SYSTEMIC VS LOCAL DRUG DELIVERY SYSTEMS …SYSTEMIC VS LOCAL DRUG DELIVERY SYSTEMS IN THE TREATMENT...

APON ET AL : SYSTEMIC V/S LOCAL DRUG DELIVERY WORLD J ADV SCI RES

VOL. 1 ISSUE 2 NOV – DEC 2018 1

SYSTEMIC VS LOCAL DRUG DELIVERY SYSTEMS IN THE

TREATMENT OF PERIODONTAL DISEASES-A REVIEW.

Dr.Adiya Apon1, Dr.Praneeta kamble2

1 Post-graduate student, 2 Additional Professor,

Dept of Periodontology, Nair Hospital Dental College, Mumbai, Maharashtra, India.

ABSTRACT

Periodontitis is an inflammatory response to bacteriological infections that destroys the attachment of teeth resulting

in periodontal pocket formation. Treatment of periodontitis varies widely from non-surgical to surgical options

depending on how far the disease has progressed. Nonsurgical methods are systemic delivery of antimicrobials,

scaling and root planing and local delivery of drug. Each drug delivery system has its merits and demerits. The

success of any drug delivery system designed to target periodontal infections depends upon its ability to deliver the

antimicrobial agents to the base of the pocket at a bacteriostatic or bactericidal concentration. This article highlights

the impact of Systemic Vs Local drug delivery in the treatment of Periodontal diseases.

KEYWORDS

Periodontitis, Systemic drug delivery, Local drug delivery, Periodontal Pockets.



INTRODUCTION

Periodontitis is defined as "an inflammatory disease of the supporting tissues of the teeth caused by specific

microorganisms or groups of specific microorganisms, resulting in progressive destruction of the periodontal

ligament and alveolar bone with pocket formation, recession or both."[1] The inflammation in the periodontal tissue

is initiated by microbial plaque and bacterial infection. The nature of the periodontal disease depends on the

interaction among the bacterial agent, environment, and host’s defense mechanisms to the bacterial challenges

mainly in form of gram negative anaerobic bacteria.[2]

It is considered to be an infection because there is a bacterial etiology and an immune response. Once

destruction of tissue occurs, the condition is referred to as a disease. Usually, the host response can contain

subgingival bacterial challenges and subclinical infections, which are resolved without any clinical manifestation or

pathosis.[3] However, if the host-parasite equilibrium is lost, an exuberant host response can result in destruction of

the periodontium too. It is a well-established fact that periodontal disease is the result of local bacterial infection

with pathogenic microflora such as Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Prevotella

intermedia, Bacteroids forsythus, Peptostreptococcus micros, Campylobacter rectus, Eikenella corrodens,

Fusobacterium nucleatum, Eubacterium spp, Treponema denticola, Selemonas spp., beta hemolytic streptococci, a

variety of enteric rods and pseudomonas, enterococci, staphylococci and possibly also yeasts within the periodontal

pocket.[2,4]

Aim of the periodontal treatment is to eradicate gingival inflammation, bleeding, periodontal pocket depth

and to arrest destruction of bone, by removal of the bacterial deposits, thus shifting the pathogenic microbiota to one

compatible with periodontal health. Mechanical scaling and root planing (SRP) is the therapeutic approach for

periodontitis.[5] However, the effectiveness of the conventional treatment is limited by the lack of accessibility to

bacteria in deeper periodontal area leading to reinfection of these sites.[6] ] It was concluded that such cases could be

related to persistence of pathogens in the pocket or production of specific virulence factors interfering with the host

cell (eg. leukotoxin) or recolonization of treated sites from reservoirs of bacteria in dentinal tubules and soft

tissues.[7] Inspite of the excellent results achieved, mechanical debridement alone, has shown to leave behind a

significant number of pathogenic microorganisms in relatively inaccessible areas.[8]

A microbiological approach to periodontal therapy aims primarily at suppressing specific

pathogenic bacteria and permitting subsequent recolonisation of microbiota compatible with health.[8]Studies

conducted, revealed antimicrobial agents to be helpful as adjuncts in treating periodontal disease, hence

investigators sought different methods to deliver these antimicrobials to periodontal pockets. The various methods

employed, have included rinsing, irrigation, systemic administration and local application using sustained and

controlled delivery devices. [8]

For an antibiotic to be effective in periodontal treatment, it must penetrate well into the gingival sulcus

and produce gingival fluid concentrations higher than the minimum inhibitory concentrations (MIC) of the

suspected pathogens.[9] Understanding of etiology and pathogenesis of periodontitis have led to increasingly



effective pharmacological interventions. In this regard, safe and intrinsically efficacious medications can be

delivered into periodontal pockets to suppress or eradicate the pathogenic microbiota or modulate the inflammatory

response, thereby limiting tissue destruction.

Each drug delivery system has its merits and demerits. The success of any drug delivery system designed to

target periodontal infections depends upon its ability to deliver the antimicrobial agents to the base of the pocket at a

bacteriostatic or bactericidal concentration. It must also facilitate retention of the medicament long enough to ensure

an efficacious result.[11]

SYSTEMIC DRUG DELIVERY

In the last 25 years, reports stating that systemically administered antibiotics are excreted via saliva and gingival

fluid, have triggered great interest in antibiotic therapy.[10]It has been shown that systemic administration of

antibiotics results in changes in plaque flora, reduction in gingivitis and decrease in the rate of bone resorption. In

systemic administration, however, the drug must be given in high doses in order to maintain effective concentration

of the drug in the gingival crevicular fluid.[11]

Systemic periodontal antimicrobial therapy is based on the premise that specific microorganisms cause

destructive periodontal disease and that the antimicrobial agent in the periodontal pocket can exceed the

concentration necessary to kill the pathogens.[11] The systemic antimicrobial agents enter periodontal pockets

following their intestinal absorption and passage from the blood stream into oral tissues, gingival crevicular fluid

and saliva.[12]

Various systemic delivery antimicrobials available –

Single drug therapies with penicillins, tetracyclines, metronidazole or clindamycin have been used frequently in

periodontal practice.[8] However, since periodontitis lesions often harbor a mixture of pathogenic bacteria, drug

combination therapies have gained increased importance.[8,13] Valuable combination therapies include

metronidazole–amoxicillin for A. actinomycetemcomitans and various anaerobic periodontal infections[14,15] and

metronidazole–ciprofloxacin for mixed anaerobic and enteric rod/ Pseudomonas periodontal infections.[16]

Advantages[11]

1. Systemic antibiotics can reach microorganisms at the base of deep periodontal pockets and furcation areas, via the

serum.

2. Affects tissue invasive organisms – residing within the connective tissues.

3. Eradication of periodontal pathogens colonizing the oral mucosa and other extra dental sites – the potential

reservoirs of bacterial reinfection.

4. Multiple sites are treated simultaneously.



5. Less time consuming (when compared to local drug delivery).

6. A variety of drugs are available.

Disadvantages[11]

1. Development of resistant bacterial strains.

2. Superimposed infections.

3. Uncertain patient compliance.

4. Possible allergic sensitization of patients.

5. The drug must be given in high doses in order to maintain an effective drug concentration in the gingival

crevicular fluid. This may result in various side effects like nausea, vomiting and gastrointestinal disturbances.

IMPACT OF SYSTEMIC DRUG DELIVERY IN PERIODONTAL THERAPY

Systemic antibiotic therapy does not significantly affect supragingival plaque accumulation. Reduction in

dental plaque depends mostly on patients’ oral hygiene efforts. However, Ng & Bissada (1998) [17] reported that

systemic doxycycline administration for 6 weeks was associated with significantly reduced plaque accumulation and

gingival inflammation at week 12 post treatment compared with placebo.

Systemic antibiotics might not have a significant effect on gingival inflammation, with the possible

exception of metronidazole, doxycycline and metronidazole–amoxicillin combinations. It might be that systemic

antibiotic therapy is ineffective against gingival inflammation related to supragingival plaque but may help decrease

gingivitis caused by susceptible subgingival microorganisms.

Several systemic antibiotic therapies have no significant impact on periodontal pocket depth compared

with controls. However, Noyan et al.(1997)[21] and Elter et al.(1997)[22] reported that 7 days of metronidazole

therapy reduced pocket depth significantly compared with controls. Winkel et al.(2001)[23] showed that 7 days of

metronidazole–amoxicillin combination therapy produced greater probing depth reduction and significantly

increased the proportion of periodontal sites gaining clinical attachment than did control medication, especially in

pockets having initial depths greater than or equal to 7 mm. Various studies showing the impact of systemic drug

delivery in periodontal therapy shown in Table 1.



Table 1;-

Study

Number of

subjects(age)

and

Periodontal

Condition

Systemic antibiotic

regimen

Periodontal

treatment

Results

Ng &

Bissada

(1998)17

32 patients

(32–72 years)

Generalised moderate

adult periodontitis

Doxycycline 200 mg

for the first day and

then 100 mg, once

daily for 6 weeks

Each group was

divided into Split-

mouth design: half of

the mouth received

one session of root

planing; the other

half received no local

Therapy.

Significant reduction in

the proportion of

plaque accumulation

and gingival

inflammation at week

12 post treatment

compared with

placebo.

Watts et al.

(1986)18

Test: 13 patients

Control: 7 patients

Adult periodontitis

Metronidazole 200

mg, three times daily

7 days Placebo, three

times daily,

7 days

Scaling and root

planing followed by

random assignment to

either antibiotic or

placebo group.

Significant reduction

in the proportion of

gingival bleeding sites

compared with controls

Lopez & co-

workers

(1998)19

Test: 23 patients

(mean age: 44 years)

Placebo: 21 patients

(mean age:

44 years)

Moderate to advanced

adult periodontitis

Metronidazole200


+amoxicillin 375mg,

three timesdaily, 8

days

Subjects were

randomly assigned to

receive antibiotics or

placebo. No effort

was made to change

the oral hygiene

habits of the patients.

Less gingival bleeding

for up to 12 months

compared with

placebo.

Noyan et al.

(1997)21

10 patients

(35–51 years)

Test: 5

Metronidazole 250


7 days

Patients divided into

2 groups (5 patients

each) consisting of 1)

Reduced pocket depth

significantly as

compared with



Control: 5

Adult periodontitis

Scaling and root

planing 2)Systemic

metronidazole

treatment . Only data

for systemic

antibiotic group

(test), and

scaling and root

planing

group (control) were

presented.

controls.

Winkel et

al.

(2001)23

22 patients

(29–54

years)

A.actinomymycetemco

nmitans positive

periodontitis combined

with either

P.gingivalis,

B.forsythus,

P.intermedia co-

infection

Metronidazole 250


+amoxicillin 375mg,

3 times daily, for 7

days

Scaling and Root

planing with oral

hygiene instructions

were given.6 weeks

later, Repeated the

same with antibiotic

therapy and placebo

was given.

Probing depth reduced,

significantly increase

in proportion of clinical

attachment levels.

Collins et al.

(1993)24

30 patients

(23–70 years)

Refractory

periodontitis

Amoxicillin 250 mg

with Clavulanic acid

(125 mg), four times

daily, 14 days in

conjunction with

subgingival delivery

of povidone–iodine,

and chlorhexidine

mouthwash rinses

twice daily.

Refractory treatment

protocol consisted of

systemic antibiotic

therapy, topical

povidone–iodine, 3%

hydrogen peroxide

rinse to remove

coronal staining, and

twice-daily with

chlorhexidine

(0.12%) rinse

Reduced probing depth

with 56% decrease in

the number of pockets

> 6 mm at 6 weeks post

treatment. Clinical

attachment gain of at

least 1 mm in 41% of

deep sites at 3 years

post treatment.



The value of systemic antibiotics in patients with chronic periodontitis is not clear.With the adverse

effects such as development of microbial resistance,host hypersensitivity and superimposed infections,management

of severe types of periodontitis should not rely solely on systemic antibiotics but upon a combination of mechanical

debridement possibly in conjunction with surgery ,subgingival administration of antiseptics by dental professionals,

Patient’s oral hygiene efforts and effective and safe systemic antibiotics.[24]

LOCAL DRUG DELIVERY

Ever since the introduction of systemic antibiotics, various drugs have been used in the treatment of periodontitis.

The various disadvantages of systemic antibiotics had led to the introduction of local drug delivery as the treatment

option. It was in the year 1979, Dr. Max Goodson et al first proposed the concept of controlled delivery in the

treatment of periodontitis. Since then, a number of studies have been carried out over the years with different

antimicrobial agents and in different clinical situations.[25]

Local antibiotic therapy involves the direct placement of an antimicrobial agent into sub gingival sites,

minimizing the impact of the agent on non oral body sites.[5] The primary goal in using an intra-pocket device for the

delivery of an antibacterial agent is the achievement and maintenance of therapeutic levels of the drug for the

required period of time. This inhibits or kills the pathogens, without any harm to the tissues. Studies suggest that the

critical period of exposure of the pocket to an antibacterial agent is in the range of 7-10 days.[25]

Local delivery of drug proves to be more superior than systemic drug administration in periodontitis patients

as Local drug delivery provides,High drug concentration, Minimal side effects and less reliance on patient

compliance for taking the medication.[25]

Noyan et al (1997)[21] reported local metronidazole in combination with scaling and root planing to be more

effective than systemic metronidazole in terms of producing both clinical and microbial improvements in adult

periodontitis patients .

Akalin et al (2004)[26] compared the clinical efficacies of systemic Doxycycline (SD) and local Doxycycline

(LD) in the treatment of chronic periodontitis in 45 patients and the results showed that the Local Doxycycline

treatment provided significantly higher Probing Depth reduction than the Systemic Doxycycline treatment.

.

Indications for LDD [27,28]

1) Isolated periodontal pockets (>5mm), with successful phase 1 therapy (scaling and root planing),

2) Medically compromised patients where surgical therapy is contraindicated.

3) As an adjunct to mechanical debridement,

4) In patients suffering from recurrent or refractory periodontitis.



5) Periodontal Maintenance Therapy

Contraindication of LDD [27,28]

1) Periodontal patients with known hypersensitivity reaction to any of the antimicrobials for periodontal therapy.

2) Patients susceptible to infective endocarditis are contraindicated for irrigation devices to avoid the risk of

bacteremias

3) Delivery of antimicrobial agents using ultrasonic scalers are contraindicated in asthmatics, infective conditions

(AIDS, TB etc) and those with cardiac pacemakers.

4) In pregnant and lactating mothers where use of the particular antimicrobial is contraindicated.

Various local delivery antimicrobials available are[29,30]

1. Tetracycline – non resorbable fibres

2. Metronidazole gel

3. Minocycline ointment

4. Chlorhexidine chips

5. Doxycycline hyclate in a resorbable polymer

6. Resorbable tetracycline in fibrillar collagen

7. Minocycline microspheres

8. Azithromycin gel

Vehicles that have been employed for sustained delivery in periodontics include pastes, ointments, gels, fibers,

strips, spheres, discs and chips.

Advantages of LDD [31]

1. Improved patient compliance

2. Improved pharmacokinetics

3. Improved drug access to the site of disease

4. Lowers the total drug dosage

5. No risk of emergence of resistant microorganism

6. Drug can reach the site of action in adequate concentration

7. Maintain the drug level for a sufficient period of time



Disadvantage of LDD [32]

1. Time consuming and laborious

2. Difficulty in placing therapeutic concentration of antimicrobial agent into deeper periodontal pockets and

furcation lesions

3. Personal application of antimicrobial agents by patients as a part of their home self-care procedure is

compromised.

IMPACT OF LOCAL DRUG DELIVERY IN PERIODONTAL THERAPY

Goodson et al in 1979 first proposed the concept of controlled delivery in the treatment of periodontitis.[25] It has

been observed that the local route of drug delivery can attain 100-fold higher concentrations of an antimicrobial

agent at subgingival sites compared with a systemic drug regimen. This reduces the total patient dose by over 400

fold thereby reducing the potential problems with the use of systemic antibiotic drug regimens and development of

drug-resistant microbial populations at non oral body sites. These can be safely used in medically compromised

patients for whom surgery is not an option and contraindicated in patients with known hypersensitivity to the

antimicrobial used, asthmatics and infective conditions such as AIDS, Tuberculosis.[31]

Feasibility of treating periodontal disease by controlled drug delivery of antimicrobials from within the

pocket with tetracycline filled hollow fibers placed in the gingival sulcus to have a dramatic effect both on the

periodontal microflora and the clinical manifestations of the disease. The fibers released the entire drug in the first 2

hours.

Various studies showing the impact of local drug delivery in periodontal therapy are shown in Table 2.

Table;-2

Study

Number of

subjects(age)

and

Periodontal

condition

Local drug

therapy used

Periodontal Treatment

Results

Lindhe et al

(1979)33

5 patients with

Adult

periodontitis

Local tetracycline

delivery using

hollow fibre

devices for 2 days

Each patient had four pairs

of contralateral sites that

were treated either by

scaling or tetracycline

application and one pair was

used as an untreated control.

Improvement seen in both

microbial and clinical

parameters similar to

scaling and root planing

during the short term

evaluation.



Minabe et al

(1991)34

16 patients with

Periodontal

disease.

Tetracycline cross

linked collagen

film for 9 weeks.

Selected patients were

randomly allocated to ;-

1) 4 consecutive

administration of

tetracycline immobilized

cross linked collagen film

(TC film) at intervals of 1

week (TC group);

2) Root planing treatment

(RP group);

3) Combination (TC + RP

group);

4) No treatment (control

group).

By the end of 9 weeks all

the groups showed a

reduction in the clinical

parameters. TC+RP group

showed significant

reduction in bleeding on

probing and gain in

clinical attachment levels.

Jones et al

(1992)35

Adult

periodontitis

2% minocycline All patients were given a

single sitting of scaling and

root planing then divided

into experimental and

control groups. The

experimental group received

2% minocycline while the

control group received only

SRP

Sub gingival minocycline

as an adjunct to SRP

produced significant

clinical benefits over SRP

alone in patients with

adult periodontitis.

Polson et al

(1997)36

180 patients

Moderate to

Severe

Periodontitis

Subgingivally

delivered

biodegradab-le

drug delivery

system containing

either 10%

doxycycline

hyclate, 5%

sanguinarium for 9

months

10% doxycycline hyclate

delivered in a

biodegradable delivery

system was found to be an

effective means of

reducing the clinical signs

of adult periodontitis.

Jeffcoat et al

(2000)37

45 subjects

Adult

periodontitis

Chlorhexidine-

gelatin chip for 9

months

Control groups received

either placebo + Scaling or

Root planing or SRP alone.

SRP treated subjects

experienced loss of bone

in 1 or more sites, no



Test groups received active

CHX chip or SRP alone.

subject treated with active

chip+SRP lost bone.CHX

chip when used as an

adjunct to scaling and

root planing significantly

reduce alveolar bone loss.

Eickholz et

al (2002)38

111 patients

Moderate to

Severe

periodontitis.

Application of

Doxycycline

adjunctive to non

surgical

periodontal therapy

over a period of 6

months.

In each patient,3 different

treatment modalities

assigned-SRP alone,SRP

with subgingival vehicle

control and SRP with

subgingival application of

15%Doxycycine gel.

Adjunctive use of sub

gingival doxycycline was

found to be safe and

provide more favourable

relative attachment level

gain and probing depth

reduction.

Gopinath et

al (2009)39

15 patients

chronic

periodontitis

Minocycline

microspheres for

over 180 days

Scaling and Root planing

given to all patients.


plus Minocycline

microspheres was more

effective and safer than


alone in reducing the

signs of chronic

periodontitis.

Sustained or controlled release local delivery antimicrobial agents are available for use as adjuncts to

scaling and root planing in the treatment of periodontitis. These products are placed into periodontal pockets in order

to reduce subgingival bacterial flora and clinical signs of periodontitis. A high level of the active agent is deposited

in the periodontal pocket and the delivery vehicle facilitates prolonged drug delivery.

Studies assessing the efficacy of local delivery antimicrobial agents generally show statistically

significant improvement in clinical and microbial parameters. However, whether they can reduce the need for

surgery, improve long-term tooth retention or are cost effective would need to be ascertained in further studies.

Clinicians can thus consider the use of local delivery antimicrobial agents in treatment of chronic

periodontitis as an adjunct to scaling and root planning;when localized recurrent and/or residual probing depth ≥

5mm with inflammation is still present following conventional therapies.



CONCLUSION

The requirements for treating periodontal disease include means for targeting an anti-infective agent to infection

sites and sustaining its localized concentration at effective levels for a sufficient time while concurrently evoking

minimal or no side effects. At present, there is no single universal drug or delivery device that would be effective in

all situations. Currently, a lot of research is being undertaken, incorporating a variety of drugs and the different

modes or vehicles to dispense them. The clinician’s decision to use drug deliveries should be based upon a

consideration of clinical findings, the patient’s dental and medical history, scientific evidence, patient preferences,

and advantages and disadvantages of alternative therapies.

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