II Pharm D Pharmacology I

II Year Pharm D (2011-2011)
Commencement Date-11-11-2011 Sub-Pharmacology I (Theory)
Total No of classes = 75h 3h/week Sub I/C= K.P.S.Gowda Asst.Prof, Dept
of Pharmacology, P.E.S.College of Pharmacy, Bangalore-50.
--------------------------------------------------------------------------------------------------
Date-11-11-2011(Friday)
1.General Pharmacology-
a.Introduction, definitions and scope of Pharmacology.
Pharmacology The word pharmacology is derived from the Greek words pharmakon (drug) and
logos (study). The Pharmacology is the study of drugs, which includes the study of history,
source, physical and chemical properties, formulation, biochemical and physiological effects,
mechanism of action, absorption, distribution, biotransformation excretion, therapeutic and other
uses of drugs. The first Pharmacology book was written by Samuel Dale in 1693. Oswald
Schmiedberg(1838-1921) is known as the Father of Modern Pharmacology.
Following are the major subdivisions of Pharmacology
Pharmacokinetics is a branch of pharmacology. The term is derived from the Greek word
'kinesis' meaning a movement. It deals with the time course of drug absorption, distribution,
metabolism and excretion. In other words, it means "What the body does to the drug?
Pharmacodynamics (Greek 'dynamics' means force) is the study of physiological and
biochemical effects of drugs, mechanisms of action of drugs. In other words, it means "What the
drug does to the body".
Pharmacotherapeutics (Greek 'therapia' means medical treatment) deals with the use of drugs
in the diagnosis, treatment or prevention of a disease. In other words, it is the clinical application
of the pharmacokinetic and pharmacodynamic knowledge of the drug.
Therapeutics deals with the science and art of treatment of diseases. When therapy is based on
clinical evidence it is called Empirical Therapeutics. It means the drug is effective, although its
mode of action is unknown.
Chemotherapy deals with the use of chemotherapeutic agents to inhibit or destroy invading
microbes, parasites or cancer cells with minimal effect on healthy living tissues.
Toxicology (Greek 'toxicon' means poison) is the science of poisons. It deals with the adverse
effects of drugs and poisonous effects of various chemicals (household, environmental, industrial

or homicidal). It is also concerned with their source, chemical composition, action, tests for
detection and antidotes.. Clinical toxicology is the science of detection, diagnosis and treatment
of poisoning.
Pharmacogenetics is a relatively new field. It deals with genetically mediated variations in drug
responses.
Clinical Pharmacology is a branch of pharmacology that deals with the pharmacological effects
of drugs in man. It gives useful data about the potency, usefulness, doses and toxicity of new
drugs for their safe clinical use.
Biopharmaceutics deals with the development of new drug delivery systems and new dosage
forms. It also provides information how these dosage forms can influence the pharmacodynamic
and pharmacokinetic properties of a drug.
Sources & nature of drugs
The word drug has also a French origin-- 'drogue' (dry herb). In clinical practice, drug is a
chemical substance that is used for the diagnosis, prevention and treatment of diseases.
Essential drug concept: It was introduced by W.H.o in 1977 to avoid the complications of drug
use faced by the physician. A list containing essential drugs is available for the physicians in
clinical practice. Essential drugs are those drugs which satisfy the health care needs of the
majority of the population. These drugs should be available at all times in adequate amounts, in
appropriate dosage forms and at reasonable cost.
Orphan drugs- These drugs are used for the treatment, prevention or diagnosis of rare diseases
like kala-azar, cancers, viral diseases, etc and in heavy metal poisoning. Though they may be life
saving for some patients, but they are less produced commercially due to high cost of
manufacture and small number of patients requiring the drug.
Sources of drugs are as follows:
I. Synthetic sources
At present majority of drugs used in clinical practice are prepared synthetically, such as aspirin,
oral antidiabetics, antihistamines, amphetamine, chloroquine, chlorpromazine, general and local
anaesthetics, paracetamol, phenytoin, synthetic corticosteroids, sulphonamides and thiazide
diuretics.
Advantages of synthetic drugs are: They are chemically pure. The process of preparing them is
easier and cheaper. Control on the quality of the drug is excellent. Since the pharmacological
activity of a drug depends on its chemical structure and physical properties, more effective and
safer drugs can be prepared by modifying the chemical structure of the prototype drug.

II. Natural sources
Drugs are obtained from the following natural sources:
A- Plants:
Following categories of drugs are derived from roots, leaves or barks of plants:
a) Alkaloids
These are nitrogenous heterocyclic bases, which are pharmacologically active principles of
plants. They are composed of carbon, hydrogen, nitrogen and oxygen. They are bitter in taste and
are often poisonous. These are, therefore, used in small doses. They are insoluble in water.
However, they form salts with acids which are soluble in water.
Some examples of alkaloids and their sources.
Atropine -Atropa belladonna
Quinine- Cinchona bark
Morphine -Papavarum somniferum
Reserpine-Rauwolfia serpentina
Nicotine-Tobacco
Digoxin-Digitalis lanata
Caffeine-Coffee, Tea, Cocoa
b) Glycosides
They are ether-like combination of sugar moiety with non-sugar moiety. They are called
glucosides, if the sugar moiety is glucose. Sugar moiety is not essential for the pharmacological
activity but it governs the pharmacokinetic properties of the glycoside. In the body it may be
removed to liberate aglycone. Pharmacological activity resides in the non-sugar moiety that is
called aglycone (or genin).
Some examples are digitoxin, digoxin and ouabain.
c) Oils . They are liquids which are insoluble in water. They are of three types and are used for
various medicinal purposes.
i) Essential Oils (or volatile oils): Essential oils are obtained from leaves or flower petals by
steam distillation, and have an aroma. They have no caloric or food value. They do not form
soaps with alkalies. They do not leave greasy stain after evaporation. On prolonged stay, they do

not become rancid (foul smell). They are frequently used as carminatives and astringents in
mouth-washes. Some of these oils are solid at room temperature and sublime on heating e.g.
menthol and camphor.
Other examples are clove oil, peppermint oil, eucalyptus oil and ginger oil.
ii) Fixed oils are glycerides of stearic, oleic and palmitic acid.
They are obtained from the seeds that are present within the cells as crystals or droplets. They are
non-volatile and leave greasy stains on evaporation. They have caloric or food value. They form
soaps with alkalies. On prolonged stay, they become rancid. They do not have marked
pharmacological activity and have little pharmacological use except castor oil (purgative) or
arachis oil (demulcent). They may be of vegetable origin e.g. olive oil, castor oil, croton oil and
peanut oil or of animal origin e.g. cod liver oil, shark liver oil and lard .
iii) Mineral Oils are mostly petroleum products and extracted by fractional distillation.
These are mixtures of hydrocarbons of the methane and related aliphatic series. These are
extracted in various consistencies - hard paraffin, soft paraffin and liquid paraffin. Hard and soft
paraffins are used as vehicles for preparation of ointments while liquid paraffin is employed as a
purgative.
d) Gums are colloidal exudates from plants which are polysaccharides chemically and yield
simple sugars on hydrolysis. Upon addition of water, some of them swell or dissolve or form
adhesive mucilage or remain unchanged.
Uses: - In gut agar and psyllium seeds act as hydrophilic colloids and function as bulk
purgatives. Gum acacia and gum tragacanth are used as suspending agents in making emulsions
and mixtures.
e) Resins are solid polymers of volatile found in plants. They are produced by oxidation and
polymerization of volatile oils. They are insoluble in water but soluble in alcohol, chloroform
and ether.
Examples: oleoresins (aspidium); gum resins (asafoetida); oleogum resin (myrrh); balsams
(benzoin, tolu, peru); benzoin shellac, podophyllum.
Uses: Benzoin is used as inhalation in common cold.
Tincture benzoin is applied as antiseptic protective sealing over bruises.
Colophony (an oleoresin) is used as an ingredient in various plasters.
Shellac (from Lucifer lacca) is used for enteric coating of tablets.

Balsams are used in the treatment of cough and bronchitis for their antiseptic and protective
properties.
Podophyllum is used as an irritant purgative.
f) Tannins are non-nitrogenous phenolic plant constituents which have an astringent action.
Pyrogallol tannins are glycosides of glucose that occur in oak galls. Pyrocatechol tannins are
sugar-free derivatives of catechol that are present in catechu and eucalyptus. Tannic acid is a
tannin that is obtained from oak galls and is used for treating burns and diarrhoea.
B-Animal sources
Some animal sources continue to be used to procure some modern drugs because of cumbersome
and expensive procedures for the synthesis of such chemicals. For example:
Insulin, extracted from pork and beef pancreas, is used for the treatment of diabetes mellitus.
Thyroid powder for treating hypothyroidism. Heparin is used as an anticoagulant.n Hormones
and vitamins are used as replacement therapy.
Vaccines (cholera, T.B., smallpox, polio and antirabic) and sera (antidiptheria and antitetanus)
are used for prophylaxis/treatment.
C-Microbiological sources
Many life-saving drugs are obtained from fungi, moulds and bacteria e.g. penicillin from
Penicillium notatum, chloramphenicol from Streptomyces venezuelae, grisofulvin (an anti-fungal
drug) from Penicillium griseofulvum, neomycin from Streptomyces fradiae and streptomycin
from Streptomyces griseus.
D-Mineral sources
Minerals or their salts are useful pharmacotherapeutic agents. For example: Ferrous sulfate is
used in iron deficiency anaemia. Magnesium sulfate is employed as purgative. Magnesium
trisilicate, aluminium hydroxide and sodium bicarbonate are used as antacids for hyperacidity
and peptic ulcer. Kaolin (aluminium silicate) is used as adsorbent in antidiarrheal mixtures.
Radioactive isotopes of iodine, phosphorus, gold are employed for the diagnosis/ treatment of
diseases particularly malignant conditions.
III. Semisynthetic sources
Sometimes semi-synthetic processes are used to prepare drugs when the synthesis of drugs
(complex molecules) may be difficult, expensive and uneconomical or when the natural sources

may yield impure compounds. Some examples are semisynthetic human insulin and 6-
aminopenicillanic acid derivatives.
IV. Biosynthetic sources (genetically engineered drugs)
This is relatively a new field which is being developed by mixing discoveries from molecular
biology, recombinant DNA technology, DNA alteration, gene splicing, immunology and
immunopharmacology. Some of the recent developments are genetically engineered novel
vaccines (Recombinex HB - a hepatitis-B vaccine), recombinant DNA engineered insulins
(Humulin- human insulin) for diabetes and interferon-alpha-2a and interferon-alpha-2b for hairy
cell leukaemia.
Date- 12-11-2011 (Saturday)
Routes of drug administration- Routes can be broadly divided into those for a) local action and
b) systemic action.
I.Local routes-The drugs are applied locally for local effects. Systemic absorption of the drug
from these routes is minimal or absent. Hence systemic side effects or toxicity are absent or
minimal.
1.Topical- This refers to external application of the drug to the surface for localized effect.
a.Skin- Drug is applied as ointment, cream, lotion, paste, powder, dressing, spray, etc.
b.Mucous membrane-
Mouth and pharynx- As paint (Mandle’s paint), lozenges (strepsils), mouth washes and
gargles (povidone iodine gargle).
Eyes, ear and nose- As drops, ointments, irrigation, nasal spray.(Zomig Zolmitriptan nasal spray
for migraine), Otrivin nasal spray to reduce nasal congestion. chlopamphenicol eye ointment.
Gastrointestinal tracts-Non absorbable drugs are given orally. Magnesium hydroxide,
sucralfate, neomycin.
Bronchi and lungs- As inhalations, aerosols- e.g. salbutamol (β2 adrenergic receptor agonist),
cromolyn sodium.
Urethra- As jellies E.g. Lidocaine (xylocaine)- For the surface anesthesia of male or female
urethra.

Vagina- As pessaries-(clotrimazole vaginal pessaries), vaginal tablets (canestine-clotrimazole,
estradiol vaginal tablets), Vaginal inserts (spermicide, lubrin vaginal inserts),Vaginal creams
(ovestin-estriol vaginal cream),powders, vaginal douches (betadine vagina douch)
Anal canal- Ointment-(nitro glycerin anal ointment), suppositories- (glycerin suppositories,
hydrocortisone suppositories).
2. Deeper tissues-Using syringe and needle drug is administered to deeper tissues, but the drug
is not absorbed into systemic blood circulation.
Intra-articular injections- Long term intra-articular hydrocortisone injection in osteoarthritis.
Intrathecal injection-Intrathecal administration of vincristine in cancer chemotherapy,
administration of lidnocaine, amphotericine B.
Retrobulbar injection- Injection in to the space behind the globe of eye balls. Ocular anesthesia
for cataract surgery.
3.Arterial supply- Intra-arterial route is used in angiography- Angiography is the x-ray
(radiographic) study of the blood vessels. An angiogram uses a radiopaque substance, or contrast
medium, to make the blood vessels visible under x ray- cerebral, pulmonary, coronary, renal
angiography.
II Systemic routes-
1. Oral Route: - In this route the drug is placed in the mouth and Swallowed. It is
also called per oral (p.o.). The solid dosage forms- tablets, capsules, powders, spansules,
moulded tablets and liquid dosage forms- syrups, mixtures, elixirs, emulsions, etc can be given
orally.
Advantages of oral route
a. Convenient - Can be self administered, Pain free, easy to take
b.Absorption - Takes place along the whole length of the gastro intestinal tract.
c.Cheap - Compared to most other parenteral routes
Disadvantages of oral route
a.Action is slower and thus not suitable for emergencies.
b.Unpalatable drugs-e.g. paraldehyde aredifficult to administer.
c.May cause nausea and vomiting.(e.g. emetine)
d.Not suitable for uncooperative/unconseous/vomiting patients.
e. Some drugs are destroyed by gastric juice- e.g. insulin, vasopressin.
f.Some times inefficient - only part of the drug may be absorbed

G.First-pass effect - drugs absorbed orally are initially transported to the liver via the portal vein.
2. Sublingual or buccal route-The tablet or pellet containing the drug is placed under the
tongue or crushed in the mouth and spread over the buccal mucosa. It is not swallowed. The drug
is absorbed from the buccal mucosa. Drugs given sublingually are- nitroglycerine,
methyltestosterone, isoprenaline, clonidine.
Advantages-
a. Quick absorption and action.
b. Drug enters directly into blood circulation.
c. No first pass metabolism. (FPM).
d. Action can be terminated by spitting out the tablet.
e. No drug destruction by the gastric juice.
Disadvantages-
a. Not available for all drugs.
b. All drugs are not absorbed by this route.
c. Not suitable for unpalatable drugs.
3. Rectal route of administration- Certain irritant and unpleasant drug can be put into rectum as
suppositories or retention enema for systemic effect. It is preferred for the patient with recurrent
vomiting. Drugs given rectally are –aminophylline, indomethacin, paraldehyde, diazepam,
ergotamine, etc.
4. Transcutaneous- Highly lipid soluble drugs can be applied over the skin for slow and
prolonged absorption. It is further classified as
a.Iontophoresis- In this method, a drug is driven deep into the skin by means of a galvanic
current e.g.salicylates. Anode iontophoresis is used for positively charged drugs and cathode
iontophoresis is used for negatively charged compounds. The force of repulsion between similar
charges drives the drug deep into the tissues.
b.Inuction- It is rubbing the drug on the skin. The drug gets absorbed and produces systemic
effects. E.g. nitroglycerin ointment for angina.
c. Jet injection- This method does not require a syringe. So it is painless. Using a gun like
instrument with a micro-fine orifice, the drug solution is projected as a high velocity jet
(dermojet). The drug solution passes through superficial layers of skin and gets deposited in the
subcutaneous tissue. This method is useful for mass inoculation.
d.Adhesive patches-It is a transdermal preparation. It is available in the form of adhesive unit. It
delivers the drug slowlly. So it produces prolonged systemic effect. E.g. belladona plaster.
5.Inhalation-Volatile liquids and gases are given by inhalation for systemic action.The drugs
administered by this route are- general anesthetics, amylnitrite.
Advantages-
a.Gases can be administered by inhalation route only.
b.Rapid absorption occurs from large surface of alveoli.
Disadvantages-
a.Only non irritant drugs can be administered.

b.Special apparatus and technique are required.
6.Nasal- The mucous membrane of the nose can readily absorb many drugs. This route prevents
the drug inactivation by the gastric juice and also prevent the first pass effect.The drugs like
desmopressin (ADH analog), GnRH, etc containing nasal sprays are administered through this
route.
7.Parenteral route of administration. (par-beyond, enteral-intestinal)
In this route of administration the drug does not pass through the gastrointestinal tract. It directly
reaches to the blood. The drugs are administered by injections. Injections can be given in many
different ways e.g.intradermal (id), subcutaneous(sc), intramuscular (im), intravenous(iv),
intraperitoneal (ip),etc.
Advantages-
1. Injections can be given even in unconscious, uncooperative patients.
2. Quick absorption-hence suitable in emergencies.
3. There is no GIT related problems.
4. Dose requirement is less compared to oral route.
5. Accurate dose adjustment is possible.
6. No first pass metabolism.
7. Drugs having unpleasant smell or taste can be given.
Disadvantages-
1. Inconvenient- injections can be painful, costly.
2. Tissue injury, inflammation and may cause infection.
3. Costly.
4. Self medication is difficult.
5. Withdrawal of the drug is not possible.
a.Intradermal injection (id)-Only 0.1 to 0.2ml can be administered by id route. The drug is
injected into the layers of the skin. It is painful. E.g. vaccines (BCG vaccine), test dose of drugs
(penicillin), are given by id injections.
b.Subcutaneous injection(sc)-Absorption from sc route is slow but steady. Volume 1-2ml
only.SC injection should not be given in patients with shock, because during shock, blood flow
to subcutaneous tissue is reduced. Drugs usually given by sc route are insulin, adrenaline, and
local anesthetics. The drugs are given along with hyaluronidase or adrenaline to enhance or to
retard drug absorption.
c.Intramuscular injection(im)-In this route of administration the drug is given into the skeletal
muscles like deltoid, triceps, gluteus maximus, rectus femoris, etc. Drug once reaches to the
muscles, absorbs into the blood. Mild irritant or nonirritant drugs can be administered as there is
less supply of sensory nerves. But muscles are more vascular, hence absorption is faster.Up to
5ml can be given by im route.
d.Intravenous injection(iv)- After iv injection drug enters directly in to the blood and goes to
the heart. Drug may cause irritation to the vein. Large volume can be given. Onset of action is

very quick and the bioavailability is 100%. The dose requirement is small. Withdrawal of the
drug is not possible.
e.Intra peritoneal (ip)- In this route the drug is injected in to the peritoneal cavity. By this route
fluids like glucose and saline can be given to the children. It is also used for peritoneal dialysis. It
is one of the common routes for administering the drugs to rats and mice.
Newer methods and devices for drug delivery.
1. Occusert and progestasert- Occusert is a device that is placed under the eyelid. It contain
pilocarpine, the drug is absorbed slowly from the conjunctiva. It is used in the treatment of
glaucoma. Progestasert is an intrauterine device that contains progestin. The drug is released
slowly over several months.
2. Subcutaneous contraceptive implants.
3. Targeted delivery system- Drug is attached to a carrier-liposome or monoclonal antibody.
The carrier takes the drug to the site of action. This method is useful in anticancer drugs. Anti-
cancer drugs are highly toxic. To prevent the toxic effect of these drugs on healthy cells and to
deliver the drug directly to the cancer cells, this method is useful.
4. Slow /sustained release (SR) preparations. With certain drugs frequent (3-4 times/day). The
SR tablets are given special coating to ensure slow and sustained release.
5. Metered dose inhaler (MDI)- It is a device that releases a fixed quantity of the drug in an
aerosol form each time when the button is pressed.
6. Rotahaler, spinnihalar, rotacap- These are the devices used for delivering microfined
powder.
7. Nebulizer-It is a device that generates very fine particles (about 0.3 to 0.5 microns) of the
drug in the form of mist.
--------------------------------------------------------------------------------------------------
(General Pharmacology is to be continued later)
----------------------------------------------------------------------------------------------------
2. Pharmacology of drugs acting on ANS
a) Adrenergic and antiadrenergic drugs
b) Cholinergic and anticholinergic drugs
c) Neuromuscular blockers
d) Mydriactics and miotics
e) Drugs used in myasthenia gravis
f) Drugs used in Parkinsonism
a) Adrenergic and antiadrenergic drugs
Adrenergic drugs: Adrenergic drugs produce effects similar to those of adrenaline or
stimulation of postganglionic sympathetic nerves. As most of them contain an amino group
(NH2) in their chemical structure, they are called sympathomimetic amines.
Classification-

A Chemical classification
1. Catecholamines- (contain catechol ring)
These are a) Natural: Adrenaline,Dopamine, Noradrenaline,
b) Synthetic drugs: Isoprenaline, Dobutamine.
2. Non-catecholamines- (contain benzene/phenol ring): Amphetamine,
Dexamphetamine,Ephedrine,Pseudoephedrine,Terbutaline.
B. Classifi cation based on mechanism of action
1 Both directly and indirectly acting sympathomimetics- Ephedrine
2. Directly acting sympathomimetics-Adrenaline,Isoprenaline, Noradrenaline,Salbutamol.
3 Indirectly acting sympathomimetics:
Amphetamine,methylamphitamine,Tyramine.
C. Classifi cation based on receptor selectivity
1. Mainly –Alpha receptor agonists
α1-agonists-Phenylephrine, Xylometazoline
α 2-agonists-methyldopa, Clonidine
α1 and α2 combined agonists- Oxymetazoline
2. Mainly beta-receptor agonists
β1 agonists- Dobutamine
β 2 agonists- Ritodrine, salbutamol, terbutaline.
Selective β1 and β2 agonists- Isoprenaline, orciprenaline
3.Alpha and beta agonist- Adrenaline, amphetamine, ephedrine, noradrenaline
4. Adrenergic and dopaminergic agonists- Dopamine
Discussion of adrenergic drugs:
Natural catecholamines: Adrenaline (Epinephrine), noradrenaline (norepinephrine).
Source of adrenaline and noradrenaline- Adrenaline is the major (80%) of adrenal medulla,
where it is produced by chromaffin cells. It is also released from post ganglionic adrenergic
nerve endings (20%). Noradrenaline is mainly produced (80%) in the post ganglionic adrenergic
nerves. It is also produced in the chromaffin cells (20%). Both adrenaline and noradrenaline are
the central and peripheral neurotransmitters.
Adrenal medulla

Biosynthesis of adrenaline and noradrenaline-
Tyrosine enters the neuron through aromatic L-amino acid transporter along with Na+
ions.
Tyrosine hydroxylase converts tyrosine into dihydrophenylalanine (dopa). Dopa gets converted
into dopamine by aminoacid decarboxylase. Dopamine enters the synaptic vesicle through
vesicular monoamino transporter (VMAT), in exchange with H+
ions. Within the vesicle
dopamine gets converted into noradrenaline by dopamine β hydroxylase. In adrenal medullary
cells, NE returns to the cytosol, phenylethanolamine N-methyltransferase (VMAT) converts NE
to adrenaline. The adrenaline is then return back into the vesicle for storage.
Release of adrenaline or noradrenaline: The arrival of an action potential at these nerve
endings opens voltage- gated Ca2+
channels; the calcium ions enter the neurons. This leads to
exocytosis (vesicle fusion at the cell membrane), the adrenaline or noradrenaline get released
into the synaptic cleft. The released neurotransmitters combine with adrenergic receptors to
produce their effects.

exocytosis NT release at synaptic cleft.
Chemistry- Both adrenaline and noradrenaline are the catecholamines.
R = H Noradrenaline
R = CH3 Adrenaline
Location of adrenergic receptors-Adrenergic receptors.
All adrenergic receptors are G-protein coupled receptors. These receptors have 7
transmembrane loops. The agonist binding site is located in the extracellular domain. In the
resting ( unstimulated ) state, the cytoplasmic domain is non covalently linked to a G- protein
that consists of α and βγ subunits. Upon activation, the subunit exchanges GDP for GTP. The
GTP subunit than dissociated from the βγ subunit and these subunits interact with different
effectors. These effectors include adenylyl cyclase (AC), phospholipase C (PLC), various ion
channels and other classes of proteins.
One major role of the G- proteins is to activate the production of secondary messengers, i.e.
signaling molecule, that convey the input provided by the first messenger. Eg AC ( adenylyl
cyclase). Which catalyze the production of secondary messenger cAMP (cyclic adenosine
3,5,monophosphate ) and GC (guanylyl cyclase,) which catalyzes the production of cGMP (
cyclic guanosine 3,5 monophosphate. In addition, G proteins can activate the enzyme PLC
(phospholipase ) which regulates the concentration of intracellular Ca2+
. Upon activation by a G

protein, PLC cleaves the membrane PIP2 ( phospholipid- phosphatidylinositol,4,5 bis phosphate)
to the second messengers diacyl glycerol (DAG) and inositol-1,4,5 bisphosphate IP3. The IP3
triggers the release of Ca2+
from intracellular stores. DAG activates protein kinase C (PKC).
Major G- proteins and examples of their actions
G- stimulatory (Gs)- Activates Ca2+
channels, activates AC.
G- inhibitory (Gi)- Activates K+
channels, Inhibits AC
Gq-------------- Activates PLC
Adrenergic receptors are mainly classified into two types
Alpha receptors and beta receptors.
Alpha receptors- There are two subclasses of α receptors. α1 and α2.
Alpha 1 adrenergic receptors-(α1 ) These receptors are expressed in vascular smooth muscles,
genitor urinary smooth muscles, intestinal smooth muscles, heart and liver.
Majority of α1 receptors mediated through Gq type.
Actions through α1 receptors.
1. Vascular smooth muscle cells- Stimulation of α1 receptors by its agonists ( adrenaline, NA
) causes the activation of PLC, PIP2 gets converted into DAG and IP3. DAG directly
activates the PKC. The activated PKC phosphorylate the cellular proteins. The
phosphorylated proteins are responsible for its pharmacological actions. The released IP3
bind on the Ca2+
channels, this opens the channel and release of Ca2+
takes place. Then Ca2+
combines with protein calmodulin (CaM). The resultant Ca2+
CaM complex activates
myosin light chain kinase (MLCK.) The activated MLCK phosphorylates the myosin light
chain (MLC). This causes the muscle contraction.

2. Genitourinary smooth muscle- Contraction of prostate gland.
3. Heart – Adrenaline binds with α1 receptors located on the myocardium and increases muscle
contraction (ionotropy) and cardiac output.
4. Liver- Increases glycogenolysis and gluconeogenesis.
5. Radial muscle of iris- contraction-(mydriasis).

6. Piloerector muscle- contraction.
7. Male sex organ- Causes ejacuation.
Sweating
8. Sweat gland- Localized sweating.
9. In intestinal muscle α1 receptor is of Gi type. The activation of this receptor leads to the
inhibition of AC; this decreases the concentration of cAMP. The activation of these receptors
also causes the activation of K+
channels. This leads to the opening of K+
channels. More loss of
K+
ions leads to hyperpolarization. This causes relaxation of the muscle.
Alpha 2 adrenergic receptors- ( α2 )- These receptors are expressed on both pre and post
synaptic membrane. These receptors expressed in pancreatic β cells, platelets, nerve (
presynaptic ) and vascular smooth muscles. α2 are of Gi type.
MOA- a. Inhibition of AC decreases the cAMP. b. Activation of K+
channels. c. Inhibition of
neuronal Ca2+
channels.
Actions mediated through α2 receptors-
1. Preganglionic nerve terminal- Inhibition of catecholamine release.
2. Beta cells of islets- reduced insulin secretion.
3. Platelets- increase the platelet aggregation.

4. Adipocytes- inhibition of lipolysis.
5. Vascular smooth muscle- vasoconstriction.
Beta adrenergic receptors- These are of 3 types- β1, β2, and β3.
All 3 classes of beta receptors activate stimulatory G protein-Gs. Gs activate adenylyl cyclase,
leading to an increase in the level of intracellular cAMP. Increased cAMP activates protein
kinases (especially protein kinase A), which phosphorylate cellular proteins, including ion
channels.
β1- Adrenoceptors are localized mainly on juxta glomerular cells, where receptor activation
causes rennin release. β1- Adrenoceptors are also expressed on the heart- ( SAN,AVN and
myocardium ). Stimulation of these receptors causes an increase in both inotropy (force of
contraction) and chronotropy (heart rate). Stimulation β1- adrenoceptors located in the SAN and
AVN is responsible for its chronotropic effect and stimulation β1- adrenoceptors located in the
myocardium is responsible for its inotropic effect.
β2- Adrenoceptors- These receptors are expressed in smooth muscle, liver and skeletal muscle.
In smooth muscle receptor activation stimulates Gs, AC, cAMP and PKC. Activated PKC act on
several proteins, leading to relaxation of the contractile apparatus. In bronchial muscle activation
of the receptor also stimulates K+
channel, this leads to hyperpolarization, causing the relaxation.
In hepatocytes activation of these receptors result in phosphorylation of cellular proteins (
enzymes) which causes glycogenolysis and gluconeogenesis. In skeletal muscles also receptor
activation result in glycogenolysis.
β3- Adrenoceptors- These are expressed on adipose cells. These are also of Gs type. Its
activation results in lipolysis.
ADME-CAs not absorbed orally. Fate-Metabolism by MAO ( MAO-A in GIT wall) or COMT
or both. Fate- Adrenaline-1. COMT ->Metanephrine. 2.MAO+ COMT->VMA

Prep- Adrenaline HCl 1mg/ml.SC action lasts for 30min to 2 h. Direct iv inj lead to cardiac
arrhythmias, NA bitartrate-2% 2ml amp. It is given along with 5D. It is rarely used.
ADRs-1.CVS-Palpitation, tachycardia, arrhythmias, hypertension, cerebral hemorrhage,
2. Local- VC- necrosis, gangrene. 3.CNS-Anxiety, fear, nervousness, tremors, restlessness,
headache, dizziness, insomnia,
CI- Angina, hypertension,hyperthyroidism, acute LVF.
T.Uses-1. Cardiac resuscitation, 2. Anaphylactic shock.3. Combined with local anesthetic to
prolong its effect. 4. It is used to control hemorrhage, in dental practice. 5. In bronchial asthma
Chapter 2. Pharmacology of drugs acting on ANS
b. Cholinergic and anticholinergic drugs
Cholinergic pharmacology-
Parasympathetic or cholinergic nerves emerge from cranial and sacral portion of the spinal cord.
These nerves consist of preganglionic and post ganglionic nerves. The neurotransmitter at its
ganglion is the acetylcholine and the receptors are the nicotinic receptors (Ng), which are
expressed on the post synaptic membrane. The neurotransmitter at the post ganglionic nerve
ending is the acetylcholine and the receptors are muscarinic receptors which are expressed on
presynaptic or post synaptic membrane. At the somatic nerve (which innervates the skeletal
muscles) ending also the neurotransmitter is the acetylcholine.
Synthesis, storage and degradation of acetyl choline.

Synthesis-Acetyl choline is synthesized locally in the cholinergic nerve ending. Acetyl
coenzyme A is required for the synthesis of acetyl choline is derived from glycolysis.
ATP+Acetate+CoenzymeA --(acetate activating reaction)----- Acetyl coenzyme A
Acetyl coenzyme A + Choline ---(choline acetyltransferase) Acetyl choline + CoenzymeA+
water.
Acetyl coenzyme A synthesis takes place in the mitochondria. Citrate serves as the carrier for
acetyl coenzyme A from the mitochondria to the cytoplasm. In the cytoplasm of the cholinergic
nerve ending acetyl coenzyme A combines with choline to form acetylcholine.
Storage- After its synthesis in the cytoplasm, Ach (acetylcholine) is transported into synaptic
vesicles for storage. Ach enter the synaptic vesicle through Ach-H+
antiporter present on the
synaptic vesicles. An Atpase proton pump located on the synaptic membrane aids this process.
Each synaptic vesicle contains about 1000 to 50000 molecules of acetylcholine.
Release of Ach. Because of arrival of an impulse the Ca2+
channel present on the membrane gets
opened. This leads to inflow of Ca2+
ions, depolarization, exocytosis, repture of synaptic vesicles
and release of Ach molecules into the synaptic cleft. The released Ach molecules than combines
with the muscarinic or nicotinic receptors located on the presynaptic or post synaptic
membranes of the cholinergic nerves to produce pharmacological effects.

Degradation of acetylcholine- Acetylcholine in the synaptic cleft is degraded by membrane
bound acetylcholinesterase (AchE) into choline and acetate. There are two types of AchE. These
are acetylcholinesterases (true), which are present on cholinergic sites and pseudocholinesterases
which are present in the blood plasma, liver and intestine. The choline gets reentered into the
cholinergic nerve ending, which may utilize for the fresh synthesis of acetylcholine.
Cholinergic receptors- There are two types of cholinergic receptors.
a.Muscarinic receptors, b. nicotinic receptors.
a.Muscarinic receptors- These are 7 transmembrane domain G protein coupled receptors. There
are 5 types of muscarinic receptors. M1, M3 and M5 are associated with Gq type and hence are
responsible for the stimulation of phospholipase C (PLC). The remaining M2 and M4 are
coupled to Gi type and are responsible for adenylyl cyclase (AC) inhibition. Locations and
actions of muscarinic receptors:

M1 receptors- These receptors are expressed on the autonomic ganglia. If the M1 receptors
present on the autonomic ganglion acted by acetylcholine, it causes excitatory post synaptic
potential (EPSP). These receptors are also expressed in the CNS. Its actions are complex. Some
of the important actions are arousal, attention, analgesia.
M3 receptors- These receptors are present on the smooth muscles and secretary glands. The
acetylcholine combines with M3 receptors and produces smooth muscle contraction and
increased glandular secretion.
M 5 receptors – These receptors are expressed in the CNS and actions are complex.
MOA(of M1 , M3 , M 5 receptors) - Gq type- activation of PLC PIP2-- IP3 and DAG---
 release of Ca2+
, activation of PKC, phosphorylation of cellular proteins- pharmacological
action.

M2 receptors- These receptors are expressed on the SAN, AVN, atrial and ventricular muscles
of the heart. The receptor activation causes hyperpolarization, decreased conduction velocity.
Hence it produces negative chronotropy (decrease in the heart rate). In the atrial and ventricular
muscle the receptor activation produces negative ionotropic effect.
M4 receptors- These are expressed in the CNS and actions are complex.
MOA- (M2 M4 receptors) Gi type- inhibition of AC and activation of K+
channels,
hyperpolarization.
Nicotinic receptors- These receptors are present on the ganglia of the sympathetic and
parasympathetic nerves (N1 or NN). The nicotinic receptors are also present at the NMJ of the
somatic nerve ending (N2 or NM). Nicotinic receptors present at the ganglia are blocked by
hexamethonium( ganglionic blocker). Nicotinic receptors present at the NMJ are blocked by
tubocurarin and gallamine ( NMJ blocker).
The nicotinic receptors are transmembrane ion channel receptors. These receptors are composed
of 5 subunits- two α subunits, a β subunit, a γ subunit and a δ subunit. In the absence of Ach, the
receptor gate is closed, and cations (like Na 2+
) are not entering the channel. When Ach is both to
α subunits, the channel opens, and the cations pass through the channel into the cell.

Cholinergic drugs-( Cholinomimetic, parasympathomimetic )These are the drugs which
produce actions similar to that of acetylcholine.
Cholinergic agonists-
a. Choline esters- acetylcholine, methacholine, carbachol, bethanechol.
b. Alkaloids- muscarine, pilocarpine, arecholine.
Actions of acetylcholine (through muscarinic receptors)
1. Heart- These receptors are expressed on the SAN, AVN, atrial and ventricular muscles of the
heart. The receptor activation causes hyperpolarization, decreased conduction velocity. Hence it
produces negative chronotropy (decrease in the heart rate). In the atrial and ventricular muscle
the receptor activation produces negative ionotropic effect. Other effects are bradycardia and
decreased cardiac output.
2.Blood vessels- Acetylcholine produces vasodilatation of the blood vessels. Hence there is fall
in B.P. This is mediated through EDRF (NO).
MOA-Acetylcholine combines with muscarinic (M3) receptor present on the endothelial cells.
Through activation of PLC, PIP2--- IP3 and DAG. IP3 triggers the Ca2+
within the cytoplasm.
The Ca2+
combines with CaM. The resultant Ca2+
-CaM complex stimulates the endothelial nitric
oxide synthase (eNOS). The activated eNOS catalyzes the formation of NO from L.arginine. The
NO diffuses to the subjacent vascular smooth muscle cells, where it activates guanylyl cyclase.
The activated guanylyl cyclase catalyzes the conversion of GTP to cGMP ( guanosine 3,5,cyclic

monophosphate), which dephosphorylates myosin light chain (myosin- LC). This prevents actin-
myosin interaction. This leads to the relaxation of smooth muscle. The NO also acts on K+
channel to cause relaxation of the smooth muscle.
3.Smooth muscles - Gut, bronchial, urinary bladder muscles get contracts. These effects are
mediated through M3 receptors (Gq type). These leads to increase in intestinal motility,
bronchoconstriction, micturition. The sphincter muscle get relaxes.
4.Glands- On the secretary glands M3 receptors (Gq type) are present. Increase in sweating,
salivation, lacrimation, tracheobronchial, gastric secretions. The secretion of bile and milk is
not affected.
5.Eye- M3 receptors are present on the circular muscles, its contraction leads to miosis.
Actions of acetylcholine (through nicotinc receptors)
1.Autonomic ganglia- Both sympathetic and parasympathetic ganglia are stimulated. These
effects are mediated through nicotinic receptors (NN).

1.Skeletal muscle- The skeletal muscles are innervated by somatic nerves (voluntary nerves).
When two Ach molecules combine receptor sites present on the two α unit of the nicotinic
receptor (NM). This produces skeletal muscle contraction.
Actions of cholinergic drugs on CNS- As acetylcholine not pass the BBB, hence no central
effects. However direct injection of acetylcholine or other cholinergic drugs enter the CNS,
produce a complex pattern of stimulation followed by depression.
Pharmacokinetics- Acetylcholine is rapidly hydrolyzed and hence ineffective orally. Some
cholinergic drugs are absorbed orally. Acetylcholine is hydrolyzed by acetyl cholinesterase and
some other cholinergic drugs are hydrolyzed by pseudocholinesterase.
ADRs- Abdominal colic, bronchoconsriction, bradycardia, hypotension, sweating, urinary
urgency.
Contraindications- In peptic ulcer, asthma, coronary insufficiency (hypotension reduces
coronary circulation), and hyperthyroidism (may precipitate atrial fibrillation).
Therapeutical uses- 1. Bethanechol is used to stimulate contraction of g.i.t. and urinary bladder
in certain clinical conditions. It is given orally on an empty stomach to avoid nausea and
vomiting. It can also given by SC route.
Preparation- Bethanechol chloride tablets-5,10,25 and 50mg tabs.
2.Carbachol 0.01% solution is used in cataract extraction.
Carbachol is also used to reduce intraocular pressure.

Preparation- Carbachol ophthalmic solution.
3.Methacholine is used in the diagnosis of bronchial airway hypersensitivity.
Preparation- Methacholine chloride powder for inhalation. ( Provocholine).
4.Pilocarpine is used as miotic.
Preparation- Pilocarpine opthalmic solution
Indirectly acting cholinergic drugs ( Anticholinesterases-)
These are the agents which inhibit acetyl cholinesterase enzyme and protect the acetylcholine
from the hydrolysis. Hence the acetylcholine gets accumulated near the synaptic cleft to produce
its effect.

Classification- I Reversible- Natural: Physostigmine
Synthetic: Neostigmine, pyridostigmine, edrophonium, tetrahydroamonoacridine.
II Irriversible- a. Organophosphrus compounds- DFP- diisopropyl fluorophosphates, OMPA-
octamethyl pyrophosphatetetramide and echothiophate (used as miotics in glaucoma), parathion,
malathion and diazinon (used as insecticide and pesticide), tabun and sarin(used as nerve gases
in war fields).
b. Carbamate esters- Carbaryl (SEVIN), propoxur ( BAYGON)
MOA- these act by inhibiting the enzyme cholinesterase (ChE). This enzyme has two sites-
anionic and esteratic sites. The acetylcholine or anticholinesterases bind with these sites. Anion
site is negative and is formed by free carboxyl group of aminoacid. This site attracts positive
charge. The esteric site is neucleophil and so it attracts the elecrophilic carbon atom. It is located
at 2.5 to 5o
A from anionic site and has two groups-hydroxyl group of serine and an imidazole
group of histidine. Initially acetylcholine binds to the active site of the esterase and is
hydrolysed, producing free choline and acetylated enzyme. In a second step, the covalent acetyl-
enzyme bond is split with the addition of water.
Irriversible blockage of the enzyme

Edrophonium is the main example of a reversible anticholinesterase. It binds by electrostatic
forces to the active site of the enzyme. It does not form covalent bonds with the enzyme and so is
very short acting (2 to 10 min). The carbamate esters (eg. Neostigmine) undergo the same two-
step process like acetylcholine, except that the breakdown of the carbamylated enzyme is much
slower (30 min to 6h). Organophosphorus compounds ( eg. Parathion) result in a phosphorylated
enzyme active site. The covalent phosphorus- enzyme bond is very stable and the enzyme is
inactivated for hundreds of hours. Hence these are irreversible anticholinesterases. They are
extremely toxic and are used as insecticides (eg. Malathion, parathion).
Reversible anticholinesterase: Physostigmine (Eserine): It is an alkaloid obtained from the
plant Physostgma venenosum. It is a teritiary amine and lipid soluble. It is well absorbed in the
GIT and can easily cross BBB. It acts by preventing the destruction of acetylcholine released
from cholinergic nerve endings by nerve stimulation and causing its accumulation at cholinergic
receptor sites. It inhibits both acetylcholinesterase and butyrylcholinesterase
(pseudocholinesterase or plasma cholinesterase). Its duration is 4-8h.It produces muscarinic,
nicotinic and CNS effects like acetylcholine.
Clinical uses: It has local and systemic uses. Locally it is used as miotic drops in the treatment
of glaucoma to reduce IOP. It is also used to antagonize the mydriatic and cycloplegic effects of
atropine. Systemically it is used in the treatment of belladonna (atropine) poisoning,
phenothiazine and tricyclic antidepressants poisoning. It is used in delirium (acute confusional
state) and Alzhemer’s desease (dementia).
Alzheimer's disease Myasthenia gravis

ADRs: ADRs of physostigmine are similar to acetylcholine.
Preparations: 1.Physostigmine salicylate injection, eye drops.
Neostigmine: it is a synthetic anticholinesterase drug. It is a quaternary ammonium compound
and lipid insoluble. It is poorly absorbed from GIT and cannot cross BBB easily.
Clinical uses: It has only systemic uses. It is used in the treatment of myasthenia gravis. It is also
used for post operative decurarization (to reverse the skeletal muscle paralysis caused by d-
tubocurarine) . it is also used in postoperative complications like gastric atony (decreased
propulsive ability), paralytic ileus (obstruction of the intestine due to paralysis of intestinal
muscles) and urinary bladder atony. It is used to treat cobra snake bite. It is also used to prevent
respiratory muscles paralysis.
ADRs: Similar to acetylcholine.Less muscarinic effects than neostigmine. It has prominent
nicotinic effects on skeletal muscles.
Preparations:Neostigmine methyl salicylate injection, neostigmine bromide tablets.
Pyridostigmine: It is a synthetic anticholinesterase drug. Its structure is similar to neostigmine.
It has pharmacological actions like neostigmine. It is less potent than neostigmine, but has a
longer duration of action.
Use- For long term treatment of myasthenia gravis. Preparations:

Edrophonium: It is a synthetic anticholinesterase drug. It is a quaternary ammonium salt. It is
not absorbed from GIT. Edrophonium’s duration of action is only 2-10 minutes because it binds
by electrostatic forces (no covalent bonds) to the active sites of the enzyme.
Uses: It is used for rapid decurarization. It is used for the diagnosis of myasthenia gravis.
Preparation:
II Irriversible- a. Organophosphrus compounds- DFP- diisopropyl fluorophosphates, OMPA-
octamethyl pyrophosphatetetramide and echothiophate (used as miotics in glaucoma),
parathion, malathion and diazinon (used as insecticide and pesticide), tabun and sarin(used as
nerve gases in war fields).
b. Carbamate esters- Carbaryl (SEVIN), propoxur ( BAYGON)
Organophosphorus compounds: These are irreversible inhibitors of cholinesterase. They inhibit
butyrylcholinesterase than acetylcholinesterase. This leads to the accumulation of acetylcholine at
cholinergic receptors. Their pharmacological actions are due to acetylcholine. They have high lipid
solubility and crosses BBB and produce CNS effects.
Uses: They have limited clinical uses due to their prolonged action and high toxicity. DFP and
echothiophate are used as miotic drops (long acting) for the treatment of glaucoma. Other compounds
are used as insecticides and pesticides. Preparations:

Organophophorus or insecticide poisoning- it is quite common due to ignorance of farmers
about the correct method of handling these compounds in agriculture as pesticides and
insecticides. This poisoning is due to accidental or suicidal consumption of insecticides like
parathion, malathion, etc.
Signs and symptoms-
Muscarinic effects- Miosis of eye, watery nasal discharge, bronchospasm, increased bronchial
secretions, lacrimation, tightness in the chest, bradycardia, hypotension, cardiac arrhythmias,
involuntary defecation and urination.
Nicotinic effects- Fatiguability and weakness of muscles, involuntary twitching, and
fasciculation (involuntary contractions of voluntary muscles).
Central effects- ataxia (a lack of coordination while performing voluntary movements),
confusion, slurred speech, coma (state of unconseousness) and respiratory paralysis.

Confusion Coma
Treatment-
1. Gastric lavage- (the process of cleaning out the contents of the stomach).
2. Maintenance of respiration by oxygen inhalation or artificial respiration.
3. Supportive measures- Maintenance of BP and hydration by the administration of i.v.fluid
like normal saline and adrenaline. Control of convulsions by diazepam. To prevent infection
– ampicillin is administered..
4. Use of atropine sulphate - It prevents the muscarinic and central effects. 2 mg i.v. repeated
every 10 min till pupil dilates.
5. Use of cholinesterase reactivators- Oximes- pralidoxime (2-PAM) 1-2g injected i.v. slowly.
Atropine sulphate counteract the muscarinic and CNS effects of acetylcholine. Oximes (PAM
inj) counteract the nicotinc effects of acetylcholine.
MOA of oximes (Pyridine aldoxime of PAM) : These are synthetic drugs. These are
cholinesterase activators. Organophosphorus compounds produce irreversible inhibition of
cholinesterase by phosphorylation of the esteratic site of the enzyme. Oximes combine with the
phosphoryl group of the phosphorylated enzyme by forming soluble complex. The esteretic site
of the enzyme gets freed. The free enzyme then hydrolyzes the acetylcholine.

Pharmacology of anticholinergic drugs ( parasympatholytics)
Anticholinergics are the drugs that block the actions of acetylcholine. Acetylcholine acts through
two types of receptors: nicotinic and muscarinic. The term anticholinergic is commonly used for
muscarinic receptor blockers. Nicotinic receptor blockers include ganglionic receptor antagonists
and NMJ blockers.
Classification of anticholinergics ( muscarinic receptor blockers)-
1. Natural alkaloids- Atropine, hyoscine(scopolamine).
2. Semisynthetic atropine substitutes-
a. Used for ophthalmic purpose-Homatropine, eucotropine, cyclopentolate
b. Used as antispasmodic-Propantheline, methantheline, oxyphenonium, oxyphenonium.
c. Used in bronchial asthma- Ipratropium bromide,
d. Used in peptic ulcer- Pirenzepine
e. Used in Parkinsonism-Benztropine, benzhexol,biperiden.
Pharmacology of atropine- It is an alkaloid and a quaternary ammonium compound. It is a
competitive antagonist of acetylcholine at muscarinic receptor. It can block nicotinic receptors at
very large doses.
1. Pharmacological actions- By blocking the muscarinic receptors, atropine prevents (reverses)
the actions of acetylcholine.
a. Effects on CNS- Penetration in CNS is poor at therapeutic doses. At higher doses atropine
causes cortical stimulation. This leads to restlessness, disorientation, hallucination, delirium,
and coma. copolamine is a CNS depressant.(Restlessness- lack of quiet or rest, disorientation-
is the opposite of orientation, hallucination -is a perception in the absence of a stimulus.
delirium -acute confusional state).
Restlessness

b. CVS- heart-Atropine blocks the M2 receptors located in the SAN and AVN pacemaker cells.
This blockage causes tachycardia. Tachycardia is more significant in young individuals (due to
high vagal tone). Increase in AV conduction and decreases the refractory period.
Blood vessels –Atropine has little or no effect on blood pressure. At toxic doses of atropine
causes cutaneous vasodilatation. This leads to fall in BP.
c. Eyes- M3 receptors are present on the circular muscles of the iris of the eyes. The blockage of
these receptors by the atropine causes the relaxation of the circular muscles. This results in
mydriasis (dilatation of the pupil). This is associated with photophobia. When excess light enters
the eyes, miosis should occur, but due to paralysis of circular muscles, constriction of pupil can’t
occur. This causes photophobia. The relaxation of the circular muscles causes tightening of the
suspensory ligament, lense become flat and vision is fixed for the far objects. This is cycloplegia
or paralysis of accommodation. Atropine increases the IOP. This precipitates the glaucoma.
There is little effect on eye on systemic administration.
Photophobia
d. Smooth muscles-M3 receptors are located on the smooth muscles. Atropine blocks these
receptors and causes relaxation.
On GIT-Atropine decreases the tone, frequency of contractions and reduces the motility in all
parts of the GIT- from stomach to colon. It has spasmolytic action.
Urinary tract- Relaxation of calyx, pelvis, ureters, bladder. This leads to urinary retention.
Biliary smooth muscle- Mild antispasmodic.
Bronchiole smooth muscle- Relaxation- bronchodilatation. Its utility in bronchial asthma is less
because in asthma spasm is due to histamine.
f.Effects on secretions- Atropine blocks the M3 receptors located on the secretary glands and
decreases its secretions.
Salivary secretions- Decrease. This causes dryness of mouth, difficulty in swallowing and
difficulty in speech.

Gastric secretions- Decrease. Decrease in acid secretion.
Other secretions- decrease in secretions from nasopharynx, bronchial glands, sweating
(hyperthermia),
There is much less effect on lacrimal secretions.
g.Local anesthetic -Atropine has a mild anesthetic action on the cornea.
2. Pharmacokinetics-Atropine can be given orally or by i.v/im injection. On local application
significant systemic absorption can occur. Atropine partly metabolized, partly excreted
unchanged. Hyoscine is more completely metabolized.
Atropine SO4 0.6mg/ml for im/iv, 1% eyedrops.
Hyoscine bromide 0.3 to 0.5mg PO/ im/ transdermal patch.
Dryness of mouth Constipation
3.ADRs-a.Dryness of mouth
b. Blurring of vision, photophobia.
c.Tachycardia
d. Urinary retention.
e. Constipation
f. Precipitate glaucoma
g. Hyperthermia
h. Local allergic reactions
i. Acute belladonna poisoning-Fatal dose 10-20mg in children, 20-50mg in adults.
Symptoms- Dryness of mouth, tachycardia, mydriasis, photophobia, cycloplegia,
hyperthermia,restlessness,urinary retention.

Diagnosis- Administration of physostigmine or edrophoneum- failure to increase secretions.
Treatment- Gastric lavage with tannic acid, lowering of body temperature, administration of IV
fluids, catheterize the bladder, administration of physostigmine-1-4mg i.v slowly 1-2 hrly.
Physostigmine and neostigmine act by inhibiting the acetyl cholinesterase enzyme. This
increases the concentration of acetylcholine. In atropine poisoning there are CNS symptoms. A
drug capable of penetrating CNS is therefore required. Physostigmine is a teritiary compound
crosses the BBB, while neostigmine is a quaternary compound and cannot crosses the BBB.
Hence physostigmine is preferred over neostigmine in atropine poisoning. The patient should be
kept in dark room to prevent damage to retina. Diazepam is used to control convulsions.
4. Drug interactions- a. With antacids,
b. With other drugs with anticholinergic side effects,
c. Delayed absorption of drugs from intestine as anticholinergics slow down the passage of
contents of stomach into intestine.
5.Uses- a. In organophosphorus poisoning.
b.Preanesthetic medication- to decrease salivary secretions, respiratory secretions, to prevent
laryngospasm, etc.
c. Used as antispasmodic- Atropine is used in severe intestinal, biliary colics.
d. CVS- heart block, to prevent reflex vagal inhibition of heart.
e. Eye- atropine is used to produce cycloplegia in accommodative esotropia.
Accommodative esotropia
6. Contraindications-In children and elderly males, glaucoma.
c.Neuromuscular (NMJ) blockers:
Neuromuscular junction blockers are the agents which block the nicotinic receptors (N M type)
and bring about the relaxation of the skeletal muscles. These are also called as skeletal muscle

relaxants, and are used to produce relaxation of the skeletal muscles, paralysis during surgery
and for the treatment spastic disorders.
Classification- I. Non depolarizing (competitive) blockers (curare).
a. Long acting- d-Tubocurarine, gallamine, pancuronium, doxacurium, pipecurium.(30-80min)
b. Intermediate acting – Vecuronium, , atracurium, alcuronium.(20-40min)
c. Short acting- Mivacurium.(10-20min)
II. Depolarizing blockers- Succinylcholine, Decamethonium.
d-Tubocurarine- It is a peripherally acting skeletal muscle relaxant. It was used by South
American tribals as arrow poison for game hunting. The animal got paralysed even if not killed
by the arrow. It was first clinically used in 1930.
MOA- d-tubacurarine is a competitive blocker for the nicotinic receptors (NM) present on the
post synaptic membrane(sarcolemma of the skeletal muscle). If the concentration of the dTC is
more, then these molecules bind with receptor site present on the αα sub units of the receptor.
The dTC is having only affinity with the receptor, but lack of intrinsic activity. Hence the
receptors get blocked by dTC, as dTC is not having intrinsic property. This interaction prevents
the skeletal muscle contraction action of acetylcholine; hence there is skeletal muscle relaxation.
The dTC also inhibits Ach release by blocking the pre-junctional nicotinic receptors; however
this action is not significant.
Ptosis Dysphagia
Pharmacological actions of dTC- 1. Skeletal muscles- It prevents the acetylcholine induced
skeletal muscle contraction. It is given i.v. Onset of action is within 1 minute, small, rapidly
moving muscles are effected first: eye> jaw->fingers-> large muscles of limbs->neck-> trunk->
intercostals muscles-> lastly diaphragm. Within one minute patient experiences dizziness,
warmth, weakness of the jaws, he can’t speck, there is ptosis, dysphagia, -> respiratory paralysis.
(ptosis- abnormal drooping of the upper eyelids, disphagia- difficulty in food swallowing)

2. Respiratory effects- dTC occationally produces bronchoconstriction , hypotension, increased
repiratory secretions due to the release of histamine. It should be used with caution in asthmatic
patients.
3. Effect in metabolic abnormalities- dTC effect is potentiated in respiratory acidosis ( due to
accumulation of carbon dioxide in hypoventilation ),and hypokalaemia.
4. Autonomic ganglia- It also blocks the nicotinic receptors (NN) at higher doses.
5. CVS- dTubacurarine produces significant fall in BP. This is due to ganglionic blockage,
histamine release, and reduced venous return- a result of paralysis of limb and respiratory
muscles. Heart rate may increase due to vagal ganglionic blockage. Newer nondepolarizing
drugs have negligible effects on heart rate and BP.
6. GIT- DTC may enhance the post operative paralytic ileus after abdominal operations. This is
due to ganglionic blockage of parasympathetic nerves of GIT.
7. CNS- All NMJ blockers are quaternary compounds. They do not cross the BBB, hence no
central effects.
ADME-Being quaternary compounds, they are not absorbed orally. They are administered by
i.v. route. Duration of action is short, due to rapid redistribution to non muscular tissues. dTC do
not crosses placenta or BBB. d-Tubocurarine, pancuronium, doxacurium, and pipecurium are
excreted unchanged by the kidneys. Others get metabolized in the liver, and the metabolites are
excreted in the urine.
ADRs- 1. Respiratory muscle paralysis. 2.Hypotension, 3.Bronchoconstriction and precipitation
of asthma due to the release of histamine.
Uses - For skeletal muscle relaxation in abdominal, orthopedic and thoracic surgeries. Surgeries
of longer durations. Preparations:
Gallamine inj Pipecurium bromide inj

II Depolarizing blockers-
Succinylcholine- MOA- Succinylcholine is composed of two covalently bound acetycholine
molecules. Like acetylcholine, it binds to one or both of the alpha subunits of the nicotinic
receptors at the postsynaptic site of the neuromuscular junction (NMJ). This results in
depolarization of the post junctional membrane. This depolarization is seen as fasciculations
followed by paralysis. Subsequent neuromuscular transmission is inhibited so long as adequate
concentration of succinylcholine remains at the receptor site. The termination of action of
succylcholine is depended on diffusion away from the neuromuscular junction into the
extracellular fluid where it is metabolized by butyrylcholinesterase (pseudocholinesterase;
plasma cholinesterase).
Pharmacological actions-
1.Skeletal muscles- First there are fasciculations-> followed by paralysis. Sequence: neck->arm-
>legs->phryngeal, laryngeal -> respiratory muscles. Succinylcholine is given i.v.-onset of action
is with in 1 minute, effects last for 5-10min.
2. Due to acetylcholine like action it acts on CVS and autonomic ganglia (stimulation). This
results in bradycardia and arrythmia.
ADME- It is also quaternery ammonium compound- not given orally. It is metabolized by
pseudocholinesterase. It crosses the placenta. It’s dose is 0.1 to 0.5mg/kg.
ADRs- 1.Respiratory paralysis- Prolonged apnoea in patients with atypical pseudocholinesterase.

Apnoea Muscle soreness
2. Muscle soreness (muscle fever-pain and stiffness felt in muscles several hours). 3. CVS
disturbances- Hyperkalemia.
Uses- Short surgical procedures like endo-tracheal intubation (placement of a tube into trachea),
endoscopies, correction of fracture/dislocations, electroconvulsive therapy, status epilepticus (it
is a life-threatening condition in which the brain is in a state of persistent seizure).
Endotrachial intubation upper endoscopy
Fractures and dislocations Electro convulsive therapy

Preparations:
DI- 1. Succinyl choline and thiopentone sodium should not mix in the same syringe- (as they
react chemically.
2. General anaesthetics, verapamil, diuretics, amino glycosides potentiate the effects of dTC.
3. Anticholinesterases like neostigmine reverse the action of dTC.
4. Adrenaline decreases the actions of dTC.
d.Drugs used in myasthenia gravis
Drugs used in myasthenia gravis.
Myasthenia gravis (Myo means “muscle” astheinia means “weakness’ and gravis means
“great”) is an autoimmune disease of skeletal muscle at neuromuscular junction causing
defective synaptic transmission. There is development of antibodies for nicotinic (NM) receptors
at motor end plate causing decrease in the number of NM receptors by structural damage of the
motor end plate. It is manifested as progressive muscular weakness and easy fatigability of the
muscles. MG is affecting about 1 in 10,000 population. These diseases may be either congenital
or acquired (autoimmune attack on an ion channel. Up to 75% of MG patients have an
abnormality of the thymus; 25% have a thymoma, a tumor of the thymus. In MG, some auto-
antibodies impair the ability of acetylcholine to bind to receptors; others lead to the destruction
of receptors. Decreased numbers of functioning nAChRs therefore impairs muscular contraction
by limiting depolarization.
Signs and symptoms- Disturbances in the movements of eye, eyelid, facial expression, talking,
swallowing. ptosis, diplopia (double vision), dysphagia, shortness of breath, dysarthria (impaired
speech), respiratory paralysis.

Diplopia Ptosis dysphagia
Diagnosis of MG- 1.Physical examination- Example- Looking upward and sidewards for 30
secs: positive if there is development of ptosis and diplopia. 2.Blood test- It is performed to
detect certain antibodies. 3.Electromyography- Stimulation of muscle fiber with electrical
impulse. 4.Edrophonium test. 5.Chest X ray- To detect thymoma. 6.Spirometry- Lung function
test.

Electromyography spirometry
Drug treatment in MG- Neostigmine is the drug of choice in MG. It is administered orally as
neostigmine bromide tablet in the dose of 15 to 30g thrice daily. Its disadvantages are short
duration of action (3 to 5h), development of tolerance and waning (decrease of muscle strength
gradually) of the muscle. For long term treatment pyridostigmine bromide (60 to 240mg once
daily) is used. Ephedrine sulphate and potassium chloride are used as adjuvants to
anticholinesterase in MG. Immunosuppressants like glucocorticoids (prednisolone 30 to 60mg
orally once daily), azathioprine or cyclosporine have been found effective in some patients who
can’t be controlled by anticholinesterases and adjuvant drugs.

f.Drugs used in Parkinsonism
Drugs used in Parkinson’s disease (PD)
Parkinson's disease is a neurodegenerative disease that severely affects the brain. Usually it
occurs in aged peoples (about 60 years). Within the cerebral cortex there are three nuclei (masses
of gray matter) termed basal ganglia. These nuclei are globus pallidus, putamen and caudate
nucleus. The globus pallidus and putamen are collectively called as the lentiform nucleus.
Together, the lentiform and caudate nuclei are known as the corpus striatum. Nearby structures
that are functionally linked to the basal ganglia are the substantia nigra and subthalmic nuclei.
The basal ganglia regulate the muscle tone required for specific body movements and also
control subconscious movements of the skeletal muscles. Neurons that extend from the sustantia
nigra to the putamen and caudate nucleus, where they release NT dopamine, degenerate in PD.
The caudate nucleus contains neurons that liberate the NT acetylcholine. This results in
imbalance of neurotransmitter activity (Ach-excitatory and DA-inhibitory). This results in
symptoms of PD.
Signs and symptoms of PD-
1. Fixed facial expression (inability to smile).
2. Lack of blinking.
3. Tremor or trembling- various uncontrolled movements typically occurring in fingers, hands,
arms, legs, jaw, and face.
4. Walking symptoms-Difficulty in walking, stooping posture, , loss of postural reflexes, rigid
back, impaired balance and coordination, falling forwards and backwards.
5. Rigidity- Stiffness of the limbs and trunk (alkinesia).

4. Walking symptoms-Difficulty in walking, stooping posture, , loss of postural reflexes, rigid
6. Bradykinesia-Slowness of movement.
7. Difficulty in swallowing-(dysphagia).
8. Speech changes-Difficulty talking, voice changes, softer voice,
Anti Parkinsonian drugs-
1. Drugs affecting brain dopaminergic system-
a. Dopamine precursor- Levodopa.
b.Peripheral decarboxylase inhibitors- Carbidopa, Benserazide.
c.Dopaminergic agonist- Bromocriptine, Pergolide.
d. MAO-B inhibitor- Selegiline.
e.COMT inhibitors- Entacapone, Tolcapone.
2. Drugs affecting brain cholinergic system.
a. Central anticholinergics- Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden,

b. Antihistamines- Orphenadrine, Promethazine.
Levodopa- It is a prodrug. Dopamine cannot cross the BBB, levodopa can cross the BBB. Inside
the brain levodopa is converted into dopamine by the DOPA decarboxylase enzyme.
Pharmacological actions of levodopa-
1. CNS- It has no action in normal individuals. It improves all features of Parkinsonism. Both D1
and D2 receptors present in the striatum and are involved in the therapeutic response to levodopa.
2. CVS- Due to peripheral conversion of LD to DA-> acts on the heart and peripheral blood
vessels-> increase in FC and HR, cardiac arrhythmia.
3. Endocrine effect- Dopamine act on the dopamine receptors (D2) present on the lactotrophs of
the pituitary gland. This decreases the prolactin secretion. DA also stimulates the GH secretion.
But in PD there is decreased secretion of GH.
4. CTZ- Dopamine acts on its receptors (D2) on this area and induces nausea and vomiting.
ADME- Levodopa is given orally. Only about 1 % enters the brain, rest is converted to DA
outside the brain by the enzyme DOPA decarboxylase (catalysed by pyridoxine). Absorption
from the GIT and entry of levodopa into the brain is by active transport process.

ADRs- 1. Nausea, vomiting due to stimulation of CTZ.
2. CVS- Tachycardia, palpitation, arrhythmia.
3. Postural hypotension.
4. Behavioral-anxiety, hallucinations, confusion, psychosis.
5. Dyskinasia (diminished voluntary movements).
Preparations and dose- Start with 250mg. Usual dose is 2-3g/day. Levodopa 500mg tabs.
b.Peripheral decarboxylase inhibitors- Carbidopa, Benserazide.
They inhibit decarboxylase enzyme peripherally, not in the CNS, because they cannot cross the
BBB. They increase the bioavailability of levodopa in the CNS. They are used only in
combination with levodopa.
Advantages of the combination
1. Less dose of levodopa is required.
2. Quicker onset of action.
3. Less CV side effects (less conversion of LD to DA.).
Disadvantages of the combination
More dyskinasia and behavioral disturbances, more postural hypotension-> are all due to
increased DA in the CNS.
Dose-LD100mg + Carbidopa 25mg

c.Dopaminergic agonist- Bromocriptine, Pergolide.
Bromocriptine- It is a D2 receptor agonist. It has a very quick onset of action. Duration is 5 to
10 h. The drug is costly. It is used as adjuvant to LD.
d. MAO-B inhibitor- Selegiline.
It is a MAO-B inhibitor-> prolongs the action of available LD/DA. It is effective in early stages.
Metabolites of DA are thought to cause the PD. Selegiline, by inhibiting metabolism of DA,
reduces the generation of toxic metabolites.
ADRs- Postural hypotension. Dose-5mg
e.COMT inhibitors- Entacapone, Tolcapone.
COMT is the enzyme that metabolizes catecholamines (including DA) as well as levodopa. Thus
these drugs increase the bioavailability of DA and LD.
Dose- Entacapone-100mg tid.

a. Central anticholinergics- Benzhexol, Procyclidine, Biperidin,
Atropine is not used because it has actions on many other sites of the body. They restore the
balance between dopaminergic and cholinergic systems by blocking the cholinergic pathway.
These are used in mild and early cases of PD. They are also used in drug induced PD.
Dose-Benzhexol 2-10mg/day, Biperidine 2-10mg/day.
g.Mydriatics and miotics
g. Mydriatics and miotics: Mydriatics are the drugs which produce mydriasis (dilatation of the
pupil).
Mydriasis Miosis
Classification:
Mydriatics: a.M3 blockers: Atropine, homatrapine, tropicamide (used in adults), cyclopentolate
(used in childrens), scopolamine. These produce mydriasis and cycloplegia.
b.α1 agonist: Phenylephrine- Only mydriasis, no cycloplegia as no α1 receptors on ciliary
muscles.

MOA: Blockage of M3receptors located in the circular muscles– Gq-PLC-IP3 and DAG-
pathway. Already discussed in the previous chapters.
Atropine and scopolamine are tertiary agents can easily enter the brain.
ADRs of M3 blockers: (atropine)
1.Mydriasis. 2.Cycloplegia. 3.Photophobia. 4.Tachycardia. 5.Dry mouth. 6.Hyperthermia.
7.Agitation, 8.Delirium, 9.Confusion.9.Precipitate glaucoma by increasing IOP.10.Dryness of
the conjunctiva. (sandy eyes).
b.α1 agonist: Phenylephrine- It is a non catechol adrenergic agonist acting directly on α1
receptors.
MOA: – Activation of α1receptors located in the radial muscles - α1receptors- Gq-PLC-IP3 and
DAG- pathway. Already discussed in the previous chapters.
ADRs- Hypertension, cardiac arrhythmias.
Marketed preparations- Atropine sulfate eye drops, homatropine eye drops, tropicamide
drops,cyclopentolate HCl drops,
Uses of mydriatics: 1. Mydriatics are used to enlarge the pupil for eye examinations to allow the
eye doctors to see the optic nerve, retina and the lense.
2.Some mydriatics are used to get cycloplegia, this helps for the accurate measurement of the
correct glasses prescription.

3.In some cases in childrens, used to prevent scar tissue formation during eye surgery.
$.Mydriatics are used during cataract surgesy.
Miotics: Miotics are the drugs which produce miosis (constriction of the pupil).
Muscarinic agonists produce miosis. The following are the muscarinic agonists which produce
miosis.Acetylcholine, pilocarpine,methacholine, carbachol, bethanechol.
MOA: Contraction of circular muscles present in the eye-M3 receptors-Gq type-PLC-IP3 and
DAG pathway.
ADRs: 1.The use of miotic medications for the treatment may causes pain in the eyes or the
region around the eyes.
2. Use of miotics result in excessive watering of the eyes.
3. Use of miotics result in cataract formation and retinal detachment may occur rarely.
Uses of miotics: Miotics are used in the treatment of glaucoma. Glaucoma is a disease caused by
increased IOP. If it is not treated it causes damage to the optic nerve and leads to blindness.
Marketed preparations:
------------ ---------------------KPS Gowda Asst.Professor------

II Pharm D Pharmacology I

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Viewers also liked

Viewers also liked (12)

Similar to II Pharm D Pharmacology I

Similar to II Pharm D Pharmacology I (20)

More from Dr.Shivalinge Gowda KP

More from Dr.Shivalinge Gowda KP (20)

Recently uploaded

Recently uploaded (20)

II Pharm D Pharmacology I