GENERAL PRINCIPLES OF PHARMACOLOGY

Pharmacology is the study of interaction between exogenously administered substances and the
living systems. The interactions between drugs and the body are classified into two categories;
1. Pharmacokinetic processes
2. Pharmacodynamic processes

1 PHARMACOKINETICS
The aim of the drug therapy is to treat diseases by administering drugs. To achieve this adequate
drug should be delivered to the target site. In most instances it is not possible to apply the drug
directly to the target tissue. Most of the drugs are administered to one of the body’s
compartments e.g. gut or muscle and the drug must move from site of administration to the site
of action in another compartment e.g. brain. Therefore drug should be absorbed into the blood
stream from the site of administration and then distributed to the site of action. Finally, drug
action must be terminated either by metabolism or excretion from the body or by combined effect
of these processes. Therefore the pharmacokinetic processes include absorption, distribution,
metabolism and excretion of drugs.

1.1. Absorption
Absorption is the rate at which drug leave its site of administration. Rate and efficacy of
absorption depend on route of administration e.g. in intravenous administration absorption is
complete while by other routes mostly incomplete.

1.1.1. Factors influencing the absorption of drugs

Absorption regardless the site of administration depends on;
• Solubility of the drug: Aqueous solutions are more rapidly absorbed than oily solutions,
suspensions or solid forms.
• Local condition: E.g. pH of the media, presence of food in the gut, etc.
• Concentration of the drug: passive and facilitated diffusion depends on concentration gradient
thus concentrated dugs are absorbed rapidly.
• Circulation: An increase in the circulation at the site of absorption increases the absorption.
• Area available for absorption: If the area is larger, the absorption of drugs occurs more
rapidly.

Factors related to drug that affect absorption

• Physical state: E.g. solution, suspension or solid form.

1
• Particle size: Smaller particles dissolve quickly therefore enhance the absorption.
• Chemical nature: Unionized form of the drug is lipophilic and favour the absorption
• Excipients or adjutants present in the drug: They may influence the rate and extent of drug
absorption
• Disintegration time: Time taken to break the solid form into small drug particles
• Dissolution time: Time take to dissolve the drug in gastric or intestinal juice.
(Both disintegration time and dissolution time may influence the absorption of solid dosage
forms)
• Specialized preparations of drug: E.g.controlled release or sustained release preparations,
enteric coated tablets, etc. These are designed to produce slow, uniform absorption of drug
over longer duration.

Factors related to absorbing medium that affect absorption

• Gut motility: Since most drugs are absorbed in small intestine delay in gastric emptying
delays absorption of drugs and vise versa.
• pH of the medium: pH of the medium determines the degree of ionization of weak acids and
bases and thereby influences the absorption of these drugs.
• Presence of food and other drugs in the gut: Food delay the gastric emptying therefore delay
they absorption of many drugs. In addition, some drugs may form insoluble complexes and
retard the absorption of those drugs e.g. tetracycline forms such complex with the calcium
present in milk.
• Vascularity of the area: Increased vascularity of the absorbing tissue increases drug
absorption.
• Site of administration: Absorption from intramuscular site is more rapid than that of
subcutaneous site.
• Presence of efflux pumps: Reduced bioavailability of digoxin and cyclosporine is partly due
to the presence of P-glycoprotein in gut epithelium

1.1.2. Transport of drugs across the cell membrane

To be absorbed, drug should cross the cell membrane. The passage of drug across the cell
membrane is by;
 Diffusion
 Carrier mediated transport
 Active transport
 Facilitated diffusion

2
  Endocytosis
 Other transport mechanisms that are of little importance in the absorption of drugs
 Filtration
 Ion-pair transport

1.1.2.1. Passive diffusion:

Passive diffusion is the most important process by which majority of drugs enters the tissues. It
depends on;
– Solubility – Lipid solubility increase the diffusion
– Ionisation - Lesser the ionization greater the diffusion of drug
– pH – Many drugs are weak acids or weak bases; their state of ionization varies
with pH (Henderson-Hasselbalch equation) thereby influences the diffusion of
these drugs.
Drug diffuses across the membrane in the direction of concentration gradient and the membrane
has no active role in this process.

1.1.2.2. Carrier mediated transport:

Many cells possess specialized transport mechanism involves a carrier molecule, the membrane
transporter to regulate the passage of physiologically important molecules. Carrier mediated
transport is important in the transport of drug that are chemically related to endogenous
substances. In the case of carrier mediated transport, drug combines with a membrane transporter
and the complex then translocates from one face of membrane to the other. Since it involves a
binding step, shows the characteristic of saturation. Competitive inhibition of carrier-mediated
transport can occur in the presence of a second ligand.

There are only few sites where carrier mediated transport is important, which include;
 Blood brain barrier
 Gastrointestinal tract
 Renal tubule
 Biliary tract
 Placenta
Carrier mediated transport includes
• Active transport
o Primary active transport
o Secondary active transport

3
 • Facilitataed diffusion

Membrane Transporters
Membrane transporters are membrane proteins that control the influx of nutrients and ions and
the efflux of cellular waste and environmental toxins and xenobiotics. There are two major super
families of transporters;
 ABC (ATP binding cassette)
 SLC (solute carrier)
Most of the ABC transporters are primary active transporters. The SLC transporters are either
facilitated transporters or secondary active transporters.
Clinical significance of membrane transporters;
 They involve in the selective absorption and elimination of endogenous substances and
xenobiotics.
 They can be target for many drugs. E.g. serotonin reuptake inhibitors (SSRI), tricyclic
antidepressants, diuretics, etc.
 Presence of specific transporters in a particular cell type / tissue may attribute to tissue
specific drug distribution.
 Membrane transporters work along with metabolizing enzymes to eliminate drugs and their
metabolites.
 Uptake and efflux transporters determine the plasma and tissue concentrations of drugs and
thereby adverse drug reactions. E.g. OCT1 mediated uptake of biguanide plays an important
role in lactic acidosis.
 Transporters may serve as protective barriers for a particular tissue or organ. E.g. P-gp efflux
pumps in blood brain barrier.
 Genetic polymorphism in the expression and affinity of transport protein may result in
individual variations in pharmacokinetic and pharmacodynamic effects.
 They also may involve in the pathogenesis of neuropsychiatric disorders. E.g. Alzheimer’s
disease, Parkinsonism.
 Membrane transporters play an important role in the development drug resistance in
anticonvulsants, anticancer and antiviral drugs.

Active transport
This transport mechanism is responsible for transport of drug across the cell membrane against
concentration gradient. It involves endogenous molecules and expends cellular energy. This

4
 process is more rapid and shows high degree of selectivity and saturabilty. Active transport can
be;
• Primary active transport: It is also called direct active transport, which directly uses
energy to transport molecules across a membrane. In mammals it mediates the unidirectional
efflux of solutes across the membrane i.e. transports substances from the cytoplasm to the
outside or into an intracellular organelle such as endoplasmic reticulum or mitochondria. E.g.
P-glycoprotein (P-gp) efflux pump in blood brain barrier.
• Secondary active transport: In contrast to primary active transport, there is no direct
coupling of ATP; instead, the electrochemical potential difference created by pumping ions
out of the cell is used. The two main forms of secondary active transporters are;
• Counter-transport (antiport) – substances move in the opposite direction. E.g. Na+- H+
transporter in renal tubule.
• Co-transport (symport) – substance move in the same direction. E.g. Na+-glucose/
Na+-amino acid transporters in renal tubule.

Facilitated diffusion
This process is mediated by facilitated transporters and occurs more rapidly than simple diffusion
but, slower than active transport. Movement of drugs across the cell membrane is selectively
facilitated by carrier protein (facilitated transporter), which is also called as uniport. Non-
diffusible substrates also can be transported. Unlike active transport it occurs along the
concentration gradient and does not require energy. E.g. transport of glucose by GLUT4
transporter into muscles and fat cells.

Electrochemical Electrochemical
High potential gradient High potential gradient
of the substrate Low of the substrate Low

Passive
diffusion Symport
Secondary
active transport
Antiport

Facilitated
diffusion
ATP Primary active
transport
ADP 5

A . Passive transport B . Active transport

Figure 1: Drug transport across the membrane

1.1.2.3. Endocytosis:
The mechanism of transport by endocytosis involves the cellular uptake of exogenous molecules
or complexes inside a membrane-derived vesicles. There are two categories
– Pinocytosis (uptake of fluids)
– Phagocytosis (uptake of particles)
Both these process require expenditure of cellular energy, but, do not require any carrier. Proteins
and other big molecules are transported by this mechanism. It contributes little in the transport of
drugs.

1.1.2.4. Filtration:
Filtration is the passage of drugs through aqueous pores in the membrane or through paracellular
space. Only a few drugs with low MW (e.g. Ethanol) are transported by this process it plays
minor role in the transport of drugs within the body except glomerular filtration, which is an
important mechanism of drug excretion.

1.1.2.5. Ion-pair transport:

In this process highly ionized compounds form a neutral ion pair complex with endogenous
organic anions (mucin of GIT). This complex penetrates the membrane by simple diffusion. It
plays a minor role in the transport of drugs.

1.2. Routes of Drug Administration

The successful treatment not only depends on selection of correct drug and dosing schedule, but
also on choice of most appropriate route of administration. The objective of drug administration
is to achieve an adequate concentration of drug at the site of action for an adequate period of
time. In the other words route of administration plays an significant role in determing the
bioavailability of drugs. Drugs can be delivered to the site of action;
1. Via systemic circulation
a) Enteral route – via gastrointestinal tract (in Greek “enteron” – intestine).
b) Parenteral routes – via sites other than gastrointestinal tract (in Greek “par” –
aside form).
2. By site specific administration
a) Topical application
b) Site specific injections

6
1.2.1. Factors influencing the choice of route
• Physical & chemical properties of the drug
– Solid/ liquid/ gas
– Solubility
– Stability
– pH
– Irritancy
• Site of desired action
– Localized and approachable
– Generalized and not approachable
• Rate and extent of absorption of the drug from different routes
• Effect of digestive juices and first pass metabolism on the drug
• Rapidity with which the response is desired -routine treatment or emergency
• Accuracy of dosage required – intravenous route and inhalation can provide fine tuning
• Condition of the patient – unconscious, vomiting
• Presence of membrane barriers – e.g. blood brain barrier

1.2.2. Enteral Routes

• Oral
• Sublingual & buccal
• Rectal

1.2.2.1. Oral administration

Most common route; But, it uses most complicated pathway to tissues. Majority of drugs are
absorbed from duodenum and some are from stomach. Most of the drug given by this route for
systemic effect, but, sometimes used for their local action (antacids, antidiarrhoeal, some
antibiotics).
Advantages
• Safer and more convenient
• Does not need assistance
• Non-invasive
• Often painless
• Medicament need not be sterile
• Cheaper
Limitations of oral route

7
• Action is slower & not suitable for emergencies
• Unpalatable drugs are difficult to administer
• May cause nausea & vomiting
• Cannot be used in uncooperative/ unconscious/ vomiting patients
• Certain drugs are not absorbed orally – Highly polar agents (aminoglycoside antibiotics) or
quaternary salts (D-tubocurarine , suxamethonium)
• Some are destroyed by gastric juice (penicillin G, insulin) or in liver (nitroglycerine,
lignocaine, etc.)
• Can form non-absorbable complexes with food – e.g. tetracycline and milk

Oral dosage forms

o Solid dosage forms – powders, tablets, capsules, etc.
o Liquid dosage forms – elixirs, syrups, emulsions, mixtures, etc.
o Enteric coated dosage form – drugs that are destroyed by gastric secretion or that cause
gastric irritation sometimes administered as enteric coated dosage form. Pills and tablets
are coated with cellulose-acetate phthalate, gluten and anionic co-polymers of
methacrylic acid and its esters. These substances resist the gastric juice and prevent
dissolution in acidic gastric content. Enteric coating is done;
• to prevent gastric irritation
• to prevent alteration of the drug in the stomach
• to achieve desired concentration of the drug in the small intestine
• to retard the absorption of the drug
If the coating is very hard the tablet or pill may pass out without being dissolved in the
gut and may fail to produce the therapeutic effect.
o Control released, sustained /extended released preparation or time release preparation
(Timesules, Spansules)– they are designed to produce slow uniformed absorption of the
drug over an extended period of time (8hrs or longer). Such preparations have the
particles of drug covered with coatings which dissolve at different time intervals. The
coating which dissolves early release an amount of the drug which establishes its action
quickly; the coating which dissolves more slowly ensures a slow release of the reminder
of the drug, thus providing uniform medication over a prolonged period. Potential
advantages are;
• Reduction in frequency of administration thus improving compliance
• Maintenance of therapeutic effect overnight

8
 • Decreased incidence and/or intensity of both undesired effect (by eliminating the
peak concentration) and non-therapeutic blood levels (by eliminating trough
concentration)
Drawbacks are;
• Inter-patient variability in systemic concentration is more than intermediate
dosage forms
• Dosage form may fail and dose dumping may occur with resulting toxicity may
occur because total dose of the tablet may be several times that of conventional
preparations. Factors contributing dumping effects are;
• Stomach acidity
• Administration along with high fat meal

1.2.2.2. Buccal and Sublingual administration

Tablet is placed under the tongue (sublingual) e.g. glyceryl trinitrate, nifidepin or crushed in the
mouth & spread over buccal mucosa e.g. morphine, ergometrine. Sublingual route is used where
rapid action is needed while buccal route is used for prolonged absorption.
Advantages;
• These routes can be used when there is a need to bypass the intestinal tract or portal
circulation to avoid degradation by gastric acid and first pass metabolism in GIT & liver
• Quick onset of action as rapid absorption takes place directly into the systemic circulation
• Can spit out the tablet once desired effect has occurred
Disadvantages;
• Poor absorption of many polar substances
• May causes inconvenience and irritation to mucosa
• Drugs of higher molecular weights are not well absorbed trough this route

1.2.2.3. Rectal administration

This is an alternative route when oral administration is not feasible due to;
– palatability problems
– nausea/vomiting
– patients’ inability to cooperate (E.g. unconscious patients)

Drug such as indomethacin, paracetamol, diazepam, morphine, theophylline etc. can be

administered per rectally

9
Advantages;
• Absorption is unaffected by food intake
• Drugs that are irritatant to stomach (Theophyllin, Indomethacin) can be given by this route.
• Hepatic first pass effect is minimized because only supra haemorrhoidal vein drains in to
portal system, others enter the systemic circulation
Disadvantages are
• Relatively small mucosal area is available for absorption
• Inadequate drug retention can occur due to leakage or defecation
• Absorption may be unpredictable especially if the rectum is full of faeces
• Some drugs (indomethacin, theophyllin) may inflame the rectal mucosa
• Inconvenient and embarrassing to the patient
Rectal dosage forms
o Suppositories
o Rectal capsules
o Enema - administration of a medicament in liquid form
– Evacuvant enema – e.g. soap water enema – aim is to remove the faecal matter
and flatus
– Retention enema – fluid containing the drug is retained in the rectum for local
action (prednisolone enema for ulcerative colitis) or may act systemic absorption
through mucous membrane (diazepam for control of seizures in small children)

1.2.3. Parenteral Administration

Major routes for parenteral administration are;
• Intra venous injection
• Intra muscular injection
• Subcutaneous injection
Other prenteral injections include;
• Intradermal injection
• Intraperitoneal
• Intrathecal

Apart from parenteral injection there are some other modes to deliver the drug systemically.
They include;
• Transdermal administration
• Nasal administration

10
 • Inhalation
• Endotracheal route

1.2.3.1. Intravenous injection

Drugs are given directly into a vein produce rapid action and the desired blood concentration can
be obtained rapidly with a well defined dose. Drugs can be given by this route as bolus dose or
infusion.
Advatages;
• Allows precise control of the dose delivery into the circulation & can be terminated promptly
• Give swift, effective and highly predictable blood concentration and also allows rapid
modification of dose
• Useful in emergencies
• Suitable for administration of drugs, which cannot be absorbed from gut or too irritant to be
given by other routes (anticancer agents)
• Can be employed in unconscious or uncooperative patients and in those are unable take orally
due to nausea and vomiting
Disadvantages
• Self administration is not possible
• Strict aseptic conditions are needed
• High cost of treatment
• Painful
• Increased risk of serious side effect and risky because once the drug is injected cannot be
recalled
• Possibility of phlebitis or tissue necrosis usually with prolonged infusion and bolus doses of
irritable formulation, e.g. diazepam
• Incompatibility: Certain drugs adhere to plastic e.g. diazepam and IV nitrates are
incompatible to polyvinyl chloride (PVC); their potency will be lost

1.2.3.2. Intramuscular injection (IM)

Drug is injected in one of the large muscles such as deltoid & triceps (arm), gluteus maximus
(buttocks), rectus femoris (thigh). This route is reliable and suitable for mild irritant drugs.
Rate of IM absorption is determined by;
– Solubility of the preparation

11
 – Pharmaceutical characteristic (some depot formulation result in sustained blood
level for several weeks)
– The degree of local perfusion –
• Local massage increases the rate of absorption by dispersing the drug to
larger area and by increasing blood flow.
• Muscle is less richly supplied with sensory nerves (less irritation) and rich
in blood supply (absorption is faster)
Advantages;
• Depot preperation (Penicilline, neuroleptics, medroxyprogesterone) can be used at monthly or
longer intervals
• Their absorption is rapid than subcutaneous injection
Disadvantage;
• Not acceptable for self-administration
• Aseptic condition is needed
• Pain or muscular damage can be caused by the irritating action of solvent or drug.
• If adverse effects occur to a depot formulation it cannot be removed
• The bioavailability of many drugs injected intra muscularly is incomplete

1.2.3.3. Subcutaneous injection

Drug is deposited in the subcutaneous tissue; rich in nerve supply and less vascular.
Rate of absorption depends on;
o Blood flow
o Local heating or massaging
o Site and depth of injection
o Drug formulation
o Degree of local degradation
o Exercise to the injected limp
Advantages;
• Route is reliable and acceptable for self-administration
• Smooth but slower absorption for a longer period compared to IV or IM route
Disadvantages;
• There will be poor absorption in peripheral vascular failure
• Absorption from this site is slower than muscle
• Since subcutaneous tissue is rich in sensory nerve supply irritant drugs cannot be injected
• Repeated injections to one site can cause lipodystropy and resulting in erratic absorption

12
Different forms of subcutaneous administration
o Subcutaneous injections - insulin
o implantable delivery systems
• Palette implantation – solid palette is introduced with trochar and cannula; rovides
sustained release of drug for weeks & months (testosterone)
• Sialistic (non-biodegradable) & biodegradable implants – crystalline drug is
packed in tubes causes slow and uniform release of drug over months providing
constant blood levels. Non-biodegradable ones are removed later not the
biodegradable ones. E.g. hormones and contraceptives
o Dermojet – needle is not used; a high velocity jet of drug solution is projected from a
micro-fine orifice using a gun like implement. Solution passes through superficial layers
to be deposited in subcutaneous tissue; painless suited for mass inoculation.
E.g. local anaesthetics; steroids, antibiotics antifungals in dematological conditions

1.2.3.4. Other parenteral injections

Intradermal Injection
Drug is injected into skin raising a bulb (BCG vaccine, sensitivity testing) or scarring/ multiple
puncture of drug (small pox vaccine) and is employed only for these specific purposes. Only
small quantity can be administered and the injection may be painful.

Intraperitoneal injection
This route is sometimes used in infants for giving fluids like glucose saline. Since peritoneum has
large surface area absorption is rapid. Also used for peritoneal dialysis and antirabies injection.
The procedure is painful and risky due to the chances of adhesion and infection in the peritoneal
cavity. Strict aseptic conditions must be maintained.

Intrathecal injection
Introduction of drugs into subarachnoid space, e.g. spinal anaesthesia, thus drugs canact directly
on central nervous system and meninges. This route provides high concentrations in the
subarachnoid space e.g. certain antibiotics and anticancer drugs. But, strict aseptic condition is
needed. It is painful and risky procedure.

1.2.3.5. Transdermal administration

13
Low molecular weight drugs have adequate solubility in water and oil and can cross the skin to
reach systemic circulation. Absorption by this route is slow and prolonged. Drug is incorporated
as cream/ ointment & applied over specific area of skin; absorption is not reliable. Now a special
delivery system calles as transdermal delivery system (TDS) is used to deliver drugs by this
route. The drug is incorporated to stick on patch (transdermal patches), e.g. glyceryl trinitrate
(angina), oestrogen patch (hormone replacement therapy following menopause) and hyoscine
(seasickness)
Advantages
• In TDS rate of release is set below steady state flux of drug across the skin; no dumping
effect occurs even in patients with usually high skin permeability
• Constant rate of absorption can be achieved & minimizes fluctuation in plasma concentration
-nitrates and clonidine
• With appropriate formulation absorption can be prolonged for several days or even weeks
therefore, have increases the compliance
• Drug administration can be terminated relatively rapidly by removing the patch.
• First-pass effect can be avoided or markedly reduced, e.g. glyceryl trinitrate
• Side effects due to exposure in high concentration to gut and liver are minimized.
Disadvantages;
• As the surface area of these patches cannot exceed certain limits the route is only suitable for
potent drugs with a parenteral daily dose below 5mg
• As absorption of the drug from TDS depends on pharmaceutical formulation, site of
application and local skin condition (hydration and blood flow) and bioavailability may vary
between individuals
• Patient may develops tolerance – e.g. nitrates
• Local reaction such as sever contact dermatitis can occur

1.2.3.6. Nasal administration

Mucous membrane of the nose can readily absorb many drugs. Drugs are applied in the forms of
nasal drops, creams and sprays. E.g. - peptide like ADH, desmopressin, oxytocin, calcitonin
LHRH and its more potent analogues (buserelin, leuprolide and nafarelin)
Advantages;
• Digestive juices and liver are bypassed
• Relative ease of administration
Disadvantages
• Systemic bioavailability may vary considerably

14
• Substances may reach the brain via lymphatic, thus no potentially toxic substances should not
be administered by these route

1.2.3.7. Inhalation
Inhalation is the route used for the administration of volatile and gaseous agents to induce
systemic effect. E.g. gas – volatile anaesthetics, aerosol – ergometrine for migraine.
Advantages;
• Absorption occurs in vast surface of alveoli
• Action is very rapid and on discontinuation of administration drug diffuses back and rapidly
eliminated in expired air
• Thus, controlled administration is possible with moment to moment adjustment.
Disadvantage;
• Irritant vapors (ether) cause inflammation of respiratory tract & increased secretions

1.2.3.8. Endotracheal route

In patients with indwelling endotracheal tube, certain drugs can be administered by this route for
an immediate effect (e.g. adrenaline, atropine, diazepam, naloxone and lignocaine). The drug is
diluted in 5-10 ml of isotonic saline before administration.

1.2.4. Site Specific Administration

Site specific administration is used for localized lesions at accessible sites. In this case systemic
absorption is minimal or absent and high concentrations are attained at desired site with relatively
smaller doses. Thus systemic side effects or toxicity is minimal or absent.
Site specific administrations include;
 Topical application
 Inhalation
 Site specific injections

1.2.4.1. Topical application

It means the direct application of a drug close to the site of action. Examples are;
 Skin - dermatological preparation
 oral and nasal mucosa - antimicrobial mouth wash and nasal decongestants
 Trachea - surfacetant for respiratory distress syndrome
 Rectum - mesalazine enema for ulceration colitis

15
 Conjunctiva - for treatment of glaucoma timolol eye drop and pilocarpine delivery system,
ocular insert which continuously deliver the drug over longer duration with little systemic
effect
 Endometrium - progesterone inserts for contraception.
 Vagina - various chemotherapeutic agents as vaginal creams or pessaries
Local irritation or sensitization can occur. Systemic reaction can occur due to absorption of
topically applied drugs especially when there is tissue destruction.

1.2.4.2. Inhalation therapy

By this route drugs can be administered as aerosol which can be liquid (fog) or solid particle
(smoke), e.g. -adrenoceptor agonist or powder form e.g. sodium cromoglycate. Drugs used in
the management of asthma (2-agonist, anticholinergics, cromoglycate, corticosteroids) are
administered via this route to deliver the drugs directly to the site of action with minimal
systemic exposure
Advantages;
• Self-administration is possible
• Systemic absorption thereby systemic side effects are minimal
• Smaller doses are adequate
• Quicker onset of action
Disadvantages;
• Specialized apparatus and high degree of coordination are needed
• High degree of coordination is required to administer drug via this route
• Systemic side effects can occur
• Local adverse effects such as candida infection with poorly absorbed steroids
• Propellants in pressurized aerosol may cause irritation and systemic effect such as myocardial
sensitization to catacholamines
• Dry- powder inhalation may cause cough or local irritation in some patients
• Therapy may fail if there is bronchial obstructs (e.g. mucus plague in asthma)

1.2.4.3. Site specific injection

• Subarachenoid and epidural injection
When a drug penetrates poorly into blood brain barrier, these routes are use to achieve
adequate concentration of drug in the meninges and central nervous system. But, systemic
effects also can occur. E.g. spinal anesthesia and epidural analgesia.
• Intra-arterial

16
 Occasionally drugs may be directly injected to arteries to localize its effect to particular tissue
or organ with reduced systemic exposure. This method is used in diagnostic studies and in
embolization therapy. E.g. injection ofcontrast media (angiography, etc) and certain
anticancer agents. Great expertise and strict aseptic conditions are required.

• Other site-specific injections

– Intracardiac injection
– Intrapleural injection
– Intraperitoneal injection
– intra articular injection

1.2.5. Special Drug Delivery Systems

1.2.5.1. Biologically erodable microspheres
These are made of biologically erodable polymers, can be engineered to adhere to mucosal
epithelium of gut. Such microspheres can be loaded with drugs in order to improve the
absorption. But, this technique has yet to be used clinically. This technique may be utilized to
produce systemic absorption of insulin and of DNA following oral administration.

1.2.5.2. Prodrugs
Prodrugs are inactive precursors that are metabolized to active metabolites. This principle can be
utilized for targeted drug delivery.
• Zidovudine is phosphorylated to active metabolite only in cells containing appropriate
reverse transcriptase, thus conferring selective toxicity towards cell infected with HIV
• Valaciclorvir, prodrug of aciclorvir is converted to its active form in virally infected cells.

1.2.5.3. Antibody-drug conjugate

Cytotoxic drug may be attached to an antibody directed against a tumor-specific antigen, which
bind selectively to tumor cell. This is one of the possibilities to improve the selectivity of
cytotoxic agents.E.g. cytotoxic agent calicheamicin is linked to an antibody directed to an
antigen found in the surface of certain leukaemic cells.

1.2.5.4. Package in liposomes

Liposomes can be filled with non-lipid soluble drugs or nuclic acids. The drug containing
liposomes can be taken up by reticuloendothelial cells (amphotericin in systemic mycoses). They
are also concentrated in malignant tumours and there is a possibility of achieving selective
delivery.
17
1.2.5.5. Coated implantable devices
Impregnated coating of devices permits localized delivery of drugs from these devices.
• Drug eluting coronary artery stents with sirolimus
• Intrauterine contraceptive device for hormonal delivery to endometrium

1.2.6. Methods for Delaying Drug Absorption

It may be desirable to delay the absorption from intramuscular or subcutaneous site either to
reduce the systemic effects where drugs are used to produce a local effect or to increase the
duration of drug action.
Methods used for this purpose are;
1. Addition of adrenaline or nor adrenaline to local anesthetics. This will reduce the
absorption of these agents into systemic circulation, which in turn prolongs the local
anesthetic effect as well as reduces the systemic toxicity.
2. Administration of drug in relatively insoluble slow release form. This can be achieved by
converting them into poorly soluble salt ester or complex
E.g. Procaine penicillin (it is a salt of penicillin),
Esterification of steroid hormon (medroxy progesterone acetate, testesterone
propionate) and antipsychiatric drugs (fluphenazine decanoate)
3. Alteration of physical characteristic of a preparation. E.g. Insulin zinc suspension: The
physical form of the complex formed by insulin and zinc can be altered by varying the
pH. One form is a fine amophorous suspension, which is relatively rapidly absorbed,
while the other is a suspension of large crystals, which are slowly absorbed. These two
preparations can be mixed and produce an intermediate sustained effect.
4. Subcutaneous implantations of solid pellets are also used to achieve slow and continuous
absorption of drugs. This method is used for certain steroid hormones, e.g. Oestradiol.
As the rate of absorption is proportional to the surface area of the implant, a flat pellet
gives more uniform rate of absorption than a spherical one.

18
1.3. Distribution
Once drug gained access to the blood stream it gets distributed to other tissues that initially had
no drug. Distribution usually occurs in the in the direction of concentration gradient, from plasma
to tissue. This distribution is usually uneven and some may selectively bind to plasma protein or
localized within particular tissue. Site of localization influences its action while the extent and
strength of protein or tissue binding determine the time it remains in the body and its duration of
action. Extent of distribution depends on;
• Factors related to the drug itself
o Lipid solubility
o Ionization at physiological pH
o Extent of binding to plasma protein
o Affinity for different tissues
• Other factors
o Regional blood flow
o Diseases like chronic heart failure, ureamia, cirrhosis, etc.
o Presence of membrane barriers such as blood brain barrier, placenta, blood-testis
barrier

1.3.1. Protein binding.

Drugs in the circulation may bind to plasma protein especially to albumin or circulate in the free
form. Free form is pharmacologically active while bound form acts as drug reservoir. Free and
bound forms are in equilibrium in the body. When free drug is removed from the body, it is
replaced by drug released from the bound fraction. Albumin is the main binding protein for many
drugs and endogenous substances. Acidic drugs generally bind to albumin (barbiturates,
benzodiazepines, NSAIDs, phenytoin, sulphonamide, tolbutamide, warfarin, etc.) and basic drugs
to α1 acid glycoprotein (β-blockers, verapamil, quinidine, ect.). There are some specific binding
proteins present in the plasma e.g. transferring (iron), ceruloplasmin (copper), transcortin
(corticosteroids), thyroxin binding globulin (thyroid hormone) and sex hormone binding globulin
(sex hormones).

Factors that alter the protein binding;

 Hypoalbuminaemia: plasma albumin concentration les than 25mg% e.g. chronic renal failure
and chronic liver failure
 Third trimester of pregnancy; partly because of hynoalbuminaemia

18
 Conditions associated with an increase in acute phase reaction (cancer, arthritis, myocardial
infarction, etc.) raise the α1 acid glycoprotein in the blood and thereby alter the binding of
basic drugs
 Chronic renal failure may reduce protein binding of drugs (phenytoin) as a result of
hypoalbuminaemia and retention of metabolites that compete for protein binding
 Displacement from binding site by other drugs

1.3.2. Tissue distribution

Drug may accumulate in specific organs or tissues either by active transport or binding to
specific tissue constituents. Many lipid soluble drugs enter fat stores e.g. benzodiazepines,
verapamil, and lignocaine. Extensive tissue binding delays the elimination of drug and account
for the long t½ of some drugs e.g. chloroquine, amiodorone. Drugs that are sequestrated into
tissues tend to have larger volume of distribution. Accumulation of drug within a tissue or organ
may be toxic e.g. tetracycline (bones and teeth), chloroquine (retina).

1.3.3. Penetration into CSF

Blood brain barrier (BBB) is lipoidal, thus limit the entry of non-lipid soluble drugs
(streptomycin, neostigmine, hexamethonium) into the the central nervous system. It has
specialized tight junction between adjacent cells to limit the entry of substances through
paracellular space. Efflux carriers e.g. P-glycoprotien, are present in BBB, which extrude many
drugs that enter brain by other process. It also has enzymatic barriers e.g. monoamine oxidases,
choliesterases which prevent catacholamines, 5-HT, and acetylcholine from entering the brain in
active form.

1.3.4. Penetration across placenta

Placenta is lipoidal and allows free passage of lipophilic drugs while restricting the entry of
hydrophilic drugs. Like blood brain barrier efflux pumps limit feotal exposure to maternally
administered drugs. Restricted amounts of non-lipid soluble drug can enter if given at high
concentration or for long period. Thus, it is an incomplete barrier and almost any drug taken by
mother can affect the feotus or newborn

1.3.5. Blood-testis barrier

Seminiferous tubules are isolated from general circulation by blood-testis barrier which is
comparable to BBB. Tight junctions between the adjacent sertoli cells prevent free diffusion from
the interstitial fluid to seminiferous tubules. Thus it regulates the conditions inside the tubule.

19
1.3.6. Clinical value of drug distribution
• Bound forms can act as a drug reservoir.
• Prolongation of drug action (longer t ½ ).
• Determine the volume of distribution e.g. drugs that are sequestrated into tissue tend to
have larger volume of distribution (e.g. digoxin).
• May help to reach the intended site of action e.g. distribution of frusemide to kidneys
essential for its diuretic action. In renal failure resistant to frusemide can occur as a result
of failure to reach the kidneys in required concentrations.
• May help to lessen the adverse effects e.g. conventional antihistamines (e.g.
chlopheniramine) due to their lipid solubility cross the blood brain barrier while modern
antihistamines (e.g. loratidine) do not cross blood brain barrier. Therefore, central side
effects are less with the modern antihistamines.
• Some drugs are chosen for treatment because of their high affinity towards certain tissues
than other drugs e.g. tetracycline for cholecystitis and flucloxacillin for bone infections.
• Some may cause undesirable effects e.g. effect of tetracycline on growing bones and teeth
and chloroquine on retina.
• They may be subjected to displacement interaction e.g. salicylates displace
sulphonylureas, phenytoin displaces warfarin, sulphonamides and vitamine K displaces
bilirubin from the binding site.

1.3.7. Redistribution
Highly lipid soluble drugs when given intravenously or by inhalation initially get distributed to
organs with high blood flow (brain, heart, kidney,etc.) and later to less vascular more bulky
tissues (muscle, fat). When plasma concentration falls the drug is withdrawn from these sites. If
site of action is highly perfused tissue, redistribution results in termination of action. Drugs with
greater lipid solubility are redistributed quickly (e.g. anaesthetic agent thiopentone). If the drug is
given repeatedly or continuously, over long period, poorly perfused high capacity sites get filled
progressively and the drug become longer acting.

20
1.4. Metabolism
Metabolism of drug is the biotransformation of drugs into more hydrophilic metabolites to
enhance elimination of drug from the body and termination of their biological activity.
Biotransformation means enzyme catalyzed chemical transformation of drug within living
organism. During this process substances with different pharmacological activities will be
formed. Drug metabolism occurs mainly in liver. Other organs such as kidneys, intestine, adrenal
cortex, lungs, placenta and skin (dead tissues like hair nails, do not involve in biotransformation
of drugs) also involve to some extent.
There are 3 types of metabolisms
1. Inactivation of an active drug: This is the most common type of metabolism and most
drugs are metabolized into inactive metabolites
2. Conversion of active drug to another active substance: This may prolong the drug action.
Active drug Active Metabolite
Diamorphine Morphine
Codiene
Diazepam Tenazepam, Oxazepam
Amitriptyline Nortriptyline
Chloroquine Hydroxychloroquine
Spironolactone Canrenone
3. Activation of inactive drug: These are called ‘Pro-drug’. Pro-drug is not itself active but
the metabolite is active.
Prodrug Active metabolite Advantage
Benorylate Salicylic acid and Reduced gastric toxicity
paracetamol
Enalapril Enalaprilat Less risk of first dose hypotension
Lavodopa Dopamine Levadopa can cross BBB, but dopamine cannot
Talampicillin Ampicillin Less diarrhoea

1.4.1First-pass metabolism / Pre systemic elimination

Inactivation of drugs before they enter into the circulation is called as first-pass metabolism or
presystemic elimination. The first-pass metabolism decreases the amount of drug that reaches the
site of action and thereby reduces the systemic bioavailability. Most often first-pass metabolism
occurs in the liver and to a lesser extent it can occur in lungs, gut and skin. The first pass
metabolism is an important determinant of oral bioavailability of drugs. Drugs which undergo
extensive pre-systemic metabolism are given parenterally to achieve adequate blood
concentration e.g. lignocaine is extensively metabolized in the liver and give given intravenously
21
for systemic use. Oral dose of propronolol is twenty times larger than intravenous dose because
of first-pass metabolism. The oral bioavailability of drugs that undergo extensive first-pass
metabolism is increased in liver diseases. In the presence of liver disease oral dose of these drugs
should be lowered. It is possible to bypass the liver, thereby the first-pass effect by using other
routes;
Sublingual e.g. glyceryl trinitrate
Transdemal e.g. nitrates, oestrogen
Per rectal e.g. ergometrine, morphine

1.4.2. Chemical Pathways of Drug Metabolism

Drug metabolism or biotransformation is commonly grouped into two types.
 Phase I reactions
 Phase II reactions

Kidney

Conjugation Phase II Urine

Drug Oxidationn Phase I
metabolites metabolites
Bile

Gall bladder

Figure 2: The major routes of drug metabolism.

1.4.2.1. PhaseI Reactions:

These are degradative reactions and the drug is diminished to a smaller polar / non-polar
metabolite. These reactions are mainly microsomal but can be non-microsomal as well. PhaseI
reactions include oxidation, reduction and hydrolysis. The metabolite formed may be active or
inactive.
Examples for phaseI reactions;
Epoxidation E.g. Carbamazepine
Hydroxylation E.g. Phenytoin
Deamination E.g. Amphetamine
Dealkalation E.g. Diazepam
Sulphoxidation E.g. Penicillamine
Desulphuration E.g. Thiopenton
Dehalogenation E.g. Halothane

22
Most of these reactions are that these are carried out by a heterogeneous group of enzymes,
collectively known as cytochrome P450. Some enzymes do not belong to this group e.g.
xanthine oxidase (metabolizes azathioprine and mercaptopurine), alcolol dehydrogenase and
monoamine oxidase. The products of phase I reaction may be excreted or further metabolized by
conjugation.

1.4.2.2. Phase II Reactions (conjugation reaction):

This involves union of drug with one of several polar endogenous molecules (synthetic or
conjugative reaction). These reactions are catalyzed by microsomal, mitochondrial or
cytoplasmic enzymes. The metabolites formed are usually polar and water soluble and mostly
inactive (exception is glucuronide metabolite of morphine is more potent than the parent
compound).
Conjugation reaction includes.
Acetylation E.g. Isoniazid
Methylation E.g. Thiouracil
Glucuronidation E.g. Paracetamol, Salicylate, morphine
Sulphation E.g. Paracetamol, oestragen

Drug Metabolizing Enzymes

Enzyme Reaction
Phase I oxygenases
CYP-450 C & O Oxidation, dealkylation & others
Flavin containing monoxygenase(FMO) N, S & P oxidation
Epoxide hydoxylases Hyrdolysis of epoxide
Phase II transferases
UDP-glucuronyl transferase (UGT) Addition of glucuronic acid
Sulfotransferases (SULT) Addition of sulfate
Glutathione-S-transferase Addition of glutathione
N-acetyltransferase Addition of acetyl group
Methyltransferases Addition of methyl group
Other enzymes
Alcohol dehydrgenase Reduction of alcohols
Aldehyde dehydrogenase Reduction of aldehydes
NADPH-quinone oxidoreduction (NQO) Reduction of quinines
23
1.4.2.3. Cytochrome P450 enzyme system (CYPs)
Cytochromr P450 enzymes are heam proteins, comprising large super family of related enzymes
and are greatly expressed in liver. They are also expressed throughout the gastrointestinal tract,
and to a lesser extent in lungs, kidneys and central nervous system. These enzymes are grouped
into number of families (denoted by a number) and subfamilies (denoted by a letter). Each
subfamily consists of several isoenzymes (denoted by another number) e.g. CYP3A4 is family 3,
subfamily A and isoenzyme 4 of subfamily A.
Most active CYPs in drug metabolisms are;
• CYP2C, CYP2D, CYP3A subfamilies
• CYP3A4 is the most abundantly expressed isoenzyme and involve in about 50% of
metabolisms of clinically used drugs
They have the ability to metabolize a large .number of drug due to
• Multiple forms of CYPs
• Capacity of a single CYP to metabolize many structurally diverse chemicals (A single
compound can also be metabolized by different CYPs at different rates)
The intense overlapping of substrate specificity causes drug-drug interaction. Inhibition of
enzyme activity by competing for binding with enzyme is one of the common causes for adverse
drug reactions while induction of these enzymes may result in therapeutic failure. There is large
individual variation in the expression of CYPs, due to genetic polymorphism and differences in
gene regulation.

1.4.3. Enzyme induction

Several drugs and environmental pollutants on repeated administration can induce or stimulate
the de novo synthesis of cytochrome P450 proteins. This leads to an increase in the rate of
metabolism and decrease in the availability of parent drug. When the exposure falls off, the
enzyme production lessens and the metabolism of drugs returns to normal. Some drugs can
induce the metabolism of other compounds as well as its own metabolism is called as auto-
induction e.g. carbamazepine. Since enzyme induction requires protein synthesis, it takes 1-2
weeks to attain maximal effect and after stopping the drug reversal also delayed till the lifespan
of newly synthesized enzymes. Enzyme induction is most prominent in liver, but also occurs in
lungs, placenta and kidneys to some extent. Examples for enzyme inducers include rifampicin,
carbamazepine, phenoborbitones, griseofulvin, phenytoin, ethanol, DDT, tobacco smoke, etc.

24
Clinical value of enzyme induction
1. Important drug interactions may cause failure of therapy: Failure of oral contraceptive or
loss of anticoagulation control in the presence of enzyme inducers.
2. Disease may result: Antiepileptic drugs increase the breakdown of vitamin D (dietary as
well as endogenous) result in vitamin D deficiency, which can cause osteomalacia.
3. Tolerance to drug therapy can occur: E.g. Anticonvulsant.
4. Variability in drug responds: Chronic alcohol drinking and smoking can cause enzyme
inductions which may result in failure of an individual to achieve expected response with
normal dose of drug.
5. Drug toxicity can occur: Patients taking rifampicin are more likely to develop liver
toxicity after paracetamol overdose due to an increase production of hepatotoxic
metabolites.

1.4.4. Enzyme inhibition

Due to the competition for binding site of a metabolizing enzyme by drugs results in enzyme
inhibition. Inhibition of drug metabolic enzymes causes an increased level of parent drug and
prolongation of its effects. It also increases the incidence of drug-induced toxicity. Enzyme
inhibition is more rapid than enzyme induction. Consequences of enzyme inhibition can be more
profound than those of enzyme induction. The effects of enzyme inhibition on drugs also tend to
be more selective than those of enzyme induction. When an enzyme inhibitor is withdrawn the
metabolism of target drug returns to normal. Examples for enzyme inhibitors include
Cimetidine, Erythromycine, Chloramphencol, Ciprofloracin, Ketoconazole, sodium valproate etc.

1.4.5. Factors affecting drug metabolism

Age: In infants especially neonates (immature metabolizing mechanism) and elderly (reduced
metabolizing capacity with age) drugs are metabolized poorly.

Nutrition and disease: Severe liver disease and poor nutrition impair drug metabolism.
Metabolisms of some drugs are altered in thyroid disease. E.g. Proponolol is rapidly metabolized
in hyperthyroidism and may need higher doses.

Alcohol and tobacco: Chronic alcoholism may induce enzyme activity while an alcoholic binge
may inhibit the metabolism. Substance in tobacco may increase enzyme activity e.g. smokers
need higher doses of theophyllin than non-smokers.

25
Genetic factors: The genetic variation amongst individuals in the ability to metabolizing the
drugs is classified as extensive (rapid) or poor (slow) metabolizers. In some there will be a
inherited deficiency of particular enzymes.
• Acetylators: N-acetylation can be either fast or slow depending on the amount of enzyme
present. The drugs which are metabolized by this pathway are isoniazid, procainamide,
hydralazine, phenelzine, dapsone and some sulphanamides. The speed of acetylation
influences the risks of adverse effect e.g. slow acetylators are more prone to develop
neuropathy with isoniazied and lupus like syndrome with hydralazine.
• Hydroxylation: There are poor and extensive hydroxylators. The drugs that are
metabolized by hydroxylation include phenytoin, flecainide, metoprolol, mexiletine,
nortniptyline, perhexilene and pheonformin. Poor metabolisors are more prone to adverse
effects of these drugs.
• Sulphoxidation: Poor sulphoxidation of penicillamine is associated with an increased risk
of adverse effect. This also may occur with gold salts, which contains thiol group.
• Pseudocholinesterase: Pseudocholinesterase terminates the action of succinylcholine.
some individual are inheritantly deficient in this enzyme. In these individuals there is a
risk of failure to breathe spontaneously after surgical operation and need assisted
ventilation for hours.

1.5. Pharmacogenetics
Pharmacogenetics is the study of the genetic basis of variations in drug response. This is due to
the polymorphism in drug metabolizing enzyme receptors or transporters.

Metabolism
Individual variations in drug metabolism are due to polymorphism in the expression of drug
metabolizing enzymes. E.g. mentioned above

Receptors
Polymorphism in receptor expression also may cause variation in drug response.
E.g. Polymorphism in 2 receptors results in increased susceptibility to agonist-induced
(salbutamol) desensitization and cardiovascular adverse effects.
Polymorphism in dopamine receptors results in variations in responses and side effect
profile to antipsychotic agents.

26
Transport proteins
Polymorphism in the expression of transport protein also causes variations in drug responses.
E.g. an increased expression of P-glycoprotein in cell results in reduced responsiveness or drug
resistance to anticancer agents and HIV protease inhibitors.

1.5.1. Pharmacogenomics
Pharmacogenomic describes the use of genetic information to guide the drug therapy on
individual basis i.e. Difference between individuals in their therapeutic responses can be
predicted from genetic make-up. The link between specific gene variation and variation in
therapeutic or adverse effect of a particular drug should enable tailoring of treatment on the
basis of genotype of the individuals.

Clinical applications of pharmacogenetics;

 Diagnosis of the disease
 To predict the prognosis
 Choosing the right drug for the individual
 Optimization of the dose
 For prediction of adverse drug reactions
 For profiling the cancer chemotherapy
 In gene and stem cell therapy

1.6. Excretion
Drugs are eliminated as unchanged drug or as water soluble metabolites. Major routes of drug
elimination are;
• Renal
• Billiary
• Faecal
• Alvelor
Minor routes of drug elimination include breast milk, skin, hair, saliva, tears, etc.

1.6.1. Renal excretion

Kidney is the most important organ for the elimination of free drugs (gentamycin, frusemide,
digoxin, etc.). Most drugs are excreted via kidneys either as metabolite or unchanged drug. Three
mechanisms involve in the excretion of drugs by kidney;

27
1. Glomerular filtration: This process can excrete only the drugs, which are not bound to plasma
protein. At most it removes about 20% the drug reaching kidney. Factors influencing the
glomerular filtration are renal blood flow, molecular size ad plasma protein binding.
2. Active secretion: This involves active transport of strongly charged molecules. Drugs are
secreted into tubular lumen by active carrier mediated transport. There are two types, one for
acids, e.g. penicillin, frusemide, and other for bases, e.g. amloride, amphetamine
3. Passive reabsorption: This process mostly affects non-ionized weak acids and bases. Extent
of this process depends on lipid solubility and ionization constant of the drug (pKa) and pH
of the urine.
Drug elimination is enhanced by ionization (by alkalinization or acidification of urine). This
principle is used in treating the drug overdose, e.g. alkalinization for salicylate overdose and
acidification for amphetamine overdose. Strongly acidic and basic drugs remain ionized at all pH
thus, not reabsorbed and rather excreted. Quaternary ammonium and aminoglycosides are highly
polar and not reabsorbed, thus excreted.

1.6.2. Billiary Excretion

Transport analogs to those in the kidney also are present in the canalicular membrane of the
hepatocyte and these actively secrete drug and metabolites into the bile. Significant elimination
occurs by bile for certain drugs such as quinidine, cochicine, vinblastin, corticosteroids,
erythromycin, etc. These drugs are subsequently eliminated in faeces.

1.6.2.1. Enterohepatic recirculation of drugs:

Drugs that are excreted in the bile they may be reabsorbed from gastrointestinal tract and this
process is known as enterohepatic recirculation e.g. warfarin and digitoxin. This may prolong
the duration of action of these drugs. Thus enterohepatic circulation prolongs the duration of drug
action by serving as a small circulatory reserve.
Mechanisms responsible for enterohepatic recirculation are;
 Resorption of secreted active drug in the intestine e.g. digitoxin and indomethacin which
is partly secreted in free form.
 Conjugated metabolites (particularly glucuronides) can be deconjugated/ hydrolyzed
enzymatically by intestinal flora and release the parent active drug which is then
reabsorbed e.g oestrogen, thyroxin, morphine, tetracycline, etc.
 Elimination of these drugs is increased when they bind to other substance and form
unabsorbable complexes, e.g. resin (cholestyramin) binds with digitoxin and warfarin and
increases their rate of elimination.

28
1.6.3. Faecal elimination
Drug which are eliminated in faeces by different ways;
 The drugs that are taken by mouth, a proportion may remain in the bowel and excreted
with faeces.
 In some cases objective of the therapy is that drug should not be absorbed and are used
for their local effect and will be excreted in faeces e.g. neomycin and certain purgatives.
 Drugs that are secreted in bile and not reabsorbed in the intestine e.g. erythromycin,
corticosteroids, etc.
 Drugs in the blood may diffuse partly into the gut lumen and excreted in faeces.

1.6.4. Alveolar excretion

Gases and volatile liquids (general anaesthetics, nitrous oxide, ether, paraldehyde, and alcohol)
are eliminated through breath irrespective of lipid solubility because excretion depends on their
partial pressure in the blood. Certain essential oils (eucalyptus oil, garlic oil) are eliminated
through expectoration.

1.6.5. Breast milk;

This route of elimination is important because of the effects on nursing infant. Drugs are
transferred to the breast milk according to the pH. Milk is slightly acidic pH, thus basic drugs are
excreted more than acidic drugs (chloramphenicol, tetracycline, bromocriptin, diazepam, etc.).
Non-electrolyte (ethanol) readily enter the breast milk independent of pH.

1.6.6. Excretion via minor routes

Excretion of drugs through these routes is qualitatively unimportant. Elimination through sweat,
saliva and tears mainly depend on diffusion.
 Drugs in saliva (iodine, lithium, phenytoin) usually swallowed; concentration of some
drugs parallel that in plasma
 Excretion into hair and skin also quantitatively unimportant. Detection of drugs in these
tissues have forensic significance e.g. detection of arsenic and mercury salts (hair
follicles) in chronic poisoning.
 Griseofulvin is secreted through keratin precursor cells.
 Certain amines and urea derivatives are secreted in sweat.
 Rifampicin is excreted in sweat and tears.

29
1.7. Clinical Pharmacokinetics
Clinical pharmacokinetics describes relationship between pharmacological effect and accessible
concentration of the drug and the most important parameters include;
• Bioavailability
• Elimination half-life
• Volume of distribution
• Clearance

1.7.1. Systemic availability (Bioavailability)

This indicates the proportion of drug that reaches the site action after the administration, taking
into accounts both absorption and local metabolic degradation. It is defined by FDA as “the rate
at which and the extent to which the active concentration of the drug available at the desired site
of action (or practically speaking in the blood stream)”.

1.7.1.1. Factors influencing the systemic bioavailability

Mode of administration: If drug is given intravenously systemic availability is 100% whereas
by other routes (e.g. oral) the bioavailability would be less than 100%.
Drug formulation: It differs among different formulations of the same drug depending on the
physical factors;
o Tablet compression and bulk excipient affect the rate of tablet disintegration.
o Other tablet exipients affect the interaction of drug with aqueous intestinal juices and
thus, rate of dissolution.
o The form of the drug which determines the rate of dissolution e.g. crystalline, salt or
complexed with a tablet constituent.
o Particle size; smaller particles dissolve quickly.
Biological factors:
o Drug destruction by gastric acid. e.g. benzylpenicillin.
o Drugs may bind to food constituent and resulting complex is not absorbed e.g.
tetracycline to calcium (milk) or to iron.
Pre systemic first-pass metabolism: First-pass metabolism reduce the amount of dug reach the
circulation after enteral administration, thus significantly affect the bioavailability of the drug.

1.7.1.2. Bioequivalence
If two or more similar dosage forms of the same drug reach the blood circulation at the same
relative rate and extent, are called as bioequivalent preparations of the generic drug. Differences

30
less than 25% in bioavailability among several formulations of one drug usually have no
significant effect on clinical outcome, hence can be called bioequivalent. On the other hand
measurement of bioavailability is not significant for drugs with large therapeutic index, e.g.
vitamins (water soluble), antacids, penicillin etc. It is significant for drugs with steep dose
response, which obey zero-order kinetics or mixed-order kinetics (phenytoin, warfarin, digoxin)
and drugs with narrow therapeutic margin of safety (antiarrhythmics, antidiabetics). In such
circumstances, patients should be stabilized with one brand of formulation (should not be
changed unless the other one is bioequivalent). If these patients are changed to another brand
which is not bioequivalent, may end up in therapeutic failure (decreased bioavailability) or
toxicity (increased bioavailability).

Clinical equivalence
If two brand products of a drug provide an “identical in vivo pharmacological response” which is
measured by control of symptoms or a disease are said to be clinically equivalent.
Therapeutic equivalence
If structurally different drugs provide same therapeutic response or clinical response as another
drug are said to be therapeutically equivalent.
Chemical equivalence
If two or more dosage forms of the same drug contain the same labeled quantities of the drug as
specified in pharmacopeias called as chemically equivalent, i.e. same quantity of drug on
chemical assay.

1.7.1.3. Measurement of bioavailability

The systemic availability of a drug is defined in terms of rate and amount of administered drug
that reaches the site of action or systemic circulation;
• The amount of administered drug that reaches the systemic circulation depends on the
extent of both absorption and pre-systemic metabolism.
• At the speed (rate) at which drug reaches the systemic circulation depends on
pharmaceutical factors.
The two components of systemic availability may be assessed by plotting plasma concentration
against time. Area under the curve (AUC) is the common measure of extent of bioavailability.

31
 Cmax

Plasma concentration

tmax
Time

Figure 3: The time to peak (tmax) is a function of the speed of absorption, and the peak
concentration(C max) is a function of both the speed and extent of absorption. The total area
under the curve from zero time to infinity (AUC) is a measure of the extent of absorption.

1.7.2. Half-life (t ½)
Half-life is the time taken to eliminate half the drug from the body. Usually half-life is
determined by measuring the time taken for plasma concentration to fall by 50%.
Plasma concentration

Figure 4: Changes in plasma concentration following

an IV bolus injection of a drug, in the elimination
phase; as elimination is a first-order process the time
taken for any concentration to fall by 50% (t ½ ) is
the same.
1 1 1 1
t /2 t /2 t / 2 t /2
Time

1.7.2.1. Rate of accumulation during repeated dosing

If a drug is given repeatedly at short intervals, depending on its t ½ the blood level will rise and
then level off at a point when the amount of absorption is balanced by the amount of elimination
(Usually after 5x t ½). This is known as steady state of plasma concentration

Peak
Trough
Plasma drug concentration

Mean steady-state
concentration

Figure 5: Plasma drug concentrations during

repeated dosing without a loading dose
1 2 43 5 6
Time (number of half-lives)
32
Ideally during treatment, a steady state plasma concentration is maintained within a known
effective therapeutic range. Because at lower levels than this, the drug would be ineffective and
at higher levels it would lead to over dosage toxicity. The amplitude of fluctuations in the plasma
concentration at steady state level depends on dose interval relative to t ½ of the drug.

If it is necessary to attain the steady state quickly especially the drugs with long t ½ (in which it
takes days to reach steady state) need a initial high dose known as loading dose and followed by
repeated doses to maintain the steady state. The repeated doses are known as maintenance dose.
Plasma drug concentration

Figure 6: Plasma drug

concentrations during
repeated dosing with a
loading dose
1 2 3 4 5 6
Time (number of half-lives)

1.7.3. Volume of distribution

Volume distribution is the measure how widely a drug is distributed throughout the body.
Commonly it is expressed as the ratio of total amount drug in the body to the plasma
concentration at steady state.

1.7.3.1. Apparent volume distribution (V)

Presuming that the body behaves as a single homogenous compartment with volume V into
which drug gets immediately & uniformly distributed
Dose administered by IV
V = ---------------------------------
Plasma concentration
Actually drug is not distributed uniformly throughout the body, thus an apparent volume of
distribution can be defined as “the volume that would accommodate all the drugs in the body, if
the concentration throughout was same as in plasma”
Factors influencing apparent volume distribution

o Size of the organ into which drug is distributed

o Partition coefficient between organ and blood
o Blood flow to the organ to which drug is distributed
o Extent of binding of drug both in blood (protein binding) and in various tissues
o Affinity for different tissues
o Diseases e.g. congestive cardiac failure, uremia, cirrhosis
33
1.7.3.2. Clinical significance of volume of distribution;
• Lipid insoluble drugs do not enter cells thus, their V is approximately that of extracellular
fluid (streptomycin)
• Drugs that extensively bound to plasma protein (99%) are largely restricted to vascular
compartment and have low values (phenytoin, warfarin)
• Drugs sequestrated in other tissue may have V much more than total body water volume
(digoxin)
• Pathological states ( congestive cardiac failure, uraemia, cirrhosis) can alter V of many
drugs by altering;
o Distribution of body water
o Permeability of membrane
o Binding to plasma proteins
o Accumulation of metabolites that displaces the drug from binding site

1.7.4. Clearance (CL)

It is the measure of the rate at which the drug is eliminated from the body; Clearance is not t ½
CL = Rate of elimination/C
(C – plasma concentration)
Clearance time is the time required for complete elimination of drug from the body. T ½ is
affected by both clearance and volume of distribution whereas clearance is independent of
volume of distribution. If the clearance is decreased t ½ is prolonged.
Plasma drug concentration

t ½ = 8 hours

(As a result of
decreased clearance)

t½=4
hours

0 4 8 12 16 20 24 28 32 36 40
Time (hours)

Figure7: Way in which a change in drug clearance alters the time to steady
state and the eventual steady-state concentration

34
1.7.5. Time courses of drug concentration and effect
The rate at which kinetics of drugs take place is called as the “order of the kinetics or process”.
The order of kinetics is classified into;
• First-order kinetics (exponential kinetics)
• Zero-order kinetics (non-exponential kinetics)

1.7.5.1. First order Kinetics

In most cases absorption, distribution, metabolism and excretion of drug are proportional to the
concentration of the drug. If the rate of these kinetic processes are proportional to concentration
of the drug, it is said to be first-order kinetics. In doses used clinically most drugs follows first-
order kinetics. A constant fraction of drug is eliminated at a constant interval of time. Rate of
drug elimination is directly proportional to plasma concentration.
50% 50% 50%
200µg 100µg 50µg 25µg and so on
2hrs 2hrs 2hrs
The t ½ of any drug following first order kinetics would always remain constant irrespective of
the dose. If a fixed doses is administered at every t ½, thus five t ½ are needed to reach steady
state, i.e. rate of absorption equals the rate of elimination, thus subsequent administration of same
dose thereafter have hardly any effect on plasma concentration.. If the dose the drug is doubled
its duration of action is prolonged by one more t ½. Plasma concentration of the dug is
predictable from the dose.

1.7.5.2. Zero-order kinetic

In some cases when amount of drug in the body rises, any metabolic process that has limited
capacity become saturated i.e. the rate of process reaches a maximum and then remains constant
due to limited amount of enzyme. Further increase in the rate is impossible despite an increase in
the dose of drug. The rate of reaction is not proportional to dose. This type of kinetics is called
zero-order or saturation kinetics.
The characteristic features of zero-order kinetics are;
 A constant or fixed quantity of the drug is eliminated (or absorbed) per unit time
25µg 25µg
50µg 25µg nil
2hrs 2hrs
 Rate of elimination is proceeding at a fixed rate, independent of the dug concentration,
thus increase in dose not result in proportionate rise in elimination

35
  The t ½ of drugs following zero-order kinetics is never constant
 Plasma concentrations cannot be predicted from dose

Some drugs at smaller doses are handled by first order kinetics and at higher doses the rate of
elimination becomes zero-order because metabolizing enzyme or elimination process get
saturated. Some drugs obey mixed order elimination kinetics e.g. phenytoin, digoxin, warfarin,
dicumarol, tolbutamide and aspirin (higher doses). This change in kinetics might produce a risky
and unpredictable kinetic state as t ½ changes with dose. T ½ may remain constant at low doses
but, might increase if dose is further increased. Clinical use of such drugs needs proper
monitoring and the maintenance of their plasma concentration because small increase in dose
would shoot up the plasma concentration resulting in drug toxicity.

36
2. PHARMACODYNAMICS
Pharmacodynamic is concerned with the mode of action of the drug. In other words it is
concerned with the effect on body. Drugs can be classified according to the prominent effect.
Eg. Antibacterial, antihypertensive, bronchodilators etc.

Mechanisms of action
Most drugs act by interfering with cellular function (either of the body or of invading micro
organisms), thus altering the control system. To produce the pharmacological response drug
molecules exert some chemical influences on one or more constituents of cells. Most drugs
produce their effect by binding, in the first instant, to protein molecules. There may be some
exceptions to this
 Some act by interacting with membrane lipids. E.g. General anesthetic substances
 Some act on DNA. E.g. Anticancer drugs and antimicrobials.
The commonly involved protein targets for drug action are;
 Ion channels
 Enzymes
 Carrier molecules
 Receptors

2.1. Ion channels

Drugs can act on ion channels (E.g. Ligand gated, voltage gated or G-protein-coupled ion
channels) by blocking or modulating their action. Drug act directly or indirectly on the channels
and is one of the most important mechanisms by which pharmacological effects are produced at
cellular level.

Ion Channles Blockers Modulators

Voltage gated Na+ channel Local anaesthetics
Tetrodotoxin
Renal tubules Na+ channel Amiloride Aldosterone
Voltage gated Ca2+ channels Divalent Ca ions (Eg Ca2+) Dihydropyridine, -blockers
Voltage gated K+ channel 4-aminopyridine
ATP sensitive K+ channels ATP Cromokalim, suphonylureas
GABA-gated Cl- Channel Picrotoxin Benzodiazepines
Glutamate gated Cation Ketamine Glycine
channels

37
2.2. Enzymes
Many drugs are targeted on enzymes. Most commonly they resemble the natural substrate of the
enzyme (i.e. substrate analogue). Their action on enzymes can be;

Reversible inhibition: When drug act on the enzyme, competitively and inhibit the enzyme
activity, interaction is reversible. (E.g. Carbidopa competes with levodopa for decarboxylase.
Action of neostigmine on acetylcholine esterase).

Irreversible inhibition: When drug binds to the enzyme by covalent bound, interaction is
irreversible. Recovery of the activity depends on the formation of new enzyme. E.g. Covalent
binding of aspirin to prostaglandin G/H synthesis inhibits the enzyme in platelets for their entire
life span as platelets are unable to synthesis new protein and this is why low aspirin doses are
sufficient for antiplatelet action.Irreversible inhibition also occurs with organophosphorous
insecticides and chemical warfare agents, which bind covalently with the active site of
acetylcholine esterase.

False substrate: Sometimes drug can act as a false substrate. Here drug molecule undergoes
chemical transformation to form an abnormal product, which subverts the normal metabolic
pathway. Eg. Methyldopa, which mimics noradenaline precursor dopa, converted into methyl
nor-adrenaline (false transmitter) causing nor-adrenalin to be partly replaced by methyl nor-
adrenaline thus affecting the function of sympathetic nervous system.

2.3. Carrier molecules

Transport of ions and small organic molecules may need a carrier protein of some kind, since
they are often too polar (insufficiently lipid soluble) to cross the lipid cell membrane. The
recognition site for molecule in the carrier protein is specific for particular permeating species.
This recognition sites also can be targets for drugs and may block the transport system.

Carrier Inhibitors
Choline carrier (nerve terminal) Hemicholinium
Nor-adrenaline uptake 1 Tricyclic antidepressants,
cocaine
Nor-adrenaline uptake (vesicular) Reserpine
Weak acid carrier (Renal tubule) Probenecid
Na+ / K+ /2Cl - Co-transporter Loop diuretics
Na+ /K+ pump Cardiac glycoside
Proton pump (gastric mucosa) Omeprozole

38
2.4. Receptors
Receptor is a specific tissue protein either membrane bound or intracellular, capable of binding to
members of a specific group of drug or endogenous substances. Drug or endogenous substance,
which binds to a receptor, is called as ligand. Interaction between drug and its receptor will lead
to pharmacological effect through series of mechanisms.
The ligands forreceptors include
 Endogenous ligands
• Various hormones
• Transmitters
• Other mediators
 Drugs
 Toxins
Many therapeutically useful drugs act either as;
 Agonist – mimics activity of endogenous ligand
 Antagonist – blocks activity of endogenous ligand

Many drugs act on receptors are selective because physiological receptors are specialized to
recognize and respond to individual signaling molecules with great selectivity. Molecular
heterogeneity is the feature of all kinds of receptors, which result in several molecular varieties or
subtypes. Receptors may be divided into subtypes on the basis of selectivity for a range of
agonists or antagonists. E.g. Histamine receptor has H1 and H2 subtypes. H1 is target for
conventional antihistamine while H2 is the target for cimetidine and ranitidine.

2.4.1. Types of receptors

There are four types of receptors
Type 1- Inotropic receptors (ligand-gated ion channels) – takes milliseconds to produce effect.
Type 2- G-Protein Coupled Receptors (GPCRs)/ Metabotropic receptors - takes several seconds
to minutes to produce the effect.
Type 3-Enzyme/ Kinase linked and related receptors - takes hours to produce effect.
Type 4- Nuclear receptor - takes hours to days to produce effect.

2.4.1.1. Inotropic Receptors

Inotropic receptors are ligand-gated ion channels and. Receptor activation by binding of agonist
to receptor results in opening of ion-channel. They control fastest synaptic events in nervous

39
system and other tissues. Action of neurotransmission reaches peak in a fraction of millisecond
and decays within a few milliseconds.
E.g. Nicotinic Achl receptors, GABAA receptor

2.4.1.2. G-Protein Coupled Receptors (GPCRs)

These are membrane receptors coupled to an intracellular effector system via a protein called “G-
Protein” which constitutes a large family and includes receptors for many hormones and slow
transmitters. GPCRs include muscarinic receptors, adrenoceptors, chemokine receptors,
dopamine receptor, 5-HT receptors, receptor for many peptides, opiate receptors, purine
receptors and many orphan receptors.
Activation of G-protein by receptor stimulation resulted in subsequent interaction of G protein
with other cellular effectors, which result in alteration in the concentration of second messengers
or ions. The main targets for G-protein action are;
• Adenyl cylase – enzyme responsible for cAMP formation
• Phospholipase C – enzyme responsible for inositol triphosphate and diacyl glycerol
formation
• Ion channels – particularly Ca2+ and K+ channels
Products of effectors are called as second messenger which play a role in conduction and
amplification of signals. Second messengers include
– cAMP
– IP3
– DAG
– Ca2+
A single agonist receptor complex can activate several G protein molecules which also contribute
to amplification of signals. These 2nd messengers can activate series of reaction and result in
further amplification before final cellular response. Drugs can act by stimulating or inhibiting the
receptors and thereby modulating the second messenger activity and the cellular responses.

2.4.1.3. Enzyme-liked and related receptors

They are quite different in structure and function from inotropic receptors and GPCRs. These
receptors mediate actions of a wide variety of protein molecules such as growth factors,
cytokines, hormones like insulin and leptin.
They have very large extracellular ligand binding and intracellular effector domains. On
stimulation they undergo dimerisation, autophosphorylation and activation of the intrinsic kinase.

40
The phosphorylated receptor phosphorylates the target molecules that subsequently activate other
cellular signals. This cascade of activation results in amplification of initial signal.

2.4.1.4. Nuclear receptors

These receptors have the ability to bind with DNA and regulate gene expression. Receptor
mediated regulation of DNA transcription is characteristic of steroid and thyroid hormones; quite
different from mechanisms of other receptor types. All nuclear receptor operate same basic
nuclear mechanism; binding of ligand with its receptor causes dissociation of repressor peptide
and activation of receptor. The activated ligand-receptor complex binds to specific DNA
sequences and regulates the gene expression. They are able to induce or repress specific genes
– Glucocortcoids inhibits transcription of COX-2
– Mineralocorticoids stimulates production of various transport protein involved in
renal tubular function
Other ligands for nuclear receptors are Vitamin D and Retinoic acid.
Peroxisone proliferator activated receptors (PPARs) play a key role in the control of lipid
metabolism and in the pathogenesis of various forms of metabolic and cardiovascular disease and
thus, targets for drug action;
• PPARα – target for drugs such as clofibrate, used to reduce cholesterol.
• PPARγ – target for thiazolidinedone, used in the treatment of diabetes mellitus

2.4.2. Control of receptor Activity

Receptors are in dynamic state and the receptor density, occupancy and affinity change in
response to the concentration of ligands.
Short-term control
• Desensitization
– Receptor phosphorylation
– Receptor internalization
Long-term regulation
Long term regulation of receptor activity involves alterations in receptor expression (either
stimulation or suppression of gene expression, thereby controls receptor density).

2.4.2.1. Receptor Desensitization

Receptor mediated responses to drugs and hormones often desensitizes with time. After reaching
an initial high level, the response diminishes over seconds or minutes even in the continuing
presence of the agonist. This desensitization usually reversible and occurs due to

41
  Receptor internalization
 Receptor phosphorylation

2.4.2.2. Up- and Down-regulation of Receptors

In the body number of receptors does not remain constant and changes in response to the
concentration of the specific ligands (agonist or antagonist). If is believed that change in receptor
density is achieved by receptor moving inside and outside (internalization and externalization) at
least for some.
Down- regulation:
Prolonged exposure to agonist causes reduction in number of receptors is known as down-
regulation. This may results from enodocytosis or internalization of recepors which cause
tachyphylaxis (loss of efficacy with frequently repeated doses)
E.g. withdrawal of clonidine (2 adrenoceptor agonist used to reduce BP) can produce
hypertensive crisis, probably because of down regulation of 2 receptors
Up-regulation:
Prolonged exposure to antagonist causes increase in number of receptors is known as up-
regulation. This is probably by externalization of receptors and the up-regulation leads to an
increase in receptor sensitivity. This may be one explanation for the worsening of angina pectoris
or ventricular dysrrhythmia in some patients following abrupt withdrawal of -blockers, as
normal concentration of circulating catecholamine now has access to an increased (up-regulated)
population of -receptors

2.4.3. Functions of receptors

• Propagation of regulatory signals from outside to intracellular effector molecules
• Amplification of signals
• Integration of intracellular and extracellular regulatory signals
• Adaptation to short-term/ long-term changes in the internal environment and maintenance
of homeostasis

2.4.4. Receptor activity

Receptors can exist in two conformational forms;
• Ra – active
• Ri - inactive

42
These states are in equilibrium
Ra Ri
Inactive form predominates in the absence of agonist or drug. The extent to which the
equilibrium is shifted toward active state is determined by the relative affinity of the drug for the
two conformations.
Drug that has higher affinity for active conformation will be an agonist
– Full agonists - shift the equilibrium completely to active state & produce full
biological response of the receptor
– Partial agonists - has intermediate affinity & cannot produce full biological
response of the receptor
Drug that bind with equal affinity to either conformation will not alter the equilibrium, act as
competitive antagonists.
Drug that has preferential affinity for Ri state produces opposite effects to that of agonist are
inverse agonist.

Figure 8. Drug-receptor interaction

2.4.4.1. Agonist
An agonist is a ligand, which can produce appropriate response when it binds to its appropriate
receptor. Drugs that resemble the natural transmitter or hormone may act as agonists. Their
values in clinical practice depend on their greater capacity to resist degradation; therefore, can act
longer than natural substances they mimic. E.g. Bronchodilation produced by salbutamol lasts
longer than that induced by adrenaline.

43
2.4.4.2. Antagonist
An antogonist is a ligand, which binds to the receptor without activating the response (insert
occupant) thereby preventing (blocking) the natural agonist from exerting its effect. Antagonism
can be reversible or irreversible.

Reversible antagonism: If forces that bind to drug to receptor are weak (hydrogen bonds, van-
der-Waals bonds, electrostatic bonds) the binding will be easily and rapidly reversible. If an
antagonist binds reversibly to a receptor, it can be replaced by mass action of the agonist (and
vise versa). If the concentration of agonist is increased sufficiently above that of the antagonist
the response is restored. This phenomenon is commonly seen in clinical practice. E.g.
Propronolol, if it is administered in doses sufficient to block the effects of catacholamine at basal
levels, when there is a increase in these catacholamine level as a result of sympathetic activation
(E.g. Stress or exercise) may diminish the prevailing degree of receptor blockade. Therefore
whose resting heart is low at rest due to -blockade by propanolol can be increased by exercise.
These agonist and antagonist compete to occupy the receptor according to the law of mass action.
This type of action is termed competitive antagonism.

When the log of concentration of agonist is plotted against the effect obtained, usually gives a
sigmoid curve. If it is drawn in the presence of an antagonist the curve will be parallel to the
original one but shifted to the right. Here agonist to be surmountable.

100
Figure 9:
Effect (% maximum)

Absence
Presence
Stylized dose-response curve
showing the parallel shift
50
between the absence and
presence of an antagonist

EC50 – is the concentration of

EC50 drug that produces 50% of
Log [agonist]
maximal effect.

Irreversible antagonism: If the binding forces are strong (covalent bonds) the binding is
irreversible. E.g. Phenoxybenzamine, to -adrenoceptor. Some toxins also act in this way (E.g.
-bungarotoxin, content of some snake and spider venoms). Since such drugs cannot be

44
displaced by agonist, the response cannot be fully restored by an increase in agonist and it is said
to be insurmountable. Curve will not be parallel. Restoration of response after irreversible
binding requires elimination of the drug and formation of new receptor by the body. Therefore
effect may persist long after the cessation of administration. These agents have little place in
clinical practice.

2.4.4.3. Partial agonist

Some substances have properties intermediate between agonist and antagonist and are known as
partial agonists. It acts as an antagonist because it does not produce maximum agonist response
when it occupy the available receptors fully and also capable of preventing action of other
agonist by blocking the binding of agonist to the receptors. E.g. Pindolol, oxiprenolol.

100
Response (% maximum)

Full agonist

50
Partial agonist

EC50
Concentration of agonist (log scale)

Figure 10: Dose-response curve for partial agonist.

2.4.4.4. Inverse agonist

Some substances produce effects that are opposite to those of agonist, these are called inverse
agonists. E.g. Agonist action of benzodiazepines on benzodiazepine receptor in CNS produces
sedation, anxiolysis, muscle relaxation and control of convulsion, while a substance called -
carbolines also binds to the same receptor causes stimulation, anxiety, increased muscle tone and
convulsion. Both drugs act by modulating neurotransmitter gamma-amino butyric acid (GABA)

2.4.4.5. Other forms of antagonisms

Physiological (functional) antagonism:

Physiological antgonism means the interaction of two drugs whose opposing actions in the body
tend to cancel each other. Eg. Extreme bradycardia due to -blocker overdose can be relieved
by atropine, which accelerates the heart by blocking parasympathetic activity. In anaphylactic
45
shock broncho-constriction caused by histamine released from most cells can be counteracted by
adrenaline, which relaxes the bronchial smooth muscles (-adrenoceptor effect) and the
pharmacological effect is overcome by a second drug acting though a different physiological
mechanism. Therefore it is called as physiological or functional antagonism.

Chemical antagonism
This is an uncommon situation where the substance combines in solution result in inactivation of
drug or substance. E.g. toxicity caused by heavy metals (lead, cadmium etc.) is reduced by
chelating agents (e.g. dimercapril), which binds the metal ions tightly to form an inactive
complex.
Pharmacokinetic antagonism
Here antagonist reduces the concentration of the drug at the site of action. It can occur in various
ways.
 By increasing rate of metabolism of active drug. E.g. reduction of anti-coagulant effect
of warfarin by enzyme inducers (phenobarbitone)
 By reducing rate of absorption. E.g. Calcium / iron form a complex with tetracycline and
reduce the absorption of tetracycline.
 By increasing the rate of excretion. E.g. Frusemide increases the rate of excretion of
indometheon and lowers its plasma concentration.

Allosteric antagonism
Allostatic effects are produced by binding of the drug to a site which is distinct from that of
agonist and thereby changing the affinity of the receptor agonist. If a drug drug binds to these
sites and decreases the affinity of agonist is known as allostatic antagonism. Some allosteric
effects potentiate the effects of agonists e.g. benzodiazepine on GABAA receptor.

2.4.5. Spare Receptors

Many receptors have the ability to amplify duration and intensity of the signal transduction.
Because of this amplification only a fraction of receptors need to be occupied to elicit maximal
response. Systems or tissues exhibits such behavior is said to have spare receptors. E.g. insulin
receptor, β-adrenergic receptor in the heart. Presence of spare receptors may determine the
sensitivity of a tissue, i.e. spare receptors make the tissue more sensitive.

Orphan receptors
Receptors that have been identified, but their ligands are presently unkown are called as “orphan
receptors”.
46
3. QUANTITATIVE ASPECT OF PHARMACODYNAMICS
Quantitative aspect of pharmacology means the right amount of action required, and in some
drugs the dose should be very precisely adjusted to deliver this. The dosing should not be too
little or too much to avoid inefficacy and toxicity. (E.g. Digoxin, Lithium, Gentamycin)

3.1. DOSE- RESPONSE

The extent to which the desired response alters as the dose is changed, termed as dose-response.
Usually it is described by the shape of the dose-response curve, in which dose (horizontal axis) is
plotted against response (vertical axis).
Dose-response can be
 Graded dose-response
 All or non response or Quantal-dose response

3.1.1. Graded response

A continuously changing drug concentration often gives rise to a continuously changing (graded)
response. This type of response will occur if the reaction is reversible. The dose-response
relationship is usually expressed as a sigmoid curve and as the dose is increased the magnitude of
the response also increased until a stage at which further increase in dose does not cause further
increase in effect or response this stage is called as maximal response (MR) or ceiling response
and the corresponding dose is called as maximal dose. A steep rising and prolonged curve
indicates that a small change in dose produces a large change in drug effect.
Response

2 4 8 16 32 64

10 100
Dose

Figure 11: Log dose-response relationship.

Dose response curve helps to find out;
 ED50 of the drug (effective dose of the drug that produce 50% of maximum response) -
means the effective dose producing 50% of maximal response
 Potency of the drug
 Affinity of the drugs for the receptor

47
  Differences in potency and efficacy of drugs that produce the same effect

3.1.2. All or none response (quantal response)

Many pharmacological effects (E.g. Control of cardiac arrhythmia) or toxic effects (E.g. death)
cannot be measured on continuous basis. They are all-or –non-effects, which can be, described
only in terms of incidence within a population i.e. it either happens or it does not.
Graphic curve is obtained by plotting different doses against number of subjects providing a
prefixed response; which provides a bell-shaped curve. This type of curve cannot be used for
calculations of ED50 and LD50 (dose that lethal to 50% of animals). To overcome this, a curve is
plotted with log dose against cumulative percentage of animals or subjects responding.

3.2.2 POTENCY AND EFFICACY

Potency: Potency is a measure of how much drug is required to produce a certain response.

Efficacy: Efficacy of a drug is defined as the maximum response it can produce.

At low doses Benzofluazide is more potent diuretic than frusemide, but is less efficacious as at
maximum dose it produces less diruresis than frusemide.

B
Response

Dose

Drug “ a” is more potent than drug “b” but drug “b” is more efficacious than drug “a”.
Figure 12: Potency and efficacy

3.2.3. THERAPEUTIC INDEX

Usually when the dose of drug is increased progressively, the desired response will rise to a
maximum, beyond that further increase in dose will not produce significant benefits, but
produces unwanted effects. The therapeutic index of a drug means the ratio between maximum
tolerance dose and minimum curative dose in a group of subject i.e.

Therapeutic index = Maximum non toxic dose

Minimum effective dose
48
Since such single dose cannot be determined accurately the index is never calculated in this way
in man. And variability between individuals is not taken into account in this definition. The
widely used definition which taken into account individual variation
Therapeutic index = LD50 / ED50
LD50 – Lethal dose for 50% of a group of animal tested.
ED50 – Effective dose required to produce a response in 50% of the subjects tested.

Though it gives some idea of the margin of safety in use of a drug, it has obvious limitation.
Therefore it is vary rarely quoted as a number. Its main short comes are;
- LD-50 – is based on animal data, which may not reflect forms of toxicity that are important
clinically.
- ED50 – is often not definable since it depends on what measure of effectiveness is used. E.g.
analgesic drug are given in different dosage according to the native and severity of the
patient.
- It takes no account of idiosyncratic toxic reactions.

Therefore, even therapeutic index express a valid general concept, it provide no measure of the
actual usefulness of a drug. E.g. warfarin has narrow therapeutic index while penicillin has wide
therapeutic index.

Drug A Drug B
Wanted effect Unwanted effect Wanted effect
Unwanted effect
Response

ED50 ED50 ED50 ED50

Dose

Figure 13: Dose-response curves for two hypothetical drugs.

Drug A: the dose that causes maximum wanted effect causes no unwanted effect. The ratio ED50
(unwanted effect) / ED50 (wanted effect) indicates that it has a large therapeutic ratio: it is thus
highly selective in its action. Drug B causes unwanted effects at doses well below that which
produces its maximum benefit. The ratio ED50 (unwanted effect) / ED50 (wanted effect) indicates
that it has a small therapeutic ratio: it is thus nonselective.
49
Therapeutic Window
Sometimes therapeutic effect of a drug declines as the does is increased beyond an optimum
point. The intermediate range in which effective action is obtained is called as therapeutic
window. In other words, is the optimal therapeutic range of plasma concentration of a drug, at
which most patients experience desired effect. E.g. tricyclic antidepressants exert antidepressive
effect when their plasma concentration is maintained between 50 – 150ng/ ml.

3.2.4 SELECTIVITY
As no drug is completely specific in their action, drugs are only selective rather than specific. It
is exceedingly unlikely that any kind of drug molecule binds only to single molecular species of
target.
Drugs with selectivity for a receptor subtype can produce maximum effect at the other subtype if
given in adequate amounts. This is particularly important if the beneficial effects are achieved by
one receptor subtype and the unwanted effects by the other. E.g. Though Atenolol is considered
a 1-selective blocker it has some effects on 2 receptors, therefore it is absolutely
contraindicated in asthmatic patient in whom any reduction in 2-mediated broncho dilatation
may be dangerous.
Selectivity is useful in clinical practice only when the ratio of the effect of drug on 2 receptor
sites is 100 or more. If selectivity is low, it is difficult to predict drug dose that will exploit the
difference in subtype activity. Selectivity is most likely to be achieved at the lowest effective
dose.

Approaches to obtain selectivity

a) Modification of structure: Selectivity can be increased by designing drugs structurally
similar to natural substances of the body, thus they can achieve selectivity of action by
replacing or competing with natural substances. E.g. Adrenoceptor antagonists, histamine
antagonists. But, there are also biological constrains of selectivity. E.g. Anticancer drugs
that act on rapidly proliferating cells lack selectivity because they also damage normal tissues
with high cell proliferation rate.
b) Selective delivery drug targeting: Selective delivery of a drug to particular target can be
achieved by
 Simple topical application e.g. skin, eye.
 Special drug delivery system e.g. inhaled pressurized metered dose aerosol for asthma.
 Selective targeting to less accessible sites e.g. Attaching drug to antibodies selective for
cancer cells.

50
c) Stereo selectivity: Drugs can be a mixture of non-identical molecular (non-identical mirror
images), known as enantiomorphism can exhibit very different biological activity. E.g.
Warfarin exist in S (-) and R (+) forms. Drug of single enatiomers shows greater selectivity
of action and lesser risk of toxicity.

3.2.5 VARIATIONS IN DRUG RESPONSIVENESS

Idiosyncrasy:
An idiosyncratic reaction is a qualitatively abnormal and usually harmful drug effect, which
occurs in a small proportion of individuals. This reaction may occur with small dose. Usually it
is due to genetic abnormality e.g. porphyria. The mechanisms of this reaction are often poorly
understood probably genetic predisposition may play a role.

Tolerance:
Tolerance is said to have developed when it becomes necessary to increase the dose of a drug to
obtain an effect, previously obtained with smaller doses. The decrease in response is gradual
takes days or weeks to develop tolerance. Tolerance can be natural or acquired.
Acquired tolerance: It may be resulted form receptor down-regulation. Also can be due to
increased metabolism as a result of enzyme induction or it can be a result of cross tolerance
between drugs of similar structure (sometime between those of dis-similar structure)

Natural tolerance: It is not induced by drug but is due to inherent factors.

Tachyphylaxis: It describes the rapid deminishion of responsiveness after administration of

drug. It often occurs more rapidly, in the course of a few minutes. The distinction between
tolerance and tachyphylexia is not sharp one.

Drug resistance:
This term is used to describe the loss of effectiveness of antimicrobials drugs.

Refractoriness: It is the term sometimes used, mainly in relation to loss of therapeutic efficacy.

3.3. BIOASSAY AND STANDARDISATION

Bioassay: It is the process by which the activity of substance is measured on living malarial. It
is used only when chemical or physical methods are not practicable. E.g. Mixture of active
substance, preparation is not pure. The activity of the tested preparation is expressed relative to
that of a standard preparation. Standardization is a specialized form of bioassay involves

51
matching of material of unknown potency with international or national standards with the
objective of providing a preparation for use in therapeutics and researches.

100
log M A2
Response (%maximal)

Unknown

A1
Standard
log M

0
0 1 2 3
Log10 volume administered (l)

Figure 14: Comparison of the potency of unknown and standard by bioassay.

Note that comparing the magnitude of responses produced by the same dose (i.e. volume) of
standard and unknown gives no quantitative estimate of their relative potency. (The differences,
A1 and A2 depend on the dose chosen.) Comparison of equi-effective doses of standard and
unknown gives a valid measure of their relative potencies. Since the lines are parallel, the
magnitude of the effect chosen for the comparison is immaterial; i.e log M is the same at all
points on the curves.

Main problem in bioassay is biological variation. Therefore bioassays should be designed to aim
at;
 Minimizing variation
 Avoiding systemic errors resulting from variation
 Estimating the limits of error of the assay result.

52
4. DRUG DOSAGE
4.1 FACTORS INFLUENCE THE DRUG DOSAGE
Four important variables are considered in this aspect.
1. The amount of drug to be administered at one time.
2. The route of administration
3. Interval between doses (can be a continuous input or series of intermittent doses,
usually equal size and given at approximately equally spaced intervals)
4. Period or time over which drug administration is to be continued.
The dose may need to be adjusted according to body weight. But adjustment according to body
surface area may be more appropriate because it is directly related to metabolic rate. This can be
obtained by taking body weight to the power of 0.7.

4.2 KINDS OF DRUG DOSES

1. Fixed dose: Here desired effect can be obtained at doses well below toxic doses and enough
drug can be given to render individual variation clinically insignificant.
2. Variable dose with crude adjustment: Here fine adjustment makes comparatively
insignificant difference and the therapeutic end-point may be hard to be measured
(depression, anxiety), may change only slowly (thyrotoxicosis) or may vary because of
pathophysiological factors (analgesics, adrenal steroids for suppressing disease).
3. Variable dose with fine adjustments: Here a vital function (blood pressure, blood sugar),
that often changes rapidly in response to dose changes and can be easily measured repeatedly
and provides the end point. In these cases adjustment of dose should be accurate.
4. Maximum tolerated dose: It is used when ideal therapeutic effect is unable to be achieved
due to the occurrence of unwanted effects (anticancer drugs, some anti microbials). Here dose
is increased until unwanted effect begins to appear and then it is reduced slightly or plasma
concentration is monitored.
5. Minimum tolerated dose: It is not a common one. It is used in long-term therapy of
adrenocorticosteroids against inflammatory or immunological conditions. E.g. In asthma, in
rheumatoid arthritis. For the symptomatic relief dose may be so high and may cause serious
adverse effect, which cannot be avoided if continued indefinitely

4.3 DOSING SCHEDULE

Dosing schedules are aimed at achieving desired therapeutic effects without toxic effect

53
Objectives of a dosing regimen where continuous effect is required:
Specifying an initial dose:
It should obtain the desired effect rapidly without causing toxicity. Often the dose that is used to
initiate the effect is same as that is required to maintain the effect. However, with repeated
dosing it takes 5x t ½ to reach steady state concentration; this relapse time may be undesirable. It
may be desirable, especially in the case of drugs with long t ½, to administer a loading / priming
dose (larger than maintenance dose) to promptly rise the plasma concentration to the projected
steady state value.

Loading dose = Amount in the body immediately following the loading dose
Volume of distribution x Target concentration

Specifying a maintenance dose:

Here amount of drug as well as frequency of intake must be determined. Intuitively, it might be
half the initial priming dose at intervals equal to its plasma t ½. This approach may or may not
be satisfactory / practicable Maintenance dose is administered to maintain a steady state of drug
in the body i.e. drug is given in each dose to replace the drug eliminated from the previous dose.
Maintenance dose = dosing rate x dosing interval
Dosing rate = Rate of elimination
= Clearance x target concentration
Dosing interval largely depends on half life of the drug.
 If t ½ 6-12hrs – Here replacing half the initial dose at intervals equal to the t ½ may be
satisfactory because dosing every 6 – 12hrs is acceptable.
 If t ½ > 24hrs – Here it can be given as once daily dosing (will increase the compliance),
giving half the primary dose. If t ½ > 24hrs drug entering the body and will accumulate
indefinitely. Therefore the dose should replace only the amount of drug that leaves the body
in 24hrs.
 If t ½ <3hrs – If dosing interval is equal to the t ½, it would be so frequent, that is
unacceptable. If the t ½ is too short e.g. dopamine (t ½ - 2min) use of continuous
intravenous infusion is appropriate. If t ½ is relatively longer (e.g. lignocaine t ½ - 90min)
priming dose as intravenous bolus followed by constant intravenous infusion. But
intermittent administration of a drug with short t ½ is also appropriate provided large
fluctuations in plasma concentration are acceptable (i.e. large therapeutic index). E.g.
Benzyl penicillin (t ½ - 30min), but it is effective in 6 hourly regimen, because it is so

54
 nontoxic and can be given safely at doses which result in plasma concentration many time
higher than the minimum inhibitory concentration for sensitive organisms.

4.4 PROLONGATION OF DRUG ACTION

a) A large dose is the most obvious way to prolong the drug action. But it is not always
feasible.
b) Vasoconstriction will reduce local blood flow so distribution of drug away from an
injected site will be reduced. E.g. Adrenaline with local anaesthetics.
c) Slowing the metabolism. E.g. Carbidopa, a deoxy carboxylase inhibitor combined with
levodopa (co-careldopa), which will slow the metabolism out side the CNS.
d) Delayed excretion: It is seldom used. E.g. Probenecid block renal tubular excretion of
penicillin.
e) Conversion of active drug into active metabolite. E.g. various benzodiazepines.
f) By means of different pharmaceutical preparations.
 Sustained release oral forms.
 Controlled release delivery system
 Depot injections
 Subcutaneous implants.

4.5 FIXED DOSE DRUG COMBINATION

It refers to the combination of drugs in a single pharmaceutical formulation; it doesn’t refer to
concomitant drug therapy.
Prescription of fixed dose combination formulation is appropriates if;

1) There is a good reason to consider that patient needs all drugs in the formulation, such as

 Where 2 drugs are used at constant doses over a longer period for asymptomatic
condition. E.g. Thiazide diuretic and  blocker in mild to moderate hypertension.
 Where enhance effect is needed. E.g. In the treatment of tuberculosis simultaneous use of
2 drugs will prevent or delay the emergence of resistant organisms. (Combination of
Rifampicin and Isoniasid)
 Oral contraceptives: Have to enhance the contraception oestrogen and projesteron
combination is used.
2) The doses in the fixed dose combination are appropriate.
3) Dose will not need to be adjusted separately.

55
Prescription of these combinations is inappropriate;
1) Where dose of one or more component of the drug may need to be adjusted
independently.
2) If drug actions demand different intervals between administration of the components.
3) If irregularity of administration is desired for some ingredients but not for others.

Benefits of fixed dose combination

1) Convenience with increased compliance as fewer tablets are to be taken. Especially in
elderly, because they receive more drugs as they have multiple pathology.
2) Enhanced effect. E.g. OCP, anti TB drugs.
3) Minimizes unwanted effect. E.g. Combination of levodapa with carbidopa or
benserazide, reduces the metabolism of levodopa outside the CNS, therefore it reduces
the required amount of levodopa thereby reduces the side effects.

5. EFFECTS OF LONG TERM TREATMENT

In some conditions long-term treatment may cause significant hazards to the patient. And it may
be more harmful than disease if it is not skillfully managed. Therefore, long-term therapy should
be aimed at safe management or at least with minimum risk of hazards.

5.1. INTERFERENCE WITH SELF-REGULATORY SYSTEM

If self-regulatory physiological systems (usually controlled by feed back system) are subjected
to interference, they try to minimize the effect of interference and to restore previous state. If the
body restores the previous steady state (which can be normal or abnormal), then patient becomes
tolerant to the drug.

5.1.1. Feedback system

Endocrine glands are capable of increasing or decreasing their output, usually by means of
negative feed back mechanisms. An administered hormone or hormone analogue also can
activate the receptors of negative feed back system. Therefore at high doses they can cause
suppression of production of natural hormone. On withdrawal of administered hormone
restoration of normal production of natural hormone will take time. E.g. Hypothalamic /
pituitary / adrenal cortical system takes months to restore normal effect. Sudden withdrawal of
administered corticosteroids can result in acute deficiency of hormone and may endanger the life
of the patient.

56
5.1.2. Regulation of receptor
Density of receptors on cell can change in response to the concentration of the specific ligands
(agonist or antagonist). If is believed that change in receptor density is achieved by receptor
moving inside and out side (internalization and externalization) at least for some.
Down- regulation: Prolonged exposure to agonist causes reduction in number of receptors. This
is known as down-regulation.
Up-regulation: Prolonged exposure to antagonist causes increase in number of receptors. This is
known as up-regulation.

5.2. ABRUPT WITHDRAWAL

Abrupt withdrawal following prolonged used drug may result in;
1) Rebound phenomenon: It means recurrence at intensified degree of symptoms for which the
drug was given. E.g. Rebound hypertension on withdrawal of clonidine, -Blockers.
2) Withdrawal syndrome (Abstinence syndrome): It means appearance of new additional
symptom. E.g. Alcohol, opioids.

3) Resurgence: It means reappearance of disease, which is suppressed earlier by the drug. In

chronic disease, which has progressed although its consequents have been partly or wholly
suppressed becomes obvious after the withdrawal of effective therapy. E.g. Levodopa in
Parkinsonism, corticosteroids in autoimmune disease.
4) Drug discontinuation syndrome: It is used to describe rebound, withdrawal and resurgence
phenomena together.

Rebound and withdrawal phenomena are more likely to occur with drugs heaving short half-life
and pure agonist or antagonist. They are less likely to occur with drugs having long half-life and
probably with drugs showing partial agonist activity.
Clinically important consequences are known to occur with the following.

 Cardiovascular system:
Antihypertensive- clonidine, -blockers.
 Nervous system:
Hypnotics, sedatives, alcohol, opioids, antiepileptics, antiparkinsonism agents, tircyclic
antideppressants.
 Endocrine system:
Adrenal steroids
 Immune inflammation:
Adrenal steroids.

57
5.3. OTHER ASPECTS OF CHRONIC DRUG USE
1. Long-term use of drugs may produce metabolic change which can result in disease. E.g.
Thiazide diuretics – Diabetes mellitus, Adrenal cortical steroids – Osteoporosis, phenytoin –
Osteomalacia.
2. Specific cell injury or cell functional disorders may occur with a particular drug or drug class.
E.g. Tarditive dyskinasia – dopamine receptor blockers,
Retinal damage - Chloroquine, phenothiazine
Retroporitoneal fibrosis - methysergide
Nephropathy - NSAIDS
Cancer Oestrogen (endometrial cancer)
3. Dangerous intercurrent illness can occur. E.g. Anticoagulants, adrenal steroids,
immunosuppressives.
4. Interactions can occur with other drugs.

NB: Drug holiday: It describes the deliberate interruption of long-term therapy to restore
sensitivity, which has been lost, or to reduce the risk of toxicity. E.g. Levodopa for
Parkinsonism, Methysergide for refracting migraine.

6. INDIVIDUAL VARIATION IN DRUG RESPONSE

Variability in drug response may cause serious problems when drugs are used clinically; if it is
not taken into account it can result in,
 Lack of efficacy
 Unexpected side effects.
The types of variability may be classified as
 Pharmacokinetic
 Pharmacodynamic
 Idiosyncratic

MAIN CAUSES OF VARIABILITY

1. Age

a) In infants rectal absorption is efficient and is preferred in uncooperative infant. In them

I.M. and S.C. routes give unpredictable plasma concentrations, therefore, intravenous route
is preferred in severely ill children. Infants have high risk of toxicity of drugs applied to
the skin as substances are readily absorbed because of the thin stratum cornium and
increased hydration.

58
 b) At birth and in old age renal and hepatic functions are generally impaired relative to other
ages, so drugs effects are prolonged and accumulation tend to occur. Neonates, especially
premature ones have particularly poor renal and hepatic functions in relation to metabolism
and clearance, especially for oxidation and for conjugation with glucuronic acid. (Failure
to inactivate chloramphenicol causes fatal ‘grey’ syndrome.). These functions mature in
the first few weeks of life. Renal and hepatic functions decline slowly and variable after
middle age, so inter individual variation is greater in elderly. Hepatic first-pass effect is
reduced in elderly and may need to lower the dose of drug, which undergo extensive
hepatic first-pass metabolism. E.g. Most neuroleptics, tricyclic antidepressants, cardiac
dysarrhythmic drugs. There is also increased risk of adverse effect in elderly with the
drugs those are mainly excreted by kidneys and have small therapeutic ratio. E.g.
Aminoglycosides, Chlopropamides, Digoxin, Lithium.

c) Physiological factors in elderly may qualitatively alter drug effects. E.g. Drugs act on
CNS appear to produce an exaggerated response in elderly and hypnotics and sedatives
may have a pronounced hang over effect. Respiration depression is more likely to occur in
elderly because their vital capacity and maximum breathing capacity are reduced.

 Response to -agonists and antagonist may be blunted in old age partly due to
reduction in number of receptors.
 Baroreceptor sensitivity is reduced in elderly; this may leads to potential for orthostatic
hypotension with drugs that reduces BP.

d) Pathological factors that influence drug metabolism are common in elderly.

e) Elderly people consume more drugs so the potential for drug interaction is increased.

2 Genetic factors

All metabolic reactions are subjected to genetic control therefore different individuals have
different capacities to metabolize the same drug. These differences are resulted from multiple
factors, some genetic factors, and some environmental factors, collectively contribute for the
response of the individual to the drug. These differences are usually unimodally distributed in
the population.

However, a few reactions are bimodally distributed i.e. there are tow separate populations of
distinctly different mean metabolizing capacities. This variation most commonly occurs when
the response to the drug is controlled by a single gene. Inherited factors causing different
responses to drugs are commonly biochemical because single genes govern the production of the
enzymes.
59
a) Inheritable conditions causing increased or toxic responses
Acetylation: There are slow and fast acetylators. Inherited as autonomal recessive trait. Slow
acetylators are at greater risk of adverse effect.

Hydroxylation and sulphoxidation: For both reactions there are poor and extensive
hydroxylation and suphoxidators respectively. Here poor metabolizers are more prone to adverse
effects. There is also inherited as autosomal recessive trait.

Glucose-6-phophate dehydrogenase deficiency (G6PD deficiency): Glucose-6-phosphate

dehydrogenase an enzyme in red cells is important to maintain the content of reduced glutathione
(GSH) in red cells, GSH being necessary to prevent haemolysis. The integrity of red cell
membrane is maintained by chain of reactions.

 This enzyme is an important source of NADPH, which maintains the reduced glutathione
(GSH) form.
 GSH is necessary to keep Hb in reduced ferrous state, which is important for oxygen
carriage. (Ferric state (methaemoglobin) is useless for oxygen carriage).
 Accumulation of methaemoglobin in the erythrocytes impairs the function of sulphadryl
groups especially these association with cell membrane stability.

In patients with G-6-PD deficiency may suffer from haemolysis if they are exposed to certain
oxidants (which are harmless to normal cells), including some drugs. This is inherited as sex-
linked recessive trait. Affected subjects show differing susceptibility to haemolysis. Hetero
zygotic females show no tendency to haemolysis (have increased resistance to malaria).

Drugs which causes definite risk of haemolysis in most G-6-PD deficient subjects:

Dapsone and other Sulphorus, methylene blue, niridazole, nitrofarantoin, Primaquine, pamaquin,
quinolone, some Sulphonamides.

Drugs, which cause a possible risk of haemolysis in some G-6-PD deficient subjects:
Aspirin, menadoine, Probenecid, quinedine, Chloroquine and quinine.
Affected individual also susceptible to the expose to nitrates, anilines and naphthalene. Some
result in haemolysis after eating broad bean also.

Pseudocholenesterase deficiency:
It is responsible for metabolism of suxamethonium. Patients deficient in this enzyme can have
prolonged apnoea after surgical operation. It is inherited as autosomal recessive trait.

60
b) Heritable conditions causing decrease drug response
 Resistance to coumarin anticoagulants.
It’s a rare abnormality involves a variant of enzyme that convert Vit. K to reduced and
active forms. Coumarin inhibits this enzyme. These patients need 20 times or more usual
dose to obtain effective clinical response.
 Resistance to heparin.
Patients with antithrombin III deficiency require larger doses of Heparin to achieve
therapeutic effect.
 Resistance to suxamethonium.
It is a rare condition where increased pseudocholinesterase activity and thus, failure to
cause muscle relaxation with normal doses of suxamethonium.
 Resistance to Vit D:
Patients with rickets need huge doses of Vit. D to respond
 Bacterial resistance to antimicrobials.

3 Physiological state:
Pregnancy:
During pregnancy profound physiological changes occur, including fluid and tissue composition.
This causes variability in drug effect.
 Gastric motility may decrease in pregnancy especially during labour. Therefore it may
delay the appearance of orally administered drugs in plasma. But i.m. administration is
effective as tissue perfusion is increased in pregnancy.
 Body water increases in pregnancy and result in haemodilation and reduction in plasma
albumin concentration. The free form is increased of drugs, which bind to albumin. But
the drug free to distributed and metabolized the free concentration is not altered although
total plasma concentration is reduced (E.g. phenytoin). In pregnancy it is advisable to
maintain concentration at the lower end of recommended range.
 In pregnancy body fat also increases by about 4Kg, therefore increased reservoir for lipid
soluble drugs.
 During pregnancy hepatic metabolism increases but not the blood flow. Therefore there
will be an increase in clearance of drug whose rate of elimination depends on hepatic
enzyme activity. E.g. phenytoin, theophyllin, while the clearance of drugs whose
elimination depends on rate of delivery to the liver is unaltered e.g. propronolol.
 In pregnancy renal blood flow almost doubles therefore more rapid elimination of drugs
that are excreted by kidneys. E.g. Amoxycillin. Doses of the drugs should be doubled for
systemic infection (but not for UTI.).
61
 Placenta: It acts as barrier between foetal and maternal blood. It allows the passage of lipid
soluble substances but not water-soluble compounds, especially MW exceeding 600. This
exclusion is particularly important for short-term use as in caesarian section. E.g. Tubocurarine
and gallarrine do not affect the neonate. But in long-term use all drugs eventually enter foetal
circulation to some extent.

4 Pathological state
Disease state can cause pharmacokinetic variation as well as pharmacodynamic variations.
Pharmacokinetic alteration
Absorption
 Absorption is slowed in gastric stasis. E.g. Migraine.
 Malabsorption can occur in ileal or pancreatic disease and due to oedema of ileal
mucosa (E.g. heart failure, nephritic syndrome).
 Resection of gut also may lead to malabsorption.
E.g. partial gastrectomy causes malabsorption of iron folic acid and fat-soluble
vitamins.
Ileal resection causes malabsorption of vitamin B12
 Severe low out put cardiac failure and shock delays the absorption from subcutaneous
and muscular sites.
Distribution
 Hypoalbuminaemia (E.g. Burn, malnutrition, sepsis, CRF, chronic liver failure)
increases free forms of drugs in the plasma.
 Altered plasma binding e.g. phenyton in CRF.
 Impaired passage across blood brain barrier e.g. Penicillin in meningitis.

Metabolism
 Hepatic cirrhosis and portal hypertension impair hepatic metabolism thus, increase the
drug level, which undergo hepatic first pass metabolism extensively (E.g. propronolol,
labetalol and cholrmethiazine). Many other drugs’ t ½ is prolonged (E.g. Diazepam,
tolbutamide, rifampicin).
 Thyroid disease: Drug metabolism is accelerated in hyper thyroidism and diminished in
hypothyroidism.

Excretion
 Acute / chronic renal failure may increase the actions of drugs that are eliminated by
kidneys.

62
Pharmacodynamic alteration
 Diseases that influence the receptors
 Myasthenia gravis – auto allergic disease characterized by antibodies to acetylcholine
receptors at neuromuscular junction (worsened by quinine and quinidine and patients
are intolerant of competitive neuromuscular blocking agents and amino glycosides).
 X-lined nephrogenic diabetic insipidus – abnormality in vasopressin receptors.
 Familial hypercholesterolaemia – inherited disease of LDL receptors.

 Disease influences the signal transaction mechanisms.

 Pseudohypoparathyroidism – impaired coupling of receptors with adenylate cyclase
 Familial precocious puberty and hyperthyroidism due to functioning thyroid adenoma. –
Due to mutation in G-protein coupled receptors, which are turned on all the time even in
the absence of natural agonists (Hormone).

 Diseases causing malfunctioning respiration center (raised intra cranial pressure, severe
pulmonary insufficiency) can cause intolerance to opioids. And any sedative may precipitate
respiratory failure.

 Myocardial infarction may predispose cardiac dysrrhythmia with digitalis or

sympathomemetics.
 Increased sensitivity to pethidine in hypothyroidism (mechanism not known)

5 Food
 Presence of food in stomach (especially with fatty foods), delays gastric emptying, thus
absorption of certain drugs (Ampicillin, Rifampicin). Particularly food may interfere the
absorption of drugs e.g. calcium and tetracycline, grape juice increase the absorption of
cyclosporin, Calcium channel blockers etc.
 Substituting protein for carbohydrates / fat may increase the drug oxidation rate
 Specific dietary factors may induce metabolizing enzymes. E.g. Alcohol, charcoal grilled
beef, cabbage
 Protein malnutrition reduces hepatic metabolizing capacity and hypoproteinaemia.

6 Drug interaction: Given below.

7 Others
 Cigarette smoking induces metabolism of some drugs.
 Individual workers exposed to certain pesticides metabolize certain drugs rapidly.

63
7. DRUG INTERACTION
If a second drug alters the response of the first drug, a drug interaction is said to have occurred.
It may be desirable or undesirable.

7.1. CIRCUMSTANCES WHERE CLINICALLY SIGNIFICANT ADVERSE DRUG REACTIONS ARE

LIKELY TO OCCUR

 Drug with steep dose response curve and small therapeutic index. E.g. Digoxin, Lithium.
 Drugs which are known enzyme induces or inhibitors.
 Drug shows saturation /zero-order kinetics where small interference with kinetics may lead to
large alteration in plasma concentration of the drug. E.g. Phenytoin, Theopylline.
 Drugs, which might interact, are given to treat same disease (this increase the chances of
concurrent usage of such drugs). E.g. Theophylline and sulbutamol are used for asthma; their
concurrent use may cause cardiac arrhythmias.
 Drugs, which are used long-term and need precise plasma concentration. E.g. Oral
contraceptives,antiepileptic drugs,antiarrhythmic agents, lithium.
 In patients at risk of interaction.
o Elderly patients with polypharmacy.
o Patients with complex, severe illness – Symptoms may be constantly changing and it may
be difficult to differentiate effect of drugs from, those of underlying disease. E.g.
Cardiogenic shock, aplastic anaemia, hepatic pre-coma.
o Patients with unstable disease treated with chronic drug therapy – An interaction may
precipitate an exacerbation or produce concentration dependent toxicity. E.g. Cardiac
arrhythmia, brittle diabetics, severe asthma.
o Patients dependent on drug prophylaxis. Loss of therapeutic effect may result from
disease breakthrough or unwanted physiological effect. E.g. Connective tissue disease,
Addison’s disease, renal transplant and contraception.
o Disease affecting major organs of drug elimination. -Disease affecting hepatic or renal
function may favour drug interaction.
o Patients with severe intercurrent illness – Acute infection may influence drug handling or
response. E.g. Pneumonia, viral hepatitis, pyelonephritis.
o Patients with two or more prescribing doctors. – May result in unfortunate drug
combination.

64
7.2. PHARMACOLOGICAL BASIS OF DRUG INTERACTION
Two important kinds of drug interaction are,
1) Pharmacokinetic interaction: This interaction may occur during the absorption,
distribution, metabolism or excretion (i.e. interact remotely from the site of action). It
may alter the concentration of drug at the site of action therefore therapeutic effect is
altered. E.g. Enzyme inhibition and induction.
2) Pharmacodynamic interaction: Here both drugs act on target site by exerting synergism
or antagonism. They may act on same or different process at the target site.
In addition, there are some interactions occur out side the body also.

Antagonism: Sometimes addition of second drug diminishes the effectiveness of first drug.
They may have two opposite pharmacodynamic effect. E.g. Histamine and adrenalin on bronchi
(Physiological antagonism) or may compete reversibly for the same drug receptor. E.g.
Isoprenaline and -blockers exhibit competitive antagonism.

Addition: Where combination of 2 drugs of same action will result in summation or addition of
effects. (E.g. -blocker & thiazids diuretic have additive antihypertensive effect.)

Synergism: Sometimes combination of two drugs may result in effect greater than that could be
expected from simple addition of drugs. I.e. potentiation of effect occurs. E.g. Trimethopron &
Sulphonamides, Beneserazide & Levodopa.

7.3. PHARMACOKINETIC INTERACTION

7.3.1. Absroption
a) Intraluminal chemical interactions:
These reactions may cause significant reduction in absorption. E.g. Antacids containing
divalent and trivalent cations form insoluble complexes with some drug. (E.g. Tetracycline,
Iron and prednisolone) Iron salts also interfere in the same way with penicillamine and
levadopa bioavailability. Anion exchange resin, cholestyramine binds acidic drugs such as
Digoxin and Warfarin as well as bile salts. Sucralfate reduces the absorption of Phenytoin.
These interactions depend on the simultaneous presence of both drug in the stomach and it
can be avoided by separating the doses by at least 2 hours.
b) Gut Motility:
Gut motility may be altered by drugs. As most drugs are absorbed optimally in the upper
small bowel, drugs that delay gastric emptying (E.g. Anticholinergics, Tricyclic

65
 antidepressants, Antihistamines, Phenothiazines, Opiates) will delay the absorption of other
drugs.
Erythromycin increases the absorption of cyclosporin and the bioavailability of cyclosporin is
almost doubled. The exact mechanism involved is not yet known, but may involve inhibition
of its metabolism in the gut wall.
Purgatives reduces the time spent in small intestine and give less opportunity of absorption of
poorly soluble substances such as adrenal steroids and digoxin.
c) Mucosal damage:
Drugs that cause local mucosal damage (e.g. Necomycin colchicine, Cytotoxic agents) can
reduce the absorption of poorly absorbed substances such as phenytoin and digoxin.
d) Alteration in gut flora:
Antimicrobials may potentiate the effect of oral anticoagulants by reducing bacterial
synthesis of vit K.
Some women taking oral contraceptive pills may be at risk of becoming pregnant with broad-
spectrum antibiotics (Ampicillin, Tetracycline) for minor infections. The mechanism
responsible is thought to be the interference of enterohepatic recycling of hormones by
eradicating gut bacteria which is responsible for deconjugation of drug metabolite
(deconjugated metabolite is reabsorbed by gut mucosa)
e) Interactions at sites other than gut:
Use of hyaluronidase, which depolymirises hyaluronic acid causes rapid spread of the drug
over a wide area. Therefore, absorption is quicker.
Addition of vasoconstrictors, (E.g. Adrenaline, Felypressin) to local anaesthetics to delay
their absorption and prolong the local anaesthesia.

7.3.2. Interaction during distribution

a) Displacement from plasma protein binding:
A drug that is bound to plasma protein can be displaced by a competing drug. It may result in
transient rise in free drug level of the first drug. As there is compensatory rise in metabolism
and exertion of the displaced drug, the free concentration of displaced drug quickly returns to
its original value. However, the total plasma concentration of the displaced drug falls.
This type of interaction becomes clinically important in situation the protein binding
displacement is accompanied by enzyme inhibition.
E.g. Phenyl butazone potentiating warfarin anticoagulant effect and sodium valproate
precipitating phenytoin toxicity.

66
 Aspirin and probenocid displace methotrerate from its protein-binding site and reduce its rate
of secretion by renal tubules and result in serious methotrerate toxicity. Some drugs displace
bilirubin from protein binding (E.g. Sulphonamides, vitamin K, X-ray contrast media,
Indomethacin) might cause significant risk of kernicterus in neonates.
Direct interaction between drugs also can take place in plasma. E.g. Protamine with heparin,
Desferioxamine with iron, Dimercaprol with arsenic. (All are useful)
b) Displacement from tissue binding:
Quinidine and other antiarrhythmic drugs such as verapamil and amiodarone displace digoxin
from its renal excretion resulting in sever dysarrhythmia due to digoxin toxicity.

7.3.3. Interaction during metabolism

Enzyme induction
Drugs or substances that induce enzymes will accelerate metabolism of drug and may result in
therapeutic failure. To avoid this, the dose of enzyme-induced drug must be increased. If
therapeutic drug monitoring is not available, the clinical effect must be assessed. (E.g.
prothrombin time, brakthrough bleeding for warfarin and oral contraceptives respectively) Some
examples for target drugs for enzyme induction;
 If oral contraceptive and phenytoin are taken together, latter will induce the metabolism of
oral contraceptive and may result in unwanted pregnancy.
 With enzyme inducers failure of anticoagulant control of warfarin can occur as metabolism of
warfarin is increased.
 Chronic alcohol consumption can cause enzyme induction and may result in tolerance to
hydrocarbon anaesthetics and tolbutamide.
 Cyclosporin is extensively metabolized and its concentration is markedly reduced by enzyme
induction by Rifampicin. This may result in inadequate immunosuppression and endanger
the organ or marrow transplant.
When enzyme inducers are withdrawn, the metabolic process, which they induce will be back to
normal. This will result in reduction of enzyme; thereby increase the plasma level of target drugs
and which may produce unexpected toxicity. (E.g. Haemorrhage with warfarin)

Enzyme inhibition
Enzyme inhibition, particularly of cytochrome P-450 occurs with a number of drugs. This will
slow the metabolism and hence, increase the concentration as well as action of various other
drugs. The most clinically relevant target drugs for inhibitory interaction have narrow
therapeutic ratio and exhibit concentration dependent toxicity (E.g. Warfarin, Verapamil,
Carbamazepine, Chlorpromazine)
67
Some examples for clinically important inhibitory interaction;
 Cimetidine inhibits microsomal cytochrome P450 and potentiates large number of drugs such
as Propronolol, Theophylline, Warfarin, Phenytoin. Depending on the drug, it inhibit upto
50% of metabolism with doses 2000mg /day.
 Antibiotics, Erythromycin, Metranidazole and number of Sulphonamides are particularly
dangerous as they are enzyme inhibitors and often prescribed for severely ill patents who are
already receiving a number of powerful drugs.
 Quinolone antimicrobials inhibit the isoenzyme of cytochrome P-450 responsible for
metabolism of methylxanthines (E.g. Theophyllin).
 Allopurinol a xanthine oxidase inhibitor substantially increase the concentration of 6-
Mercaptopurine and azothioprine which are metabolized in part by xanthine oxidase.
 Monoamine oxidase inhibitor (MAOI) may impair the metabolism of tricyclic anti
depressants, some sympathomimetics (phenylpropanalamine), Amphetamine, Opioids
(Pethedine) and mercaptopurine.
 Sodium valproate appears to be a non-specific inhibitor and impair the metabolism of
phenytoin, phenobarbitone and primidone.
When an enzyme inhibitor is withdrawn the metabolism of target drug will be increased and the
concentration of the drugs will fall thereby causes a fall in therapeutic effect. But these outcomes
are unpredictable as they depend on;
 The initial concentration of the target drug.
 The extent of inhibition.
 The susceptibility of the patient
 The magnitude of clinical response
Examples of drugs that induce or inhibit drug-metabolizing enzymes
Drug modifying enzyme action Drugs whose metabolism is affected
Enzyme induction
Phenobarbitone and other barbiturates Warfarin
Rifampicin Oral contraceptives
Griseofulvin Corticosteroids
Phenytoin Cyclosporin
Ethanol (as well as drugs listed in left had column)

Enzyme inhibition
Disulfiram Warfarin
Allopurinol Mercaptopurine, azathioprine
Ecothiopate and other anticholinesterases Suxamethonium, procaine, propane
68
Cholramphenicol Phenytoin
Corticosteroids Varoius drugs, e.g. tricyclic antidepressants,
cyclophosphamide
Cimetidine Many drugs, e.g. amiodarone, phenytoin
pethidine
MAO inhibitors Pethidine
Erythromycin Cyclosporin, theophylline
Ciprofloxacin Theophylline

7.3.4. Interaction during drug excretion

Clinically important interaction during the excretion by kidneys can be beneficial or potentially
harmful to the patient. To produce clinically significant effect the target drug must be excreted
unchanged in significantly large amount (i.e. drug must be water soluble) by kidneys. It also
must have narrow therapeutic ratio to produce toxicity.
The main mechanisms by which drugs interfere the rate of renal excretion of the other drugs are;
 Interference with passive diffusion:
By altering the pH of urine by a drug. The excretion of other drugs can be increased or
decreased.
 Interference with tubular secretion:
Weak acids and bases are actively secreted by tubular transport system and drugs compete
with each other for renal excretion
This is the basis of using Probenecid to increase the penicillin and Cephalosporins level. At
the same time Probenecid also potentiate methotrexate toxicity, which is undesirable. Phenyl
butazone enhances the hypoglycaemic effect of chlopropamide in the same way. Other
example for this category are;Methotrexate by aspirin,, Zidovudine by Probenecid, Digoxin
by quinidine. These are potentially harmful interaction.

Examples of drugs that inhibit renal tubular secretion

Drugs causing inhibition Drugs whose t ½ may be affected
Probenecid
Sulphinpyrazone
Phenylbutazone Penicillin
Sulphonamide Axidothymidine
Aspirin Indomethacin
Thiazide diuretics

69
Indomethacin
Verapamil
Amiodarone Digoxin
Quinidine

Diuretics Lithium
Indomethacin Frusemide
Aspirin
Methotrexate
NSAIDs

7.4. PHARMACODYNAMIC INTERACTION

7.4.1. Synergism
It is the most common type of interaction occurring between two drugs that act on the same
system, organ, cell or enzyme. It is clinically useful with the components of oral contraceptives
and cotrimoxazole. But with the drugs that have depressant effect on CNS (E.g. Ethanol,
benzodiazepines, tricyclic antidepressant, antihistamine, phenothiazines, methyldopa, clonidine)
can potentiate each other’s sedative effect, which is undesirable.
All NSAIDs reduce platelet adhesiveness, thereby, potentiating the warfarin anticoagulant.
Theophyllin potentiate -adrenoceptors effects (Eg salbutamol) and cardiac dysrrhythmia may
result.
Calcium antagonist and -blockers if used together may precipitate cardiac failure in susceptible
patients as both have negative inotrophic action.
Potassium supplement can cause dangerous hyperkalaemia with potassium sparing diuretics
(amiloride, spironolactone, ACE inhibitor)

7.4.2. Antagonism
Drugs, which act on the same cellular system, may also antagonize each other’s pharmacological
effect. Most of such interactions are obvious and easily avoided. E.g. Vitamin K and warfarin,
Thiazide diuretics and oral hypoglycaemic agents.
Less predictable antagonistic interaction as abolition of ulcer healing effect of carbenoxolone by
spironolactone, attenuatin of benzodiazepine sedation by theophylline derivatives.
Unexpected interaction also could occur. E.g. Antagonism of antihypertensive effect of thiazides
and -blockers by NSAIDs. This is thought to be due to interference with a local renal
prostaglandin mediated mode of action of antihypertensive agents.

70
7.4.3. Cellular transport system
Some drugs enter the cells by using cellular transport system. Such transport systems can be
inhibited by some other drugs and hence, antagonizes the action of drugs that enter the cell by
these transport systems. E.g. Tricyclic antidepressants and high dose neuroleptic reduce the
access of adrenergic neuron blocking drugs (bethanidine, debrisoquine, quanethidine) to the
nerve endings by blocking amine pump. Pizotifen and maxindol appear to interact with
adrenergic neuron blocking drugs by similar mechanism.

7.4.4. Receptors
Interaction between drugs receptor level can produce beneficial effects as well as unwanted
effects. Beneficial effects are used in the treatment of drug over dose or poisoning. E.g. use of
naloxone for morphine overdose (opioid receptor), atropine for anticolinesterase i.e. insecticide
poisoning (acetyl choline receptor), isopronaline for -blocker overdose.
Unwanted interaction – loss of anti hypertensive effect of  blocker with drugs used for common
cold containing ephedrine, phenyl-propanolamine, phenylephrine.

7.4.5. Fluid and electrolyte imbalance

Diuretics can cause drug interaction in number of ways. Digoxin and potassium ion compete for
the same binding site of Na+ /K+ ATPase, this is why increased diogxin toxicity in hypokalaemia
in patients treated with high dose of diuretics. Similarly a reduction in serum concentration of K+,
during the treatment with diuretics, cortico steroids or amphoteracin will increase the risk of
ventricular arrhythmia with sotolol, quinidine, procainamide and amiodarone.

7.5. INTERACTIONS OUTSIDE THE BODY

Interaction can occur between intravenous fluids and drug that is added to it. Also drugs can
interact with the apparatus used to for administration. E.g. IV nitrates are incompatible with
PVC.

71
8. THERAPEUTIC DRUG MONITORING
After absorption and distribution equilibrium is established between unbound form in the plasma
and that are taken up in the body fluids and tissues. It is assumed that effect is related to the
concentration of the drug at the site of action, which in turn is likely to be related to the plasma
concentration. For many drugs correlation between plasma concentration and effect is better than
that between dose and effect. But plasma concentration is not always measured and such
information is valuable only for drugs which,
 the immediate clinical response is difficult to assess.
 the safe dose range is narrow.
 the serum concentration and therapeutic and /or toxic effects are predictably related.
Measurement of serum drug concentration as a guide to dose adjustment is known as therapeutic
drug monitoring (TDM). As TDM is expensive, it is not done routinely and request should be
made only if the results will facilitate decisions about the drug treatment.

8.1. INDICATION FOR TDM

Treatment ineffective: It can be used to know whether dose is too low and may help to decide
up to what level the dose can be increased without causing unwanted effect.
Toxicity suspected: When symptoms of toxicity is difficult to distinguish from those of
underlying disease. E.g. Digoxin in cardiac failure.
Poor compliance suspected: But this may need serial sampling and at least one sample must be
taken following a period of supervised ingestion.
Pharmacokinetic drug interactions: When two or more drugs are administered concomitantly
and interaction is suspected (need serial measurements). If necessary the drug dosage can be
adjusted.
Drug disease interactions: If liver or kidney functions are impaired and there is a suspicion of
impairment of drug clearance, TDM may help to find out whether the maintenance dose must be
reduced and if so, by how much.

8.2. TIMING THE SAMPLE

Sample for TDM must be taken at correct time in relation to dosage intervals.
 To get the steady state concentration time equivalent to 5 x t½ must be elapsed after
commencement of treatment or changing the dose.
 Sampling earlier will give information if loading dose is given or toxicity is suspected but of
little value in other aspects.
 If t ½ is short the oscillation between doses is more and peak and trough concentrations
should be measured (E.g. Gentamicin t ½ - 2½ hrs.).
72
 For drugs with long t ½ usually best to sample just before a dose is due. (E.g. cyclosporin t½
- 27 hrs).
 If dosing interval is equal to t ½ the typical peak-to-trough drug concentration ration is 2:1.
A sample drawn in the middle of the dosing interval will be a good estimate of steady
concentration if 3 t ½ s have elapsed after starting regular dosing.
 If the t ½ is much longer than the dosing interval, the oscillation of concentration between
doses will be little more than that during continuous infusion and sampling need not to be
accurately timed.
 If dosing interval is more than 4 t ½ of the drug, very little drug will accumulate and peak
concentration is enough to guide the dose adjustment.

However, clinician must decide whether peak or trough or steady state concentration is the best
guide for dose adjustment.
 Peak concentrations occur 1 hour after injections (15min after I.V dose) and 1-2 hours after
oral dose (4-6 hours with sustained release formulations).
 Trough concentration occurs immediately before an injected dose and 10-20 min after oral
dose (during lag time before absorption.).
 Average concentration is best estimated by sampling approximately between two consequent
doses.

8.3. INTERPRETATION OF RESULTS

 Accurate dosing history is important.
 Defined optimum range of plasma concentrations must be known.
 Sampling should be correctly timed.
 Should make sure that patient has taken the drug for sufficient time to reach steady state
concentration (5 x t ½ must be elapsed). E.g. For auto inducers (carbamazepine and
phenytoin) it is better to allow 2-4 weeks to elapse between dose change and plasma
concentration measurement.
 Serum drug concentration should never be interpreted in isolation and the patient’s clinical
condition also must be taken into account. Usually target range lies between lowest effective
concentration and highest safe concentration. But there are patients whose clinical condition
is satisfactory at concentrations outside the stated range.

73
8.4. CORRELATION BETWEEN PLASMA CONCENTRATION AND EFFECT OF DRUG
In certain circumstances measurement of plasma concentration is not worth enough. Here the
correlation between dose and effect is well established and the effect can be quickly and easily
measured.
E.g. Antihypertensives and BP.
Diuretics and body weight.
Oral anticoagulant and prothrombin time
Hypoglycaemics and blood sugar.
Some times plasma concentration may have no correlation with the effect at all. This occurs with
drugs that act irreversibly (hit and run drugs) and their effect will persist long after drug has left
the plasma. They destroy or inactivate the target tissue (receptors or enzymes). Restoration of
effect occurs only after resynthesis, which takes days or weeks. E.g. some MAOI., aspirin on
platelets, some anticholenesterase and anticancer drugs.

Plasma concentration may correlate poorly with effect.

 Inflammatory process: This may mislead where only total concentration of drug in the
plasma is measured. During inflammation acute phase proteins (e.g. acid glycoprotein) will
be elevated and many basic drugs (lignocaine, disopyramide) bind to them. As a result of this
bound form (inactive) is increased but not the free form (active) and the correlation will be
poor if the total concentration is measured. Best correlation can be achieved if free
concentration of the drug in the plasma is measured, but, it is technically difficult and usually
total drug concentration in the plasma is measured.
 Therapeutic window: Sometimes therapeutic effect of a drug declines as the does is increased
beyond and optimum point. E.g. Nortriplytine (amine pump inhibitor) is most effective in
concentrations between 50g -150g/l. Lack of inhibitory effect on amine pump at
concentrations below 50g/l is expected but loss of this inhibitory effect beyond 150g is
unexpected (may be because at high concentration its -adrenoceptor block becomes
effective). It occurs when a drug has more than one actions which depend on the dose used.
The intermediate range in which effective action is obtained is called as therapeutic window.
 Sometimes assessing process may not measure the pharmacologically active metabolite of the
drug (e.g. some benzodiazepines) or only measure the metabolites, which are not
pharmacologically active. In both case the correlation between plasma concentration and
effect is poor.

74
Instances where plasma concentration correlates well with the effect.
There are situations where therapeutic effect is difficult to measure and dosage may be needed to
be monitored accurately by means of plasma concentration in relation to defined optimum range.
They are;
 When desired effect is achieved by suppressing infrequent sporadic events. E.g. epileptic
seizures, episodes of cardiac dysrrhythmias.
 Where there is no quick and reliable assessment of effect (e.g. mood changes in depression)
and where social and environmental factors play a greater role.
 When it is difficult to distinguish that disease is due to lack of efficacy or toxicity. E.g.
Digoxin is used in the treatment of dysrrhythmia at the same time it can cause dysrrhythmia
by itself. Measuring the concentration of drug will help to find whether it is due to too small
or too much drug.
 To reduce adverse effects of drugs when doses are closer to toxic dose. E.g. Ototoxicity with
Aminoglycoside, CNS effects of lithium.
 To check the patient’s compliance when failure of therapy occurs with effective dose.
 While treating drug overdose.

Drugs for which TDM is essential: (Drug with low therapeutic index) Lithium; phenytoin,
aminoglycosides.
Drugs for which TDM is advisable: Theophyllin, carbamazepine.
Drugs for which TDM is sometimes necessary: Digoxin, anticonvulsants other than phenytoin
and carhamazepine (ethusaximide, phenobarbitone, sodium valproate and premidone, which is a
prodrug (here its active metabolite phenobarbitone is measured).

75