The Local Route of Drug Administration: Revisiting an Overlooked Gateway in Pharmacology
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Routes of Drug Administration — Focus on Local Routes | Pharmacology Chapter Extract
Author: Baasir Umair Khattak (MPhil Pharmacology, QAU)
Description:
Pharmacological traditions have long struggled to classify routes of drug administration, yet no single framework has captured their full compl...
Slide Content
General Pharmacology Section-1 Drug
166 BAASIR UMAIR (MPhil in Pharmacology)
Chapter 6: Routes of Drug Administration
6.1 Introduction:
In pharmacotherapy, few choices are as consequential as the route of administration. This decision
dictates the fraction of the drug that reaches systemic circulation, determines the onset, intensity,
and duration of action, and shapes the balance between efficacy and toxicity. The same active
compound may behave as a safe therapeutic agent in one route yet produce intolerable adverse
effects through another—underscoring the clinical weight of this fundamental choice.
In pharmacology, the route of administration refers to the pathway by which a drug is delivered
into the body to achieve its intended site of action. This pathway governs how the drug is absorbed,
distributed, metabolized, and eliminated, and whether its primary effect is local or systemic. The
route, therefore, is not simply a procedural choice but a mechanistic determinant of both
pharmacokinetic behavior and pharmacodynamic outcomes.
Selection of a particular Route:
A complex interplay of factors determines the route of drug administration:
Pharmacological requirements:
Rapid onset in emergencies (e.g., IV adrenaline in anaphylaxis).
Sustained release in chronic diseases (e.g., transdermal fentanyl patch).
Localized action to minimize systemic exposure (e.g., topical steroids in eczema).
Drug properties:
Physicochemical stability, lipid solubility, ionization, and molecular size.
Susceptibility to first-pass metabolism (oral vs. parenteral/novel delivery).
Formulation feasibility (e.g., depot injections, nanoparticle carriers).
Patient factors:
Age, level of consciousness, swallowing ability, comorbidities.
Tolerance for invasive procedures/injections.
Adherence considerations (e.g., rectal diazepam in children, patches for elderly).
Healthcare setting:
Availability of trained personnel and sterile facilities.
Urgency and practicality (oral vs. IV in emergencies).
Institutional protocols and infrastructure.
Pharmacoeconomic considerations:
Cost-effectiveness, affordability, and accessibility.
Insurance/reimbursement coverage.
Resource-limited settings favor oral over expensive injectables.
Physician/clinical judgment:
Physician’s training, familiarity, and comfort with a route.
Risk–benefit evaluation tailored to patient population.
166 BAASIR UMAIR (MPhil in Pharmacology)
Chapter 6: Routes of Drug Administration
6.1 Introduction:
In pharmacotherapy, few choices are as consequential as the route of administration. This decision
dictates the fraction of the drug that reaches systemic circulation, determines the onset, intensity,
and duration of action, and shapes the balance between efficacy and toxicity. The same active
compound may behave as a safe therapeutic agent in one route yet produce intolerable adverse
effects through another—underscoring the clinical weight of this fundamental choice.
In pharmacology, the route of administration refers to the pathway by which a drug is delivered
into the body to achieve its intended site of action. This pathway governs how the drug is absorbed,
distributed, metabolized, and eliminated, and whether its primary effect is local or systemic. The
route, therefore, is not simply a procedural choice but a mechanistic determinant of both
pharmacokinetic behavior and pharmacodynamic outcomes.
Selection of a particular Route:
A complex interplay of factors determines the route of drug administration:
Pharmacological requirements:
Rapid onset in emergencies (e.g., IV adrenaline in anaphylaxis).
Sustained release in chronic diseases (e.g., transdermal fentanyl patch).
Localized action to minimize systemic exposure (e.g., topical steroids in eczema).
Drug properties:
Physicochemical stability, lipid solubility, ionization, and molecular size.
Susceptibility to first-pass metabolism (oral vs. parenteral/novel delivery).
Formulation feasibility (e.g., depot injections, nanoparticle carriers).
Patient factors:
Age, level of consciousness, swallowing ability, comorbidities.
Tolerance for invasive procedures/injections.
Adherence considerations (e.g., rectal diazepam in children, patches for elderly).
Healthcare setting:
Availability of trained personnel and sterile facilities.
Urgency and practicality (oral vs. IV in emergencies).
Institutional protocols and infrastructure.
Pharmacoeconomic considerations:
Cost-effectiveness, affordability, and accessibility.
Insurance/reimbursement coverage.
Resource-limited settings favor oral over expensive injectables.
Physician/clinical judgment:
Physician’s training, familiarity, and comfort with a route.
Risk–benefit evaluation tailored to patient population.
General Pharmacology Section-1 Drug
167 BAASIR UMAIR (MPhil in Pharmacology)
Influence of guidelines and evidence-based practice.
Cultural and ethical acceptance:
Some patients refuse rectal, vaginal, or injectable routes.
Religious or cultural beliefs may limit certain formulations.
Technological availability:
Novel devices (vaginal rings, microneedle patches, auto-injectors).
Controlled-release implants and inhaler innovations.
Pharmacokinetic aspects influenced by the route of administration:
1. Bioavailability (BA)
The fraction of unchanged drug reaching systemic circulation depends heavily on the route.
Example: IV → 100% BA; oral propranolol → reduced BA due to first-pass metabolism.
2. First-pass metabolism (FPM)
Drugs given orally undergo gut wall and hepatic metabolism before reaching circulation.
Routes such as sublingual, transdermal, parenteral, rectal (lower), inhalational, avoid or
reduce FPM.
Example: Sublingual nitroglycerin bypasses FPM; oral nitroglycerin is ineffective.
3. Rate of absorption (onset of action)
IV → immediate plasma levels; inhalational → very rapid pulmonary absorption;
oral/rectal → slower and variable.
Example: IV diazepam acts within seconds vs. oral, requiring ~30–60 min.
4. Extent of absorption
Physicochemical properties (lipid solubility, ionization, molecular size, stability) interact
with the route to determine how much drug enters systemic circulation.
Example: Neostigmine (charged, hydrophilic) is poorly absorbed orally vs. physostigmine
(lipophilic), which has better absorption.
5. Variability of absorption
GI pH, motility, food interactions, and formulation differences introduce variability with
oral/rectal routes.
Example: Digoxin tablets historically showed wide variability in BA; IV digoxin avoids
this.
6. Distribution pattern influenced by route
Some routes allow drug to reach compartments directly without equilibration.
Example: Intrathecal methotrexate → high CNS levels not achievable by systemic
administration.
7. Duration of action (linked to absorption kinetics)
Routes that allow depot formation or controlled absorption prolong exposure.
Example: IM depot antipsychotics; transdermal fentanyl with slow, sustained release.
167 BAASIR UMAIR (MPhil in Pharmacology)
Influence of guidelines and evidence-based practice.
Cultural and ethical acceptance:
Some patients refuse rectal, vaginal, or injectable routes.
Religious or cultural beliefs may limit certain formulations.
Technological availability:
Novel devices (vaginal rings, microneedle patches, auto-injectors).
Controlled-release implants and inhaler innovations.
Pharmacokinetic aspects influenced by the route of administration:
1. Bioavailability (BA)
The fraction of unchanged drug reaching systemic circulation depends heavily on the route.
Example: IV → 100% BA; oral propranolol → reduced BA due to first-pass metabolism.
2. First-pass metabolism (FPM)
Drugs given orally undergo gut wall and hepatic metabolism before reaching circulation.
Routes such as sublingual, transdermal, parenteral, rectal (lower), inhalational, avoid or
reduce FPM.
Example: Sublingual nitroglycerin bypasses FPM; oral nitroglycerin is ineffective.
3. Rate of absorption (onset of action)
IV → immediate plasma levels; inhalational → very rapid pulmonary absorption;
oral/rectal → slower and variable.
Example: IV diazepam acts within seconds vs. oral, requiring ~30–60 min.
4. Extent of absorption
Physicochemical properties (lipid solubility, ionization, molecular size, stability) interact
with the route to determine how much drug enters systemic circulation.
Example: Neostigmine (charged, hydrophilic) is poorly absorbed orally vs. physostigmine
(lipophilic), which has better absorption.
5. Variability of absorption
GI pH, motility, food interactions, and formulation differences introduce variability with
oral/rectal routes.
Example: Digoxin tablets historically showed wide variability in BA; IV digoxin avoids
this.
6. Distribution pattern influenced by route
Some routes allow drug to reach compartments directly without equilibration.
Example: Intrathecal methotrexate → high CNS levels not achievable by systemic
administration.
7. Duration of action (linked to absorption kinetics)
Routes that allow depot formation or controlled absorption prolong exposure.
Example: IM depot antipsychotics; transdermal fentanyl with slow, sustained release.
General Pharmacology Section-1 Drug
168 BAASIR UMAIR (MPhil in Pharmacology)
8. Elimination kinetics are indirectly shaped by the route
Higher Cmax from rapid routes (IV, inhalational) may saturate metabolism/excretion
differently than slower routes.
Example: Theophylline IV infusion requires careful rate control to avoid accumulation,
unlike oral sustained-release formulations.
Pharmacodynamic and Clinical Implications:
The route of administration influences pharmacodynamics by dictating the rate and extent of drug-
receptor interaction, which in turn determines the magnitude, onset, and duration of effect. Rapid
routes such as intravenous injections produce an immediate rise in plasma concentration, leading
to near-instant receptor occupancy and maximal effect, making them indispensable in emergencies
like anaphylaxis or cardiac arrest. In contrast, oral or transdermal delivery generates slower, lower
peaks that engage receptors more gradually, favoring sustained but less intense responses for
chronic therapy. Localized routes, such as intranasal, inhalational, intra-articular, or topical
application, concentrate the drug at or near the target tissue, enhancing receptor-specific effects
while reducing systemic exposure and minimizing unwanted pharmacodynamic interactions at off-
target sites. Clinically, these mechanistic differences guide therapeutic choices: for instance,
inhaled β₂-agonists exploit high receptor density in bronchial smooth muscle for rapid
bronchodilation with limited cardiac stimulation, whereas systemic administration would activate
β-receptors broadly and increase adverse effects. Thus, the route determines not only how much
drug reaches the receptors, but also which receptor populations are preferentially engaged, directly
linking administration strategy to therapeutic efficacy and safety.
168 BAASIR UMAIR (MPhil in Pharmacology)
8. Elimination kinetics are indirectly shaped by the route
Higher Cmax from rapid routes (IV, inhalational) may saturate metabolism/excretion
differently than slower routes.
Example: Theophylline IV infusion requires careful rate control to avoid accumulation,
unlike oral sustained-release formulations.
Pharmacodynamic and Clinical Implications:
The route of administration influences pharmacodynamics by dictating the rate and extent of drug-
receptor interaction, which in turn determines the magnitude, onset, and duration of effect. Rapid
routes such as intravenous injections produce an immediate rise in plasma concentration, leading
to near-instant receptor occupancy and maximal effect, making them indispensable in emergencies
like anaphylaxis or cardiac arrest. In contrast, oral or transdermal delivery generates slower, lower
peaks that engage receptors more gradually, favoring sustained but less intense responses for
chronic therapy. Localized routes, such as intranasal, inhalational, intra-articular, or topical
application, concentrate the drug at or near the target tissue, enhancing receptor-specific effects
while reducing systemic exposure and minimizing unwanted pharmacodynamic interactions at off-
target sites. Clinically, these mechanistic differences guide therapeutic choices: for instance,
inhaled β₂-agonists exploit high receptor density in bronchial smooth muscle for rapid
bronchodilation with limited cardiac stimulation, whereas systemic administration would activate
β-receptors broadly and increase adverse effects. Thus, the route determines not only how much
drug reaches the receptors, but also which receptor populations are preferentially engaged, directly
linking administration strategy to therapeutic efficacy and safety.
General Pharmacology Section-1 Drug
169 BAASIR UMAIR (MPhil in Pharmacology)
Routes of administration: a conceptual reorientation
Different traditions in pharmacology have attempted to classify routes of drug administration, yet
none are without limitations. Some schemes divide them into broad categories such as enteral,
parenteral, topical, inhalational, and miscellaneous, while others prefer the simpler division into
local and systemic. However, certain routes never sit neatly within these boxes. The oral pathway,
for example, may act purely locally in the case of antacids or laxatives, yet also serves as a primary
systemic route for countless drugs. Similarly, inhalational delivery blurs boundaries, producing
either localized bronchodilation or profound systemic anesthesia, depending on the agent.
Other approaches lean toward dosage form–based classifications or even highlight advanced
delivery platforms such as nanoparticle systems and implants. While each framework offers some
clarity, they often emphasize form over function or overlook the mechanistic subtleties that define
why a particular route behaves the way it does.
This chapter, therefore, chooses local versus systemic administration as its primary framework—
not merely as a simplification, but to illuminate the underlying logic of how drugs act in the body.
Within this scheme, routes that appear ambiguous or overlapping are carefully re-examined with
rational and mechanistic detail, showing why they belong where they do. In this way, the
discussion does not simply list routes but cultivates a deeper conceptual landscape, allowing the
reader’s understanding to expand beyond conventional categories. The aim is to refresh and refine
the way we think about drug administration, turning what often feels like a dry catalog into a
guiding force for clinical reasoning and pharmacological insight.
169 BAASIR UMAIR (MPhil in Pharmacology)
Routes of administration: a conceptual reorientation
Different traditions in pharmacology have attempted to classify routes of drug administration, yet
none are without limitations. Some schemes divide them into broad categories such as enteral,
parenteral, topical, inhalational, and miscellaneous, while others prefer the simpler division into
local and systemic. However, certain routes never sit neatly within these boxes. The oral pathway,
for example, may act purely locally in the case of antacids or laxatives, yet also serves as a primary
systemic route for countless drugs. Similarly, inhalational delivery blurs boundaries, producing
either localized bronchodilation or profound systemic anesthesia, depending on the agent.
Other approaches lean toward dosage form–based classifications or even highlight advanced
delivery platforms such as nanoparticle systems and implants. While each framework offers some
clarity, they often emphasize form over function or overlook the mechanistic subtleties that define
why a particular route behaves the way it does.
This chapter, therefore, chooses local versus systemic administration as its primary framework—
not merely as a simplification, but to illuminate the underlying logic of how drugs act in the body.
Within this scheme, routes that appear ambiguous or overlapping are carefully re-examined with
rational and mechanistic detail, showing why they belong where they do. In this way, the
discussion does not simply list routes but cultivates a deeper conceptual landscape, allowing the
reader’s understanding to expand beyond conventional categories. The aim is to refresh and refine
the way we think about drug administration, turning what often feels like a dry catalog into a
guiding force for clinical reasoning and pharmacological insight.
General Pharmacology Section-1 Drug
170 BAASIR UMAIR (MPhil in Pharmacology)
6.2 LOCAL ROUTES:
The word local in its everyday sense implies restriction to a defined area—local transport within
a city, local anesthesia confined to a body region, or local governance limited to a district. When
this concept is transposed into pharmacology, the local route of drug administration denotes
delivery intended to confine the drug’s effect to a specific site of action rather than the whole
organism.
Classically, the local route is defined as the administration of a drug directly to the tissue or organ
where its therapeutic action is desired, ensuring that the pharmacological effect is achieved
primarily at the site of application while systemic exposure is minimized. This is the rationale
behind the use of topical corticosteroids for eczema, eye drops for conjunctivitis, or intra-articular
injections for arthritis. The defining aim is to maximize drug concentration at the target site while
reducing systemic levels, thereby minimizing adverse effects.
If we restrict “local” to situations where the point of application and the site of drug action are
identical, certain examples become problematic. For instance, inhaled bronchodilators are applied
through the nasal or oral airway but act primarily on bronchial smooth muscle deeper in the
respiratory tract. Similarly, amphotericin B in oral suspension is administered into the mouth but
intended to act locally on the esophageal mucosa in fungal esophagitis. In both cases, although the
site of administration and the exact site of action are not identical, the therapeutic activity remains
confined within the same organ system, so they are still validly considered local.
Other instances challenge the definition even further. Consider intravesical chemotherapy for
bladder carcinoma: the drug is instilled into the bladder lumen, but its action targets the urothelium,
not the point of instillation. Here, the “local” effect is defined by containment within a body
compartment rather than identity of application and action.
An alternative mechanistic perspective refines the definition: a route may be considered local if
the drug, when employed, does not significantly enter the systemic circulation to affect distant
tissues or generalized cell populations in a major concentration. By this view, local delivery is
characterized not by strict co-localization of administration and action, but by the absence of
substantial systemic exposure and systemic toxicity.
Thus, in pharmacological discourse, the “local route of administration” is best understood as any
mode of drug delivery designed to confine therapeutic action to a restricted site or compartment
of the body, irrespective of minor spatial differences between entry point and action, provided
systemic leakage is minimal. This broader but mechanistically grounded definition accommodates
the diversity of local drug delivery strategies seen in both classical pharmacology and modern
therapeutic innovations.
6.2.1 Topical Administration:
Topical administration means placing a medicine directly onto an external surface or accessible
mucosa with the intention that the site of application is also the site of therapeutic action. That one
sentence contains three packed ideas we must unpack and use as the organizing logic for this
section:
1. Point of application = intended point of action (this is what makes a route “local”).
170 BAASIR UMAIR (MPhil in Pharmacology)
6.2 LOCAL ROUTES:
The word local in its everyday sense implies restriction to a defined area—local transport within
a city, local anesthesia confined to a body region, or local governance limited to a district. When
this concept is transposed into pharmacology, the local route of drug administration denotes
delivery intended to confine the drug’s effect to a specific site of action rather than the whole
organism.
Classically, the local route is defined as the administration of a drug directly to the tissue or organ
where its therapeutic action is desired, ensuring that the pharmacological effect is achieved
primarily at the site of application while systemic exposure is minimized. This is the rationale
behind the use of topical corticosteroids for eczema, eye drops for conjunctivitis, or intra-articular
injections for arthritis. The defining aim is to maximize drug concentration at the target site while
reducing systemic levels, thereby minimizing adverse effects.
If we restrict “local” to situations where the point of application and the site of drug action are
identical, certain examples become problematic. For instance, inhaled bronchodilators are applied
through the nasal or oral airway but act primarily on bronchial smooth muscle deeper in the
respiratory tract. Similarly, amphotericin B in oral suspension is administered into the mouth but
intended to act locally on the esophageal mucosa in fungal esophagitis. In both cases, although the
site of administration and the exact site of action are not identical, the therapeutic activity remains
confined within the same organ system, so they are still validly considered local.
Other instances challenge the definition even further. Consider intravesical chemotherapy for
bladder carcinoma: the drug is instilled into the bladder lumen, but its action targets the urothelium,
not the point of instillation. Here, the “local” effect is defined by containment within a body
compartment rather than identity of application and action.
An alternative mechanistic perspective refines the definition: a route may be considered local if
the drug, when employed, does not significantly enter the systemic circulation to affect distant
tissues or generalized cell populations in a major concentration. By this view, local delivery is
characterized not by strict co-localization of administration and action, but by the absence of
substantial systemic exposure and systemic toxicity.
Thus, in pharmacological discourse, the “local route of administration” is best understood as any
mode of drug delivery designed to confine therapeutic action to a restricted site or compartment
of the body, irrespective of minor spatial differences between entry point and action, provided
systemic leakage is minimal. This broader but mechanistically grounded definition accommodates
the diversity of local drug delivery strategies seen in both classical pharmacology and modern
therapeutic innovations.
6.2.1 Topical Administration:
Topical administration means placing a medicine directly onto an external surface or accessible
mucosa with the intention that the site of application is also the site of therapeutic action. That one
sentence contains three packed ideas we must unpack and use as the organizing logic for this
section:
1. Point of application = intended point of action (this is what makes a route “local”).
General Pharmacology Section-1 Drug
171 BAASIR UMAIR (MPhil in Pharmacology)
2. Minimal intended systemic exposure — systemic drug levels are usually low and clinically
irrelevant, so systemic toxicity is uncommon.
3. Exceptions exist — some topical products are deliberately formulated to be absorbed
systemically (transdermal systems, nitroglycerin ointment); others give systemic spill-over
unintentionally (timolol eye drops causing bradycardia).
In the following section, the principles underlying topical administration are explored in detail,
with emphasis on its conceptual basis, mechanistic determinants, and clinical applications.
Why a topical route is “local”:
A route is considered local when the drug’s therapeutic target is at or near the site of application
and the formulation and dose are designed to produce a local drug concentration sufficient for
effect without producing meaningful systemic concentrations. Examples: a steroid cream for
eczema, an antibiotic eye drop for conjunctivitis, or mesalazine suppository for distal colitis.
Mechanistically, local action relies on generating and maintaining a high concentration gradient at
the target tissue while either preventing or minimizing the drug’s diffusion into systemic
capillaries. Whether that succeeds depends on:
the barrier properties of the site (skin stratum corneum vs nasal mucosa),
the physicochemical properties of the drug (lipid solubility, molecular size, ionization),
the formulation (ointment vs gel, presence of penetration enhancers, occlusion), and
local physiology/pathology (blood flow, inflammation, ulceration).
If any of these shifts (e.g., damaged skin, occlusion, high blood flow), the local therapy can become
systemic — intentionally (transdermal delivery) or unintentionally (toxicity).
The biopharmaceutics of local topical absorption:
Percutaneous/mucosal passage is a diffusion problem. In simplest practical terms:
The net flux (rate) of drug into tissue is proportional to the concentration at the
skin/mucosal surface and inversely proportional to the thickness of the barrier. A practical
expression often used for steady-state permeation is:
where
J = flux (amount/time/unit area),
D = diffusion coefficient in the barrier,
K = partition coefficient (drug’s preference for barrier vs vehicle),
h = barrier thickness,
C = concentration at the surface.
Implications: Increase concentration (C), increase partitioning into the barrier (K), reduce
barrier thickness (h) or increase diffusion (D) → greater flux.
Drug properties that favor local action at a given site: appropriate logP (skin: moderate
lipophilicity helps), molecular weight generally < 500 Da for good dermal penetration, and
171 BAASIR UMAIR (MPhil in Pharmacology)
2. Minimal intended systemic exposure — systemic drug levels are usually low and clinically
irrelevant, so systemic toxicity is uncommon.
3. Exceptions exist — some topical products are deliberately formulated to be absorbed
systemically (transdermal systems, nitroglycerin ointment); others give systemic spill-over
unintentionally (timolol eye drops causing bradycardia).
In the following section, the principles underlying topical administration are explored in detail,
with emphasis on its conceptual basis, mechanistic determinants, and clinical applications.
Why a topical route is “local”:
A route is considered local when the drug’s therapeutic target is at or near the site of application
and the formulation and dose are designed to produce a local drug concentration sufficient for
effect without producing meaningful systemic concentrations. Examples: a steroid cream for
eczema, an antibiotic eye drop for conjunctivitis, or mesalazine suppository for distal colitis.
Mechanistically, local action relies on generating and maintaining a high concentration gradient at
the target tissue while either preventing or minimizing the drug’s diffusion into systemic
capillaries. Whether that succeeds depends on:
the barrier properties of the site (skin stratum corneum vs nasal mucosa),
the physicochemical properties of the drug (lipid solubility, molecular size, ionization),
the formulation (ointment vs gel, presence of penetration enhancers, occlusion), and
local physiology/pathology (blood flow, inflammation, ulceration).
If any of these shifts (e.g., damaged skin, occlusion, high blood flow), the local therapy can become
systemic — intentionally (transdermal delivery) or unintentionally (toxicity).
The biopharmaceutics of local topical absorption:
Percutaneous/mucosal passage is a diffusion problem. In simplest practical terms:
The net flux (rate) of drug into tissue is proportional to the concentration at the
skin/mucosal surface and inversely proportional to the thickness of the barrier. A practical
expression often used for steady-state permeation is:
where
J = flux (amount/time/unit area),
D = diffusion coefficient in the barrier,
K = partition coefficient (drug’s preference for barrier vs vehicle),
h = barrier thickness,
C = concentration at the surface.
Implications: Increase concentration (C), increase partitioning into the barrier (K), reduce
barrier thickness (h) or increase diffusion (D) → greater flux.
Drug properties that favor local action at a given site: appropriate logP (skin: moderate
lipophilicity helps), molecular weight generally < 500 Da for good dermal penetration, and
General Pharmacology Section-1 Drug
172 BAASIR UMAIR (MPhil in Pharmacology)
chemical stability in that environment. Very polar or very large molecules penetrate poorly
unless special technologies (microneedles, nanoparticles) are used.
Appendageal routes: (hair follicles, sweat glands): although they account for a small
surface fraction, they can be entry points for certain molecules and particulates (important
for nanoparticle targeting).
Reservoir effect: the stratum corneum can act as a depot—drug partitions into it and slowly
releases, prolonging local effect even after removal of formulation.
General determinants of “local vs systemic” outcome:
1. Site barrier: intact skin (strong barrier) vs mucosa (more permeable).
2. Surface area of application: larger area → more potential absorption.
3. Drug concentration and vehicle: higher concentration and solvents/penetration enhancers
→ greater uptake.
4. Occlusion and heat: occlusion raises hydration and temperature → markedly increases
absorption.
5. Blood flow under site: high local blood flow clears drug into systemic circulation faster.
6. Disease state: inflamed/ulcerated mucosa or broken skin → more absorption.
7. Patient factors: age (neonates have thin skin), hepatic function (matters if drug is
systemically metabolized after absorption).
8. Dose and intended kinetics: single small topical dose vs sustained reservoir (patch/implant)
changes systemic exposure.
172 BAASIR UMAIR (MPhil in Pharmacology)
chemical stability in that environment. Very polar or very large molecules penetrate poorly
unless special technologies (microneedles, nanoparticles) are used.
Appendageal routes: (hair follicles, sweat glands): although they account for a small
surface fraction, they can be entry points for certain molecules and particulates (important
for nanoparticle targeting).
Reservoir effect: the stratum corneum can act as a depot—drug partitions into it and slowly
releases, prolonging local effect even after removal of formulation.
General determinants of “local vs systemic” outcome:
1. Site barrier: intact skin (strong barrier) vs mucosa (more permeable).
2. Surface area of application: larger area → more potential absorption.
3. Drug concentration and vehicle: higher concentration and solvents/penetration enhancers
→ greater uptake.
4. Occlusion and heat: occlusion raises hydration and temperature → markedly increases
absorption.
5. Blood flow under site: high local blood flow clears drug into systemic circulation faster.
6. Disease state: inflamed/ulcerated mucosa or broken skin → more absorption.
7. Patient factors: age (neonates have thin skin), hepatic function (matters if drug is
systemically metabolized after absorption).
8. Dose and intended kinetics: single small topical dose vs sustained reservoir (patch/implant)
changes systemic exposure.
General Pharmacology Section-1 Drug
173 BAASIR UMAIR (MPhil in Pharmacology)
6.2.1.1 Skin (Dermal Topical Route/Mucous:)
Rationale for its Local effect:
A cream/ointment placed on the skin deposits the drug at the epidermal surface; for local
dermatoses, the intended action is within the epidermis/dermis. If the molecule’s permeation is
limited or the formulation is designed to limit systemic uptake, a local effect occurs with negligible
systemic levels.
How absorption proceeds:
Figure 6.1: Showing absorption from topical route
Important mechanistic points:
The SC is the main barrier. Hydration, solvents, chemical enhancers (ethanol, propylene
glycol, DMSO), and occlusion increase D and/or K and therefore flux.
Lipophilicity helps partitioning into SC, but too lipophilic drugs may remain sequestered
in SC and not reach viable tissue. There’s an optimum range.
Hair follicles and sweat ducts provide shunt pathways for particles and certain
formulations.
Topical Administration via the Skin:
The skin is the most accessible site for topical drug application. A variety of dosage forms are
employed depending on the therapeutic objective and drug properties:
Ointments (occlusive, greasy, increase penetration): e.g., clotrimazole ointment
(antifungal), hydrocortisone ointment (anti-inflammatory).
Creams (oil-in-water or water-in-oil emulsions, cosmetically acceptable): e.g.,
betamethasone cream (eczema), terbinafine cream (fungal infections).
Gels (water- or alcohol-based, fast drying, suitable for hairy areas): e.g., diclofenac gel
(NSAID), adapalene gel (acne).
Lotions and sprays (cover large areas, useful in exudative lesions): e.g., permethrin lotion
(scabies, lice).
Powders (moist intertriginous areas): e.g., antifungal powders like clotrimazole powder.
Partitioningfromthe
vehicleintothe
stratumcorneum
(SC).
Diffusionthroughthe
lipidmatrixofSC
(rate-limitingformost
drugs).
Partition into viable
epidermis/dermis.
Uptakeintodermal
capillaries(systemic
entry)orbindingat
localreceptors(local
action).
173 BAASIR UMAIR (MPhil in Pharmacology)
6.2.1.1 Skin (Dermal Topical Route/Mucous:)
Rationale for its Local effect:
A cream/ointment placed on the skin deposits the drug at the epidermal surface; for local
dermatoses, the intended action is within the epidermis/dermis. If the molecule’s permeation is
limited or the formulation is designed to limit systemic uptake, a local effect occurs with negligible
systemic levels.
How absorption proceeds:
Figure 6.1: Showing absorption from topical route
Important mechanistic points:
The SC is the main barrier. Hydration, solvents, chemical enhancers (ethanol, propylene
glycol, DMSO), and occlusion increase D and/or K and therefore flux.
Lipophilicity helps partitioning into SC, but too lipophilic drugs may remain sequestered
in SC and not reach viable tissue. There’s an optimum range.
Hair follicles and sweat ducts provide shunt pathways for particles and certain
formulations.
Topical Administration via the Skin:
The skin is the most accessible site for topical drug application. A variety of dosage forms are
employed depending on the therapeutic objective and drug properties:
Ointments (occlusive, greasy, increase penetration): e.g., clotrimazole ointment
(antifungal), hydrocortisone ointment (anti-inflammatory).
Creams (oil-in-water or water-in-oil emulsions, cosmetically acceptable): e.g.,
betamethasone cream (eczema), terbinafine cream (fungal infections).
Gels (water- or alcohol-based, fast drying, suitable for hairy areas): e.g., diclofenac gel
(NSAID), adapalene gel (acne).
Lotions and sprays (cover large areas, useful in exudative lesions): e.g., permethrin lotion
(scabies, lice).
Powders (moist intertriginous areas): e.g., antifungal powders like clotrimazole powder.
Partitioningfromthe
vehicleintothe
stratumcorneum
(SC).
Diffusionthroughthe
lipidmatrixofSC
(rate-limitingformost
drugs).
Partition into viable
epidermis/dermis.
Uptakeintodermal
capillaries(systemic
entry)orbindingat
localreceptors(local
action).
General Pharmacology Section-1 Drug
174 BAASIR UMAIR (MPhil in Pharmacology)
Systemic spillover and toxicity from dermal applications:
Although the therapeutic goal of dermal drug delivery is local action, systemic absorption can
occur, especially when large areas, damaged skin, or high-potency agents are involved. Some
classical and clinically important examples include:
Table 6.1: Topical agents and their potential systemic toxicities
Agent Topical Use Systemic Effects (on absorption)
Silver sulfadiazine Burn patients – antibacterial
prophylaxis
Hepatic dysfunction, crystalluria, bone
marrow suppression (due to sulfonamide
absorption)
Tannic acid Historically for burns and ulcers
(astringent)
Hepatic necrosis, severe liver injury →
abandoned for this indication
Topical corticosteroids
(e.g., clobetasol,
betamethasone)
Inflammatory/autoimmune skin
disorders
Cushing’s syndrome, adrenal suppression,
growth retardation in children (especially
with prolonged use/occlusion)
Salicylic acid Psoriasis therapy Salicylate poisoning: tinnitus, metabolic
acidosis (if applied over large areas)
Iodine preparations (e.g.,
povidone-iodine)
Burns, wound antisepsis Iodine-induced thyroid dysfunction with
excessive use
Phenol Formerly antiseptic CNS depression, cardiac arrhythmias
(when absorbed via damaged skin)
Nitroglycerin
ointment/patches
Angina prophylaxis (systemic
action intentionally desired)
Therapeutic systemic vasodilation,
headache, hypotension
Formulation & device notes (practical):
Ointments (occlusive) increase penetration; gels and lotions are less occlusive.
Patches: reservoir, matrix, and rate-controlling membrane designs control flux.
Microneedles/nanocarriers can purposefully increase permeability for peptides/vaccines.
Clinical examples and exceptions:
Local examples: topical corticosteroids (hydrocortisone, betamethasone) for eczema;
antifungal creams (clotrimazole, terbinafine). These are intended to act in the
epidermis/upper dermis.
Intended systemic via skin (exception): nitroglycerin ointment and transdermal patches
(nicotine, fentanyl, estradiol). These are formulated (reservoir or matrix patches, rate-
controlling membranes) to deliver drug across the skin into systemic circulation—they
are transdermal, not topical in intent.
Unintended systemic spillover: applying potent steroids under occlusion over large
areas or on inflamed skin can produce Cushingoid effects; infants are at high risk due
to thin skin.
Clinical pearl: Avoid large-area occluded application of potent steroids; calculate dose per
unit area when high systemic absorption is a risk.
174 BAASIR UMAIR (MPhil in Pharmacology)
Systemic spillover and toxicity from dermal applications:
Although the therapeutic goal of dermal drug delivery is local action, systemic absorption can
occur, especially when large areas, damaged skin, or high-potency agents are involved. Some
classical and clinically important examples include:
Table 6.1: Topical agents and their potential systemic toxicities
Agent Topical Use Systemic Effects (on absorption)
Silver sulfadiazine Burn patients – antibacterial
prophylaxis
Hepatic dysfunction, crystalluria, bone
marrow suppression (due to sulfonamide
absorption)
Tannic acid Historically for burns and ulcers
(astringent)
Hepatic necrosis, severe liver injury →
abandoned for this indication
Topical corticosteroids
(e.g., clobetasol,
betamethasone)
Inflammatory/autoimmune skin
disorders
Cushing’s syndrome, adrenal suppression,
growth retardation in children (especially
with prolonged use/occlusion)
Salicylic acid Psoriasis therapy Salicylate poisoning: tinnitus, metabolic
acidosis (if applied over large areas)
Iodine preparations (e.g.,
povidone-iodine)
Burns, wound antisepsis Iodine-induced thyroid dysfunction with
excessive use
Phenol Formerly antiseptic CNS depression, cardiac arrhythmias
(when absorbed via damaged skin)
Nitroglycerin
ointment/patches
Angina prophylaxis (systemic
action intentionally desired)
Therapeutic systemic vasodilation,
headache, hypotension
Formulation & device notes (practical):
Ointments (occlusive) increase penetration; gels and lotions are less occlusive.
Patches: reservoir, matrix, and rate-controlling membrane designs control flux.
Microneedles/nanocarriers can purposefully increase permeability for peptides/vaccines.
Clinical examples and exceptions:
Local examples: topical corticosteroids (hydrocortisone, betamethasone) for eczema;
antifungal creams (clotrimazole, terbinafine). These are intended to act in the
epidermis/upper dermis.
Intended systemic via skin (exception): nitroglycerin ointment and transdermal patches
(nicotine, fentanyl, estradiol). These are formulated (reservoir or matrix patches, rate-
controlling membranes) to deliver drug across the skin into systemic circulation—they
are transdermal, not topical in intent.
Unintended systemic spillover: applying potent steroids under occlusion over large
areas or on inflamed skin can produce Cushingoid effects; infants are at high risk due
to thin skin.
Clinical pearl: Avoid large-area occluded application of potent steroids; calculate dose per
unit area when high systemic absorption is a risk.
General Pharmacology Section-1 Drug
175 BAASIR UMAIR (MPhil in Pharmacology)
Historical Lesson: Tannic Acid in Burn Therapy
6.2.1.2 Eye (Ophthalmic Topical Route):
The eye is a unique site for local drug delivery due to its anatomical barriers and high sensitivity.
Drugs are usually applied topically as eye drops, ointments, gels, suspensions, emulsions, or inserts
to achieve local action on the conjunctiva, cornea, or intraocular structures. While the primary aim
is local therapy, several pharmacokinetic exceptions mean that systemic effects may also occur.
Formulations for Local Purpose:
Eye drops (aqueous solutions): e.g., Tropicamide (mydriatic), Moxifloxacin (antibiotic).
Ointments and gels: e.g., Erythromycin ointment (conjunctivitis), Ganciclovir gel (herpetic
keratitis).
Suspensions: e.g., Prednisolone acetate suspension (uveitis).
Emulsions: e.g., Cyclosporine emulsion (chronic dry eye).
Inserts/implants: e.g., Ocusert (pilocarpine insert), Dexamethasone intravitreal implant.
Rationale for its Local effect:
Drops or ointments placed in the conjunctival sac are intended to act on the cornea, conjunctiva,
or anterior chamber structures. The tear film and corneal epithelium govern local exposure.
Barriers & kinetics:
Corneal epithelium (lipophilic) limits hydrophilic drug entry; stroma (hydrophilic) limits
lipophilic drug passage. Successful corneal penetration requires molecules or vehicles that
can traverse both environments. Tear turnover and blinking rapidly wash away drops,
limiting contact time.
Clinical implications & examples:
Local use: dorzolamide or latanoprost for glaucoma; topical antibiotics for conjunctivitis.
Mitigation: punctal occlusion or eyelid closure for 1–2 minutes reduces systemic uptake
significantly.
Routes to systemic circulation (spillover):
Nasolacrimal drainage delivers drug into the highly vascular nasal mucosa (rapid systemic
absorption).
Conjunctival absorption can also lead to systemic uptake via conjunctival capillaries
During the late 19th and early 20th centuries, tannic acid was widely applied to severe burns
because of its protein-precipitating and astringent properties. Initially thought to reduce fluid
loss and infection, it was soon recognized that substantial systemic absorption occurred
through denuded skin. Reports described patients developing fulminant hepatic necrosis and
fatal liver failure following its use in extensive burns. By the mid-20th century, tannic acid
was largely abandoned from clinical practice. This episode remains a classic reminder that a
drug intended for local effect may exert lethal systemic toxicity if absorption is overlooked.
175 BAASIR UMAIR (MPhil in Pharmacology)
Historical Lesson: Tannic Acid in Burn Therapy
6.2.1.2 Eye (Ophthalmic Topical Route):
The eye is a unique site for local drug delivery due to its anatomical barriers and high sensitivity.
Drugs are usually applied topically as eye drops, ointments, gels, suspensions, emulsions, or inserts
to achieve local action on the conjunctiva, cornea, or intraocular structures. While the primary aim
is local therapy, several pharmacokinetic exceptions mean that systemic effects may also occur.
Formulations for Local Purpose:
Eye drops (aqueous solutions): e.g., Tropicamide (mydriatic), Moxifloxacin (antibiotic).
Ointments and gels: e.g., Erythromycin ointment (conjunctivitis), Ganciclovir gel (herpetic
keratitis).
Suspensions: e.g., Prednisolone acetate suspension (uveitis).
Emulsions: e.g., Cyclosporine emulsion (chronic dry eye).
Inserts/implants: e.g., Ocusert (pilocarpine insert), Dexamethasone intravitreal implant.
Rationale for its Local effect:
Drops or ointments placed in the conjunctival sac are intended to act on the cornea, conjunctiva,
or anterior chamber structures. The tear film and corneal epithelium govern local exposure.
Barriers & kinetics:
Corneal epithelium (lipophilic) limits hydrophilic drug entry; stroma (hydrophilic) limits
lipophilic drug passage. Successful corneal penetration requires molecules or vehicles that
can traverse both environments. Tear turnover and blinking rapidly wash away drops,
limiting contact time.
Clinical implications & examples:
Local use: dorzolamide or latanoprost for glaucoma; topical antibiotics for conjunctivitis.
Mitigation: punctal occlusion or eyelid closure for 1–2 minutes reduces systemic uptake
significantly.
Routes to systemic circulation (spillover):
Nasolacrimal drainage delivers drug into the highly vascular nasal mucosa (rapid systemic
absorption).
Conjunctival absorption can also lead to systemic uptake via conjunctival capillaries
During the late 19th and early 20th centuries, tannic acid was widely applied to severe burns
because of its protein-precipitating and astringent properties. Initially thought to reduce fluid
loss and infection, it was soon recognized that substantial systemic absorption occurred
through denuded skin. Reports described patients developing fulminant hepatic necrosis and
fatal liver failure following its use in extensive burns. By the mid-20th century, tannic acid
was largely abandoned from clinical practice. This episode remains a classic reminder that a
drug intended for local effect may exert lethal systemic toxicity if absorption is overlooked.
General Pharmacology Section-1 Drug
176 BAASIR UMAIR (MPhil in Pharmacology)
Systemic spillover and toxicity from Ophthalmic applications:
Table 6.2: Ocular drug absorption and systemic consequences
Agent / Property Ocular/Topical Use Systemic or Local Effect
Physostigmine Antiglaucoma; lipid-soluble,
un-ionized
Good corneal penetration
Neostigmine Anticholinesterase; highly
ionized
Poor corneal penetration
Timolol (β-blocker drops) Glaucoma therapy Bradycardia, hypotension, bronchospasm
(may precipitate asthma)
Epinephrine (historical use) Glaucoma Hypertension, tachyarrhythmias
Atropine (in children) Mydriasis, cycloplegia Flushing, fever, delirium (anticholinergic
toxicity)
Topical corticosteroids (e.g.,
dexamethasone drops)
Ocular inflammation ↑ Intraocular pressure, cataract, possible
adrenal suppression in infants
β-blocker gels/drops (with
punctal occlusion)
Glaucoma Reduced systemic toxicity with lacrimal sac
occlusion
Cyclosporine emulsion Keratoconjunctivitis sicca Minimal systemic absorption → safe,
localized effect
Devices & advances:
Drug-eluting contact lenses and in situ gels aim to prolong local residence and reduce
dosing frequency.
Intravitreal implants are used when deeper retinal drug levels are required (these are local
ocular but invasive, covered elsewhere).
Figure 6.2: Intravitreal implants
Clinical pearl: instruct patients to perform punctal occlusion after instilling β-blocker eye
drops to reduce systemic side effects.
176 BAASIR UMAIR (MPhil in Pharmacology)
Systemic spillover and toxicity from Ophthalmic applications:
Table 6.2: Ocular drug absorption and systemic consequences
Agent / Property Ocular/Topical Use Systemic or Local Effect
Physostigmine Antiglaucoma; lipid-soluble,
un-ionized
Good corneal penetration
Neostigmine Anticholinesterase; highly
ionized
Poor corneal penetration
Timolol (β-blocker drops) Glaucoma therapy Bradycardia, hypotension, bronchospasm
(may precipitate asthma)
Epinephrine (historical use) Glaucoma Hypertension, tachyarrhythmias
Atropine (in children) Mydriasis, cycloplegia Flushing, fever, delirium (anticholinergic
toxicity)
Topical corticosteroids (e.g.,
dexamethasone drops)
Ocular inflammation ↑ Intraocular pressure, cataract, possible
adrenal suppression in infants
β-blocker gels/drops (with
punctal occlusion)
Glaucoma Reduced systemic toxicity with lacrimal sac
occlusion
Cyclosporine emulsion Keratoconjunctivitis sicca Minimal systemic absorption → safe,
localized effect
Devices & advances:
Drug-eluting contact lenses and in situ gels aim to prolong local residence and reduce
dosing frequency.
Intravitreal implants are used when deeper retinal drug levels are required (these are local
ocular but invasive, covered elsewhere).
Figure 6.2: Intravitreal implants
Clinical pearl: instruct patients to perform punctal occlusion after instilling β-blocker eye
drops to reduce systemic side effects.
General Pharmacology Section-1 Drug
177 BAASIR UMAIR (MPhil in Pharmacology)
The Ophthalmic Route — A Story of Systemic Surprises
Figure 6.3: locally applied or instilled eye drops toxicity in history
6.2.1.3 Ear (Otic Topical Route):
The otic route is primarily employed for local therapy of infections, inflammation, pain, or wax
impaction within the external auditory canal and middle ear. While most agents act locally,
absorption through the tympanic membrane or damaged mucosa may occasionally produce
systemic effects.
Formulations for Local Therapy:
Antibiotic drops: Ciprofloxacin, Ofloxacin, Neomycin/polymyxin B combinations → otitis
externa, chronic suppurative otitis media.
Antibiotic–steroid combinations: Ciprofloxacin + Dexamethasone → bacterial otitis with
inflammation.
Antifungal drops: Clotrimazole solution → otomycosis.
Analgesic drops: Benzocaine, Phenazone → otalgia (rarely used now).
Cerumenolytics (wax softeners): Carbamide peroxide, Glycerin, Hydrogen peroxide →
impacted cerumen.
Drying agents: Acetic acid–alcohol mixtures → swimmer’s ear prophylaxis.
Rationale for its Local effect:
Ear drops or pastes are applied to the external auditory canal for local action (antisepsis,
inflammation control). When the tympanic membrane is intact, systemic absorption is minimal.
Formulation point: viscous vehicles enhance contact time and retention in the canal.
Early 20th Century
(1910s–1920s):
Atropine drops in
children widely used
→ reports of fatal
anticholinergic
poisoning → systemic
absorption recognized
as a serious risk.
1967:Timolol
introduced as first
topical β-blocker for
glaucoma → within
years, cases of severe
asthma, bradycardia
reported → systemic
toxicity highlighted.
1990s–2000s:Punctal
occlusion technique +
gel/once-daily β-
blocker formulations
developed → reduced
systemic absorption
and improved safety.
Present Era:
Nanoparticle-based
ocular delivery &
sustained-release
intravitreal implants
(e.g., anti-VEGF
drugs) → paradigm
shift from drops to
targeted delivery with
minimal systemic
exposure.
177 BAASIR UMAIR (MPhil in Pharmacology)
The Ophthalmic Route — A Story of Systemic Surprises
Figure 6.3: locally applied or instilled eye drops toxicity in history
6.2.1.3 Ear (Otic Topical Route):
The otic route is primarily employed for local therapy of infections, inflammation, pain, or wax
impaction within the external auditory canal and middle ear. While most agents act locally,
absorption through the tympanic membrane or damaged mucosa may occasionally produce
systemic effects.
Formulations for Local Therapy:
Antibiotic drops: Ciprofloxacin, Ofloxacin, Neomycin/polymyxin B combinations → otitis
externa, chronic suppurative otitis media.
Antibiotic–steroid combinations: Ciprofloxacin + Dexamethasone → bacterial otitis with
inflammation.
Antifungal drops: Clotrimazole solution → otomycosis.
Analgesic drops: Benzocaine, Phenazone → otalgia (rarely used now).
Cerumenolytics (wax softeners): Carbamide peroxide, Glycerin, Hydrogen peroxide →
impacted cerumen.
Drying agents: Acetic acid–alcohol mixtures → swimmer’s ear prophylaxis.
Rationale for its Local effect:
Ear drops or pastes are applied to the external auditory canal for local action (antisepsis,
inflammation control). When the tympanic membrane is intact, systemic absorption is minimal.
Formulation point: viscous vehicles enhance contact time and retention in the canal.
Early 20th Century
(1910s–1920s):
Atropine drops in
children widely used
→ reports of fatal
anticholinergic
poisoning → systemic
absorption recognized
as a serious risk.
1967:Timolol
introduced as first
topical β-blocker for
glaucoma → within
years, cases of severe
asthma, bradycardia
reported → systemic
toxicity highlighted.
1990s–2000s:Punctal
occlusion technique +
gel/once-daily β-
blocker formulations
developed → reduced
systemic absorption
and improved safety.
Present Era:
Nanoparticle-based
ocular delivery &
sustained-release
intravitreal implants
(e.g., anti-VEGF
drugs) → paradigm
shift from drops to
targeted delivery with
minimal systemic
exposure.
General Pharmacology Section-1 Drug
178 BAASIR UMAIR (MPhil in Pharmacology)
Systemic spillover and toxicity from Ophthalmic applications:
Table6.3: Topical ear drops: safety, risks, and systemic effects
Condition / Agent Topical Otic Use Potential Systemic or Local
Effect
Normal tympanic membrane (intact) Most otic drops (antibiotics,
analgesics)
Minimal systemic absorption due
to poor permeability
Damaged tympanic membrane
(perforation, surgery)
Aminoglycosides (Neomycin,
Gentamicin)
Ototoxicity → sensorineural
hearing loss, vestibular toxicity
Polymyxin B Possible neurotoxicity if absorbed
through perforation
Steroid drops (e.g., dexamethasone,
hydrocortisone)
Local anti-inflammatory in
otitis externa, post-surgery
Risk of fungal overgrowth with
prolonged use
Phenazone/Antipyrine (historical
analgesic drops)
Ear pain relief Rare systemic salicylism in
children (fever, vomiting, acidosis)
Alcohol-containing drops (e.g.,
isopropyl alcohol, glycerin mixtures)
Drying agent for otitis externa Local mucosal irritation, mild
systemic absorption
Quinolones (Ciprofloxacin, Ofloxacin) Otitis externa, otitis media with
perforation
Safe even with perforated TM
(preferred over aminoglycosides)
Chloramphenicol (historical use) Otitis media Risk of aplastic anemia if absorbed
(rare, now largely avoided)
Clinical Pearls:
Always check tympanic membrane integrity before prescribing aminoglycoside ear
drops.
Fluoroquinolone drops (e.g., Ofloxacin, Ciprofloxacin) are preferred in chronic
suppurative otitis media because of low ototoxicity risk.
Combination drops (antibiotic + steroid) improve compliance but may mask fungal
infections.
Ear wicks soaked in drops are used for refractory otitis externa to improve penetration.
178 BAASIR UMAIR (MPhil in Pharmacology)
Systemic spillover and toxicity from Ophthalmic applications:
Table6.3: Topical ear drops: safety, risks, and systemic effects
Condition / Agent Topical Otic Use Potential Systemic or Local
Effect
Normal tympanic membrane (intact) Most otic drops (antibiotics,
analgesics)
Minimal systemic absorption due
to poor permeability
Damaged tympanic membrane
(perforation, surgery)
Aminoglycosides (Neomycin,
Gentamicin)
Ototoxicity → sensorineural
hearing loss, vestibular toxicity
Polymyxin B Possible neurotoxicity if absorbed
through perforation
Steroid drops (e.g., dexamethasone,
hydrocortisone)
Local anti-inflammatory in
otitis externa, post-surgery
Risk of fungal overgrowth with
prolonged use
Phenazone/Antipyrine (historical
analgesic drops)
Ear pain relief Rare systemic salicylism in
children (fever, vomiting, acidosis)
Alcohol-containing drops (e.g.,
isopropyl alcohol, glycerin mixtures)
Drying agent for otitis externa Local mucosal irritation, mild
systemic absorption
Quinolones (Ciprofloxacin, Ofloxacin) Otitis externa, otitis media with
perforation
Safe even with perforated TM
(preferred over aminoglycosides)
Chloramphenicol (historical use) Otitis media Risk of aplastic anemia if absorbed
(rare, now largely avoided)
Clinical Pearls:
Always check tympanic membrane integrity before prescribing aminoglycoside ear
drops.
Fluoroquinolone drops (e.g., Ofloxacin, Ciprofloxacin) are preferred in chronic
suppurative otitis media because of low ototoxicity risk.
Combination drops (antibiotic + steroid) improve compliance but may mask fungal
infections.
Ear wicks soaked in drops are used for refractory otitis externa to improve penetration.
General Pharmacology Section-1 Drug
179 BAASIR UMAIR (MPhil in Pharmacology)
From Hazardous Powders to Targeted Drops:
Figure 6.4: Historical account of eyes drops with systemic toxicity
6.2.2 Nasal (Local Nasal Route):
The nasal route is a versatile local drug delivery pathway, targeting the nasal mucosa and paranasal
sinuses. It is primarily used for symptomatic relief in rhinitis, sinusitis, allergic inflammation, and
for local antisepsis. Because the nasal mucosa is highly vascular and permeable, most nasal
formulations achieve a local effect, though systemic absorption and adverse effects may occur as
important exceptions
6.2.2.1 Rationale for its Local effect:
Point of application = site of action: drugs target the nasal mucosa for decongestion, anti-
inflammatory effects, or antisepsis.
Concentration gradient: high local drug levels at the mucosal surface with minimal
systemic distribution (when the mucosa is intact and the drug is poorly absorbed).
Vehicle design: sprays, drops, and gels ensure retention in nasal passages, enhancing local
contact.
(Inhalational and nasal route for systemic action is discussed later in the chapter)
6.2.2.2 Mechanisms & special opportunities:
High vascularity → rapid absorption (good for local and systemic action).
Olfactory region provides a potential path to the CNS (direct nose-to-brain transport via
olfactory/trigeminal nerves) exploited experimentally for CNS delivery.
Mucociliary clearance limits residence time; mucoadhesive formulations and powders can
increase contact time.
19th century:
Mercury and
silver nitrate
solutionswere
instilled in the
ear for infections,
often causing
severe
ototoxicity.
1945–1960s:
Aminoglycoside
drops (Neomycin,
Framycetin)
became popular
but led to
widespread cases
of irreversible
hearing loss
when used with
tympanic
perforation.
1970s–80s:
Steroid
combinations
were added to
reduce
inflammation but
increased fungal
overgrowth.
1990s onwards:
Introduction of
fluoroquinolone
drops
(Ciprofloxacin,
Ofloxacin)
revolutionized
otic therapy by
offering high
efficacy with
minimal
ototoxicity, now
considered the
safest standard.
Present era:
Nanoparticle-
based otic
formulations and
hydrogel systems
are under
development to
improve drug
retention in the
ear canal and
middle ear
179 BAASIR UMAIR (MPhil in Pharmacology)
From Hazardous Powders to Targeted Drops:
Figure 6.4: Historical account of eyes drops with systemic toxicity
6.2.2 Nasal (Local Nasal Route):
The nasal route is a versatile local drug delivery pathway, targeting the nasal mucosa and paranasal
sinuses. It is primarily used for symptomatic relief in rhinitis, sinusitis, allergic inflammation, and
for local antisepsis. Because the nasal mucosa is highly vascular and permeable, most nasal
formulations achieve a local effect, though systemic absorption and adverse effects may occur as
important exceptions
6.2.2.1 Rationale for its Local effect:
Point of application = site of action: drugs target the nasal mucosa for decongestion, anti-
inflammatory effects, or antisepsis.
Concentration gradient: high local drug levels at the mucosal surface with minimal
systemic distribution (when the mucosa is intact and the drug is poorly absorbed).
Vehicle design: sprays, drops, and gels ensure retention in nasal passages, enhancing local
contact.
(Inhalational and nasal route for systemic action is discussed later in the chapter)
6.2.2.2 Mechanisms & special opportunities:
High vascularity → rapid absorption (good for local and systemic action).
Olfactory region provides a potential path to the CNS (direct nose-to-brain transport via
olfactory/trigeminal nerves) exploited experimentally for CNS delivery.
Mucociliary clearance limits residence time; mucoadhesive formulations and powders can
increase contact time.
19th century:
Mercury and
silver nitrate
solutionswere
instilled in the
ear for infections,
often causing
severe
ototoxicity.
1945–1960s:
Aminoglycoside
drops (Neomycin,
Framycetin)
became popular
but led to
widespread cases
of irreversible
hearing loss
when used with
tympanic
perforation.
1970s–80s:
Steroid
combinations
were added to
reduce
inflammation but
increased fungal
overgrowth.
1990s onwards:
Introduction of
fluoroquinolone
drops
(Ciprofloxacin,
Ofloxacin)
revolutionized
otic therapy by
offering high
efficacy with
minimal
ototoxicity, now
considered the
safest standard.
Present era:
Nanoparticle-
based otic
formulations and
hydrogel systems
are under
development to
improve drug
retention in the
ear canal and
middle ear
General Pharmacology Section-1 Drug
180 BAASIR UMAIR (MPhil in Pharmacology)
6.2.2.3 Clinical examples:
Local decongestants: oxymetazoline (risk of rebound rhinitis if overused).
Intranasal corticosteroids: fluticasone for allergic rhinitis.
Peptide delivery: desmopressin and calcitonin intranasal formulations exploit rapid
absorption for systemic effect.
6.2.2.4 Systemic Spillover:
Table 6.4: Intranasal drugs: safety, risks, and systemic effects
Agent / Class Intranasal Use Potential Systemic or Local Effect
Adrenergic decongestants
(Oxymetazoline, Phenylephrine,
Xylometazoline)
Relief of nasal congestion Hypertension, tachycardia if
overused/swallowed; rebound congestion
(rhinitis medicamentosa) with chronic use
Intranasal corticosteroids
(Fluticasone, Budesonide,
Beclomethasone, Mometasone)
Allergic rhinitis, chronic
rhinosinusitis, nasal
polyps
Local: epistaxis, nasal irritation; Systemic (rare,
high/prolonged dose): HPA axis suppression,
growth retardation in children
Intranasal β-blocker (Timolol,
trial use)
Investigated for epistaxis,
glaucoma therapy via
nasal route
Bradycardia, bronchospasm → abandoned due
to systemic risk
Cocaine (historical/ENT
anesthesia)
Local anesthesia, nasal
surgeries
Arrhythmias, hypertension, seizures, CNS
stimulation, addiction
Intranasal antihistamines
(Azelastine, Olopatadine)
Allergic rhinitis Local irritation, bitter taste; rare systemic
sedation
Desmopressin (DDAVP) Central diabetes
insipidus, nocturnal
enuresis, hemophilia
Water retention, hyponatremia, seizures with
overdose
Intranasal vaccines (e.g., live-
attenuated influenza vaccine,
FluMist®)
Immunization Mild systemic flu-like symptoms; rare wheezing
in children
Intranasal analgesics (Ketorolac,
experimental use)
Post-operative pain Risk of systemic NSAID effects (GI upset, renal
toxicity)
Fentanyl nasal spray (palliative
care)
Breakthrough cancer pain Desired systemic opioid effects (analgesia) but
also risk of respiratory depression, dependence
Clinical Pearls:
Nasal mucosa bypasses hepatic first-pass metabolism — small drugs can enter systemic
circulation quickly if formulations are designed that way (basis of intranasal systemic
therapy, e.g., desmopressin).
Local vs systemic depends on formulation: saline or corticosteroid sprays act locally,
while some drugs (e.g., desmopressin spray) are deliberately systemic.
Rebound congestion is a hallmark complication of overusing topical adrenergic
decongestants.
Patients should be taught correct spray technique (directed away from the septum) to
avoid mucosal injury and bleeding
180 BAASIR UMAIR (MPhil in Pharmacology)
6.2.2.3 Clinical examples:
Local decongestants: oxymetazoline (risk of rebound rhinitis if overused).
Intranasal corticosteroids: fluticasone for allergic rhinitis.
Peptide delivery: desmopressin and calcitonin intranasal formulations exploit rapid
absorption for systemic effect.
6.2.2.4 Systemic Spillover:
Table 6.4: Intranasal drugs: safety, risks, and systemic effects
Agent / Class Intranasal Use Potential Systemic or Local Effect
Adrenergic decongestants
(Oxymetazoline, Phenylephrine,
Xylometazoline)
Relief of nasal congestion Hypertension, tachycardia if
overused/swallowed; rebound congestion
(rhinitis medicamentosa) with chronic use
Intranasal corticosteroids
(Fluticasone, Budesonide,
Beclomethasone, Mometasone)
Allergic rhinitis, chronic
rhinosinusitis, nasal
polyps
Local: epistaxis, nasal irritation; Systemic (rare,
high/prolonged dose): HPA axis suppression,
growth retardation in children
Intranasal β-blocker (Timolol,
trial use)
Investigated for epistaxis,
glaucoma therapy via
nasal route
Bradycardia, bronchospasm → abandoned due
to systemic risk
Cocaine (historical/ENT
anesthesia)
Local anesthesia, nasal
surgeries
Arrhythmias, hypertension, seizures, CNS
stimulation, addiction
Intranasal antihistamines
(Azelastine, Olopatadine)
Allergic rhinitis Local irritation, bitter taste; rare systemic
sedation
Desmopressin (DDAVP) Central diabetes
insipidus, nocturnal
enuresis, hemophilia
Water retention, hyponatremia, seizures with
overdose
Intranasal vaccines (e.g., live-
attenuated influenza vaccine,
FluMist®)
Immunization Mild systemic flu-like symptoms; rare wheezing
in children
Intranasal analgesics (Ketorolac,
experimental use)
Post-operative pain Risk of systemic NSAID effects (GI upset, renal
toxicity)
Fentanyl nasal spray (palliative
care)
Breakthrough cancer pain Desired systemic opioid effects (analgesia) but
also risk of respiratory depression, dependence
Clinical Pearls:
Nasal mucosa bypasses hepatic first-pass metabolism — small drugs can enter systemic
circulation quickly if formulations are designed that way (basis of intranasal systemic
therapy, e.g., desmopressin).
Local vs systemic depends on formulation: saline or corticosteroid sprays act locally,
while some drugs (e.g., desmopressin spray) are deliberately systemic.
Rebound congestion is a hallmark complication of overusing topical adrenergic
decongestants.
Patients should be taught correct spray technique (directed away from the septum) to
avoid mucosal injury and bleeding
General Pharmacology Section-1 Drug
181 BAASIR UMAIR (MPhil in Pharmacology)
6.2.2.5 The Nasal Route (From Cocaine to Corticosteroids):
Figure 6.5: Historical account of local nasal route with systemic toxicity
6.2.2.6 Recent Advances (Local Nasal Delivery):
Mucoadhesive nanoparticles & gels: prolong residence time on nasal mucosa, enhancing
efficacy of antifungals and corticosteroids.
Nasal microbiome–targeted sprays: under research for managing chronic sinusitis by
rebalancing local flora.
Device-assisted irrigation systems: controlled pressure saline irrigation improves clearance
in chronic rhinosinusitis.
Smart sprays with dose counters & mist technology: improving adherence and deposition
pattern.
1884: Carl
Koller
demonstrated
cocaine as a local
anesthetic via
nasal and ocular
mucosa,
revolutionizing
ENTsurgery —
but cocaine’s
addictive and
systemic toxic
potential soon
became
notorious.
Mid-20th
century:
Adrenergic
vasoconstrictors
(ephedrine,
phenylephrine)
were developed
as safer
alternatives,
though still
linked to rebound
congestion when
overused.
1970s–80s:
Introduction of
intranasal
corticosteroids
provided
effective long-
term control of
allergic rhinitis
with minimal
systemic toxicity
—establishing
the nasal route as
first-line for
allergy
management.
1990s onwards:
Antihistamine
sprays
(azelastine) and
combination
therapy further
improved local
allergic control.
Present era: The
nasal route has
expanded beyond
local therapy into
systemic delivery
and vaccines but
remains essential
for rapid local
relief in rhinitis
and sinus disease.
181 BAASIR UMAIR (MPhil in Pharmacology)
6.2.2.5 The Nasal Route (From Cocaine to Corticosteroids):
Figure 6.5: Historical account of local nasal route with systemic toxicity
6.2.2.6 Recent Advances (Local Nasal Delivery):
Mucoadhesive nanoparticles & gels: prolong residence time on nasal mucosa, enhancing
efficacy of antifungals and corticosteroids.
Nasal microbiome–targeted sprays: under research for managing chronic sinusitis by
rebalancing local flora.
Device-assisted irrigation systems: controlled pressure saline irrigation improves clearance
in chronic rhinosinusitis.
Smart sprays with dose counters & mist technology: improving adherence and deposition
pattern.
1884: Carl
Koller
demonstrated
cocaine as a local
anesthetic via
nasal and ocular
mucosa,
revolutionizing
ENTsurgery —
but cocaine’s
addictive and
systemic toxic
potential soon
became
notorious.
Mid-20th
century:
Adrenergic
vasoconstrictors
(ephedrine,
phenylephrine)
were developed
as safer
alternatives,
though still
linked to rebound
congestion when
overused.
1970s–80s:
Introduction of
intranasal
corticosteroids
provided
effective long-
term control of
allergic rhinitis
with minimal
systemic toxicity
—establishing
the nasal route as
first-line for
allergy
management.
1990s onwards:
Antihistamine
sprays
(azelastine) and
combination
therapy further
improved local
allergic control.
Present era: The
nasal route has
expanded beyond
local therapy into
systemic delivery
and vaccines but
remains essential
for rapid local
relief in rhinitis
and sinus disease.
General Pharmacology Section-1 Drug
182 BAASIR UMAIR (MPhil in Pharmacology)
Figure 6.6: Intranasal special delivery system designed for local effect
6.2.3 Oral Local Route (Oropharyngeal Local Route):
The oral cavity and upper gastrointestinal tract represent a major entry route for drugs. While oral
delivery is most often associated with systemic therapy, a distinct subset of agents is formulated
specifically for local action within the mouth, pharynx, esophagus, or gut lumen. These drugs
demonstrate the principle that a drug administered orally is not necessarily systemic—its
formulation, solubility, and site of action determine whether it remains local.
6.2.2.1 Formulations and Local Use Cases:
a. Oropharyngeal Preparations (local topical action):
Lozenges, troches, gargles, sprays for antisepsis and analgesia.
Examples:
o Chlorhexidine gargles — oral antisepsis, gingivitis.
o Povidone-iodine gargles — pharyngitis.
o Benzocaine, dyclonine lozenges — local anesthetic effect.
o Clotrimazole troches — oral candidiasis.
b. Esophageal Therapy (local luminal action):
Some oral suspensions are not absorbed systemically.
Example:
o Amphotericin B suspension for esophageal candidiasis — poorly absorbed, acts
locally, minimal systemic toxicity in conventional oral dosage form.
c. Gastric & Intestinal Preparations (local GI action):
Antacids (aluminum hydroxide, magnesium hydroxide, calcium carbonate): neutralize
gastric acid locally without systemic absorption (except small ionic fractions).
182 BAASIR UMAIR (MPhil in Pharmacology)
Figure 6.6: Intranasal special delivery system designed for local effect
6.2.3 Oral Local Route (Oropharyngeal Local Route):
The oral cavity and upper gastrointestinal tract represent a major entry route for drugs. While oral
delivery is most often associated with systemic therapy, a distinct subset of agents is formulated
specifically for local action within the mouth, pharynx, esophagus, or gut lumen. These drugs
demonstrate the principle that a drug administered orally is not necessarily systemic—its
formulation, solubility, and site of action determine whether it remains local.
6.2.2.1 Formulations and Local Use Cases:
a. Oropharyngeal Preparations (local topical action):
Lozenges, troches, gargles, sprays for antisepsis and analgesia.
Examples:
o Chlorhexidine gargles — oral antisepsis, gingivitis.
o Povidone-iodine gargles — pharyngitis.
o Benzocaine, dyclonine lozenges — local anesthetic effect.
o Clotrimazole troches — oral candidiasis.
b. Esophageal Therapy (local luminal action):
Some oral suspensions are not absorbed systemically.
Example:
o Amphotericin B suspension for esophageal candidiasis — poorly absorbed, acts
locally, minimal systemic toxicity in conventional oral dosage form.
c. Gastric & Intestinal Preparations (local GI action):
Antacids (aluminum hydroxide, magnesium hydroxide, calcium carbonate): neutralize
gastric acid locally without systemic absorption (except small ionic fractions).
General Pharmacology Section-1 Drug
183 BAASIR UMAIR (MPhil in Pharmacology)
Sucralfate: forms a protective barrier over ulcer craters, acting topically on gastric mucosa.
Laxatives / anti-constipative agents:
o Bulk-forming: psyllium, methylcellulose — act locally to increase stool bulk.
o Osmotic: lactulose, polyethylene glycol — retain water in lumen.
o Stimulant: bisacodyl, senna — locally stimulate mucosal nerves.
Locally acting antibiotics/adsorbents:
o Rifaximin — poorly absorbed, used for traveler’s diarrhea and hepatic
encephalopathy.
o Kaolin-pectin suspensions — local adsorbent action in diarrhea.
6.2.2.2 Rationale for its Local effect:
Point of application = site of action:
o Lozenges, gargles, sprays → mucosa of mouth/throat.
o Antacids, sucralfate, laxatives → gastric or intestinal lumen.
Minimal absorption: drugs designed with poor solubility or high polarity (e.g.,
amphotericin B suspension, sucralfate) remain in the GI tract.
Formulation trapping: viscous gels, suspensions, or tablets that disintegrate slowly ensure
the drug acts locally without systemic spread.
(Oral systemic route is discussed in a later section of the chapter)
6.2.2.2 Systemic Spillover From local oral administration:
Table 6.5: Oral drugs with local action: potential systemic effect
Agent / Class Local Oral Use Potential Systemic or Local Effect
Magnesium-containing
antacids
Heartburn, dyspepsia Hypermagnesemia in renal impairment → hypotension,
arrhythmia, muscle weakness
Aluminum hydroxide Heartburn, acid
neutralization
Hypophosphatemia with prolonged use → bone
demineralization, osteomalacia
Bisacodyl (stimulant
laxative)
Constipation Diarrhea, electrolyte imbalance, and hypokalemia if
abused
Chlorhexidine
gargles/mouthwash
Oral antisepsis,
gingivitis
Tooth staining, taste alteration, mucosal irritation; rare
systemic absorption
Benzocaine
lozenges/sprays
Oral/ throat local
anesthesia
Methemoglobinemia (rare, dose-dependent)
Sodium bicarbonate
antacids
Heartburn, acid reflux Metabolic alkalosis, fluid overload in renal/cardiac patients
Kaolin-pectin Diarrhea management Rare constipation: systemic absorption is minimal but can
bind drugs → reduce absorption of co-administered drugs
Oral sucralfate Ulcer coating agent Aluminum absorption → neurotoxicity in renal failure
Local anesthetic viscous
lidocaine
Oral pain relief
(stomatitis, mucositis)
Systemic toxicity if excessive: CNS depression, cardiac
arrhythmias
Nystatin oral suspension Oral candidiasis Rare systemic effects; hypersensitivity possible
183 BAASIR UMAIR (MPhil in Pharmacology)
Sucralfate: forms a protective barrier over ulcer craters, acting topically on gastric mucosa.
Laxatives / anti-constipative agents:
o Bulk-forming: psyllium, methylcellulose — act locally to increase stool bulk.
o Osmotic: lactulose, polyethylene glycol — retain water in lumen.
o Stimulant: bisacodyl, senna — locally stimulate mucosal nerves.
Locally acting antibiotics/adsorbents:
o Rifaximin — poorly absorbed, used for traveler’s diarrhea and hepatic
encephalopathy.
o Kaolin-pectin suspensions — local adsorbent action in diarrhea.
6.2.2.2 Rationale for its Local effect:
Point of application = site of action:
o Lozenges, gargles, sprays → mucosa of mouth/throat.
o Antacids, sucralfate, laxatives → gastric or intestinal lumen.
Minimal absorption: drugs designed with poor solubility or high polarity (e.g.,
amphotericin B suspension, sucralfate) remain in the GI tract.
Formulation trapping: viscous gels, suspensions, or tablets that disintegrate slowly ensure
the drug acts locally without systemic spread.
(Oral systemic route is discussed in a later section of the chapter)
6.2.2.2 Systemic Spillover From local oral administration:
Table 6.5: Oral drugs with local action: potential systemic effect
Agent / Class Local Oral Use Potential Systemic or Local Effect
Magnesium-containing
antacids
Heartburn, dyspepsia Hypermagnesemia in renal impairment → hypotension,
arrhythmia, muscle weakness
Aluminum hydroxide Heartburn, acid
neutralization
Hypophosphatemia with prolonged use → bone
demineralization, osteomalacia
Bisacodyl (stimulant
laxative)
Constipation Diarrhea, electrolyte imbalance, and hypokalemia if
abused
Chlorhexidine
gargles/mouthwash
Oral antisepsis,
gingivitis
Tooth staining, taste alteration, mucosal irritation; rare
systemic absorption
Benzocaine
lozenges/sprays
Oral/ throat local
anesthesia
Methemoglobinemia (rare, dose-dependent)
Sodium bicarbonate
antacids
Heartburn, acid reflux Metabolic alkalosis, fluid overload in renal/cardiac patients
Kaolin-pectin Diarrhea management Rare constipation: systemic absorption is minimal but can
bind drugs → reduce absorption of co-administered drugs
Oral sucralfate Ulcer coating agent Aluminum absorption → neurotoxicity in renal failure
Local anesthetic viscous
lidocaine
Oral pain relief
(stomatitis, mucositis)
Systemic toxicity if excessive: CNS depression, cardiac
arrhythmias
Nystatin oral suspension Oral candidiasis Rare systemic effects; hypersensitivity possible
General Pharmacology Section-1 Drug
184 BAASIR UMAIR (MPhil in Pharmacology)
6.2.2.3 Oral Local Therapy (From Charcoal to Amphotericin B):
Figure 6.7: Historical account of local oral route with systemic toxicity
6.2.2.4 Recent Advances:
Mucoadhesive lozenges/troches: prolonged residence time in oral cavity, better antifungal
activity.
Nanoparticle antacids & gastroprotection’s: improved local adhesion to mucosa, slower
neutralization profile.
Colon-targeted probiotics and adsorbents: engineered formulations reaching the colon
intact for local microbiome modulation.
3D-printed oral dosage forms: customizable release patterns for site-specific local action.
Ancient medicine:
charcoal and clay
were administered
orally to adsorb
poisons —the first
“local GI therapies.”
19th century:
magnesium and
sodium salts were
introduced as
purgatives,
demonstrating
selective local GI
effects.
Mid-20th century:
Amphotericin B
suspension was
developed for
esophageal candidiasis
—a pivotal
demonstration that
even potent systemic
antifungals can be
reformulated for local
use by exploiting poor
absorption.
Late 20th century:
antacids and sucralfate
became standard for
peptic ulcer disease,
long before proton-
pump inhibitors.
Clinical Pearls:
Local oral drugs are therapeutic “site-selective” agents—their efficacy is due to
confinement to the mucosa or lumen.
Physicians should anticipate exceptions: even a “non-absorbed” drug may cause systemic
issues in special populations (renal disease, pediatric, elderly).
Correct formulation choice (suspension vs solid, pH-dependent coatings) determines
whether an oral drug acts locally or systemically.
184 BAASIR UMAIR (MPhil in Pharmacology)
6.2.2.3 Oral Local Therapy (From Charcoal to Amphotericin B):
Figure 6.7: Historical account of local oral route with systemic toxicity
6.2.2.4 Recent Advances:
Mucoadhesive lozenges/troches: prolonged residence time in oral cavity, better antifungal
activity.
Nanoparticle antacids & gastroprotection’s: improved local adhesion to mucosa, slower
neutralization profile.
Colon-targeted probiotics and adsorbents: engineered formulations reaching the colon
intact for local microbiome modulation.
3D-printed oral dosage forms: customizable release patterns for site-specific local action.
Ancient medicine:
charcoal and clay
were administered
orally to adsorb
poisons —the first
“local GI therapies.”
19th century:
magnesium and
sodium salts were
introduced as
purgatives,
demonstrating
selective local GI
effects.
Mid-20th century:
Amphotericin B
suspension was
developed for
esophageal candidiasis
—a pivotal
demonstration that
even potent systemic
antifungals can be
reformulated for local
use by exploiting poor
absorption.
Late 20th century:
antacids and sucralfate
became standard for
peptic ulcer disease,
long before proton-
pump inhibitors.
Clinical Pearls:
Local oral drugs are therapeutic “site-selective” agents—their efficacy is due to
confinement to the mucosa or lumen.
Physicians should anticipate exceptions: even a “non-absorbed” drug may cause systemic
issues in special populations (renal disease, pediatric, elderly).
Correct formulation choice (suspension vs solid, pH-dependent coatings) determines
whether an oral drug acts locally or systemically.
General Pharmacology Section-1 Drug
185 BAASIR UMAIR (MPhil in Pharmacology)
6.2.4 Rectal Local Route (local use):
The rectum provides a unique anatomical and physiological setting for local drug administration.
Unlike the upper gastrointestinal tract, it lacks digestive enzymes and exhibits a relatively neutral
pH, making it a favorable site for delivering drugs intended to act directly on rectal mucosa. Local
therapy via the rectum is particularly useful in conditions where oral therapy is impractical, where
targeted local effect is desirable, or where systemic side effects of conventional therapy must be
minimized.
6.2.4.1 Rationale for its Local effect:
When drugs are administered rectally for local purposes, they primarily act on the mucosal lining
or directly on rectal contents. The local pharmacological effect is determined by:
Surface interaction: Suppositories releasing drugs such as bisacodyl act directly on mucosal
nerve endings, stimulating peristalsis.
Osmotic or irritant action: Agents like glycerin suppositories or saline enemas draw water
into the lumen, softening stool and inducing defecation.
Direct mucosal contact: Anti-inflammatory drugs (e.g., mesalamine suppositories) achieve
high local concentration at the site of inflammation in ulcerative proctitis.
(systemic rectal route is discussed in the later section)
6.2.4.2 Examples of Local Rectal Applications:
Laxatives and stool softeners:
o Bisacodyl suppositories → irritant action on mucosa.
o Glycerin suppositories → osmotic action.
o Docusate enemas → surfactant effect.
Anti-inflammatory agents:
o Mesalamine (5-ASA) suppositories or enemas for ulcerative proctitis.
o Hydrocortisone foam in proctitis and hemorrhoids.
Local anesthetics and vasoconstrictors:
o Lidocaine gels or suppositories for hemorrhoidal pain.
o Phenylephrine suppositories to reduce vascular engorgement.
Antimicrobial agents:
o Metronidazole or nystatin suppositories for rectal infections.
6.2.4.3 Systemic Spillover and Exceptions:
Table 6.6: Rectal drugs with local action: potential systemic effects
Agent / Class Intended Local Use (Rectal
Route)
Potential Systemic Effects / Toxicity
Bisacodyl suppositories Constipation relief (stimulant
laxative)
Rare systemic cramping, diarrhea,
electrolyte imbalance (if excessive use)
Hydrocortisone
suppositories/foam
Hemorrhoids, proctitis, IBD
(local inflammation)
With prolonged/chronic use → adrenal
suppression, Cushingoid features, growth
retardation in children
Mesalamine
enemas/suppositories
Ulcerative colitis, proctitis Mostly local; systemic absorption (rare) →
interstitial nephritis, renal toxicity
Glycerin suppositories Constipation (osmotic effect) Minimal systemic absorption; occasional
diarrhea, dehydration in children if
overused
185 BAASIR UMAIR (MPhil in Pharmacology)
6.2.4 Rectal Local Route (local use):
The rectum provides a unique anatomical and physiological setting for local drug administration.
Unlike the upper gastrointestinal tract, it lacks digestive enzymes and exhibits a relatively neutral
pH, making it a favorable site for delivering drugs intended to act directly on rectal mucosa. Local
therapy via the rectum is particularly useful in conditions where oral therapy is impractical, where
targeted local effect is desirable, or where systemic side effects of conventional therapy must be
minimized.
6.2.4.1 Rationale for its Local effect:
When drugs are administered rectally for local purposes, they primarily act on the mucosal lining
or directly on rectal contents. The local pharmacological effect is determined by:
Surface interaction: Suppositories releasing drugs such as bisacodyl act directly on mucosal
nerve endings, stimulating peristalsis.
Osmotic or irritant action: Agents like glycerin suppositories or saline enemas draw water
into the lumen, softening stool and inducing defecation.
Direct mucosal contact: Anti-inflammatory drugs (e.g., mesalamine suppositories) achieve
high local concentration at the site of inflammation in ulcerative proctitis.
(systemic rectal route is discussed in the later section)
6.2.4.2 Examples of Local Rectal Applications:
Laxatives and stool softeners:
o Bisacodyl suppositories → irritant action on mucosa.
o Glycerin suppositories → osmotic action.
o Docusate enemas → surfactant effect.
Anti-inflammatory agents:
o Mesalamine (5-ASA) suppositories or enemas for ulcerative proctitis.
o Hydrocortisone foam in proctitis and hemorrhoids.
Local anesthetics and vasoconstrictors:
o Lidocaine gels or suppositories for hemorrhoidal pain.
o Phenylephrine suppositories to reduce vascular engorgement.
Antimicrobial agents:
o Metronidazole or nystatin suppositories for rectal infections.
6.2.4.3 Systemic Spillover and Exceptions:
Table 6.6: Rectal drugs with local action: potential systemic effects
Agent / Class Intended Local Use (Rectal
Route)
Potential Systemic Effects / Toxicity
Bisacodyl suppositories Constipation relief (stimulant
laxative)
Rare systemic cramping, diarrhea,
electrolyte imbalance (if excessive use)
Hydrocortisone
suppositories/foam
Hemorrhoids, proctitis, IBD
(local inflammation)
With prolonged/chronic use → adrenal
suppression, Cushingoid features, growth
retardation in children
Mesalamine
enemas/suppositories
Ulcerative colitis, proctitis Mostly local; systemic absorption (rare) →
interstitial nephritis, renal toxicity
Glycerin suppositories Constipation (osmotic effect) Minimal systemic absorption; occasional
diarrhea, dehydration in children if
overused
General Pharmacology Section-1 Drug
186 BAASIR UMAIR (MPhil in Pharmacology)
Indomethacin suppositories Acute gout, dysmenorrhea,
pain
Systemic NSAID effects: GI bleeding,
renal impairment, cardiovascular risk
Paracetamol (acetaminophen)
suppositories
Analgesic, antipyretic
(pediatrics, when oral route
not possible)
Dose-dependent hepatotoxicity if
overdosed
Diazepam rectal gel Acute seizures (especially
pediatric emergencies)
Desired systemic sedation; risk of
respiratory depression, dependence
Ergotamine suppositories
(historical use in migraine)
Local administration to
bypass GI upset
Vasospasm, hypertension, nausea, ischemia
due to systemic absorption
Opioid suppositories (morphine,
oxycodone – palliative care)
Severe pain, especially in
cancer
Desired analgesia but also systemic side
effects: constipation, respiratory
depression, dependence
6.2.4.3 Formulations:
Rectal dosage forms designed for local delivery include:
Suppositories: Solid base (cocoa butter, PEG) melting at body temperature.
Enemas: Aqueous or oil-based solutions (mesalamine enemas, glycerin enemas).
Foams: Expanding formulations (hydrocortisone foam) for uniform mucosal coating.
Creams/gels: Less common, occasionally used for hemorrhoidal or perianal conditions.
Figure 6.8: Different types of rectal dosage forms
186 BAASIR UMAIR (MPhil in Pharmacology)
Indomethacin suppositories Acute gout, dysmenorrhea,
pain
Systemic NSAID effects: GI bleeding,
renal impairment, cardiovascular risk
Paracetamol (acetaminophen)
suppositories
Analgesic, antipyretic
(pediatrics, when oral route
not possible)
Dose-dependent hepatotoxicity if
overdosed
Diazepam rectal gel Acute seizures (especially
pediatric emergencies)
Desired systemic sedation; risk of
respiratory depression, dependence
Ergotamine suppositories
(historical use in migraine)
Local administration to
bypass GI upset
Vasospasm, hypertension, nausea, ischemia
due to systemic absorption
Opioid suppositories (morphine,
oxycodone – palliative care)
Severe pain, especially in
cancer
Desired analgesia but also systemic side
effects: constipation, respiratory
depression, dependence
6.2.4.3 Formulations:
Rectal dosage forms designed for local delivery include:
Suppositories: Solid base (cocoa butter, PEG) melting at body temperature.
Enemas: Aqueous or oil-based solutions (mesalamine enemas, glycerin enemas).
Foams: Expanding formulations (hydrocortisone foam) for uniform mucosal coating.
Creams/gels: Less common, occasionally used for hemorrhoidal or perianal conditions.
Figure 6.8: Different types of rectal dosage forms
General Pharmacology Section-1 Drug
187 BAASIR UMAIR (MPhil in Pharmacology)
6.2.4.4 Historical Note: Rectal Route in Antiquity:
Figure 6.9: Rectal route across history
6.2.5 Vaginal Route (local mucosal application):
The vaginal mucosa is a highly vascularized and non-keratinized epithelium with an acidic
environment (pH 3.5–4.5) maintained by lactobacilli. This environment favors local therapeutic
action of drugs while simultaneously offering partial systemic absorption depending on the
physicochemical properties of the formulation. Local vaginal administration is primarily used for
gynecological and infectious conditions, contraception, and hormonal therapy.
6.2.5.1 Rationale for its Local effect:
Direct mucosal interaction: Antifungal or antibacterial drugs act on pathogens colonizing
the vaginal mucosa.
Barrier modification: Spermicides alter sperm motility and survival.
Hormone delivery to target tissue: Estrogen creams locally relieve atrophic vaginitis
without high systemic exposure.
Acidification or lubrication: Agents restore physiological vaginal environment or relieve
dryness.
Ancient
Greece&
Rome:
Hippocrates
andGalen
described
enemaswith
wine,vinegar,
andherbal
extractsfor
digestiveand
systemic
ailments.
Traditional
Chinese
medicine:
Herbal
decoctions
were
sometimes
givenrectally
totreatfevers
or“heat”
syndromes.
16th–17th
century
Europe:
Royal
physicians
prescribed
medicated
enemas
(clysters)with
opium,
purgatives,or
aromaticsfor
nobles—
sometimes
multipletimes
aday(Louis
XIV
reportedly
received
thousands
duringhis
reign).
18thcentury:
Besides
tobacco
smoke
resuscitation,
rectaldelivery
ofopiumand
laudanumwas
commonfor
painand
sedation.
19thcentury:
Rectalether
and
chloroform
enemaswere
attemptedfor
anesthesia
when
inhalationwas
notpossible.
Early20th
century:
Rectalaspirin
and
antipyretics
wereusedin
childrenand
febrile
patients
unabletotake
oral
medication.
187 BAASIR UMAIR (MPhil in Pharmacology)
6.2.4.4 Historical Note: Rectal Route in Antiquity:
Figure 6.9: Rectal route across history
6.2.5 Vaginal Route (local mucosal application):
The vaginal mucosa is a highly vascularized and non-keratinized epithelium with an acidic
environment (pH 3.5–4.5) maintained by lactobacilli. This environment favors local therapeutic
action of drugs while simultaneously offering partial systemic absorption depending on the
physicochemical properties of the formulation. Local vaginal administration is primarily used for
gynecological and infectious conditions, contraception, and hormonal therapy.
6.2.5.1 Rationale for its Local effect:
Direct mucosal interaction: Antifungal or antibacterial drugs act on pathogens colonizing
the vaginal mucosa.
Barrier modification: Spermicides alter sperm motility and survival.
Hormone delivery to target tissue: Estrogen creams locally relieve atrophic vaginitis
without high systemic exposure.
Acidification or lubrication: Agents restore physiological vaginal environment or relieve
dryness.
Ancient
Greece&
Rome:
Hippocrates
andGalen
described
enemaswith
wine,vinegar,
andherbal
extractsfor
digestiveand
systemic
ailments.
Traditional
Chinese
medicine:
Herbal
decoctions
were
sometimes
givenrectally
totreatfevers
or“heat”
syndromes.
16th–17th
century
Europe:
Royal
physicians
prescribed
medicated
enemas
(clysters)with
opium,
purgatives,or
aromaticsfor
nobles—
sometimes
multipletimes
aday(Louis
XIV
reportedly
received
thousands
duringhis
reign).
18thcentury:
Besides
tobacco
smoke
resuscitation,
rectaldelivery
ofopiumand
laudanumwas
commonfor
painand
sedation.
19thcentury:
Rectalether
and
chloroform
enemaswere
attemptedfor
anesthesia
when
inhalationwas
notpossible.
Early20th
century:
Rectalaspirin
and
antipyretics
wereusedin
childrenand
febrile
patients
unabletotake
oral
medication.
General Pharmacology Section-1 Drug
188 BAASIR UMAIR (MPhil in Pharmacology)
6.2.5.2 Examples of Local Vaginal Applications:
Antifungals and antibacterials:
o Clotrimazole, miconazole, nystatin suppositories/creams for vulvovaginal
candidiasis.
o Clindamycin for vaginitis
o Metronidazole gel for bacterial vaginosis.
Contraceptives:
o Nonoxynol-9 suppositories/foams as spermicidal agents.
o Levonorgestrel-releasing vaginal rings (though systemic absorption contributes, the
primary design is local contraception).
Hormonal preparations:
o Estradiol or conjugated estrogen creams, pessaries, vaginal rings for menopausal
vaginal atrophy, dryness, and dyspareunia.
Anti-inflammatory and lubricating agents:
o Hydrocortisone suppositories for inflammatory vaginitis.
o Polycarbophil-based moisturizers for dryness.
6.2.5.3 Systemic Spillover and Exceptions:
Table 6.7: Vaginal drugs with local action: potential systemic effects
Agent / Class Intended Local Use Systemic Effects / Toxicity
Misoprostol vaginal tablets Cervical ripening, induction
of labor, and medical
abortion
Systemic absorption → uterotonic effect
(therapeutic), cramping, diarrhea, fever
Estrogen vaginal
creams/tablets (estradiol,
conjugated estrogens)
Atrophic vaginitis,
menopausal symptoms
Low but measurable systemic absorption;
concern in breast cancer survivors (risk of
recurrence, endometrial hyperplasia)
Nonoxynol-9 spermicides Contraceptive (spermicide,
intravaginal)
Local mucosal irritation; repeated use ↑ risk of
HIV/STI acquisition
Clotrimazole, miconazole
vaginal formulations
Antifungal therapy
(candidiasis)
Minimal systemic absorption; occasional local
irritation, burning
Metronidazole vaginal gel Bacterial vaginosis Limited systemic absorption → metallic taste,
nausea in some cases
Progesterone vaginal
suppositories/gels
Assisted reproduction,
luteal support
Systemic absorption → sedation, dizziness,
breast tenderness
Lidocaine vaginal gel (local
anesthetic)
Pre-procedural anesthesia,
pain relief
Excessive absorption → CNS toxicity,
arrhythmias (rare)
6.2.5.4 Formulations:
Suppositories (pessaries): Solid dosage forms melting at body temperature.
Creams and gels: Easily spreadable, ensuring uniform coverage.
Foams: Less common, used for spermicidal action.
Vaginal rings: Flexible polymeric devices releasing drug over weeks or months.
Tablets/capsules: Designed for local disintegration (e.g., clotrimazole).
188 BAASIR UMAIR (MPhil in Pharmacology)
6.2.5.2 Examples of Local Vaginal Applications:
Antifungals and antibacterials:
o Clotrimazole, miconazole, nystatin suppositories/creams for vulvovaginal
candidiasis.
o Clindamycin for vaginitis
o Metronidazole gel for bacterial vaginosis.
Contraceptives:
o Nonoxynol-9 suppositories/foams as spermicidal agents.
o Levonorgestrel-releasing vaginal rings (though systemic absorption contributes, the
primary design is local contraception).
Hormonal preparations:
o Estradiol or conjugated estrogen creams, pessaries, vaginal rings for menopausal
vaginal atrophy, dryness, and dyspareunia.
Anti-inflammatory and lubricating agents:
o Hydrocortisone suppositories for inflammatory vaginitis.
o Polycarbophil-based moisturizers for dryness.
6.2.5.3 Systemic Spillover and Exceptions:
Table 6.7: Vaginal drugs with local action: potential systemic effects
Agent / Class Intended Local Use Systemic Effects / Toxicity
Misoprostol vaginal tablets Cervical ripening, induction
of labor, and medical
abortion
Systemic absorption → uterotonic effect
(therapeutic), cramping, diarrhea, fever
Estrogen vaginal
creams/tablets (estradiol,
conjugated estrogens)
Atrophic vaginitis,
menopausal symptoms
Low but measurable systemic absorption;
concern in breast cancer survivors (risk of
recurrence, endometrial hyperplasia)
Nonoxynol-9 spermicides Contraceptive (spermicide,
intravaginal)
Local mucosal irritation; repeated use ↑ risk of
HIV/STI acquisition
Clotrimazole, miconazole
vaginal formulations
Antifungal therapy
(candidiasis)
Minimal systemic absorption; occasional local
irritation, burning
Metronidazole vaginal gel Bacterial vaginosis Limited systemic absorption → metallic taste,
nausea in some cases
Progesterone vaginal
suppositories/gels
Assisted reproduction,
luteal support
Systemic absorption → sedation, dizziness,
breast tenderness
Lidocaine vaginal gel (local
anesthetic)
Pre-procedural anesthesia,
pain relief
Excessive absorption → CNS toxicity,
arrhythmias (rare)
6.2.5.4 Formulations:
Suppositories (pessaries): Solid dosage forms melting at body temperature.
Creams and gels: Easily spreadable, ensuring uniform coverage.
Foams: Less common, used for spermicidal action.
Vaginal rings: Flexible polymeric devices releasing drug over weeks or months.
Tablets/capsules: Designed for local disintegration (e.g., clotrimazole).
General Pharmacology Section-1 Drug
189 BAASIR UMAIR (MPhil in Pharmacology)
6.2.5.5 Vaginal Therapeutics Across Time:
Figure 6.10: Vaginal route across history
6.2.6 Inhalational Route (Local Respiratory Therapy):
When used for local respiratory therapy, the inhalational route is defined as the delivery of drugs
directly into the respiratory tract to exert their primary effect on airway mucosa, bronchial smooth
muscle, or alveolar surfaces, rather than systemic circulation.
The lung provides a large absorptive surface area, thin epithelial barrier, and rich
vasculature, so systemic absorption is possible — but the therapeutic design here aims for
high local drug concentration at the site of pathology with minimal systemic exposure.
This is why inhalation therapy is central to the management of diseases like asthma, chronic
obstructive pulmonary disease (COPD), bronchiectasis, allergic rhinitis, and local
pulmonary infections.
6.2.6.1 Dosage forms and formulations:
1. Metered-dose inhalers (MDIs): propellant-based, deliver precise doses of aerosolized drug
(e.g., salbutamol, beclomethasone).
2. Dry-powder inhalers (DPIs): breath-actuated, powder particles delivered on inspiration
(e.g., budesonide DPI, salmeterol/fluticasone combination).
3. Nebulizers (jet, ultrasonic, mesh): convert liquid into fine mist for inhalation, useful in
children/elderly or severe exacerbations.
4. Pressurized aerosols: bronchodilators, anticholinergics, inhaled steroids.
5. Inhaled antimicrobials: aerosolized amphotericin B, tobramycin (for cystic fibrosis).
Ancient Egypt
(~1550 BCE):
Ebers Papyrus→
honey, dates, and
acacia used as
contraceptives →
early vaginal
pessaries.
Medieval
Europe: Vinegar-
soaked sponges
used as
spermicides.
Mid-20th
century:
Standardized
antifungal
pessaries (e.g.,
clotrimazole,
miconazole)
introduced for
vaginal
candidiasis.
1990s: Vaginal
rings
(contraceptive,
estradiol)
developed →
sustained-release,
localized
gynecological
therapy.
Present era:
Nanoparticle-
based vaginal
formulations and
multipurpose
prevention rings
(HIV +
contraception)
mark a shift
toward dual-
protection and
advanced drug
delivery.
189 BAASIR UMAIR (MPhil in Pharmacology)
6.2.5.5 Vaginal Therapeutics Across Time:
Figure 6.10: Vaginal route across history
6.2.6 Inhalational Route (Local Respiratory Therapy):
When used for local respiratory therapy, the inhalational route is defined as the delivery of drugs
directly into the respiratory tract to exert their primary effect on airway mucosa, bronchial smooth
muscle, or alveolar surfaces, rather than systemic circulation.
The lung provides a large absorptive surface area, thin epithelial barrier, and rich
vasculature, so systemic absorption is possible — but the therapeutic design here aims for
high local drug concentration at the site of pathology with minimal systemic exposure.
This is why inhalation therapy is central to the management of diseases like asthma, chronic
obstructive pulmonary disease (COPD), bronchiectasis, allergic rhinitis, and local
pulmonary infections.
6.2.6.1 Dosage forms and formulations:
1. Metered-dose inhalers (MDIs): propellant-based, deliver precise doses of aerosolized drug
(e.g., salbutamol, beclomethasone).
2. Dry-powder inhalers (DPIs): breath-actuated, powder particles delivered on inspiration
(e.g., budesonide DPI, salmeterol/fluticasone combination).
3. Nebulizers (jet, ultrasonic, mesh): convert liquid into fine mist for inhalation, useful in
children/elderly or severe exacerbations.
4. Pressurized aerosols: bronchodilators, anticholinergics, inhaled steroids.
5. Inhaled antimicrobials: aerosolized amphotericin B, tobramycin (for cystic fibrosis).
Ancient Egypt
(~1550 BCE):
Ebers Papyrus→
honey, dates, and
acacia used as
contraceptives →
early vaginal
pessaries.
Medieval
Europe: Vinegar-
soaked sponges
used as
spermicides.
Mid-20th
century:
Standardized
antifungal
pessaries (e.g.,
clotrimazole,
miconazole)
introduced for
vaginal
candidiasis.
1990s: Vaginal
rings
(contraceptive,
estradiol)
developed →
sustained-release,
localized
gynecological
therapy.
Present era:
Nanoparticle-
based vaginal
formulations and
multipurpose
prevention rings
(HIV +
contraception)
mark a shift
toward dual-
protection and
advanced drug
delivery.
General Pharmacology Section-1 Drug
190 BAASIR UMAIR (MPhil in Pharmacology)
6.2.6.2 Representative drugs and local uses:
Bronchodilators:
o Short-acting β₂-agonists (salbutamol, terbutaline, levalbuterol).
o Long-acting β₂-agonists (salmeterol, formoterol).
o Anticholinergics (ipratropium, tiotropium).
Anti-inflammatory agents:
o Inhaled corticosteroids (beclomethasone, budesonide, fluticasone).
o Cromolyn sodium, nedocromil (mast-cell stabilizers, now less common).
Antimicrobials:
o Tobramycin inhalation solution (Pseudomonas in cystic fibrosis).
o Amphotericin B aerosol (pulmonary fungal infections in immunocompromised
patients).
Others:
o Dornase alfa (recombinant DNase for cystic fibrosis).
o Inhaled nitric oxide (local pulmonary vasodilation in neonatal pulmonary
hypertension).
6.2.6.3 Rationale for its Local effect:
The point of application = the site of action (airways/lungs).
Salbutamol inhaled via MDI relaxes bronchial smooth muscle directly, with
bronchodilation measurable within minutes.
Corticosteroid inhalers suppress local airway inflammation at the mucosa without requiring
systemic immunosuppression.
Amphotericin B aerosolized acts on fungal lesions in alveoli/bronchi but does not reach
effective systemic plasma levels in conventional inhaled doses.
(Inhalational systemic routes are discussed in the later section)
6.2.6.4 Exceptions (systemic spillover):
Table 6.8: Systemic consequences of locally inhaled drug therapy
Agent / Class Intended Use Systemic Effects
Inhaled non-selective β-agonists
Bronchodilation in
asthma/COPD
Tremor, tachycardia, and hypokalemia due to
systemic absorption
Inhaled corticosteroids
Local anti-inflammatory effect
in airways
HPA axis suppression, growth retardation in
children, oral candidiasis, systemic effects
Inhaled nitric oxide
Pulmonary vasodilator in
neonates/ARDS
Risk of systemic methemoglobinemia if
overdosed
Volatile anesthetic gases (ether,
halothane, isoflurane, sevoflurane)
Induction/maintenance of
anesthesia
Direct systemic CNS action (clear exception:
systemic rather than local therapy)
190 BAASIR UMAIR (MPhil in Pharmacology)
6.2.6.2 Representative drugs and local uses:
Bronchodilators:
o Short-acting β₂-agonists (salbutamol, terbutaline, levalbuterol).
o Long-acting β₂-agonists (salmeterol, formoterol).
o Anticholinergics (ipratropium, tiotropium).
Anti-inflammatory agents:
o Inhaled corticosteroids (beclomethasone, budesonide, fluticasone).
o Cromolyn sodium, nedocromil (mast-cell stabilizers, now less common).
Antimicrobials:
o Tobramycin inhalation solution (Pseudomonas in cystic fibrosis).
o Amphotericin B aerosol (pulmonary fungal infections in immunocompromised
patients).
Others:
o Dornase alfa (recombinant DNase for cystic fibrosis).
o Inhaled nitric oxide (local pulmonary vasodilation in neonatal pulmonary
hypertension).
6.2.6.3 Rationale for its Local effect:
The point of application = the site of action (airways/lungs).
Salbutamol inhaled via MDI relaxes bronchial smooth muscle directly, with
bronchodilation measurable within minutes.
Corticosteroid inhalers suppress local airway inflammation at the mucosa without requiring
systemic immunosuppression.
Amphotericin B aerosolized acts on fungal lesions in alveoli/bronchi but does not reach
effective systemic plasma levels in conventional inhaled doses.
(Inhalational systemic routes are discussed in the later section)
6.2.6.4 Exceptions (systemic spillover):
Table 6.8: Systemic consequences of locally inhaled drug therapy
Agent / Class Intended Use Systemic Effects
Inhaled non-selective β-agonists
Bronchodilation in
asthma/COPD
Tremor, tachycardia, and hypokalemia due to
systemic absorption
Inhaled corticosteroids
Local anti-inflammatory effect
in airways
HPA axis suppression, growth retardation in
children, oral candidiasis, systemic effects
Inhaled nitric oxide
Pulmonary vasodilator in
neonates/ARDS
Risk of systemic methemoglobinemia if
overdosed
Volatile anesthetic gases (ether,
halothane, isoflurane, sevoflurane)
Induction/maintenance of
anesthesia
Direct systemic CNS action (clear exception:
systemic rather than local therapy)
General Pharmacology Section-1 Drug
191 BAASIR UMAIR (MPhil in Pharmacology)
6.2.6.5 Historical note:
.
Figure 6.11: Historical account of the inhalational route
6.2.7 Intradermal Injection (Diagnostic and Desensitization Purposes):
The intradermal route involves the injection of a very small volume of solution (usually
0.1–0.2 mL) into the dermis, the layer of skin just below the epidermis but above the
subcutaneous tissue. The purpose here is not systemic therapy, but rather to induce a
controlled local reaction in the skin that can be clinically observed or quantified.
Because the dermis contains abundant dendritic cells, mast cells, and a dense capillary–
lymphatic network, it is a strategic site for immune testing and desensitization. The
response is local — redness, swelling, or wheal formation — and is then interpreted
diagnostically or used therapeutically to retrain the immune system.
1860s–1900s: Early
inhalers (glass
atomizers) were
used for delivering
volatile antiseptics
and
bronchodilators.
1956: Introduction
of pressurized
MDIs
revolutionized
asthma therapy —
the Medihaler-Iso
(isoprenaline) was
the first.
1970s onward:
Development of
selective β₂-
agonists
(salbutamol,
terbutaline) marked
a milestone,
shifting asthma
management from
oral/systemic to
inhalational local
therapy.
Present: Smart
nebulizers and
breath-actuated
inhalers incorporate
digital sensors to
monitor adherence
and optimize
dosing
Clinical pearls
Particle size matters:
o
10 µm — deposited in oropharynx (swallowed, minimal lung effect).
o
2–5 µm — ideal for bronchial deposition.
o
<2 µm — reach alveoli, more systemic absorption.
Technique is critical: Misuse of inhalers (incorrect breathing, poor coordination)
drastically reduces efficacy and increases oropharyngeal deposition (leading to
candidiasis with corticosteroids).
Spacer devices: Reduce oropharyngeal deposition, increase lung delivery, reduce
systemic side effects.
191 BAASIR UMAIR (MPhil in Pharmacology)
6.2.6.5 Historical note:
.
Figure 6.11: Historical account of the inhalational route
6.2.7 Intradermal Injection (Diagnostic and Desensitization Purposes):
The intradermal route involves the injection of a very small volume of solution (usually
0.1–0.2 mL) into the dermis, the layer of skin just below the epidermis but above the
subcutaneous tissue. The purpose here is not systemic therapy, but rather to induce a
controlled local reaction in the skin that can be clinically observed or quantified.
Because the dermis contains abundant dendritic cells, mast cells, and a dense capillary–
lymphatic network, it is a strategic site for immune testing and desensitization. The
response is local — redness, swelling, or wheal formation — and is then interpreted
diagnostically or used therapeutically to retrain the immune system.
1860s–1900s: Early
inhalers (glass
atomizers) were
used for delivering
volatile antiseptics
and
bronchodilators.
1956: Introduction
of pressurized
MDIs
revolutionized
asthma therapy —
the Medihaler-Iso
(isoprenaline) was
the first.
1970s onward:
Development of
selective β₂-
agonists
(salbutamol,
terbutaline) marked
a milestone,
shifting asthma
management from
oral/systemic to
inhalational local
therapy.
Present: Smart
nebulizers and
breath-actuated
inhalers incorporate
digital sensors to
monitor adherence
and optimize
dosing
Clinical pearls
Particle size matters:
o
10 µm — deposited in oropharynx (swallowed, minimal lung effect).
o
2–5 µm — ideal for bronchial deposition.
o
<2 µm — reach alveoli, more systemic absorption.
Technique is critical: Misuse of inhalers (incorrect breathing, poor coordination)
drastically reduces efficacy and increases oropharyngeal deposition (leading to
candidiasis with corticosteroids).
Spacer devices: Reduce oropharyngeal deposition, increase lung delivery, reduce
systemic side effects.
General Pharmacology Section-1 Drug
192 BAASIR UMAIR (MPhil in Pharmacology)
6.2.7.1 Dosage forms and representative uses:
1. Diagnostic testing:
o Tuberculin (Mantoux) test: Injection of purified protein derivative (PPD) into the
dermis of the forearm to assess prior exposure to Mycobacterium tuberculosis. A
delayed-type hypersensitivity reaction develops at the site if the individual is
sensitized.
o Other skin tests: Intradermal injection of lepromin (for leprosy classification),
histamine (for gastric acid secretion studies, largely historical).
2. Allergen extracts (desensitization and diagnosis):
o Dilute solutions of specific allergen extracts (e.g., pollen, house dust mite, insect
venom) are injected intradermally for:
Diagnostic allergy testing (skin prick/intradermal tests).
Therapeutic desensitization protocols in carefully controlled incremental
doses (though subcutaneous and sublingual are more common today).
6.2.7.2 Rationale for its Local effect:
The point of administration and intended site of action coincide:
o In tuberculin testing, the desired outcome is a local immune-mediated induration at
the injection site, not systemic immunity.
o In allergen testing, the wheal-and-flare reaction confined to the skin is the
diagnostic endpoint.
Only very tiny volumes are administered, and systemic drug levels remain negligible under
normal circumstances.
(ID systemic route is discussed in the later section of the chapter)
6.2.7.3 Exceptions and systemic spillover:
Although intradermal injections are generally local, systemic reactions can occur in rare
cases:
o Severe anaphylaxis has been reported with intradermal allergen testing in
hypersensitive patients — even with diluted extracts.
o Accidental higher-volume injections or injections into the subcutaneous plane can
increase systemic exposure.
Clinical pearls:
The injection must raise a small bleb or wheal on the skin — this confirms correct
dermal placement.
Site choice matters: the volar forearm is standard for tuberculin testing because of ease
of reading.
In allergy testing, intradermal is more sensitive than skin-prick testing but less specific,
leading to false positives if not interpreted cautiously.
192 BAASIR UMAIR (MPhil in Pharmacology)
6.2.7.1 Dosage forms and representative uses:
1. Diagnostic testing:
o Tuberculin (Mantoux) test: Injection of purified protein derivative (PPD) into the
dermis of the forearm to assess prior exposure to Mycobacterium tuberculosis. A
delayed-type hypersensitivity reaction develops at the site if the individual is
sensitized.
o Other skin tests: Intradermal injection of lepromin (for leprosy classification),
histamine (for gastric acid secretion studies, largely historical).
2. Allergen extracts (desensitization and diagnosis):
o Dilute solutions of specific allergen extracts (e.g., pollen, house dust mite, insect
venom) are injected intradermally for:
Diagnostic allergy testing (skin prick/intradermal tests).
Therapeutic desensitization protocols in carefully controlled incremental
doses (though subcutaneous and sublingual are more common today).
6.2.7.2 Rationale for its Local effect:
The point of administration and intended site of action coincide:
o In tuberculin testing, the desired outcome is a local immune-mediated induration at
the injection site, not systemic immunity.
o In allergen testing, the wheal-and-flare reaction confined to the skin is the
diagnostic endpoint.
Only very tiny volumes are administered, and systemic drug levels remain negligible under
normal circumstances.
(ID systemic route is discussed in the later section of the chapter)
6.2.7.3 Exceptions and systemic spillover:
Although intradermal injections are generally local, systemic reactions can occur in rare
cases:
o Severe anaphylaxis has been reported with intradermal allergen testing in
hypersensitive patients — even with diluted extracts.
o Accidental higher-volume injections or injections into the subcutaneous plane can
increase systemic exposure.
Clinical pearls:
The injection must raise a small bleb or wheal on the skin — this confirms correct
dermal placement.
Site choice matters: the volar forearm is standard for tuberculin testing because of ease
of reading.
In allergy testing, intradermal is more sensitive than skin-prick testing but less specific,
leading to false positives if not interpreted cautiously.
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