ROUTES OF DRUG ADMINISTRATION

Routes can be broadly divided into those for (a)Local action and (b) Systemic action.
LOCAL ROUTES
These routes can only be used for localized lesions at accessible sites and for drugs
whose systemic absorption from these sites is minimal or absent. Thus, high
concentrations are attained at the desired site without exposing the rest of the body.
Systemic side effects or toxicity are consequently absent or minimal. e.g. glyceryl
trinitrate (GTN) applied on the skin as ointment or transdermal patch. The local routes
are:
1. Topical: This refers to external application of the drug to the surface for localized action.
It is often more convenient as well as encouraging to the patient. Drugs can be efficiently
delivered to the localized lesions on skin, oropharyngeal/nasal mucosa, eyes, ear canal,
anal canal or vagina in the form of lotion, ointment, cream, powder, rinse, paints, drops,
spray, lozengens, suppositories or pesseries. Nonabsorbable drugs given orally for
action on g.i. mucosa (sucralfate,vancomycin), inhalation of drugs for action on bronchi
(salbutamol, cromolyn sodium) and irrigating solutions/jellys (povidone iodine, lidocaine)
applied to urethra are other forms of topical medication.
2. Deeper tissues: Certain deep areas can be approached by using a syringe and needle,
but the drug should be such that systemic absorption is slow, e.g. intra-articular injection
(hydrocortisone acetate), infiltration around a nerve or intrathecal injection (lidocaine),
retrobulbar injection (hydrocortisone acetate).
3. Arterial supply: Close intra-arterial injection is used for contrast media in angiography;
anticancer drugs can be infused in femoral or brachial artery to localise the effect for
limb malignancies.
SYSTEMIC ROUTES
The drug administered through systemic
routes is intended to be absorbed into
the blood stream and distributed all over,
including the site of action, through
circulation
1. Oral
Oral ingestion is the oldest and
commonest mode of drug
administration. It is safer, more
convenient, does not need assistance,
noninvasive, often painless, the
medicament need not be sterile and so
is cheaper. Both solid dosage forms
(powders, tablets, capsules, spansules,
dragees, moulded tablets,
 gastrointestinal therapeutic systems—GITs) and liquid dosage forms (elixirs, syrups,
emulsions, mixtures) can be given orally.
2. Sublingual (s.l.) or buccal
The tablet or pellet containing the drug is placed under the tongue or crushed in the
mouth and spread over the buccal mucosa. Only lipid soluble and non-irritating drugs
can be so administered. Absorption is relatively rapid—action can be produced in
minutes. Though it is somewhat inconvenient, one can spit the drug after the desired
effect has been obtained. The chief advantage is that liver is bypassed and drugs with
high first pass metabolism can be absorbed directly into systemic circulation. Drugs
given sublingually are—GTN, buprenorphine, desamino-oxytocin.
3. Rectal
Certain irritant and unpleasant drugs can be put into rectum as suppositories or retention
enema for systemic effect. This route can also be used when the patient is having
recurrent vomiting or is unconscious. However, it is rather inconvenient and
embarrassing; absorption is slower, irregular and often unpredictable. Diazepam,
indomethacin, paraldehyde, ergotamine and few other drugs are some times given
rectally.
4. Inhalation
Volatile liquids and gases are given by inhalation for systemic action, e.g. general
anaesthetics. Absorption takes place from the vast surface of alveoli—action is very
rapid.
5. Nasal
The mucous membrane of the nose can readily absorb many drugs; digestive juices and
liver are bypassed. However, only certain drugs like GnRH agonists and desmopressin
applied as a spray or nebulized solution have been used by this route. This route is being
tried for some other peptide drugs, like insulin.
6. Parenteral
(Par—beyond, enteral—intestinal)
This refers to administration by injection which takes the drug directly into the tissue fluid
or blood without having to cross the intestinal mucosa. The limitations of oral
administration are circumvented.
The important parenteral routes are:
(i) Subcutaneous (s.c.)
(ii) Intramuscular (i.m.)
(iii) Intravenous (i.v.)
(iv) Intradermal injection
PHARMACOKINETICS

ABSORPTION Absorption is movement of the drug from its site of administration into the
circulation. Not only the fraction of the administered dose that gets absorbed, but also the rate
of absorption is important. Other factors affecting absorption are:
Aqueous solubility: Drugs given in solid form must dissolve in the aqueous biophase before
they are absorbed. For poorly water soluble drugs (aspirin, griseofulvin) rate of dissolution
governs rate of absorption. Obviously, a drug given as watery solution is absorbed faster than
when the same is given in solid form or as oily solution.
Concentration: Passive diffusion depends on concentration gradient; drug given as
concentrated solution is absorbed faster than from dilute solution.
Area of absorbing surface: Larger it is, faster is the absorption.
Vascularity of the absorbing surface: Blood circulation removes the drug from the site of
absorption and maintains the concentration gradient across the absorbing surface. Increased
blood flow hastens drug absorption just as wind hastens drying of clothes.
Route of administration: This affects drug absorption, because each route has its own
peculiarities
BIOAVAILABILITY It is a measure of the fraction (F ) of administered dose of a drug that
reaches the systemic circulation in the unchanged form. Bioavailability of drug injected i.v. is
100%, but is frequently lower after oral ingestion because— (a) the drug may be incompletely
absorbed. (b) the absorbed drug may undergo first pass metabolism in the intestinal wall/liver
or be excreted in bile.
DISTRIBUTION Once a drug has gained access to the blood stream, it gets distributed to
other tissues that initially had no drug, concentration gradient being in the direction of plasma
to tissues. The extent of distribution of a drug depends on its lipid solubility, ionization at
physiological pH (a function of its pKa), extent of binding to plasma and tissue proteins,
presence of tissue-specific transporters and differences in regional blood flow.
Plasma protein binding: Most drugs possess physicochemical affinity for plasma proteins.
Acidic drugs generally bind to plasma albumin and basic drugs to α1 acid glycoprotein. Binding
to albumin is quantitatively more important. for example the binding percentage of some
benzodiazepines is: Flurazepam 10% Alprazolam 70% Lorazepam 90% Diazepam 99%
Passage across placenta: Placental membranes are lipoidal and allow free passage of
lipophilic drugs, while restricting hydrophilic drugs.
Penetration into brain and CSF: The capillary endothelial cells in brain have tight junctions and
lack large intercellular pores. Further, an investment of neural tissue (Fig. 2.8B) covers the
capillaries. Together they constitute the so called blood-brain barrier. these barriers are lipoidal
and limit the entry of nonlipid-soluble drugs, e.g. streptomycin, neostigmine, etc. Only lipid-
soluble drugs, therefore, are able to penetrate and have action on the central nervous system.

BIOTRANSFORMATION (Metabolism) Biotransformation means chemical alteration

of the drug in the body. It is needed to render nonpolar (lipid-soluble) compounds polar (lipid
soluble) so that they are not reabsorbed in the renal tubules and are excreted. The primary
site for drug metabolism is liver; others are—kidney, intestine, lungs and plasma.
Biotransformation reactions can be classified into: (a) Nonsynthetic/Phase I/Functionalization
reactions: a functional group is generated or exposed—metabolite may be active or inactive.
(b) Synthetic/Conjugation/ Phase II reactions— metabolite is mostly inactive; except few
drugs, e.g. glucuronide conjugate of morphine and sulfate conjugate of minoxidil are active.
Nonsynthetic reactions
(i) Oxidation: This reaction involves addition of oxygen/negatively charged radical or removal
of hydrogen/positively charged radical. Oxidations are the most important drug metabolizing
reactions. Various oxidation reactions are: hydroxylation; oxygenation at C, N or S atoms; N
or O-dealkylation, oxidative deamination, etc.
(ii) Reduction: This reaction is the converse of oxidation and involves cytochrome P-450
enzymes working in the opposite direction. Alcohols, aldehydes, quinones are reduced. Drugs
primarily reduced are chloralhydrate, chloramphenicol, halothane, warfarin.
(iii) Hydrolysis: This is cleavage of drug molecule by taking up a molecule of water. esterase
Ester + H2O ————→Acid + Alcohol Similarly, amides and polypeptides are hydrolysed by
amidases and peptidases.
(iv) Cyclization: This is formation of ring structure from a straight chain compound, e.g.
proguanil.
(v) Decyclization: This is opening up of ring structure of the cyclic drug molecule, e.g.
barbiturates, phenytoin. This is generally a minor pathway.
Synthetic reactions
(i) Glucuronide conjugation: This is the most important synthetic reaction carriedout by a group
of UDP-glucuronosyl transferases (UGTs). Compounds with a hydroxyl or carboxylic acid
group are easily conjugated with glucuronic acid which is derived from glucose. Examples
are— chloramphenicol, aspirin, paracetamol, lorazepam, morphine, metronidazole.
(ii) Acetylation: Compounds having amino or hydrazine residues are conjugated with the help
of acetyl coenzyme-A, e.g. sulfonamides, isoniazid, PAS, hydralazine, clonazepam,
procainamide. Multiple genes control the N-acetyl transferases (NATs), and rate of acetylation
shows genetic polymorphism (slow and fast acetylators).
(iii) Methylation: The amines and phenols can be methylated; methionine and cysteine acting
as methyl donors, e.g. adrenaline, histamine, nicotinic acid, methyldopa, captopril,
mecarptopurine.
(iv) Sulfate conjugation: The phenolic compounds and steroids are sulfated by
sulfotransferases (SULTs), e.g. chloramphenicol, methyldopa, adrenal and sex steroids.
(v) Glycine conjugation: Salicylates and other drugs having carboxylic acid group are
conjugated with glycine, but this is not a major pathway of metabolism.
(vi) Glutathione conjugation: Forming a mercapturate is normally a minor pathway. However,
it serves to inactivate highly reactive quinone or epoxide intermediates formed during
metabolism of certain drugs, e.g. paracetamol. When large amount of such intermediates are
formed (in poisoning or after enzyme induction), glutathione supply falls short—toxic adducts
are formed with tissue constituents → tissue damage.
(vii) Ribonucleoside/nucleotide synthesis: This pathway is important for the activation of many
purine and pyrimidine antimetabolites used in cancer chemotherapy.
FIRST PASS (PRESYSTEMIC) METABOLISM This refers to metabolism of a drug during its
passage from the site of absorption into the systemic circulation. All orally administered drugs
are exposed to drug metabolizing enzymes in the intestinal wall and liver (where they first
reach through the portal vein). Presystemic metabolism of limited magnitude can also occur
in the skin (transdermally administered drug) and in lungs (for drug reaching venous blood
through any route). The extent of first pass metabolism differs for different drugs (Table 3.1)
and is an important determinant of oral bioavailability.

EXCRETION Excretion is the passage out of systemically absorbed drug. Drugs and their
metabolites are excreted in:
1. Urine: Through the kidney. It is the most important channel of excretion for majority of
drugs.
2. Faeces: Apart from the unabsorbed fraction, most of the drug present in faeces is
derived from bile.
3. Exhaled air: Gases and volatile liquids (general anaesthetics, paraldehyde, alcohol)
are eliminated by lungs, irrespective of their lipid solubility.
4. Saliva and sweat: These are of minor importance for drug excretion. Lithium, pot.
iodide, rifampin and heavy metals are present in these secretions in significant
amounts.
5. Milk: The excretion of drug in milk is not important for the mother, but the suckling infant
inadvertently receives the drug. Most drugs enter breast milk by passive diffusion.

KINETICS OF ELIMINATION
Clearance (CL) The clearance of a drug is the theoretical volume of plasma from which
the drug is completely removed in unit time.
For majority of drugs the processes involved in elimination are not saturated over the
clinically obtained concentrations, they follow:
First order (exponential) kinetics The rate of elimination is directly proportional to the
drug concentration, CL remains constant; or a constant fraction of the drug present in
the body is eliminated in unit time. Few drugs, however, saturate eliminating
mechanisms and are handled by—
Zero order (linear) kinetics The rate of elimination remains constant irrespective of drug
concentration, CL decreases with increase in concentration; or a constant amount of
the drug is eliminated in unit time, e.g. ethyl alcohol. The elimination of some drugs
approaches saturation over the therapeutic range, kinetics changes from first order to
zero order at higher doses. As a result plasma concentration increases
disproportionately with increase in dose, (See Fig. 3.5) as occurs in case of phenytoin,
tolbutamide, theophylline, warfarin.

AGONIST AND ANTAGONIST

AGONIST – Derived from a Latin word – contender.

Aids in the enhancement of an action. Drugs that bind to physiological receptors and
mimic the regulatory effects of the endogenous signaling compounds are termed
agonists. Ligands that activate a receptor to produce to produce a biological response
are called agonists. There a several types of agonists,
(i) Endogenous agonist: Naturally present in the body and bind to and activate the
receptor
(ii) Super agonist: Capable of binding to the receptor and producing a greater
maximal response than the endogenous agonist.
(iii) Full agonist: The ligands that increase the activity of the receptors and produce
the maximal response. Eg., Morphine, mimics the action of endorphins at opioid
receptors.
(iv) Partial agonist: These ligands partially increase the activity of the receptors but
do not produce the maximal response like full agonist even when present in
 excess amount. Eg., Busspirone, is an antioxylytic drugs, used to treat anxiety
disorder
(v) Inverse agonist: The ligands which decrease the activity of an active receptors
to their inactive state. Eg., Flumazenil drugs acts as an inverse agonist for the
GABA receptor and produce anxiogenic effect.
(vi) Irreversible agonist: Binds and activates the receptor but the binding is
permanent so, this happens only once and the receptor is essentially
destroyed.

ANTAGONIST - Derived from Latin and Greek words- Competitor or opponent.

Opposes the action of agonist and block the reception. Ligands block agonist mediated
responses are called antagonists.
Antagonists bind to receptors but do not activate them. They possess affinity but lack
efficacy.
Depending on the mechanism involved, antagonism may be:
(a) Physical antagonism Based on the physical property of the drugs, e.g.
charcoal adsorbs alkaloids and can prevent their absorption—used in
alkaloidal poisonings.
(b) Chemical antagonism The two drugs react chemically and form an inactive
product, e.g. • KMnO4 oxidizes alkaloids—used for gastric lavage in
poisoning. • Tannins + alkaloids—insoluble alkaloidal tannate is formed. •
Chelating agents (BAL, Cal. disod. edetate) complex toxic metals (As, Pb).
• Nitrites form methaemoglobin which reacts with cyanide radical.
(c) Physiological/functional antagonism The two drugs act on different
receptors or by different mechanisms, but have opposite overt effects on
the same physiological function, i.e. have pharmacological effects in
opposite direction, e.g. • Histamine and adrenaline on bronchial muscles
and BP. • Hydrochlorothiazide and triamterene on urinary K+ excretion. •
Glucagon and insulin on blood sugar level.
(d) Receptor antagonism One drug (antagonist) blocks the receptor action of
the other (agonist). This is a very important mechanism of drug action,
because physiological signal molecules act through their receptors,
blockade of which can produce specific and often profound
pharmacological effects. Receptor antagonists are selective (relatively), i.e.
an anticholinergic will oppose contraction of intestinal smooth muscle
induced by cholinergic agonists, but not that induced by histamine or 5-HT
(they act through a different set of receptors). Receptor antagonism can be
competitive or noncompetitive.

Competitive antagonism (equilibrium type) The antagonist is chemically similar to the

agonist, competes with it and binds to the same site to the exclusion of the agonist
molecules. Because the antagonist has affinity but no intrinsic activity, no response is
produced and the log DRC of the agonist is shifted to the right. Since antagonist binding
is reversible and depends on the relative concentration of the agonist and antagonist
molecules, higher concentration of the agonist progressively overcomes the block—a
parallel shift of the agonist DRC with no suppression of maximal response is obtained.
The extent of shift is dependent on the affinity and concentration of the antagonist. A
partial agonist, having affinity for the same receptor, also competes with and
antagonizes a full agonist, while producing a submaximal response of its own.

Noncompetitive antagonism The antagonist is chemically unrelated to the agonist,

binds to a different allosteric site altering the receptor in such a way that it is unable to
combine with the agonist, or unable to transduce the response, so that the downstream
chain of events are uncoupled. Because the agonist and the antagonist are combining
with different sites, there is no competition between them—even high agonist
concentration is unable to reverse the block completely. Increasing concentrations of
the antagonist progressively flatten the agonist DRC. Noncompetitive antagonists have
been produced experimentally, but are not in clinical use.

Nonequilibrium (competitive) antagonism Certain antagonists bind to the receptor with

strong (covalent) bonds or dissociate from it slowly so that agonist molecules are
unable to reduce receptor occupancy of the antagonist molecules— law of mass action
cannot apply—an irreversible or nonequilibrium antagonism is produced.

RECEPTOR CLASSIFICATION

1. G-protein coupled receptors (GPCR) These are a large family of cell membrane
receptors which are linked to the effector (enzyme/ channel/carrier protein) through
one or more GTP-activated proteins (G-proteins) for response effectuation. All such
receptors have a common pattern of structural organization. The molecule has 7 α-
helical membrane spanning hydrophobic amino acid (AA) segments which run into 3
extracellular and 3 intracellular loops.
A number of G proteins distinguished by their α subunits have been described. The
important ones with their action on the effector are: Gs : Adenylyl cyclase ↑, Ca2+
channel ↑ Gi : Adenylyl cyclase ↓, K+ channel ↑ Go : Ca2+ channel ↓ Gq :
Phospholipase C ↑ G13 : Na+/H+ exchange ↑

2. Receptors with intrinsic ion channel These cell surface receptors, also called ligand
gated ion channels, enclose ion selective channels (for Na+, K+, Ca2+ or Cl¯) within
their molecules. Agonist binding opens the channel and causes
depolarization/hyperpolarization/ changes in cytosolic ionic composition, depending on
the ion that flows through. The nicotinic cholinergic, GABA-A, glycine (inhibitory),
excitatory AA (kainate, NMDA or N-methylD-aspartate, quisqualate) and 5HT3
receptors fall in this category.

3. Enzyme-linked receptors This class of receptors have a subunit with enzymatic

property or bind a JAK (Janus-Kinase) enzyme on activation. The agonist binding site
and the catalytic site lie respectively on the outer and inner face of the plasma
membrane. These two domains are interconnected through a single transmembrane
stretch of peptide chain. There are two major subgroups of such receptors. a. Those
that have intrinsic enzymatic activity. b. Those that lack intrinsic enzymatic activity, but
bind a JAK-STAT kinase on activation.

4. Receptors regulating gene expression (Transcription factors) In contrast to the

above 3 classes of receptors, these are intracellular (cytoplasmic or nuclear) soluble
proteins which respond to lipid soluble chemical messengers that penetrate the cell.
The receptor protein (specific for each hormone/ regulator) is inherently capable of
binding to specific genes, but is kept inhibited till the hormone binds near its carboxy
terminus and exposes the DNA binding regulatory segment located in the middle of the
molecule.

DRUG-RECEPTOR THEORIES

1. Occupancy Theory The occupancy theory of Gaddum and Clark states that the
intensity of the pharmacological effect is directly proportional to the number of
receptors occupied by the drug. Maximal response occurs when all the receptors are
occupied. D + R ↔ DR ⇒RESPONSE The concept of drug–receptor interactions
involve two stages: first, there is a complexation of the drug with the receptor, which
termed the affinity; second, there is an initiation of a biological effect, which termed the
intrinsic activity and the efficacy.
Affinity, is a measure of the capacity of a drug to bind to the receptor. Intrinsic activity
(α) or Efficacy is the property of a compound that produces the maximum response or
the ability of the drug– receptor complex to initiate a response. Examples of affinity and
efficacy are given in Figure 1A shows the theoretical dose–response curves for five
drugs with the same affinity for the receptor (pKd = 8), but having efficacies varying
from 100% of the maximum to 20% of the maximum. The drug with 100% efficacy is a
full agonist; the others are partial agonists.
Antagonists can bind tightly to a receptor (great affinity), but be devoid of activity (no
efficacy). A compound that is an agonist for one receptor may be an antagonist or
inverse agonist for another receptor. The response ceases when the drug–receptor
 complex dissociates. However, not all agonists produce a maximal response. Does not
rationalize how two drugs can occupy the same receptor and act differently.

2. Rate theory The response is proportional to the rate of drug-Receptor complex

formation. Effect is produced by the drug molecules based on the rates of association
and dissociation of drugs to and from the receptors. As an alternative to the occupancy
theory, Paton proposed that the activation of receptors is proportional to the total number
of encounters of the drug with its receptor per unit time. Therefore, the rate theory
suggests that the pharmacological activity is a function of the rate of association and
dissociation of the drug with the receptor and not the number of occupied receptors.
Each association would produce a quantum of stimulus. In the case of agonists, the
rates of both association and dissociation would be fast. The rate of association of an
antagonist with a receptor would be fast, but the dissociation would be slow. Partial
agonists would have intermediate drug–receptor complex dissociation rates.

3. Induced-Fit Theory The induced-fit theory of Koshland was originally proposed for the
action of substrates with enzymes, but it could apply to drug–receptor interactions as
well. According to this theory, the receptor need not necessarily exist in the appropriate
conformation required to bind the drug. As the drug approaches the receptor, a
conformational change is induced, which orients the essential binding sites. The
conformational change in the receptor could be responsible for the initiation of the
biological response (movement of residues to interact with the substrate). The receptor
(enzyme) was suggested to be elastic, and could return to its original conformation after
the drug (product) was released. The conformational change need not occur only in the
receptor (enzyme), the drug (substrate) also could undergo deformation, even if this
resulted in strain in the drug (substrate). According to this theory, an agonist would
induce a conformational change and elicit a response, an antagonist would bind without
a conformational change, and a partial agonist would cause a partial conformational
change. The induced- fit theory can be adapted to the rate theory. An agonist would
induce a conformational change in the receptor, resulting in a conformation to which the
agonist binds less tightly and from which it can dissociate more easily. If drug–receptor
complexation does not cause a conformational change in the receptor, then the drug–
receptor complex will be stable, and an antagonist will result.

4. Macromolecular Perturbation Theory 10 Having considered the conformational

flexibility of receptors, Belleau suggested that in the interaction of a drug with a receptor
two general types of macromolecular perturbations could result: A specific
conformational perturbation makes possible the binding of certain molecules that
produce a biological response (an agonist) A non- specific conformational perturbation
accommodates other types of molecules that do not elicit a response (e.g., an
antagonist). If the drug contributes to both macromolecular perturbations, a mixture of
two complexes will result (a partial agonist). This theory offers a physicochemical basis
for the rationalization of molecular phenomena that involve receptors, but does not
address the concept of inverse agonism.

5. Activation–Aggregation Theory According to this theory, even in the absence of drugs,

a receptor is in a state of dynamic equilibrium between an activated form (Ro ), which is
responsible for the biological response, and an inactive form (To ). Using this theory,
agonists bind to the Ro form and shift the equilibrium to the activated form, antagonists
bind to the inactive form (To ), and partial agonists bind to both conformations. In this
model, the agonist binding site in the Roconformation can be different from the
antagonist binding site in the To conformation.

6. The Two-State (Multistate) Model of Receptor Activation Was developed on the basis
of the kinetics of competitive and allosteric inhibition as well as through interpretation of
the results of direct binding experiments. It postulates that a receptor, regardless of the
presence or absence of a ligand, exists in two distinct states: the R (relaxed, active or
on) and T (Tense, inactive or off) states, which are in equilibrium with each other. In the
absence of the natural ligand or agonist, receptors exist in equilibrium (defined by
equilibrium constant L; Figure 4) between an active state (R*), which is able to initiate a
 biological response, and a resting state (R), which cannot In the absence of a natural
ligand or agonist, the equilibrium between R* and R defines the basal activity of the
receptor. 14 A drug can bind to one or both of these conformational states, according to
equilibrium constants Kd and K* d for formation of the drug– receptor complex with the
resting (D•R) and active (D•R*) states, respectively. Full agonists bind only to R* Partial
agonists bind preferentially to R* Full inverse agonists bind only to R Partial inverse
agonists bind preferentially to R Antagonists have equal affinities for both R and R* (no
effect on basal activity)

G-PROTEIN COUPLED RECEPTOR

These are a large family of cell membrane receptors which are linked to the effector (enzyme/
channel/carrier protein) through one or more GTP-activated proteins (G-proteins) for response
effectuation. All such receptors have a common pattern of structural organization (Fig. 4.5).
The molecule has 7 α-helical membrane spanning hydrophobic amino acid (AA) segments
which run into 3 extracellular and 3 intracellular loops. The agonist binding site is located
somewhere between the helices on the extracellular face, while another recognition site
formed by cytosolic segments binds the coupling G-protein. The Gproteins float in the
membrane with their exposed domain lying in the cytosol, and are heterotrimeric in
composition (α, β and γ subunits). In the inactive state GDP is bound to their exposed domain;
activation through the receptor leads to displacement of GDP by GTP. The active αsubunit
carrying GTP dissociates from the other two subunits and either activates or inhibits the
effector. The βγ subunits have also been shown to modulate certain effectors like
receptoroperated K+ channels, adenylylcyclase (AC) and phospholipase C.
A number of G proteins distinguished by their α subunits have been described. The important
ones with their action on the effector are: Gs : Adenylyl cyclase ↑, Ca2+ channel ↑ Gi : Adenylyl
cyclase ↓, K+ channel ↑ Go : Ca2+ channel ↓ Gq : Phospholipase C ↑ G13 : Na+/H+ exchange
↑ In addition Gn, Gk, Gt and Golf have been distinguished. A limited number of G-proteins are
shared between different receptors and one receptor can utilize more than one G-protein
(agonist pleotropy), e.g. the following couplers have been associated with different receptors.
There are three major effector pathways through which GPCRs function.
(a) Adenylyl cyclase: cAMP pathway Activation of AC results in intracellular accumulation
of second messenger cAMP (Fig. 4.6) which functions mainly through cAMP-
dependent protein kinase (PKA). The PKA phosphorylates and alters the function of
many enzymes, ion channels, transporters and structural proteins to manifest as
increased contractility/impulse generation (heart), relaxation (smooth muscle),
glycogenolysis, lipolysis, inhibition of secretion/mediator release, modulation of
junctional transmission, hormone synthesis, etc. In addition, cAMP directly opens a
specific type of membrane Ca2+ channel called cyclic nucleotide gated channel (CNG)
in the heart, brain and kidney. Responses opposite to the above are produced when
AC is inhibited through inhibitory Gi-protein.
(b) Phospholipase C: IP3-DAG pathway Activation of phospholipase C (PLc) hydrolyses
the membrane phospholipid phosphatidyl inositol 4, 5-bisphosphate (PIP2) to generate
the second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).
The IP3 mobilises Ca2+ from intracellular organellar depots and DAG enhances
protein kinase C (PKc) activation by Ca2+. Cytosolic Ca2+ (third messenger in this
setting) is a highly versatile regulator acting through calmodulin (CAM), PKc and other
effectors—mediates/modulates contraction, secretion/transmitter release, eicosanoid
synthesis, neuronal excitability, intracellular movements, membrane function,
metabolism, cell proliferation, etc. Like AC, the PLc can also be inhibited through
inhibitory G-protein when directionally opposite responses would be expected.

(c) Channel regulation The activated G-proteins can also open or close ionic channels
specific for Ca2+, K+ or Na+, without the intervention of any second messenger like
cAMP or IP3, and bring about hyperpolarization/depolarization/ changes in intracellular
Ca2+. The Gs opens Ca2+ channels in myocardium and skeletal muscles, while Gi
and Go open K+ channels in heart and smooth muscle as well as close neuronal Ca2+
channels. Physiological responses like changes in inotropy, chronotropy, transmitter
release, neuronal activity and smooth muscle relaxation follow.
ADVERSE DRUG REACTIONS
Adverse effect is ‘any undesirable or unintended consequence of drug administration’. It is a
broad term, includes all kinds of noxious effect—trivial, serious or even fatal.
Adverse effects may develop promptly or only after prolonged medication or even after
stoppage of the drug. Adverse effects are not rare; an incidence of 10–25% has been
documented in different clinical settings. They are more common with multiple drug therapy
and in the elderly. Adverse effects have been classified in many ways.
 Type A (Augmented) Reactions which can be predicted from the known pharmacology
of the drug, dose dependent, can be alleviated by a dose reduction. EG.,
Anticoagulants might cause bleeding.
 Type B (Bizzare) Cannot be predicted from the pharmacology of the drug, not dose
dependent, host dependent factors important in prescription. EG., Penicillin may cause
anaphylaxis.
 Type C (Chemical) Biological characteristics can be predicted from the chemical
structure of the drug/metabolite. EG., Paracetamol - Hepatotoxicity
 Type D (Delayed) Occur after many years of treatment. Can be due to accumulation.
EG., Chemotherapy – secondary tumours
 Type E (Exit/End of treatment) Occur on withdrawal especially when the drugb is
stopped abruptly. EG., Phenytoin withdrawal - seizures
 Type F (Failure of treatment) Common to all, often caused by drug interactions.
 Type G (Genotoxicity)
 Type H (Hypersensitivity)
 Type U (Unclassified)

Predisposing factors of ADR

1. Polypharmacy: Multiple drug therapy-more prone to develop ADR. Either due to

interaction mechanism or by synergistic effect
2. Multiple and inter-current diseases: Multiple diseases are at increased risk of
developing an ADR. Patient with renal and hepatic diseases are also at high risk. EG.,
Patient with decreased renal function treated with normal dose of aminoglycosides is
at risk of developing nephrotoxicity until dose adjustment.
3. Age: Elderly and paediatric patients are more vulnerable to ADR. Elderly patient are
more susceptible due to physiological changes. EG., Nitrates and ACEI induced
postural hypotension in an elderly patient, grey baby syndrome with chloramphenicol
in children.
4. Drug characteristics: Some drugs are toxic in nature and patients with those agents
are at increased risk of ADRs. EG., Nausea and vomiting with cytotoxic anticancer
drugs. Patients treated with narrow therapeutic index drugs are more at risks.
5. Gender: Women are reported to be more susceptible to ADRs than men. EG.,
Chloramphenicol induced aplastic anemia and phenylbutazone induced
agranulocytosis are twice and thrice as common in women as in men respectively.
6. Race and genetic factors: More prone to ADRs in genetically predisposed individuals.
EG., Patients with G6PD deficiency are at higher risk of developing haemolysis due to
primaquine.