origin: tree in wet forests of Southeast Asia,
o Mushroom eaten by Indomalaysia, Oceania, probably originally from
Siberian indigenous people as
Sulawesi (Indonesia)
hallucinogen
 Ethnobotanical use:
o Dried mushrooms repel flies
o Used as a masticatory (chew): the
areca seed is rolled in leaves of Piper
 Compounds with hallucinogenic (CNS)
betel and mixed with gambir (a spice
activity:
made from the boiled leaves of Unicaria
o Ibotenic acid
gambir) and shell lime (which changes
o Muscimole
pH to release active compounds
o Muscazone
 Ethnomedical uses:
 Active compound: muscarine o Euphoretic
o Cardiac tonic
 Chemical class: quaternary ammonium
o Energizer
alkaloid
o Antihelminthic
o Less completely absorbed from the
 Chemical structure: arecoline is an alkaloid
GIT than tertiary amines
 Chemical derivative: arecoline 
aceclidine(glaucoma treatment in Europe)
 Chemical derivative: muscarine
  Arecoline stimulates both muscarinic
oxotremorin and nicotinic receptors (in ANS and
e CNS)

 Muscarinic effects:
o Diaphoretic
o Salivation
o Lacrimation
o Visual problems
o N/V

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 PHARMACOLOGY
Lyceum Northwestern University
COLLEGE OF MEDICINE
INDIRECTLY – ACTING CHOLINERGIC membrane
AGONIST ANTICHOLINESTERASE o Duration of action: 0.5 – 2 hours
(AChE)
PHARMACOLOGIC EFFECTS
2 MAJOR CHEMICAL CLASSES  Mimics the pharmacologic effects
 CARBAMIC ACID ESTERS (CARBAMATES): of acetylcholine
reversible  Enters and stimulates the CNS
o Physostigmine  Produces miosis – can antagonize the mydriasis
o Neostigmine induced by atropine – topical use
o Pyridostigmine  Duration of action: 2 – 4 hours
 PHOSPHORIC ACID  In large doses: causes fasciculation, then
ESTERS paralysis of skeletal muscle because of the
(ORGANOPHOSPHATES): irreversible accumulation of acetylcholine at the
o
Insecticide neuromuscular junction that results when
 Parathion acetylcholine is not broken down.
 Malathion
 Diisopropyl phosphofluoridate THERAPEUTIC EFFECTS
(DFP)  Treatment of atropine, phenothiazine, and
 Echothiophate tricyclic antidepressant intoxication
o Isofurophate  Treatment of glaucoma, especially simple and
 *EDROPHONIUM: is an alcohol (NOT an ester) secondary glaucoma
 Treatment of early stages of Alzheimer’s
MODE OF ACTION disease because of degeneration of cortical
 Both carbamates and organophosphate cholinergic axons
inhibitors bind to cholinesterase and udergo
prompt hydrolysis  the alcohol portion of ADVERSE EFFECTS
themolecule is then released.  Convulsion (high dose)
 The acidic portion (carbamate ion andphosphate  Bradycardia
ion) is released more slowly, and this retained  Paralysis of skeletal muscle (ACh accumulation
portion prevents the binding and hydrolysis of at NMJ)
endogenous acetylcholine, thus amplifying
acetylcholine effects whenever the transmitter
is released. 2. NEOSTIGMINE
 Synthetic reversible anticholinesterase that
A. CARBAMATES contains a quaternary nitrogen

1. PHYSOSTIGMINE MECHANISM OF ACTION

 Moderately polar but active orally
MECHANISM OF ACTION  Does not penetrate the blood-brain-barrier 
 Forms a reversible complex at the site of minimizes the toxicity due to inhibition of
acetylcholinesterase where acetylcholine is broken down acetylcholinesterase
 Both muscarinic and nicotinic receptors  It is destroyed by plasma esterases and is
 Pharmacokinetics: excreted in the urine
o Well – absorbed from the GIT, Duration of action: 2 – 4 hours
subcutaneous tissues and mucous

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Lyceum Northwestern University
COLLEGE OF MEDICINE
PHARMACOLOGIC EFFECTS
 Mimics the pharmacologic effects of
acetylcholine
 It has a direct action on nicotinic receptors n i
addition to blocking acetylcholinesterase
 It reverses the neuromuscular blockade
produced by curare and its derivatives
 The mechanism of action involves the release of
increased amounts of acetylcholine from nerve
endings, cholinesterase inhibition, and a direct
action on skeletal muscle cholinergic receptors.
THERAPEUTIC USES
 Used to reverse the effects of competitive
blocking agents
 Management of paralytic ileus and atony of the
urinary bladder
 Symptomatic treatment of myasthenia gravis
3. PYRIDOSTIGMINE
 Used in the chronic management of myasthenia
gravis
 Duration of action: 3 – 6 hours (longer than
Neostigmine)
 Adverse effects: generalized cholinergic
stimulation
OTHER PHYSOSTIGMINE – LIKE
ANTICHOLINESTERASE
 Ambenonium – used in the symptomatic
treatment of myasthenia gravis
 Demecarium – used as an ophthalmic solution for
the treatment of chronic glaucoma
Major use is in the treatment of glaucoma
PHARMACOLOGY
*EDROPHONIUM (SIMPLE ALCOHOL)
 Reversible anticholinesterase
 Pharmacokinetics:
o More rapidly absorbed and has a
shorter duration of action than
neostigmine
o Administered parenterally
o Duration of action: 5 – 15 minutes
 Pharmacologic effects:
o Similar to neostigmine except that with
doses it can stimulate the
neuromuscular junction without
affecting muscarinic effector organ
 Therapeutic uses:
o Diagnosis of myasthenia gravis
o Antagonism of curare – like agents
B. ORGANOPHOSPHATE CHOLINESTERASE
INHIBITORS (IRREVERSIBLE
ANTICHOLINESTERASE
1. DIISOPROPLYFLUROPHOSPHATE (DFP)
 Forms a covalent bond between its phosphorus
atom and esteratic site of cholinesterase
 Limited to treatment of certain types of
glaucoma
2. PARATHION
 Used as insecticide
 Active form is the metabolite – maraoxan
 Pharmacologic effects similar to DFP
3. ECHOTHIOPHATE
 Long – acting organophosphate cholinesterase
inhibitor with pharmacologic properties similar
to DFP
 Spontaneous regeneration of phosphorylated
enzyme can occur
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 PHARMACOLOGY
Lyceum Northwestern University
COLLEGE OF MEDICINE
MECHANISM OF ACTION of MUSCARINIC
CHOLINERGIC ANTAGONIST ANTAGONIST
Dr. Perfecto Soriano
• Act like competitive pharmacologic
antagonists: their blocking effect can be
ANTICHOLINERGIC DRUGS overcome by increase concentrations of
muscarinic agonist
1. ANTIMUSCARINIC
• M1 – Selective EFFECTS:
• Non – Selective
• Tissues sensitive to atropine: salivary
glands, bronchial and sweat glands:
2. ANTINICOTINIC
Intermediate – smooth muscles heart
• Ganglionic Blockers
• Atropine is highly selective to muscarinic
• Neuromuscular Blockers
receptor
MUSCARINIC ANTAGONIST • Systemic administration - short half life of –
2h
1. ATROPINE • Topical ocular administration – longer half
• Lipid from Atropa belladonna or deadly life
nightshade o Bind to iris pigments and are
• Naturally occurring atropine 1 (-) released over days, dark irises bind
hyoscyamine more
• Tertiary amine
• Clinical uses: Eye, CNS, PHARMACOLOGIC EFFECTS -Muscarinic
Antihistamines, Antipsychotic, receptor antagonists inhibit parasympathetic nerve
Antidepressant stimulation
• Relatively lipid soluble, well-absorbed • Relax Smooth Muscle
from the gut and across conjunctival • Increase Hear Rate
membrane • Increase conductivity in the heart
• Distribution is 30 minutes - 1 hour • Inhibit exocrine gland secretion

2. SCOPOLAMINE These effects are dose dependent – the higher the

• Derived from Hyoscyamusniger or
henbane
• Well distributed in CNS, rapidly
disappear in the blood, partially
metabolized in the liver and partially
eliminated in the kidneys
• Elimination half-life - 2hours
• Duration of action – 4-8 hours
• Eyes – 72 hours or longer
3. IPATROPIUM
• Atropine Analog
dose the higher the effect
HEART
• Standard dose
o Locks the effect of vagus nerve
▪ Increase heart rate
▪ Increases AV conduction velocity
• Low dose
o When delivered by IV at low dose slows
heart rate by stimulating vagal motor
nucleus in the brain
• Used to treat sinus Bradycardia which can lead to
hypotension, ischemia if left untreated

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 PHARMACOLOGY
Lyceum Northwestern University
COLLEGE OF MEDICINE
CENTRAL NERVOUS SYSTEM GIT

• Atropine, scopolamine • Dramatic effects in motility and secretory

o Block muscarinic receptors
▪ Sedation, Excitement
• Scopolamine
o More sedating than atropine
o Used as an adjunct to anesthesia
o Rapidly and fully distributed in the CNS
than any other antimuscarinic drugs
o Slower long lasting sedative effects in the
brain
o Reduces tremors in Parkinson’s Disease
o Has marked central effects producing
drowsiness and amnesia
o Most effective drug against motion sickness
o Toxic dose: excitement, agitation,
hallucination
• Atropine
o Mild stimulation followed by a slower and
longer – lasting sedative effect
o Higher dose - > delirium, hallucination
• Ipatropium
o Atropine analog
functions of the gut
• Dry mouth is the frequent symptom
• Less effective blockade of gastric secretion
• Large dose may of atropine – decrease the acid
pepsin and mucin secretion
• Pancreatic and intestinal secretion less affected
• Motility – stomach – colon diminished
contraction
• Increased intestinal transit time
• Temporary intestinal paralysis reestablish in 1-3
days
GUT
• Ureter and bladder wall relaxed
• Have no significant effects on the uterus
SWEAT GLANDS
• Thermoregulatory sweating is suppressed by
atropine
• In adult – temperature is increased

EYES THERAPEUTIC APPLICATIONS

• Mydriasis • CNS
• Cycloplegia o Parkinson’s Disease
• Reduction lacrimal secretion o Motion Sickness
• Antimuscarinic Drugs used in Pharmacology • Ophthalmologic Disorders
Duration of effect • Respiratory Disorder
Atropine 7 – 10 days o Ipatropium is used in asthma and CPD
Scopolamine 3 – 7 days
Homatropine 1 – 3 days
Cyclopentolate 1 day • Cardiovascular disorder
Tropicamide 0.25 day
o Mark vagal discharge – pain of MI –
Sufficient depression of SA and AV
RESPIRATORY SYSTEM o Node function
▪ Impair CO
• Bronchodilator
• Gastrointestinal Disorders
• Decreases secretion in the trachea and the
• Urinary disorders
possibility of laryngospasm
o Urinary urgency urolithiasis to relieve
• Ipatropium – inhalation in case of
spasms
bronchoconstriction
o Telterodine
o Imipramine – antidepressant agent used in
incontinence
o Propiverine

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 PHARMACOLOGY
Lyceum Northwestern University
COLLEGE OF MEDICINE
• Cholinergic Poisoning
• Hyperhidrosis
EFFECTS OF GANGLIONIC BLOCKING DRUGS
ADVERSE REACTION CNS
• Atropine fever • Reduction of nicotine craving and
• Acute angle – closure glaucoma ameboration(DI KO MAINTINDIHAN :D) of
• Bladder retention tourette’s syndrome(mecamylamine)
• Constipation
• Sedation, amnesia, hallucination, delirium and Eye
convulsions • Moderate mydriasis and cycloplegia
• Intraventricular conduction blockade, dilation of
cutaneous vessels “atropine flush” Bronchi

CONTRAINDICATION • Little effect

• Hyperthemia GI Tract
• Glaucoma • Markedly reduced Motility

GU Tract
NICOTINIC RECEPTOR ANTAGONIST • Reduced contractility of the bladder impairment
• Ganglionic blocking agents (e.g. Trimethaphan) of erection and ejaculation
o Block Nn Receptors at Sympathetic and
Heart
parasympathetic
o Effect on a tissue, depends on sympathetic • Slight tachycardia in young adults, reduction in
or parasympathetic system is dominant force of contraction and cardiac output
o No longer are used to treat chronic
hypertension Blood Vessels
o Trimethaphan is occasionally used in cases • Reduction in arteriolar tone
of hypertensive emergency, when extremely • Mark reduction in venous tone
high blood pressure must be lowered rapidly
• BP decrease
• Severe orthostatic hypotension
• Ganglionic Blocking Drugs
Glands
Chemistry and Pharmacokinetics
• Reductions in salivations, lacrimations, sweating
• Synthetic amine
and gastric secretion
• Tetraethylammonium (TEA) – short
duration of action Skeletal muscle
• Hexamethonium – first effective drug used
• No significant effect
to treate hypertension
• Mecamylamine – secondary ammonium
compound with improved GI absorption –
only ganglionic blocking agent available in
the US
• Trimethapan – inactive orally; IV infusion to
treat malignant hypertension – produces
controlled hypotension

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Lyceum Northwestern University
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Neuromuscular Blocking agents
- Inhibit neurotransmission at skeletal muscle
ADRENERGIC AGONISTS
- Important for producing complete skeletal Dr. Perfecto Soriano
relaxtion in surgery
- Causing muscle weakness and paralysis ADRENERGIC AGONIST SYMPATHOMIMETIC
1. Non-depolarizing blockers DRUGS
2. Depolarizing Blockers Includes:
• Sympathomimetic drugs
NONDEPOLARIZING NEUROMUSCULAR
BLOCKING AGENTS( CURARIFORM DRUGS) • Adrenomimetic drugs
• Adrenergic agonists
• positively charged e.g. Pancuronium, Tubocurarine
• Adrenoceptor agonists
• are not well absorbed from the GUT, ence they do
not cause poisoning when ingested with • ultimate effects of sympathetic stimulation are
mediated by release of norepinephrine from nerve
contaminated meat
terminals, which then activates adrenoceptors on
• do not cross blood-brain barrier postsynaptic sites
• Competitive antagonists of Ach at Nm receptors
• epinephrine acts as a hormone, whereas
• Produces a competitive block at the end plate norepinephrine acts as a neurotransmitter.
nicotinic receptor
• Drugs that mimic the actions of epinephrine or
• Causing flaccid paralysis that last 30- 60 mins norepineph- rine have traditionally been termed
• Paralyze: sympathomimetic drugs.
o small fast moving muscles of eyes and face
o larger muscles of the limbs and trunk Sympathomimetic drugs
o the intercostal muscles and the diaphragm • direct agonists; that is, they directly interact with and
• is used for relaxation of abdominal muscles for activate adrenoceptors.
surgical procedures without producing apnea • Others are indirect agonists because their actions are
dependent on their ability to enhance the actions of
SIDE EFFECTS endogenous catecholamines.
-These indirect agents may have either of two
• stimulate mast cells to release histamine different mechanisms:
• tachycardia (1) they may displace stored catecholamines from the
• hypotension adrenergic nerve ending (eg, the mechanism
• bronchospasm of action of tyramine), or they may decrease the
clearance of released
DEPOLARIZING NEUROMUSCULAR norepinephrine either by
BLOCKING AGENTS (2a) inhibiting reuptake of catecholamines already
released (eg, the mechanism of
Succinylcholine action of cocaine
(2b) preventing the enzymatic metabolism of
• binds to Nm receptors norepinephrine (monoamine
• 1st transient muscle contraction followed by oxidase and catechol-O-methyltransferase
sustained muscle paralysis inhibi- tors).
• Ultra short duration action (5-10mins)
Review of Sympathetic Activation
• Produce muscle relaxation before and during
surgery • ‘Fight’or‘Flight’onStress
• Heart
↑HR,contractility,conductionvelocity
• Vessels (arterioles)

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Lyceum Northwestern University
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-Skin, cutaneous, visceral : constrict
-Skeletal muscle, coronary: dilate
• Vessels (Vein): constrict Types and subtypes of adrenoceptors

• Eye • Adrenergic receptors located on smooth muscle,

-Radialmuscle,iris: contract cardiac muscle, exocrine glands, endocrine glands and
-Ciliarymuscle: relaxforfarvision on nerve terminals.

• Lung • the transmitter in all adrenergic neurons is NE

-Trachealandbronchialmuscle: relax • When NE and Epinephrine interacted with an
adrenoceptor, in some tissues the response is
Stomachandintestine excitatory while in other tissues it is inhibitory
• ↓Motility and tone • Two subtypes of adrenoceptors
• Sphincters : contraction • a - excitatory in most tissues(except - intestinal
smooth muscle)
• Secretion (intestine): inhibition
• b - inhibitory in most tissues (except - heart)
• Urinarybladder
Detrusororbladderwall: relax Rank Order of Potency
Trigone,sphincter: constrict
• Posteriorpituitary: ADHsecretion
• Liver: glycogenolysis,gluconeogenesis Pancreatic
B cell---stimulate insulin releaseSkeletalmuscle
• ↓contractility, glycogenolysis, K+ uptake
• Fatcells: lipolysis
• Uterus
-non-pregnant: relax
• Sweatgland: secretion
• Hair : piloerection

Adrenomimetic drugs
• The effects of adrenomimetic drugs are similar to
sympathetic activation. 1. α- receptorsEpi > NE >> Iso
2. β- receptorsIso > Epi > NE
• But why each adrenomimetic drug can produce
different responses? Type of adrenoceptor
• The differences in affinity to adrenoceptor subtypes • α1,α2
are responsible for different responses.
• β1,β2,β3n
• DA1, DA2

Mechanism of action of Adrenomimetic Drugs

• α 1 via coupling protein Gq
• α 2 via coupling protein Gi
• β1 ,β2,β3 viacouplingproteinGs
MECHANISM OF ACTION OF

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Lyceum Northwestern University
COLLEGE OF MEDICINE

Classification of Sympathomimetics
• By chemistry
- Catecholamines
- Non-catecholamines
• By mode of action
-direct - acting
-indirect - acting
• By selectivity (to types of receptor)
Classification of Sympathomimetics
I. Catecholamines(CAs)
II. Non-catecholamines
A. Direct acting

ADRENOMIMETIC DRUGS • classifiedbyalpha,betareceptorsubtypes

• a1-selective,a2-selective,nonselective
• b1-selective,b2-selective,nonselective
Mechanism of action ofAdrenomimetic drug B. Indirect acting
-Releasers
Mechanism of action of Dopamine - Reuptake inhibitors
DA1 type
• cAMP Receptor types :
DA2 type 1. Alpha receptors
• cAMP - are coupled via G proteins in the Gq family to
Central Dopamine Receptor -different effect phospholipase C.
• D1-like: D1A, D1B, D5 - This enzyme hydrolyzes polyphosphoinositides,
leading to the formation of inositol 1,4,5-
• D2-like: D2, D3, D4 trisphosphate (IP3) and diacylglycerol (DAG). IP3
promotes the release of sequestered Ca2+ from
intracellular stores, which increases cytoplasmic free

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Ca2+ concentrations that activate various calcium-
dependent protein kinases.
- Alpha2 receptors are coupled to the inhibitory
regulatory pro- tein Githat inhibits adenylyl cyclase
activity and cause intracellular cyclic adenosine
monophosphate (cAMP) levels to decrease.
- It is likely that not only α, but also the β-γ subunits of
Gi contribute to inhibition of adenylyl cyclase.
B. Beta receptors
- Activation of all three receptor subtypes (β1, β2, and
β3) results in stimulation of adenylyl cyclase and
increased cAMP
C. Dopamine receptor
-D1 receptor is typically associated with the stimulation
of adenylyl cyclase
-D2 receptors have been found to inhibit adenylyl
cyclase activity, open potassium channels, and decrease
calcium influx.
Receptor Regulation
-desensitization may occur after exposure to
catecholamines and other sympathomimetic drugs.
~One of the best-studied examples of receptor
regulation
~ Other terms such as tolerance, refractoriness, and
tachyphylaxishave also been used
to denote desensitization
~This process has potential clinical significance
because it may limit the therapeutic
response to sympathomimetic agents.
~major mechanism of desensitization that occurs
rapidly involves phosphorylation of
receptors by members of the G protein- coupled
receptor kinase (GRK) family, of which
there are seven members.
~two major categories of desensitization of
responses mediated by G protein-coupled
receptors:
1. Homologous desensitization
refers to loss of responsiveness exclusively of
the receptors that have been exposed to
repeated or sustained activation by an agonist.
2. Heterologous desensitization
refers to the process by which desensitization of
one receptor by its agonists also results
in desensitization of another receptor that has not been
directly acti- vated by the agonist in
question.
-Phosphorylation of these receptors enhances their
affinity for arrestins, a family of four proteins, of which
the two nonvisual arrestin subtypes are widely expressed
DIRECT-ACTING SYMPATHOMIMETIC DRUGS
PHARMACOLOGY
CATECHOLAMINES: Norepinephrine and
Epinephrine
• Chemistry:
a. Tyrosine is hydroxylated on the aromatic ring by
tyrosine hydroxylase yielding dopa
(dihydroxyphenylalanine); this is the rate limiting step in
biosynthesis of adrenergic transmitters.
b. Dopa is decarboxylated to give dopamine
c. Dopamine is hydroxylated on the β-carbon to give
norepinephrine
d. Epinephrineisformedintheadrenalmedullaby
methylation of norepinephrine
Pharmacokinetics of Epinephrine and Norepinephrine
a. Absorption is poor with oral administration because
the drugs
are rapidly conjugated and oxidized.
b. Absorption is slow with subcutaneous administration
because the drugs cause local vasoconstriction
c. Nebulized and inhaled solutions usually used for their
actions on respiratory tract.
d. The drugs can be given IV, but route must be used
with caution so that the heart does not fibrillate.
e. The liver is an important in the degradation of
epinephrine and norepinephrine. The majority of the
dose is metabolized by catechol O-methyltransferase
(COMT) and monoamine oxidase (MAO), and
metabolites are excreted in the urine
Pharmacologic Effects of Epinephrine
• Interacts strongly with both β- and α-receptors.
• Its effects on some body systems depend on the
concentration of epinephrine as well as type of
receptor.
• At low concentration, β effects predominate, and, at
high concentration, α effects predominate.
Effects onBloodPressure
• A large dose of epinephrine administered IV causes
an increase in blood pressure, with the systolic
pressure increasing more than the diastolic.
• The rise in pressure is due to:
- Vasoconstriction through activation of α- receptors.
- Increased ventricular contraction through activation
of β- receptors
- An initial increase in heart rate, which in the height
of the vasopressor response, is slowed by a
compensatory vagal
discharge.
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Effects on the Heart
• A direct effect on β1-receptors, producing a slight
initial increase in heart rate, which is slowed by a
compensatory vagal discharge.
• Increased in stroke volume
• Increased in cardiac output
• A propensity toward arrhythmias
Effects on Smooth Muscle
• Depends on the predominant type of adrenergic
receptor in the muscle
• Epinephrine relaxes GI smooth muscle (α2- and β-
receptor stimulation), whereas it usually increases
sphincter contraction (α stimulation).
• Uterine contractions may be inhibited (β) or
stimulated (α), depending on menstrual phase or state
of gestation.
• In the bladder, the detrusor muscle relaxes (β), while
the trigone and sphincter contract (α)
• Bronchiolar smooth muscle relaxes (β2)
Metabolic Effects
• An increase in glucose and lactate production via
liver and
muscle glycogenolysis (β2).
• Inhibition of insulin secretion (α).
• An increase in free fatty acids, mediated by cAMP
(β1)
• An increase in oxygen consumption
• Pharmacologic Effects of Norepinephrine
• Equipotent to epinephrine in its reaction on β1-
receptors, and slightly less potent on α- receptors. It
has very little effects on β2-receptors.
• An IV infusion raises both systolic and diastolic
pressure by constriction of vascular smooth muscle
(α-receptors)
• The increased peripheral vascular resistance
produces a compensatory vagal reflex that slows the
heart rate. Cardiac output may actually decrease,
although coronary blood is increased.
Termination of Action
PHARMACOLOGY
• Transport, or uptake into the cells, is an important
mechanisms for terminating the action of many
neurotransmitters. There are two active amine
transport systems:
1. A system in the plasma membrane transports amines
from the extracellular fluids to the cytosol.
2. A system in the secretory granular membrane
transports amines into granules
• Deactivation by conversion to inactive metabolites
1. COMT adds a methyl group to the hnydroxyl of the
catechol ring.
2. MAO removes the amine group. When metabolic
breakdown or transport is prevented (as in patients
taking MAO inhibitors or tricyclic antidepressants), then
the dosage of sympathomimetic agents must be reduced.
Therapeutic Uses
1. To treat bronchospasm
2. For relief of hypersensitivity reactions; it is the
primary treatment for anaphylactic shock
3. To prolong the duration of infiltrative anesthesia
4. To restore cardiac activity in cardiac arrest
5. To facilitate aqueous drainage in chronic open-angle
glaucoma.
6. Norepinephrine is used for treating hypotension
during anesthesia when tissue perfusion is good.
Adverse Effects of Epinephrine and NE
1. Anxiety
2. Headache
3. Cerebral hemorrhage from the vasopressor effects.
4. Cardiac arrhythmias, esp. in the presence of digitalis
and certain anesthetic agents
5. Pulmonary edema from pulmonary hypertension.
Vascular Effects
• Epinephrine exerts its action on small arterioles and
precapillary sphincters. Its vascular effects include:
- Decreased cutaneous blood flow
- Increased blood flow to skeletal muscle at low
concentrations and decreased flow at higher
concentrations.
- Increased hepatic blood flow with increased
splanchnic vascular resistance.
- Increased renal vascular resistance, producing
decreased renal blood flow.
- Increased renal vascular resistance, producing,
decreased renal blood flow.
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- Increased arterial and venous pulmonary pressure.
- Increased coronary blood flow, caused indirectly by
an increase in the work of heart, and mediated by
local effectors.
Isoproterenol
• Pharmacokinetics
• Absorptionof orally administered isoproterenol is
unreliable
• It is readily absorbed when given parenterally or as
an inhaled aerosol.
• It is principally metabolized by COMT; MAO plays
a smaller role than in epinephrine or noepinephrine
metabolism.
Pharmacologic Effects
• Has an N-alkyl substitution, which makes it act
almost entirely on β-receptors and have a little effect
on α- receptors.
• IV infusion produces a reduction in peripheral
vascular resistance in skeletal muscles and in renal
and mesenteric vascular beds.
• Diastolic blood pressure falls, but because there are
increased venous return positive inotropic and
chronotropic effects, cardiac output is increased.
• Systolic blood pressure may increase, but mean
pressure decreases.
• Renal blood flow decreases in normotensive
individuals, but it increases in patients with
nonhemorrhagic shock.
• Relaxation of both bronchial and GI smooth muscle
occurs.
• A release of free fatty acids occurs; hyperglycemia is
less than
• Pancreatic islet cells are activated, stimulating
insulin secretion.
Therapeutic Uses
• Bronchodilator
• Cardiac stimulant
Adverse Effects
PHARMACOLOGY
• These are similar to the adverse effects of
epinephrine.
• Overdosage by inhalation can produce fatal
ventricular arrhythmias
• Tolerance to the desired effects occurs with overuse
in the asthmatic.
Dopamine
• Chemistry
- Intermediate in the synthesis of norepinephrine
• Pharmacokinetics
- Resembles epinephrine and noepinephrine
• Central Dopamine Receptors (D1, D2, D3)
- The central D1- receptor site is excitatory and
directlyactivates the adenylate cyclase system.
- The D2 receptor site is inhibitory in some brain
tissues and uses cAMP as 2its intracellular messenger.
Pituitary-related side effects of neuroleptics are
thought to be mediated through D2 recptors in the
pituitary.
- The D3 receptor is localized in the limbic system
and is not found in the pituitary. It is principally
associated with emotional and cognitive behavior.
Pharmacologic Effects
• Important neurotransmitter in the CNS
• Direct-agonist, acting on β1-receptors and releasing
norepinephrine from nerve terminals. The result is a
positive inotropic effect on the myocardium.
• Low or intermediate doses of dopamine reduce
arterial resistance in the mesentery and kidney; this
raises the glomerular filtration rate. The effect is
mediated by a receptor for dopamine.
• At higher dose, it acts on α-receptors and causes
vasoconstriction with a consequent reduction in renal
function.
Therapeutic Uses:
• Cadiogenic and septic shock
• Chronic refractory Congestive Heart Failure
Adverse Effects
• Excessive sympathomimetic activity
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• Anginal pain, arrhythmias, nausea and hypertension
can occur, but these effects are short-lived because
dopamine has rapid metabolism.
Dobutamine
• Pharmacokinetics
- Not absorbed when given orally
- Half-life- 2 minutes when given IV
• Pharmacologic Effects
- Resembles dopamine chemically, it is a direct β1-
receptoragonists. It has a greater inotropic than
chronotropic effect.
- Does not act on dopaminergic receptors.
• Therapeutic uses
- Used to improve myocardial function in CHF.
- Oxygen demands are less than with other
sympathetic agonists because it causes minimal
changes in heart rate and systemic pressure.
Adverse Effects
• Increases AV conduction- used with caution in atrial
fibrillation.
• Similar with other catecholamines
Phenylephrine
• Pharmacologic Effects
- Direct-acting sympathomimetic agent
- Similar to norepinephrine- but less potent and has
longer duration of action.
- Vasoconstriction, increased atrial pressure, reflex
bradycardia occurs with parenteral administration.
• Therapeutic Uses
- Nasal decongestant
- hyperresponsiveness to metacholine challenge.
Pressor agent
- Provide local vasoconstriction:
~10% ophthalmic solution
~Adjunct for use with local anesthetics
- For relief of paroxysmal atrial tachycardia
Adverse Effects
• Large doses cause cardiac irregularities.
• Ophthalmic solutions, like intranasal solutions-
systemically absorbed
PHARMACOLOGY
• In patients taking β-blockers increases the risk of
cardiac irregularities, myocardial infarction, and
intracranial hemorrhage
• Rebound nasal congestion can occur in chronic use
as nasal decongestant.
Methoxamine
• Direct-acting stimulator of α-adrenergic receptors
with pharmacologic properties similar to those of
phenylephrine.
• It produces little CNS stimulation.
• Its large pressor effects results from an increase in
total peripheral resistance.
• It causes a reflex bradycardia.
• Used therapeutically in hypotensive state and to end
attacks of paroxysmal atrial tachycardia
β2- Adrenergic Agents
• Pharmacologic Effects
- Primarily β2- agonists has a relaxing effect on
bronchial smooth muscle and show little effect on
cardiac β1- receptors.
• Therapeutic Uses:
- Used therapeutically for the treatment of bronchial
asthma or bronchospasm, where their lack of cardiac
stimulation is a decided advantage
• Administration
- Inhaled
- Oral
- Parenteral
Adverse Effects
• Similar to other sympathomimetic agents
• Regular used of short-acting β2 agonists can be
associated with increased bronchial
• Overuse of β2-agonists by patients with asthma has
been associated with increased mortality
• Even though their effects are primarily bronchial,
β2- agonists should be used in patients with
cardiovascular disease or hyperthyroidism because of
its effects on β1- receptors of the heart.
Specific Agents:
• Metaproterenol has more rapid onset of
bronchodilating
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action in asthma than either albuterol or terbutalline
• Albuterol- more bronchoselective than isoproterenol
when given as an inhalant
~ Effects is apparent within 15
min., maximal at about 60-90 min., last about 3-4 hour
• Salmeterol is a long-acting β2 selective adrenergic
agonist inhalant used for maintenance treatment of
asthma,with or without inhaled corticosteroids. It also
appears to inhibit the release of inflammatory
mediators from lung tissue
~ Not recommended for acute treatment of
bronchospasm, bronchodilation begins in 15 minutes but
can last up to 12 hours
~ Because it is a long-acting, a short acting β2-agonist
can be administered as needed to control acute
symptoms.
• Terbutalline- when used in the treatment of bronchial
asthma, has longer duration of action than
metaproterenol. It may have more side effects than
other sympathomimetic agents.
- Otheruses:Tocolyticagent
- Administration:oral,inhalation,subcutaneous
• Bitolterol is a prodrug that is converted in the lung to
colterol, an active catecholamine. It may have a
longer duration of action than terbutalline,
metaproterenol, or albuterol. It may cause tremor due
to stimulation of skeletal muscle, in addition to the
adverse effects seen with all sympathomimetic agents
• Other agents: Salbutamol, Procaterol, Bambuterol
MIXED-ACTING SYMPATHOMIMETIC DRUGS
Ephedrine
• Pharmacokinetics
- Absorbed when taken orally
- Resistant to COMT and MAO, so that its action is
prolonged.
• Pharmacologic Effects
- Mixed-acting sympathomimetic agent- both direct and
indirect actions
~ Its primary action is indirect. It causes the release of
norepinephrine from the storage in nerve terminals,
apparently by competing with norepinephrine for
transport into the granules.
~ It also produces direct stimulation of adrenergic
receptors.
PHARMACOLOGY
• When administered IV, its action is similar to that of
epinephrine. However,
1. its pressor response occurs more slowly and lasts 10
times longer.
2. Its potency is 1/120 that of epinephrine in producing
and equivalent pressor response.
• Ephedrine increases arterial pressure by causing
peripheral vasoconstriction and cardiac stimulation.
• Its effects on the bronchi and other smooth muscles
are qualitatively similar to those of epinephrine.
• It causes CNS stimulation, which can result in effect
such as insomia, nervousness, nausea and agitation.
• Tachyphylaxis occurs with repeated administration
Methamphetamine & Hydroxyamphetamine
• Methamphetamine
- Related chemically to both amphetamine and
ephedrine.
- Mixed-acting sympathomimetic agent, it is equal to
amphetamine in central stimulant activity and is more
potent than ephedrine in pressor activity.
- Therapeutic indications are limited to those that make
use of CNS effects, such as narcolepsy
• Hydroxyamphetamine
- Has an action resembling that of ephedrine but without
CNS
effects.
- It is used as a mydriatic, decongestant, and pressor
agent.
Mephentermine
• Mixed-acting sympathomimetic
• Its peripheral vasopressor actions are similar
tothoseof methamphetamine
• It lacks significant central actions
• Major therapeutic use in the treatment of
hypotension
Metaraminol
• Mixed-acting sympathomimetic that is similar to
norepinephrine in its action- less potent than NE
• Increases diastolic and systolic pressure via
vasoconstriction, and
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produces a martked reflex bradycardia
• It has little stimulant effect on the CNS
• Its major therapeutic use is in the treatment of
hypotensive state.
ADRENERGIC RECEPTOR ANTAGONISTS
• In clinical therapeutics, nonselective α antagonists are
used in the treatment of pheochromocytoma (tumors
that secrete catecholamines)
• α1-selective antagonistsare used in primary
hypertension and benign prostatic hyperplasia.
• Beta-receptor antagonist drugs are useful in the
treatment of hypertension, ischemic heart disease,
arrhythmias, endocrinologic and neurologic disorders,
glaucoma, and other conditions.
Mechanism of Action
PHARMACOLOGY
• Alpha-receptor antagonists may be reversible or
irreversible in their interaction with these receptors.
• Reversible antagonists dis- sociate from receptors,
and the block can be surmounted with sufficiently
high concentrations of agonists;
• Irreversible drugs do not dissociate and cannot be
surmounted.
• Effects of an irreversible antagonist may persist long
after the drug has been cleared from the plasma
CLASSIFICATION OF ADRENERGIC RECEPTOR
ANTAGONISTS
• α-receptor antagonist drugs cause a lowering of
peripheral vascular resistance and blood pressure
• Alpha-receptor antagonists often cause orthostatic
hypotension and reflex tachycardia
• Nonselective (α1 = α2, Table 10–1) blockers usually
cause significant tachycardia if blood pressure is
lowered below normal
A. Alpha Adrenergic Blockers
1.) Non-selective-
a.) Irreversible
b.) Reversible
2.) Alpha 1-selective
3.) Alpha 2-selective
B. Beta Adrenergic Blockers
1.) Non Selective
2.) Beta 1-selective
3.) Beta 2- selective
C. Alpha Adrenergic Receptor Antagonists
1. ALPHA RECEPTORS mediate many important
actions of
endogenous catecholamines. These include:
a. ALPHA 1 mediated VASOCONSTRICTION,
b. ALPHA 2 receptor mediated INHIBITION OF THE
RELEASEOF NE and ACh,
c. ALPHA 2 mediated INHIBITION OF INSULIN
SECRETIONAND INHIBITION OF LIPOLYSIS,
d. ALPHA 2 mediated CONTRACTION OF BLOOD
VESSELS INSKIN AND
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MUCOSA (these receptors are preferentially activated
by circulating catecholamines, whereas alpha 1 receptors
are activated by NE released at sympathetic nerve
terminals).
e. alpha 2 mediated central INHIBITION OF
SYMPATHETIC TONE.
the most important effects of alpha 1 & 2 adrenergic
antagonists are on the
CARDIOVASCULAR SYSTEM.
• these cardiovascular effects are mediated in large part
by the effects of the antagonists on sympathetic nerve
endings, and by effects on the CNS
• the antagonism which is observed in most cases is
competitive
CARDIOVASCULAR EFFECTS OF ALPHA 1
ANTAGONISTS
Blockade of α receptors in other tissues elicits miosis
(small pupils) and nasal stuffiness
1.ALPHA 1 ANTAGONISTS
• BLOCK VASOCONSTRICTION induced by
endogenous catecholamines
• the resulting fall in peripheral resistance leads to a
FALL IN MEAN BLOOD PRESSURE
• the magnitude of this effect is dependent upon the
degree of sympathetic tone at the time the antagonist
is administered.
• thus, there is less hypotension in the supine than in the
standing patient
• the decrease in blood pressure leads to a reflex
tachycardia the effects are exaggerated if
the drug also has alpha 2 antagonist effects, because
antagonism of alpha 2 receptors facilities release of NE
presynaptically to cause a further tachycardic effect
• they block the vasoconstriction and hypertensive
effects of exogenous sympathomimetics.
for example, pressor responses to phenylephrine (a pure
alpha 1 agonist) are completely blocked.
CARDIOVASCULAR EFFECTS OF ALPHA 2
ANTAGONISTS
2. ALPHA 2 ANTAGONISTS
• increase sympathetic outflow by an action on the CNS
this potentiates the RELEASE of
NOREPINEPHRINE
• from sympathetic nerve endings leading to
PHARMACOLOGY
ACTIVATION OF ALPHA 1 RECEPTORS IN
VASCULAR SMOOTH MUSCLE, and BETA 1
RECEPTORS IN THE HEART among others.
• the net result is an increase in MEAN BLOOD
PRESSURE and a REFLEX BRADYCARDIA
Other Actions of Alpha Adrenergic Antagonists
1.ALPHA 1 ANTAGONISTS
• can BLOCK ALPHA 1 RECEPTORS THAT
MEDIATE CONTRACTION OF NONVASCULAR
SMOOTH MUSCLE such as the trigone and
sphincter muscles of the bladder, leading to decreased
resistance to urinary outflow
2. Activation of Alpha 2 receptors causes inhibition of
insulin secretion
• BLOCKADE of these receptors FACILITATES
INSULIN RELEASE
ALPHA ADRENERGIC ANTAGONISTS (Specific
Agents)
1. PHENOXYBENZAMINE
• is an irreversible alpha blocker that blocks both alpha
1 and alpha 2 receptors with slight PREFERENCE
FOR ALPHA 1 RECEPTORS
• irreversible; long acting
• it causes a DECREASE IN PERIPHERAL
RESISTANCE,
and a REFLEX TACHYCARDIA due to hypotension
mediated baroreceptor effects, and also because it blocks
alpha 2 receptors, resulting in increased release of NE
• HYPOTENSIONis particularly prevalent when
sympathetic reflexes are active, such as in the
standing patient, or during stress
• a MAJOR SIDE EFFECT THEREFORE IS
POSTURAL HYPOTENSION
• also seen are cardiac arrhythmias
• others ejaculation is inhibited, miosis, nasal stuffiness,
nausea and vomiting
• Phenoxybenzamine blocks pressor responses to
exogenous catecholamines, and in fact causes reversal of
the pressor response to EPI into a depressor response
• it also inhibits the uptake of catecholamines into nerve
terminals and extraneural uptake sites
• it irreversibly inhibits 5-HT and histamine receptors
in higher doses than those reqired
for alpha receptor blockade
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• duration of the effect of the drug is 48 hours to many
days
• has short elimination half-life
• a major use of the drug is in the management
ofHYPERTENSION inPHEOCHROMOCYTOMA
prior to
surgery
• to REVERSE VASOCONSTRICTION IN SHOCK
• to RELIEVE VASOSPASM in RAYNAUD’S
phenomenon
2.PHENTOLAMINE and TALOZOLINE
• are competitive antagonists of both alpha 1 and alpha
2 receptors
• as such their effects on the cardiovascular system are
similar to those of phenoxybenzamine
• reversible , short-acting Phentolamine (non-selective);
Tolazoline (slightly selective)
• used to control ACUTE HYPERTENSIVE
EPISODES treatment test for
PHEOCHROMOCYTOMA
• treatment of PERSISTENT PULMONARY
HYPERTENSION in
neonates
• experimentally used to relieve vasospasm in
Raynaud’s
phenomenon
• duration of action:
• Oral: 2–4 days Parenteral: 20–40 minutes
• these drugs also have a parasympathetic effect on GI
smooth muscle and gastric secretions
• toxicity is like that of Phenoxybenzamine
** PHentolamine
• Pheochromocytoma Hypertensive episodes
Pulmonary Hypertension
• Adverse Effects of PHENTOLAMINE and
TOLAZOLIN: ARRHYTHMIA and ANGINAL
PAIN
can produce PARADOXICAL HYPERTENSION
induce GASTROINTESTINAL STIMULATION
ADRENERGIC RECEPTOR ANTAGONIST
1. PRAZOSIN
• is the prototype of a family of potent and VERY
SELECTIVE
ALPHA 1 RECEPTOR ANTAGONISTS
PHARMACOLOGY
• it has 1000 times greater affinity for alpha 1 vs alpha
2 receptors
• it is a short acting drug with a duration of about 7 to
10 hours
• PRAZOSIN causes a decrease in TOTAL
PERIPHERAL RESISTANCE but NOT an
INCREASE in HEART RATE (since alpha 2
receptors are not inhibited)
• DECREASE ARETERIAL PRESSURE with little
change in cardiac output
2. TERAZOSIN
• is a close structural analogue of prazosin with similar
pharmacological effects but an intermediate duration
of action, is approximately 18 hours
3. DOXAZOSIN
• is another structural analogue with similar
pharmacological effects to Prazosin, but with a long
duration of action as 36 hours.
• amajoruse ofthesedrugs,PRAZOSINanditsanaloguesis
in the treatment of HYPERTENSION
• Alpha 1 receptors in the trigone muscle of the bladder
and in the urethra contribute to the resistance to
outflow of urine.
• Alpha 1 receptor blockers reduce this resistance
especially when impaired bladder emptying is the
result of BENIGN PROSTATIC HYPERPLASIA
• Adverse effects of these drugs include the so called
“FIRST DOSE PHENOMENON”that is marked
postural hypotension & fainting 30-90 minutes after
the first dose or with the addition of a second
antihypertensive drug to a patient already taking one
of these agents
4. TAMSULOSIN
• is another alpha 1 blocker with little effect on alpha 1-
B receptors
• considerable efficacy at the alpha 1-A receptor which
is believed to be predominant in human bladder and
prostate
• it is used in the treatment of BENIGN PROSTATIC
HYPERPLASIAbecause it decreases the resistance to
urinary flow with less hypotensive effects on blood
pressure
**although all the alpha blockers have been tested and
are relatively effective in BPH
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COLLEGE OF MEDICINE
5. ALFUZOSIN 3. Sometimes used in treatment of peripheralvasospastic
Is another related compound used in the treatment of diseaseRAYNAUDS disease to
perfusion
benign prostatic hypertrophy
4. To enhance urinary flow in benign
PRazosinos
PROSTATICHYPERPLASIAmajor therapy is
Tamsolusin
SURGERY
Alfuzosin
5. Treatment of local EXCESS CONCENTRATION of
Terazosin
aVASOCONSTRICTOR in order to prevent necrosis
Doxazosiiiiiiiiiiiiiiiiiiiin – longest half-life
TOXICITY of ALPHA BLOCKERS
MISCELLANEOUSDRUGSwithAlpha
1. POSTURAL HYPOTENSION
Adrenergicblocking activity:
2. REFLEX TACHYCARDIA
• the ERGOT Alkaloids where the first adrenergic 3. Other ARRHYTHMIAS
blocking agents to be discovered Ergot is a FUNGUS 4. Parasympathomimetic effects of Phentolamine and
which grows on rye which contains many biologically Tolazoline
active components
• ERGOT ALKALOIDSare weak alpha-blocking agent
and are serotonin antagonists BETA ADRENERGIC ANATAGONISTS
CLASSIFICATION:
• PARTIAL AGONIST at alpha-adrenergic receptors
Pharmacologic Effects: 1. RECEPTOR SELECTIVITY
-CNS stimulats
-irregular respiration A.Non-selective
-confusion
-anxiety Propranolol

• Directly stimulate smooth muscle Sotalol

• Significant elevation of BP via peripheral Acetabulol (β1>β2)

vasoconstriction Timolol
Labetalol
• ERGOTAMINE tartrate treatment in MIGRAINE Nadolol
headache
Pindalol
• ERGONOVINE maleate powerful OXYTOXIC but
lacks the adrenergic blocking activity of ergotamine B. Beta 1- receptor selectivity
• causes direct contraction of uterine smooth muscles Acetabulol
and used to decrease postpartum bleeding Esmolol
Metoprolol
• METHYLERGONOVINE maleate used to decrease Nebivolol
postpartum bleeding Atenolol
• METHYLSERGIDEused as prophylactic agent for
migraine attack C. Beta 2-receptor selectivity Acetabulol
• ERGOTISMis a disease characterized by profound Butoxamine
VASOCONSTRICTION ISCHEMIA and
GANGRENE of the affected limb
D. Alpha-Beta Blockers Labetolol Carvedilol (β1
• in the Middle Ages it was known as ST. selective, α3 antagonist)
ANTHONY”S FIRE was relieved by visiting the
shrine of St. Anthony which was Cetiprolol
located in an area of France where bread was seldom
contaminated with the fungus 2. PARTIAL AGONIST ACTIVITY
Pindolol Acetabulol(causesomebronchodilation)
THERAPEUTIC USES OF ALPHA ADRENERGIC
RECEPTOR BLOCKERS: Celiprolol (β2 agonist)
1. HYPERTENSION
2. PHEOCHROMOCYTOMA

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BETA ADRENERGIC RECEPTOR BLOCKERS
• Beta- blocking drugs occupy β receptors and
competitively reduce receptor occupancy by
catecholamines and other β agonists.
• β-blocking drugs in clinical use are pure antagonists
A. INTRODUCTION
1. Cardiovascular effects of Beta Blockers
• since catecholamines have positive inotropic &
chronotropic effects on the heartBETA BLOCKERS
SLOW the HEART RATE and DECREASE
MYOCARDIAL CONTRACTILITY
• when sympathetic activation is low, these drugs have
modest effects
• however, when sympathetic activation is high, such as
during exercise & stress, beta-blockers attenuate the
expected increase in the heart rate and diminish
cardiac output
• Beta blockers tend to decrease the capacity to work
• exercise performance is impaired less by selective
Beta 1 blockers
• Beta blockers have important effects on cardiac
rhythm and automaticity
• they reduce the sinus rate, decrease the rate of
depolarization of ectopic pacemakers, and slow
conduction in the atria & AV node
• Beta blockers DO NOT LOWER BLOOD
PRESSURE in NORMAL MANhowever they do
reduce blood pressure in hypertensive man. The
mechanism of this effect has not been satisfactorily
explained
• some beta blockers have peripheral vasodilating
effects via different mechanisms which may
contribute to their capacity to lower blood pressure
(These include celiprolol and nebivolol)
• Chronic prophylactic therapy with a beta blocker in
patients who have had a myocardial infart appears to
help prevent the recurrence of a second fatal
myocardial infarct.
2. Pulmonary effects of Beta Blockers
• Beta blockade usually has little effect on pulmonary
function in normal man
• however in ASTHMATICS – they can cause the
threatening bronchoconstriction.
• Although beta 1 selective blockers maybe less likely
to cause respiratory problems in asthmatics, these
PHARMACOLOGY
drugs should be used with great caution, if at all in
patients with bronchospastic disease since even
relatively selective blockers have some affinity for the
beta 2 receptor
3. METABOLIC EFFECTS OF BETA BLOCKERS
CATECHOLAMINES
• promote glycogenolysis & mobilize
glucose in response to hypoglycemia.
• BETA BLOCKERS (Beta 3 receptor) attenuate the
lipolytic response to sympathetic nervous system
activation which is an important energy source for
exercising muscle. Selective beta 1 antagonists may
cause these effects less frequently than non-selective
antagonists.
• Nonselective Beta blockers must therefore be used
with great caution in diabetics. A selective Beta 1
blocker is usually preferable in this case.
SPECIFIC AGENT OF BETA RECEPTOR
BLOCKING DRUGS
1. PROPRANOLOL
• After oral administration, propranolol is almost
completely absorbed but undergoaes extensive first
pass metabolism in the liver
• the extent of clearance by the liver varies radically
across patients however and results ina s much as a 20
fold difference in plasma concentration of the drug
after oral administration to different persons
• this has obvious significance in patients with liver
disease
• completely absorbed in the GIT
• 90% of the drug in the circulation is bound to plasma
proteins
• elimination half-life is 3 hours, prolonged half-life in
larger dose
• WHEN USED AS AN ANTIHYPERTENSIVE
AGENT THE FULL RESPONSE ON THE BLOOD
PRESSURE MAY NOT DEVELOP UNTIL AFTER
SEVERAL WEEKS OF ADMINISTRATION
• Abrupt withdrawal of Propranolol after chronic
therapy can lead to the development of withdrawal
symptoms
PHARMACOLOGIC EFFECTS:
• decrease heart rate & cardiac output
• prolong systole
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Lyceum Northwestern University
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• decrease total coronary blood flow and oxygen
consumption
• reduces blood flow in most tissues except the brain
lowers BP
• inhibit renal secretion of rennin
• decrease Na excretion increases airway resistance by
β2 blockade interferes carbohydrate and fat metabolism
• Therapeutic uses treatment of HYPERTENSION in
combination with DIURETIC PROPHYLAXIS of
angina pectoris prophylaxis of SUPRAVENTRICULAR
and VENTRICULAR ARRYTHMIAS
• long term prophylaxis in patients who have had MI
management of HYPERTROPIC OBSTRUCTIVE
CARDIOMYOPHATIES to reduce force myocardial
contraction management of HYPERTHYROIDISM
• decrease heart rate prophylaxis for migraine
headaches
SIDE EFFECTS:
• include GI distress (relatively unopposed
parasympathetic nervous system
• CNS effects such as nightmares, insomnia, fatigue,
sexual dysfunction and depression,
• induce heart failure especially in patient with MI,
rapid withdrawal can lead to hypersensitivity of beta-
adrenergic receptors-anginal attacks
• arrhythmias or MI
• increases airway resistance
• hypoglycemic action of insulin can be augmented
rash, fever, purpura, contraindicated in patients with
Raynaud’s phenomenon
2. NADOLOL
• is a non-selective beta blocker with a LONG
DURATIONOF ACTION
• is poorly lipid soluble and incompletely absorbed
from the GI tract
• interindividual variability in its bioavailability is less
than with Propranolol
• it is extensively metabolized & is EXCRETED
INTACT IN THE URINE
• as such KIDNEY DISEASE is a cause for concern,
and may result in an accumulation of NADOLOL
because NADOLOL is poorly lipid soluble,
• it is thought that there will be lower concentrations of
Nadolol in the brain,and this may contribute to a
PHARMACOLOGY
lower incidence of CNS side effects seen with this
drug.
• Not metabolized and is excreted unchanged in urine.
• Adverse effect-similar to Propranolol
3. TIMOLOL
• it is a nonselective blocker with a SHORT
DURATION of action
• it is well absorbed from the gut and is subject to
moderatefirst pass metabolism
• it is metabolized by the liver and only a small fraction
isexcreted by the kidney in unchanged form
• Timolol is an example of a beta blocker which is used
in glaucoma to reduce the rate of synthesis of aqueous
humor
• the ocular form of timolol is well absorbed into the
circulation and adverse effects can occur in patients
with asthma or congestive heart failure
• Other new drugs with similar mechanisms of action
include Penbutolol, and Pindolol
4. LABETOLOL
• it is an example of a nonselective beta blocker which
also blocks alpha 1 receptors.
• it also inhibits uptake of NE from the synaptic cleft (a
cocaine-like effect).
• its pharmacokinetics are like those of Propranolol, is
well absorbed, highly metabolized and very variably
so on first pass through liver, mainly metabolized by
liver.
• it is used in the treatment of
PHEOCHROMOCYTOMA and HYPERTENSIVE
EMERGENCY,where its alpha 1 effects promote
vasodilation and hypotension, while its beta 1 effect
helps reduce reflex tachycardia.
• ADVERSE EFFECTS:
• postural hypotension,
• jaundice,
• same to other β-blockers
• can be administer IV in hypertensive emergencies
other new drugs with a similar mechanism of action
• include Carvedilol, and Bucindolol
5. SOTALOL
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Lyceum Northwestern University
COLLEGE OF MEDICINE
• non-selective β-blocker without intrinsic • it has a somewhat longer duration of action
sympathomimetic or local anesthetic activity thanmetoprolol.

• 6. PINDOLOL 3. ESMOLOL

• is non-selective β-blocker with intrinsic • it is a selective Beta 1 antagonist with a VERY

sympathomimetic alpha-adrenergic activity, no VERY SHORTDURATION OF ACTION which is
rebound tachycardia upon withdrawal also devoid of intrinsic sympathomimetic activity and
membrane-stabilizing activity

• 7. ACETABULOL • it is given by IV infusion

• β-blocker with mild intrinsic sympathomimetic • it has a half life of about 8 minutes in plasma, and is
activity, β1>β2 effects metabolized by plasma esterases

• ADVERSE EFFECTS: same with other β-blocker • it is used ONLY for the treatment of ATRIAL
agents, arthritis, myalgia and arthralgia • TACHYCARDIA.
PHARMACOLOGY OF SELECTIVE BETA • 4. NEBIVOLOL
BLOCKERS
• it is the MOST SELECTIVE BETA 1
ANTAGONIST clinically
• 1. METOPROLOL
• available which is devoid of intrinsic
• it is a selective Beta 1 antagonist, whose sympathomimetic activity,but has the ability to reduce
pharmacokinetics systemic vascularresistance
• are like propranolol which is also devoid of intrinsic • is effective in treating hypertension and heart failure
sympathomimetic activity and membrane-stabilizing
activity • other new drugs with a similar mechanism of action
include Bisoprolol, Acebutolol
• inhibits the inotropic and chronotropic cardiac
responses to Isoproterenol •
• 1/50th as potent as Propranolol in inhibiting the • 5. BETAXOLOL
vasodilator response to Isoproterenol • selective β1 antagonist, once daily administration,
• long acting morelipophilic than Atenolol, topical administration
for the treatment of GLAUCOMA
• well-absorbed orally
• LESS SIDE EFFECTS IN ASTHMATIC PATIENTS • AGENTS THAT INHIBIT THE ACTION OF
side effects- similar to Propanolol ADRENERGIC NERVES
1. RESERPINE
• inhibits the uptake of norepinephrine
2. ATENOLOL • BP decreases
• it is also a selective Beta 1 antagonist which is also • triggers reflex tachycardia
devoid of intrinsic sympathomimetic activity and
membrane- stabilizing activity. • Sedation-depletion of catecholamine in the brain
treatment in HYPERTENSION
• it is a poorly lipid soluble drug
• ADVERSE EFFECTS: sedation,
• about half of an oral dose is absorbed, but most of
thisreaches the systemic circulation if there is no first • psychic depression→suicide abdominal cramps and
passmetabolism in the liver diarrhea GI ulceration
• as a result, peak concentrations of this drug in the • high incidence of breast carcinoma
plasmaare not so variable across patients •
• it is excreted unchanged in the urine • 2. GUANETHIDINE

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Lyceum Northwestern University
COLLEGE OF MEDICINE
• impairs the response to sympathetic stimulation by
inhibiting the release of neurotransmitter
• displaces norepinephrine from intraneuronal storage
granules
• slow onset of action after oral administration
• rapidly cleared by the kidney
• Therapeutic use: POTENT LONG ACTING
HYPERTENSIVEAGENT
• ADVERSE EFFECTS:
• postural hypotension, syncope-esp. in strenous
activities, diarrhea,
• edema
• Contraindicated in patient taking MAO inhibitors
Antihypertension effects can be reversed by
Ephedrine or
• Phenylpropanolamine

3. GUANADREL
• similar to Guanethidine
• less morning hypotension
• less diarrhea
• contraindicated in patient with MAO inhibitors
causes water retention-given with diuretics
4. BRETYLIUM
• produces block in the release of epinephrine
• inhibits re-uptake of norepinephrine into nerve
terminal antiarrhythmic agent
• poorly absorbed orally
• strong hypotension

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