Veterinary Pharmacology and

Therapeutics I
October, 2012
• It is experimental science dealing with the pharmacokinetic and
pharmacodynamic properties of drugs and their effect on biological system

• Pharmacology includes drug knowledge like

 Physio-chemical properties

 Biochemical and physiological effects of drugs

 Mechanism of action of drugs

 Pharmacokinetic property of drug

 Drug Sources
Drug and Active Principle
• Until the end of the 19th century, medicines were natural organic or inorganic
products, mostly dried, but also fresh, plants or plant parts.
• These might contain substances possessing healing (therapeutic) properties or
substances exerting a toxic effect.
• In order to secure a supply of medically useful products not merely at the time
of harvest but year-round, plants were preserved by drying or soaking them in
vegetable oils or alcohol.
• Soaking plants parts in alcohol (ethanol) creates a tincture. In this process,
pharmacologically active constituents of the plant are extracted by the alcohol.
• Tinctures do not contain the complete spectrum of substances that exist in the plant or crude
drug, only those that are soluble in alcohol.

• In the case of opium tincture, these ingredients are alkaloids (i.e., basic substances of plant
origin) including: morphine, codeine, narcotine = noscapine, papaverine, narceine, and others.

• Therefore a natural product or extract to treat a disease thus usually entails the administration
of a number of substances possibly possessing very different activities. Moreover, the dose of
an individual constituent contained within a given amount of the natural product is subject to
large variations, depending upon :-

1. The product„s geographical origin (biotope)

2. Time of harvesting

3. Conditions and length of storage

The aims of isolating active principles are:
1. Analysis of the biological effects (pharmacodynamics) of individual
ingredients and of their fate in the body (pharmacokinetics).
2. Ensuring a precise and constant dosage in the therapeutic use of chemically
pure constituents.
3. The possibility of chemical synthesis, which would afford independence from
limited natural supplies and create conditions for the analysis of structure-
activity relationships and
4. Derivatives of the original constituent with improved therapeutic usefulness
may be developed.
 Raw Opium

Morphine
Codeine
Narcotine

etc

Preparation of Opium tincture

Drug Development

• This process starts with the synthesis of novel chemical compounds. Substances with
complex structures may be obtained from various sources, e.g., plants (cardiac glycosides),
animal tissues (heparin), microbial cultures (penicillin G), or human cells (urokinase), or by
means of gene technology (human insulin).

• As more insight is gained into structure- activity relationships, the search for new agents
becomes more clearly focused.

Preclinical testing

• yields information on the biological effects of new substances.

• Initial screening may employ biochemical-pharmacological investigations (e.g., receptor-

binding assays p. 56) or experiments on cell cultures, isolated cells, and isolated organs. Since
these models invariably fall short of replicating complex biological processes in the intact
organism, any potential drug must be tested in the whole animal.
• Only animal experiments can reveal whether the desired effects will actually occur at dosages
that produce little or no toxicity.

• Toxicological investigations serve to evaluate the potential for: (1) toxicity associated with
acute or chronic administration; (2) genetic damage (genotoxicity, mutagenicity); (3)
production of tumors (onco- or carcinogenicity); and (4) causation of birth defects
(teratogenicity).

• In animals, compounds under investigation also have to be studied with respect to their
absorption, distribution, metabolism, and elimination (pharmacokinetics).

• Even at the level of preclinical testing, only a very small fraction of new compounds will
prove potentially fit for use in humans.
Clinical testing

Phase I studies

• Starts with healthy subjects and seeks to determine whether effects observed in animal
experiments also occur in humans.

• Dose-response relationships are determined.

Phase II studies

• Potential drugs are first tested on selected patients for therapeutic efficacy in those disease
states for which they are intended.

• In this phase a beneficial action should be evident and the incidence of adverse effects has to
be acceptably small.

Phase III studies

• Involves a larger group of patients in whom the new drug will be compared with standard
treatments in terms of therapeutic outcome.
 As a form of human experimentation, these clinical trials are subject to review and approval
by institutional ethics committees according to international codes of conduct.

 During clinical testing, many drugs are revealed to be unusable. Ultimately, only one new
drug remains from approximately 10,000 newly synthesized substances.

 The decision to approve a new drug is made by a national regulatory body (Food & Drug
Administration in the U.S.A., the Health Protection Branch Drugs Directorate in Canada, UK,
Europe, Australia) to which manufacturers are required to submit their applications.

 Applicants must document by means of appropriate test data (from preclinical and clinical
trials) that the criteria of efficacy and safety have been met and that product forms (tablet,
capsule, etc.) satisfy general standards of quality control.
Phase IV studies

• Following approval, the new drug may be marketed under a trade name (p. 333) and thus
become available for prescription by physicians and dispensing by pharmacists.

• As the drug gains more widespread use, regulatory surveillance continues in the form of
postlicensing studies
Drug Administration

Dosage Forms for Oral, Ocular, and Nasal Applications

• A medicinal agent becomes a medication only after formulation suitable for therapeutic use
(i.e., in an appropriate dosage form).

• The dosage form takes into account the intended mode of use and also ensures ease of
handling (e.g., stability, precision of dosing) by patients and physicians.

• Pharmaceutical technology is concerned with the design of suitable product formulations and
quality control.

 Liquid preparations:- may take the form of solutions, suspensions (a sol or mixture
onsisting of small water- insoluble solid drug particles dispersed in water), or emulsions
(dispersion of minute droplets of a liquid agent or a drug solution in another fluid, e.g.,
oil in water).
 Solid dosage forms
• Include tablets, coated tablets, and capsules.
• Tablets have a disk-like shape, produced by mechanical compression of active substance,
filler (e.g., lactose, calcium sulfate), binder, and auxiliary material (excipients). The filler
provides bulk enough to make the tablet easy to handle and swallow.
• Disintegration of the tablet can be hastened by the use of dried starch, which swells on contact
with water, or of NaHCO3, which releases CO2 gas on contact with gastric acid.
• Auxiliary materials are important with regard to tablet production, shelf life, palatability, and
identifiability (color).
Dosage Forms for Parenteral (1), Pulmonary (2), Rectal or Vaginal (3), and Cutaneous
Application
• Drugs need not always be administered orally (i.e., by swallowing), but may also be given
parenterally.
• This route usually refers to an injection, although enteral absorption is also bypassed when
drugs are inhaled or applied to the skin.

• For intravenous, intramuscular, or subcutaneous injections, drugs are often given as solutions
and, less frequently, in crystalline suspension for intramuscular, subcutaneous, or
intraarticular injection.

• An injectable solution must be free of infectious agents, pyrogens, or suspended matter.

• It should have the same osmotic pressure and pH as body fluids in order to avoid tissue
damage at the site of injection.

Drug Administration by Inhalation

• Inhalation in the form of an aerosol, a gas, or a mist permits drugs to be applied to the
bronchial mucosa and, to a lesser extent, to the alveolar membranes.
• This route is chosen for drugs intended to affect bronchial smooth muscle or the consistency
of bronchial mucus.

Dermatologic Agents

• Pharmaceutical preparations applied to the outer skin are intended either to provide skin care
and protection from noxious influences, or to serve as a vehicle for drugs that are to be
absorbed into the skin or, if appropriate, into the general circulation.
Prescription and dispensing

• Prescription is an instruction or order written by a lisenced veterinarian, physician or

dentist to the dispenser (pharmacist) to prepare the prescribed remedy and sell it to the
patient.
Assignment
Write an assignment on the format of prescription
Legal category of drugs
• OTC drugs (over the counter)- They are drugs that can be sold to the patient or client
with out legal prescription from the veterinarian.
• Prescription drugs- Are the drugs which have to be sold after proper prescription
Requirement for prescription
1. The names of the drugs should not be abbreviated.
2. Only generic name of the drugs should be written on prescription.
3. Write using inc or officially headed paper.
4. Use legible hand writing.
5. Use metric system units, but some times we can use other measurements as convenient.
6. Store the carbon copy of every prescriptions.
• Write the species of the animal
• Proof reading
Acceptable abbreviations on the prescription paper
Sid – One time a day  ft – Make  C- with
Bid- Twice a day  h – Hour  PR – By rectum
Tid – Three times a day  m – Mix  PO – By rectum
qid- Four times a day  Sig – Lable  PV – By vagina
Od – Daily  Sol – Solution
Q.2h – Every 2 hour  Tab – Tablet
Q.3h – Every 3 hour  Cap – Capsule
O.M – Every morning  Ac – Before meal
O.N - Every night  Q.s – Sufficient
Adlib – As desired  N.r – Don‟t repeat
PRN – As required
Rational use of drug

• Rational prescription is a process of safe, effective and economic way of

prescribing drugs to the patients.
• It is a selection of proper drug and dosage regimen appropriate for specific species
and specific disease condition in order to eliminate the pathogen without affecting
the normal physiology of the animal.
Principles for rational drug use
• Efficient diagnosis of the disease.
• Exhaustion of non-drug therapy.
• Good knowledge about the clinical effect of the drug.
• Its illegal to use other peoples title or name to prescribe drug.
• Inform the patient how to handle, use and also about possible side effects of the
drug.
• Avoid indiscriminate use of drugs.
• Check the previous treatment history of the patient.
• Follow up the degree of response or adverse reactions (if there is any).
• Communicate the adverse effects of the drug to the manufacturing company or
local health authority.
• Avoid polypharmacy unless it is justified.
• Strict adherence to drug withdrawal period.
Irrational drug uses
• Over prescription
Dose
Longer druration
Longer frequency
• Under prescription
• Extravagant prescription
• Polypharmacy
Pharmaceutical calculations

Dose – Quantity of a drug administered at one time to bring desired therapeutic

response in the patient.
• Dose is calculated according to the number of mg/Kg body weight of the animal.
Factors that affect the prescribed dose of the drug
• Age
• Body weight
• Pathological condition (liver disease)
• Physiological condition (pregnancy)
• Sex
• Species
• Time of the day Eg. Diazepam
• Formula to calculate the body weight of some spp.
Bovine = H2L/10840, Swine = H2/120.6
• Ways of expressing the strength of drug solutions
Molarity, Molality, Normality, Formality, Percentage (mg/ml), Ratio (1:10), Parts
per million (PPM = 1 mg/ litter), Parts per billion (PPB = 1μg/ litter)
• Different ways of expressing solutions
1. Percent weight in volume (w/v) – Is defined as the number of grams of a drug in
100ml of solution.
Eg. 2 % - 2 gm of a drug in 100 ml of solution
2. Percent weight in weight (w/w) – Defined as a gram of a drug in 100 gm of a
vehicle.
3. Percent volume in volume (v/v) – The number of ml of a drug in 100 ml of
solution.
• Different ways of preparing solutions
1. Number of mg of a drug needed to prepare solution = Number of ml of solution X
Number of mg/ml of solution.
2. Number of grams of a drug needed = Number of ml of solution X percent of
solution in whole number/ 100
3. Number of mg of the drug in 1 ml of the solvent = % X 10
Eg. If the conc. Of the drug is 20% = 200mg/ml
4. Total dose in mg = No. of mg/ Kg of tissue (this is calculated during development
in pharmaceutical company)
Total dose in mg = No. mg/ Kg X Body weight
Dilution of stock solution
Stock solution – Are undiluted solutions produced from pharmaceutical company.
Objective of stock solution
1. Economic purpose
2. To avoid biotransformation outside animal body
Concentration ̴ 1/volume
C1V1= C2V2 C1 (Stock solution), V1 (Volume of stock solution), C2 (Concentration of
final solution) and V2 (Volume of final solution)
Examples
1. 80% of ethanol solution is to be diluted by adding 300 ml of water, if 500 ml of
ethanol was diluted what would be the volume and strength of final solution.
2. Tissue conc. Of a drug is 15 mg/Kg, if 1gm of powder is available which is to be
administered in the strength of 50 mg per 1 ml to a calf weighing 25 Kg. How many
ml can carry the total mg required.
3. An antihelmenthic bolus each containing 10 gms of active ingredient is drenched to
600 Kg stallion, if the recommended dose is 120 mg/Kg body weight. How many
boluses are required.
Cellular Sites of Action
Potential Targets of Drug Action
• Drugs are designed to exert a selective influence on vital processes in order to
alleviate or eliminate symptoms of disease.
• The smallest basic unit of an organism is the cell. The outer cell membrane,
effectively demarcates the cell from its surroundings, thus permitting a large degree
of internal autonomy.
• Embedded in the cell membrane are transport proteins that serve to mediate
controlled metabolic exchange with the cellular environment. These include energy-
consuming pumps (e.g., Na, K-ATPase), carriers (e.g., for Na/glucose-cotransport),
and ion channels e.g., for sodium or calcium.
• Functional coordination between single cells is a prerequisite for viability of the
organism, hence also for the survival of individual cells.
• Cell functions are regulated by means of messenger substances for the transfer of
information. Included among these are “transmitters” released from nerves, which
the cell is able to recognize with the help of specialized membrane binding sites or
receptors.
• Hormones secreted by endocrine glands into the blood, then into the extracellular
fluid, represent another class of chemical signals. Finally, signalling substances can
originate from neighboring cells, e.g., prostaglandins and cytokines.
• The effect of a drug frequently results from interference with cellular function.
• Receptors for the recognition of endogenous transmitters are obvious sites of drug
action (receptor agonists and antagonists). Altered activity of transport systems
affects cell function (e.g., cardiac glycosides, loop diuretics and calcium-
antagonists).
• Drugs may also directly interfere with intracellular metabolic processes, for
instance by inhibiting (phosphodiesterase inhibitors) or activating (organic nitrates)
an enzyme.
• In contrast to drugs acting from the outside on cell membrane constituents, agents
acting in the cell’s interior need to penetrate the cell membrane.
• The cell membrane basically consists of a phospholipid bilayer (80Å = 8 nm in
thickness) in which are embedded proteins (integral membrane proteins, such as
receptors and transport molecules).
• Phospholipid molecules contain two long-chain fatty acids in ester linkage with
two of the three hydroxyl groups of glycerol. Bound to the third hydroxyl group is
phosphoric acid, which, in turn, carries a further residue, e.g., choline,
(phosphatidylcholine = lecithin), the amino acid serine (phosphatidylserine) or the
cyclic polyhydric alcohol inositol (phosphatidylinositol).
• In terms of solubility, phospholipids are amphiphilic: the tail region containing the
apolar fatty acid chains is lipophilic, the remainder – the polar head – is
hydrophilic. By virtue of these properties, phospholipids aggregate spontaneously
into a bilayer in an aqueous medium, their polar heads directed outwards into the
aqueous medium, the fatty acid chains facing each other and projecting into the
inside of the membrane.
• The hydrophobic interior of the phospholipid membrane constitutes a diffusion
barrier virtually impermeable for charged particles. Apolar particles, however,
penetrate the membrane easily. This is of major importance with respect to the
absorption, distribution, and elimination of drugs.
Pharmacokinetics

• The relationship between the time course of drug concentrations attained in different
regions of the body during and after dosing is termed pharmacokinetics ('what the body
does to the drug'), to distinguish it from pharmacodynamics ('what the drug does to the
body', i.e. events consequent on interaction of the drug with its receptor or other primary
site of action).
Absorption and distribution of drugs
• In order to work, drugs need to achieve an adequate concentration in their target tissues.
• The two fundamental processes that determine the concentration of a drug at any
moment and in any region of the body are:
 Translocation of drug molecules
 Chemical transformation.
Translocation of drug molecules
Drug molecules move around the body in two ways:
 Bulk flow (i.e. in the bloodstream)
 Diffusion (i.e. molecule by molecule, over short distances).
• The chemical nature of a drug makes no difference to its transfer by bulk flow. The
cardiovascular system provides a rapid long-distance distribution system.
• In contrast, diffusional characteristics differ markedly between different drugs. In
particular, ability to cross hydrophobic diffusion barriers is strongly influenced by
lipid solubility.
• Aqueous diffusion is also part of the overall mechanism of drug transport, because
it is this process that delivers drug molecules to and from the non-aqueous barriers.
• The rate of diffusion of a substance depends mainly on its molecular size, the
diffusion coefficient for small molecules being inversely proportional to the square
root of molecular weight. Consequently, while large molecules diffuse more slowly
than small ones, the variation with molecular weight is modest. Many drugs fall
within the molecular weight range 200-1000, and variations in aqueous diffusion
rate have only a small effect on their overall pharmacokinetic behavior.
The movement of drug molecules into general circulation
1. Passive diffusion – The movement of drug molecules from high to low conc.
2. Facilitative diffusion – This diffusion is facilitated by carrier proteins to take
molecule to cell.
- It is down conc. gradient
3. Active transport – Unlike the above to mechanisms, this movement is from low to
high conc. So this transport needs energy (ATP) and carrier proteins.
 After transporting certain amount of molecules it is movement will saturate. This is
due to the limited number of carrier proteins.
 In this transport competitive antagonism is possible (some other protein can block
the transport).
4. Phagocytosis – Intake of large drugs to cell (cell eating)
5. Pinocytosis – Intake of liquid drug (cell drinking)
The rate and extent of absorption can depend on:-
1. Physico-chemical property of drug
Eg. Size of the molecule, lipid solubility of the molecule, degree of ionization of the
molecule etc.
2. Dosage form – Liquid dosage forms absorbed vast than solid dosage forms
3. Route of administration – Drugs which are administered orally have low
absorption rate as compared to intramuscular or intravenous route.
4. Surface area of absorption - High surface area = High absorption rate
5. Vascularity – It is the amount of blood supply to the specific area of the
administration (High vascular supply = High absorption).
Routes of administration
The choice of routes of administration depend on different factors
1. Onset of action
2. Site of action of the drug
3. Potential adverse effects
4. Physico-chemical property- Because of tissue necrosis irritant drugs should not be given
subcutaneously.
Oral route (PO)
There are some specific characteristic of this route
• Easiest
• Safest
• Slower onset of action
• Incomplete absorption
• Requires large dose as compared to other routes due to :- Dilution by GIT fluid, loss of
drug though feaces, first – pass effect (drugs given by mouth join portal circulation and
part of the drug is biotransformed before joining general circulation).
Limitation of PO
• Diarrhea and vomition reduce the amount of drug to be absorbed.
• Distraction of the drug by HCl
• Inhibition by GIT microflora
Parenteral route
• Route of administration without passing GIT
• It includes all forms of injection
I. Intravenous injection
Characteristic
• Has faster onset of action (life saving injection)
• Precise dose control and bioavailability is high
• Using different drugs with wide range of PH and tonicity is possible due to bloods
dilution effect
Limitations
• Toxicity (adverse effects are faster)
• Can cause haemolysis
• There is a risk of embolism
Note:- During administration of drugs intravascularly, the administration rate should be slow,
the solution must be sterile and the blood circulation have to be monitored.
II. Intramuscular/ Subcutaneous (IM/SC)
Characteristics
• Oily formulations and suspensions can be given
Limitations
• Irritant drugs can‟t be given, due to possible pain, necrosis and local irritation
• Onset of action is lower than IV
• Drugs must be at physiological PH and tonicity
III. Intraperitonial route (mostly used in lab animals)
IV. Epidural route- It is injection into spinal cored and mostly used for anesthesia
V. Intra articular – It is injection into a joint cavity or synovial fluid. It is not common
but sometimes used for severe arthritis.
VI. Intracardiac – It is injection of drug into myocardial wall. It is extra active route
VII. Intradermal – Administration of drug in between dermis and epidermis. This route can
also be used for diagnosis of some diseases (Tuberculosis)
VIII. Intra arterial – Administration of drug into specific artery. This route is
commonly used for anti cancer therapy.
IX. Inhalation – Administration of volatile drugs to the animal though inhaletion.
This route is commonly used to treat diseases of respiratory system and for general
anesthesia.
X. Local (Topical) Route – This route can be used for both medical and cosmetic
purposes. In this route drugs can be applied on the skin or mucus membranes.
Anatomical sites for different routes of administration in
different species

Species Route Site

Birds IV Alnar vein (Wing vein)
IM Pectoral (thigh muscle)
SC Lose skin at thigh
Canine IV Cephalic vein, Saphenous vein
Swine IV Marginal ear vein, saphenous vein
Shoats IV Jugular vein, Cephalic vein
Cattle IV Jugular vein
IM Gluteal muscle
Equine IV Jugular vein
IM Pectoral muscle

NB. Wild animals can be treated though food, water or sometimes we can sedate and treat
the animal
Degree of ionization of the drug

The degree of ionization of the drug depends on:-

• The PH of the drug (acidic or alkaline)
• The PH of the medium
• Pka (it is a mathematical representation of drugs ability to ionize) of the drug
For acidic drugs Pka = PH + log unionized/ionized (Hasselbach equation)
Eg. HA (acidic drug) ↔ A- + H+ Pka = PH + log [HA]/[A-]
NB. If the conc. Of ionized is equal to unionized, Pka of the drug is equal to the PH. It
means that 50% of the drug is in its ionized form
• The degree of ionization is expressed as:
For basic drugs, % ionized = 100/ 1 + antilog (PH – Pka)
For acidic drugs, % ionized = 100/ 1 + antilog (Pka – PH)
Therefore the ratio of unionized drug to ionized drug can be calculated at any given PH
by using Hasselbach equation
For acidic drugs, Unionized/ionized = PH – Pka = log [A-]/[HA]
For basic drugs, Unionized/ionized = PH – Pka = log [B]/[HB+]
• Pka = -log Ka (ionization constant)
HA ↔ H+ + A- , Ka = [H+] [A-]/[HA]
• Pka of 3 – 8 is good for drugs, therefore both weak acid and weak base drugs are good.
But if the drugs are strongly acidic or basic there will be a problem of absorption due to
ionization.
PH of the medium
• The medium can be blood, GIT fluid, urine or milk
• Therefore the tendency of acidic drugs to be ionized in acidic medium is less and the
same is true for basic drugs in basic medium.
• Acidic drugs are best absorbed in stomach than intestine and vise verse for basic drugs.
Ion trapping
• It is a phenomena when drugs gets ionized and trapped in the medium with out being
absorbed (the drug will be excreted)
The excretion or absorption of the drug can be facilitated by changing the PH of the
urine
• Acidification of urine by administering NH4Cl will increase the removal of basic
drugs.
• Alkalinization of urine by administering NaHCO3 will increase the removal of
acidic drugs.
Exercise
1. A weak acidic drug has a Pka of 4.5, what percent of the drug is ionized in the
medium that has a PH of 3.
2. 2.5 gm of acidic drug with Pka of 3.4 is swallowed. The PH of stomach fluid after
administering the drug is 2. What amount of the drug present in the stomach will be
in unionized form before any absorption takes place.
Distribution of drugs inside the body

• It is the movement of the drug molecules after being absorbed.

• Most drugs bind to plasma proteins like albumin, lipoprotein, globulin etc.
Some of the factors that affect the distribution of the drug inside the body are:-
• Lipid solubility, acidity or alkalinity of the drug, affinity of the tissue towards specific
drug, conc. gradient across membrane etc.
Redistribution
• It is the movement of the drug from its site of action to the storage organs like bone and
fatty tissue, and from the storage organs back into general circulation.
• Mostly this phenomena is observed in lipid soluble drugs.
Biotransformation (drug metabolism/ detoxification)
• It is a chemical alteration of endogenous compounds like adrenaline and xenobiotics in
to different metabolic intermediates (metabolites).
• The objective of biotransformation is to make the drug less toxic and facilitate its
clearance.
Different therapeutic and toxic characteristic of biotransformation
1. When the therapeutic efficacy of metabolite is higher than the parent drug, it is called
bio-activation. Eg. Phenacetin to acetaminophen
2. When the therapeutic efficacy of metabolite is lower than parent drug, it is called
bio-inactivation (detoxification).
3. When the metabolite is more toxic than parent compound, it is called bio-
toxification. Eg. Malathion to malaoxon
Sites of bio-transformation
• Liver, lung, intestine, kidney, spleen, skin, blood, muscles, nerve synapse etc.
NB. Lipophilic drugs have to be transformed into water soluble to be excreted though
urine.
Patterns of drug bio-transformation
1. Phase one reaction (functionalization reaction) – It involves introduction of polar
functional groups into the drug molecule. Eg. OH, COOH, NH2
• This phase will make the drug more water soluble
• Phase I reaction produce compounds with less toxic metabolite (not always) that
has high chemical reactivity. Reactions can be hydrolysis, reduction, oxidation,
decarboxylation
2. Phase two reaction – It is bio-synthetic or conjugative reaction that will attach
endogenous compounds like sulfate, glucoronic acid, glutamate, glycine, acetate,
gluthathion etc. Eg. A-NH2 – Glucoronic acid (glucoronization)
A-NH2-Glycine (glycinezation)
• The conjugates in this phase are polar, water soluble and therefore can be excreated
though urine.
First pass metabolism (presystemic metabolism)
• It is the metabolism of a drug given by oral route, inhalation and intraperitonial
route before entering into systemic circulation.
• This metabolism reduce the bioavailability of drugs.
Enzyme induction
• Xenobiotics can influence the extent of drug metabolism by activating transcription
and inducing the expression of genes encoding drug-metabolizing enzymes.
• Thus, a foreign compound may induce its own metabolism, as may certain drugs.
• One potential consequence of this is a decrease in plasma drug concentration over
the course of treatment, resulting in loss of efficacy, as the auto-induced
metabolism of the drug exceeds the rate at which new drug enters the body.
• A list of ligands and the receptors through which they induce drug metabolism is
shown in . A particular receptor, when activated by a ligand, can induce the
transcription of a battery of target genes.
• Among these target genes are certain CYPs and drug transporters. Thus, any drug
that is a ligand for a receptor that induces CYPs and transporters could lead to drug
interactions. Shows the scheme by which a drug may interact with nuclear receptors
to induce its own metabolism.

Table 3-4. Nuclear Receptors That Induce Drug Metabolism

RECEPTOR LIGANDS
Aryl hydrocarbon receptor (AHR) Omeprazole
Constitutive androstane receptor (CAR) Phenobarbital
Pregnane X receptor (PXR) Rifampin
Enzyme Inhibition
• Many xenobiotics or endogenous compounds can inhibit the biotransformation of
another drug or endogenous compound.
• When the biotransformation of a drug is inhibited the half life of the same drug will
increase and so does its toxic effect.
Eg. Chloramphinicol
Mechanism of elimination
• Drug elimination is the irreversible loss of drug from the body.
• It occurs by two processes: metabolism and excretion.
• Metabolism involves enzymatic conversion of one chemical entity to another within
the body, whereas excretion consists of elimination from the body of chemically
unchanged drug or its metabolites.
• The main routes by which drugs and their metabolites leave the body are
 The kidneys
 The hepatobiliary system
 The lungs (important for volatile/gaseous anaesthetics).
• Most drugs leave the body in the urine, either unchanged or as polar metabolites.
Some drugs are secreted into bile via the liver, but most of these are then
reabsorbed from the intestine.
• There are, however, instances (e.g. rifampicin) where faecal loss accounts for the
elimination of a substantial fraction of unchanged drug in healthy individuals, and
faecal elimination of drugs such as digoxin that are normally excreted in urine
becomes progressively more important in patients with advancing renal failure.
• Excretion via the lungs occurs only with highly volatile or gaseous agents (e.g.
general anaesthetics).
• Small amounts of some drugs are also excreted in secretions such as milk or sweat.
Elimination by these routes is quantitatively negligible compared with renal
excretion, although excretion into milk can sometimes be important because of
effects on the baby.
Biliary excretion and enterohepatic circulation
• Liver cells transfer various substances, including drugs, from plasma to bile by
means of transport systems similar to those of the renal tubule and that involve P-
glycoprotein.
• Various hydrophilic drug conjugates (particularly glucuronides) are concentrated in
bile and delivered to the intestine, where the glucuronide is usually hydrolysed,
• Various hydrophilic drug conjugates (particularly glucuronides) are concentrated in
bile and delivered to the intestine, where the glucuronide is usually hydrolysed,
releasing active drug once more; free drug can then be reabsorbed and the cycle
repeated (enterohepatic circulation).
• The effect of this is to create a 'reservoir' of recirculating drug that can amount to
about 20% of total drug in the body and prolongs drug action. Examples where this
is important include morphine and ethinylestradiol.
• Several drugs are excreted to an appreciable extent in bile. Vecuronium (a non-
depolarising muscle relaxant is an example of a drug that is excreted mainly
unchanged in bile. Rifampicin is absorbed from the gut and slowly deacetylated,
retaining its biological activity. Both forms are secreted in the bile, but the
deacetylated form is not reabsorbed, so eventually most of the drug leaves the body
in this form in the faeces.
Renal excretion of drugs and drug metabolites
• Drugs differ greatly in the rate at which they are excreted by the kidney, ranging
from penicillin, which is cleared from the blood almost completely on a single
transit through the kidney, to diazepam, which is cleared extremely slowly.
Three fundamental processes account for renal drug excretion
Glomerular filtration
Active tubular secretion
Passive diffusion across tubular epithelium
Glomerular filtration
• Glomerular capillaries allow drug molecules of molecular weight below about
20000 to diffuse into the glomerular filtrate.
• Plasma albumin (molecular weight approximately 68000) is almost completely
impermeable, but most drugs-with the exception of macromolecules such as
heparin-cross the barrier freely.
• If a drug binds appreciably to plasma albumin, its concentration in the filtrate will
be less than the total plasma concentration.
• Warfarin, a drug which is approximately 98% bound to albumin, the concentration
in the filtrate is only 2% of that in plasma, and clearance by filtration is
correspondingly reduced.
Tubular secretion
• Up to 20% of renal plasma flow is filtered through the glomerulus, leaving at least
80% of delivered drug to pass on to the peritubular capillaries of the proximal
tubule.
• Here, drug molecules are transferred to the tubular lumen by two independent and
relatively non-selective carrier systems. One of these transports acidic drugs (as
well as various endogenous acids, such as uric acid), while the other handles
organic bases.
• Some of the more important drugs that are transported by these two carrier systems
are shown in. The carriers can transport drug molecules against an electrochemical
gradient, and can therefore reduce the plasma concentration nearly to zero.
• Because at least 80% of the drug delivered to the kidney is presented to the carrier,
tubular secretion is potentially the most effective mechanism of renal drug
elimination.
• Unlike glomerular filtration, carrier-mediated transport can achieve maximal drug
clearance even when most of the drug is bound to plasma protein.
• Penicillin, for example, although about 80% protein-bound and therefore cleared
only slowly by filtration, is almost completely removed by proximal tubular
secretion, and its overall rate of elimination is very high.
• Many drugs compete for the same transport system , leading to drug interactions.
For example, probenecid was developed originally to prolong the action of
penicillin by retarding its tubular secretion.
Diffusion across the renal tubule
• Water is reabsorbed as fluid traverses the tubule, the volume of urine emerging
being only about 1% of that of the glomerular filtrate.
• If the tubule is freely permeable to drug molecules, some 99% of the filtered drug
will be reabsorbed passively.
• Lipid-soluble drugs are therefore excreted poorly, whereas polar drugs of low
tubular permeability remain in the lumen and become progressively concentrated as
water is reabsorbed. Drugs handled in this way include digoxin and aminoglycoside
antibiotics.
• These exemplify a relatively small but important group of drugs that are not
inactivated by metabolism, the rate of renal elimination being the main factor that
determines their duration of action. These drugs have to be used with special care in
individuals whose renal function may be impaired, including the elderly and
patients with renal disease or any severe acute illness.
Renal clearance
• Elimination of drugs by the kidneys is best quantified by the renal clearance (CLr).
• This is defined as the volume of plasma containing the amount of substance that is
removed by the kidney in unit time.
• It is calculated from the plasma concentration Cp, the urinary concentration Cu, and
the rate of flow of urine Vu, by the equation:
CLr = Cu X Vu
Cp
• CLr varies greatly for different drugs, from less than 1ml/min to the theoretical
maximum set by the renal plasma flow, which is approximately 700ml/min,
measured by p-aminohippuric acid (PAH) clearance (renal extraction of PAH
approaches 100%).
Rates of elimination
Order of reaction – Is the way in which conc. Of drug, determines it‟s elimination or
excretion.
Zero order kenetics
• The rate of elimination is constant and doesn‟t depend on the concentration of the
drug.
• The amount of drug eliminated from the system is constant and expressed as: Rate =
Change in concentration of drug/ Change in time.
ΔC/ Δt = - K0,
dc/dt = - K0 so the amount of drug at any time t can be calculated
as, C = - K0 t + C0
Eg. Ethanol follows zero order kinetics of elimination
• In zero order reaction half life (the time required for body to reduce conc. Of drug by
50%) is calculated as:
C0 /2 = - K0 t ½ + C0,
C0 /2 - C0 = - K0 t ½ ,
- C0 /2 = - K0 t ½
t ½ = 0.5 C0 / K0
• In zero order of reaction, half life is directly proportional to C0 and inversely
proportional to K0.
First order kinetics
• The amount of a drug is decreasing at a rate proportional to the Conc. Of drug and
the rate in this case can be expressed as:
dc/ dt = -KC, K (First order rate constant)
Therefore, we can calculate the Conc. Of a drug at any time t as:
In C(t) = -Kt + In C0,
Since In = 2.303 log,
log C(t) = -Kt / 2.303 + log C0
• In first order reaction half life is calculated as:
t ½ = 0.693 / K
• Ex. 1. Plot the following date on rectangular coordinates
Time (min) Drug conc. (mg)
10 96
20 89
40 73
60 57
90 34
120 10
A. Is it the zero order or first order elimination
B. Calculate the rate constant
C. Calculate the half life
Pharmacokinetics Parameters
1. Area under the curve (AUC)

t1 tn

• The area under curve can be calculated by trapezoid rule and we can get the
approximate blood conc. Of drug.
2. Bioavailability (F)
• The fraction of drug that enters systemic circulation without change.
F = AUC PO X 100/ AUC iv
3. Volume of distribution (Vd)
Vd = Q/ Cp, Q = dose, Cp = Plasma conc.
4. Steady state plasma concentration
• For a drug effect to persist for required period of time, the effective conc. Of a drug
must stay in plasma for production of effect.
• There are three ways of keeping the required therapeutic conc. For required period
of time:
1. Giving loading dose
2. Administration of fixed dose repeatedly at constant interval.
3. Continues intravenous infusion
Pharmacodynamics
• It‟s the mechanism of action (what drugs do to the body).
• One of the basic tenets of pharmacology is that drug molecules must exert some
chemical influence on one or more constituents of cells in order to produce a
pharmacological response.
• Pharmacological effects require, the interaction of drug molecules to particular
constituents of cells and tissues in order to produce an effect.
• These critical binding sites are often referred to as 'drug targets„.
• The mechanisms by which the association of a drug molecule with its target leads
to a physiological response constitute the major thrust of pharmacological research.
• Most drug targets are protein molecules. Even general anaesthetics, which were
long thought to produce their effects by an interaction with membrane lipid, now
appear to interact mainly with membrane proteins.
• Different from anaesthetics, and many antimicrobial and antitumour drugs, as well
as mutagenic and carcinogenic agents, interact directly with DNA rather than
protein; bisphosphonates, used to treat osteoporosis, bind to calcium salts in the
bone matrix, rendering it toxic to osteoclasts, acid neutralization by antiacids, the
effect of osmotic diuretics or purgatives.
Protein targets for drug binding
Four main kinds of regulatory protein are commonly involved as primary drug targets,
namely:
 Receptors
 Enzymes
 Carrier molecules (transporters)
 Ion channels.
• A few other types of protein are known to function as drug targets, and there exist
many drugs with sites of action that are not yet known.
• Furthermore, many drugs are known to bind (in addition to their primary targets) to
plasma proteins, and to a variety of cellular proteins, without producing any
obvious physiological effect.
Receptors
• They are functionally important tissue components with which the drug interacts to
bring a characteristic biological effect.
• Efficacy – the ability of a drug to produce a response in a given tissue, organ,
system or organism.
• Potency – The dependence of the effect of drug on its conc. Or dose.
 The higher the potency – the smaller the dose (highly potent drug)
 Highly potent drugs are prior choice for treatment.
• Affinity – The ability of a drug to attached with receptor.
• Occupancy – It‟s the proportion of the receptor occupied by the drug. Highly
potent drugs occupy less sites to produce the required therapeutic response than
impotent drugs.
• Agonist – A drug or an endogenous compound that form a complex with receptor to
produce a biological effect. It has both the affinity and efficacy.
• Antagonist - A drug or an endogenous compound that form a complex with
receptor without producing a biological effect. It has the affinity and but no
efficacy.
• Full agonist – Is a drug or an endogenous compound that produce maximum effect
by occupying a proportion of given receptor sites.
• Partial agonist - Is a drug or an endogenous compound that produce sub maximal
effect by occupying all the receptor sites.
• Specificity – Individual classes of drug bind only to certain targets, and individual
targets recognize only certain classes of drug.
Drug – receptor theories
Clark’s theory - The magnitude of response is directly proportional to the amount of
drug reversibly bound to receptors. Pharmacological effect is directly proportional
to the number of receptors occupied and the maximum response occurs when all
receptors are occupied.
 But clark‟s idea doesn‟t realize the idea of partial agonism.
Stephenson‟s theory – Drug receptor complex provides a stimulus to the tissue and that
stimulus is directly proportional to fraction of receptors occupied.
D + R ↔ D-R
R1 (The rate of forward reaction or association) = K1.[D].[R]
R2 (The rate of backward reaction or dissociation) = K2.[D-R]
 Rate is constant at equilibrium so R1 = R2
K1.[D].[R] = K2.[D-R]
K1 / K2 = [D-R]/ [D].[R]
KD = [D-R]/ [D].[R], KD (Equilibrium dissociation constant of D-R complex
 From this equation the relationship between effect and free drug conc. Is given by:
E = Maximum effect X [D] / KD + [D]
Drug interaction
• It is a phenomena which occurs when two drugs are co administered and the effect of
one drug is altered by the effect of another.
• There are three types of pharmacological interactions
1. Addition (summation) – If the combined effect of two drugs is equal to the some of
the effect of individual drugs given alone.
2. Synergism - If the combined effect of two drugs is greater than the some of the
effect of individual drugs given alone.
3. Antagonism - If the combined effect of two drugs is less than the some of the effect
of individual drugs given alone.
4. Potentiation – Increase in the effect of one drug due to the co administration of the
second one. Potentiation can occur due to different reason :
 Up regulation of receptors
 Due to the block of elimination or biotransformation of one drug
Type of drug antagonism
1. Competitive antagonism (reversible) – Occurs when both agonist and antagonist
compete for the same receptor or site. In this case antagonist occupies the receptor
and decrease the effect of agonist. But this condition is reversible by increasing the
dose of agonist.
2. Non-competitive antagonism (irreversible) – The effect of antagonist can‟t be
reversed by increasing the dose of agonist.
3. Physiological antagonism – It happens when to agonists act at different receptors
and produce opposite effect on the same physiological function. Eg. Adrenaline and
histamine, Insulin and glucagon
Harmful effects of drugs
• Clinically important adverse drug reactions are common, costly and avoidable.
• Any organ can be the principal target, and several systems can be involved
simultaneously.
• The time course of an adverse drug effect sometimes closely shadows drug
administration and discontinuation, but in other cases adverse effects are delayed,
first appearing months or years after treatment is started.
• Delayed adverse events represent a huge challenge in terms of their initial
recognition, especially if they are an increased frequency of a common problem
such as malignancy or myocardial infarction. Even when such an adverse event has
been convincingly demonstrated epidemiologically, causality can be impossible to
establish in individual patients.
• Some adverse effects occur typically at the end of treatment, when drug
administration is stopped. Consequently, anticipating, avoiding, recognising and
responding to adverse drug reactions are among the most challenging and important
parts of clinical practice.
Types of adverse drug reaction
• All drugs can produce harmful as well as beneficial effects.
• These are either related or unrelated to the principal pharmacological action of the
drug.
• Adverse effects are of great concern to drug regulatory authorities, which are
charged with establishing the safety as well as the efficacy of drugs before these are
licensed for marketing.
Adverse effects related to the main pharmacological action of the drug
• Occurs by extension of pharmacological effect of the drugs. Eg. Anticoagulant –
bleeding
Adverse effects unrelated to the main pharmacological action of the drug
• Adverse effects unrelated to the main pharmacological effect may be predictable when a
drug is taken in excessive dose (e.g. Paracetamol hepatotoxicity, during pregnancy
Thalidomide can cause teratogenicity) or by patients with a predisposing disorder (e.g.
Primaquine-induced haemolysis in patients with glucose 6-phosphate dehydrogenase
deficiency.
• Drug induced organ injury
• Photosensitization
• Infertility or genotoxicity
• Teratogenesis
Predisposing factors for adverse drug reaction
1. Chemical makeup of the drug
2. Route of administration
3. Quality of the drug
4. Hepato-renal diseases
5. Age of the paitient
6. Pregnancy
Direct causes of adverse drug reaction
1. Over dose
2. Drug interaction
3. Relative over dose (due to some diseases)
4. Accidental ingestion of unprescribed drugs
Precaution to avoid adverse drug reaction
1. Follow labels given by the manufacturing company
2. Avoid polypharmacy
3. Strict adherence to the dosage regimen
4. Avoid use of relatively toxic drugs
Treatment of adverse drug reaction
1. Once adverse drug reactions are observed, the treatment must be stoped
2. Removal of drug from the system. Eg. Vomition, diarrhea
3. Use of antidotes
4. Delay absorption by using adsorbents
Evaluating the safety of drugs
• Safety is related to adverse drug reaction, whereas quality refers to the
bacteriological sterility of particular drug.
• Drug can be evaluated both for chronic and acute toxicity that they can bring.
1. Safety margin (Therapeutic index) – It is the gap between tolerated dose and
minimum lethal dose.
SM = LD50/ED50
Neuropharmacology
• The reason why understanding the action of drugs on the central nervous system
(CNS) presents a particularly challenging problem is that the CNS is functionally
far more complex than any other system in the body, and this makes the
understanding of drug effects very much more difficult.
• Currently, the link between a drug's action at the biochemical and cellular level and
its effects on high-level brain function remain largely mysterious.
• Functional brain imaging is beginning to reveal relationships between brain activity
in specific regions and mental function, and this tool is being used increasingly to
probe drug effects. Nevertheless, the fairly gross (millimetre scale) resolution
currently achievable with imaging methods is far from being able to reveal events at
the level of individual neurons and synapses.
• Despite sustained progress in understanding the cellular and biochemical effects
produced by centrally acting drugs, and the increasing use of brain imaging to study
brain function and drug effects, the gulf between our understanding of drug action
at the cellular level and at the functional and behavioural level remains, for the most
part, very wide.
• In this chapter, we outline the general principles governing the action of drugs on
the CNS.
Chemical signaling in the nervous system
• The basic processes of synaptic transmission in the central nervous system are
essentially similar to those operating in the periphery.
• Glial cells, particularly astrocytes, participate actively in chemical signalling,
functioning essentially as 'inexcitable neurons'.
• The terms neurotransmitter, neuromodulator and neurotrophic factor refer to
chemical mediators that operate over different timescales. In general:
– neurotransmitters are released by presynaptic terminals and produce rapid
excitatory or inhibitory responses in postsynaptic neurons
– neuromodulators are released by neurons and by astrocytes, and produce
slower pre- or postsynaptic responses
– neurotrophic factors are released mainly by non-neuronal cells and act on
tyrosine kinase-linked receptors that regulate gene expression and control
neuronal growth and phenotypic characteristics
– fast neurotransmitters (e.g. glutamate, GABA) operate through ligand-gated ion
channels
– slow neurotransmitters and neuromodulators (e.g. dopamine, neuropeptides,
prostanoids) operate mainly through G-protein-coupled receptors.
• The same agent (e.g. glutamate, 5-hydroxytryptamine, acetylcholine) may act
through both ligand-gated channels and G-protein-coupled receptors and function
as both neurotransmitter and neuromodulator.
• Many chemical mediators, including glutamate, and arachidonic acid metabolites,
are produced by glia as well as neurons.
• Many mediators (e.g. cytokines, chemokines, growth factors, steroids) control long-
term changes in the brain (e.g. synaptic plasticity and remodelling), mainly by
affecting gene transcription.
• Important factor in CNS pharmacology is the existence of the blood-brain barrier,
penetration of which requires molecules to traverse the vascular endothelial cells
rather than going between them.
• In general, only small non-polar molecules can diffuse passively across cell
membranes. Some neuroactive drugs penetrate the blood-brain barrier in this way,
but many do so via transporters, which either facilitate entry into the brain or
diminish it by pumping the compound from the endothelial cell interior back into
the bloodstream.
• Drugs that gain entry in this way include L-dopa, valproate and various sedative
histamine antagonists.
• Drugs that are excluded include many antibacterial and anticancer drugs that are
substrates for the P-glycoprotein transporter. Several such transporters have been
identified, and their importance in relation to drug action in the brain is becoming
increasingly apparent.
• The study of drugs that act on nervous system can be divided into two:
 Autonomic pharmacology (sympathetic and parasympatetic nervous system)
 Central nervous system pharmacology
Drugs Acting on the Sympathetic Nervous System
• In the course of phylogeny an efficient control system evolved that enabled the
functions of individual organs to be orchestrated in increasingly complex life forms
and permitted rapid adaptation to changing environmental conditions.
• This regulatory system consists of the CNS (brain plus spinal cord) and two
separate pathways for two-way communication with peripheral organs, viz., the
somatic and the autonomic nervous systems. The somatic nervous system
comprising extero- and interoceptive afferents, special sense organs, and motor
efferents, serves to perceive external states and to target appropriate body
movement (sensory perception: threat response: flight or attack).
• The autonomic (vegetative) nervous system (ANS), adjusts internal organ
functions to the changing needs of the organism.
• The ANS operates largely beyond voluntary control; it functions autonomously. Its
central components reside in the hypothalamus, brain stem, and spinal cord.
• The ANS also participates in the regulation of endocrine functions.
• The ANS has sympathetic and parasympathetic branches. Both are made up of
centrifugal (efferent) and centripetal (afferent) nerves. In many organs innervated
by both branches, respective activation of the sympathetic and parasympathetic
input evokes opposing responses.
• In various disease states (organ malfunctions), drugs are employed with the
intention of normalizing susceptible organ functions.
• Neurotransmitors are chemicals that are used for transmission of neural messages.
• There are two types of neurotransmitors, excitatory and inhibitory
• Acetylincholine is neurotransmitor at all preganglion, postganglia of
parasympathetic nervous, postganglionic sympathetic, adrenal medulla and somatic
nervous.
• Nor adrenaline is also a neurotransmitor but only in postganglion of sympathetic
neurons.
Cholinergic transmission Nicotinic receptor
Na+ K+
Ach Ach

CAT ACHE Muscarnic receptor

Choline
Ca++
Choline + acetate
• First sodium enter and potassium will get out from the axon, this activation will
generate action potential which help to calcium to get into the axon and result in
exocytosis.
• The entry of sodium can be blocked, so there will be no action potential, by snake
venom namely tetradotoxin and suxitoxin.
• Blockage of both sodium and potassium, this is commonly absorbed phenomena in
local anesthetics.
• Calcium blocker- Excess of magnessium ion, Aminoglycosides, botalinum toxin,
bungaro toxin etc.
• Choline uptake inhibition by Hemicholinium drugs
• Inhibition of acetylcholinesterase – In this case by inhibiting the enzyme that
hydrolyse Ach, the amount of Ach and its effect on both muscarnic and nicotinic
receptor will be high.
• Use of antagonists – Blocking muscarnic and nicotinic receptors
• Use of agonists – use of drug that mimic the action of Ach
Receptor Location Effect

Muscarnic M1 Heart, CNS and stomach Increase heart rate, increase HCL secretion,
stimulation of CNS

M2 Heart, smooth muscle Contraction of smooth muscle

M3 Small vessels and endocrine Increase the secretion of products

glands

Lung Bronchial constriction

Intestine Increase peristalsis

Urinary bladder Contraction of detrossor and relaxation of trigon

muscle (Urination)

Uterus Contraction

M4 and M5 Unknown
Nicotinic effect
Nicotinic receptors are called N-receptors and are found in three place
1. Adrenal medula – increase the release of adrenaline
2. Ganglia
3. Myoneural junction of somatic nervous system
Muscarinic agonists
• Acetylecholine- Its hydrolysed by enzyme rapidly and its non-selective
• Carbachol -
• Betanechol – Prescribed for urinary retention
• Methacholine,
• Pilocarpine – Usually prescribed for Glaucoma
Side effects of muscarinic agonists
• Bronchial constriction
• Excessive secretion of saliva and lacrimal glands
• Brachycardia
• Peptic ulcer due to excessive secretion of HCL
Nicotinic agonists
• Are cholinergic drugs that activate nicotinic receptors Eg. Ach, Nicotine,
Benzylcholine, Lobelin,
Indirectly acting cholinergic drugs
• Indirectly inhibit AchE and increase Ach will accumulate

acetate Choline group

CH3 – C- – O – C – CH2 –CH2 – N+(CH3)3

O
Cholinesterase

• Edrophonium – Reversibly attached to anionicanionic

Esteratic site site of site
enzyme for short duration
• Carbamates – They are derivative of carbamic acids and this carbamates attaches with
both site of enzyme Eg. Physostigmine, Neostigmine, Pyrridostigmine
• Organophosphates – Irreversibly phosphorelated to the esteratic site of the enzyme Eg.
Malathion, Parathion, Ecothiopate, Isofluorophate, different nerve gases
Signs of Organophosphate poisoning
Muscarinic – Bronchoconstriction, Salivation, diarrhea, urination, vomition, abortion
Nicotinic – Fasciculation, tremor, paralysis, cunvultion
Clinical indications of anticholinesterase
• Glaucoma
• Mystenia gravis
• Muscle paralysis
Treatment of poisoning
1. Parasympatholytic drugs – Muscarinic blockers Eg. Atropine, Homatropine,
Scopolamine (motion sickness), Ipratropium (Asthma), Glycopyrolate, Pirenzepin
(Gastritis)
2. Reactivation of acetyl cholinesterase Eg. Paralidoxime
3. Avoid the source of poisoning
Effect of muscarinic antagonists
• Cause relaxation of smooth muscle
• Cause bronchial dilation
• Mydriasis
• Tachycardia
• Antiemetic
Nicotinic antagonist (neuromuscular blockers)
• Result in paralysis (important anesthetic characteristic)
• There are two types of neuromuscular blockers
1. Competitive neuromuscular blockers – compete for nicotinic receptors with Ach,
there action can be reversed by administration of carbamates Eg. d-tubocurarine,
Gallamine, Pancuronium
2. Non-competitive neuromuscular blockers – Persistent occupation of nicotinic
receptors (cause prolonged paralysis) Eg. Succinyl Choline, Suxamethonium
Noradrenergic transmission
• Noradrenalin – Is also called norepinephrine, it‟s a neurotransmitor for sympathetic
postganglionic neurons

DOPA Tyrosine Phenylalanine

Na+
Dopamine

MAO K+

NE

Presynaptic α2 receptor

NE

α β
Sites of drug intervention
• The change of Tyrosine into DOPA can be inhibited by α – methyl – tyrosine
• The conversion of DOPA into Dopamine can be blocked by α – methyldopa or
Carbidopa
• The storage of Dopamine can be inhibited by α – methyldopamine
• Stored Norepinephrine can be released by drugs like Tyramine and Amphitamin
• Action potential cause the interance of Ca++ and the rupture of vesicles, but this
process can be inhibited by drug like Guanithidine which is usually used for
treatment of hypertension.
• The entrance of extraneural NE (uptake 1) can be inhibited Cocaine, Imipramide,
Tricyclic antidepresants
• Cytoplasmic NE will be stored in granules but if doesn‟t it will be converted into
MAO (monoamine oxidase) which will be finally converted into normetanephrine.
There are drugs that will inhibit the conversion of both NE and Dopamine into
MAO Eg. Pargyline, Phenalzine
Adrenoceptors (α1, α2, β1, β2)
Receptor Location Effect
Eye α1 Mydriasis
Salivary glands α1 Thick saliva secretion
Intestine α1 Decrease peristalisis
Anal sphincter α1 Contract
Heart β1 Increase the rate and force of contraction
Lung β2 Bronchodialation
Blood vessels of viscera and penis α1 Vasoconstriction, ejaculation

Blood vessels of skeletal muscles β1 Vasodialation

Urinary bladder, Detrosor β2 Relaxation

Trigon α1 contraction
Pregnant uterus β2 Relaxation
Pilomotor muscles α1 Erection of hair
Liver β2 Glycogenolysis
Kidney β1 Renine secreation
Pancrease α2 Decrease insulin secretion
β2 Increase glucagone secretion
Spleen α1 Releasing blood to general circulation
Adrenoceptor agonists
• There are three types of adrenoceptors
1. Directly acting – Cause direct activation of receptors Eg. Adrenaline,
Noradrenaline, Dopamine, Dobutamine, Isoprenalin, Phenylephrine, Sabutamol,
Ridotrine, Clonidine, Methoxamine etc.
2. Indirectly acting – Cause the release of NE Eg. Thyramine, Amphetamine, etc.
3. Mixed - Eg. Ephedrine
Sympatholytic (antiadrenergic)
• Have opposite effect to adrenergic drugs
• This drugs block the adrenergic receptors
1. α –blockers – Eg. Phentolamine, Phenoxybenzamine, Prazocin, Yohimbin
2. β-blockers – Eg. Propranolol, Butoxamine, Atenolol, Timolol
 The clinical indication of these drugs is the exact opposite of adrenergic drugs.