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Diplomarbeit

Common Drugs and Complications in dental medicine – A


Systematic Review

eingereicht von
Ahmed Shamekh

zur Erlangung des akademischen Grades

Doktor der Zahnheilkunde (Dr.


med. dent.)

an der
Medizinischen Universität Wien

ausgeführt am
Lehrstuhl für Pharmakologie, Med Uni Graz

unter der Anleitung von


Univ.-Prof. i.R. Mag. Dr. Eckhard Beubler
ao. Univ.-Prof. Dr. phil. Dr. h. c. Irmgard Lippe

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Danksagung

Ich möchte an dieser Stelle Herrn Univ.-Prof. i. R. Mag. Dr. Beubler für die zuverlässige
Betreuung, Beurteilung und die Möglichkeit mein Wunschthema zu erarbeiten danken.

Ein herzlicher Dank gilt meiner Familie, insbesondere meinen Eltern, die es mir erst
ermöglicht haben mein Studium anzutreten und zu absolvieren. Dank ihrer Unterstützung
konnte ich all meine medizinischen wie auch privaten Interessen verfolgen. Im Hinblick auf
diese Arbeit bin ich meinen Eltern sehr dankbar, mich bereits in der Kindheit ermutigt zu
haben Englisch zu lernen.

Vielen Dank auch an meine Freunde aus Wien, die mich motiviert haben, angespornt haben
und immer ein offenes Ohr haben.

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Zusammenfassung

Hintergrund: Unerwünschte Arzneimittelwirkungen sind eine der Hauptursachen für


die Entwicklung von oralen Läsionen, die mit Grunderkrankungen fehldiagnostiziert
werden können.

Ziele: Das Ziel der vorliegenden Studie war es, die Nebenwirkungen einiger
Medikamente auf die Mundgesundheit und die Kontrollen bei der Anwendung dieser
Medikamente zu beschreiben und zu zeigen, wie diese Nebenwirkungen beseitigt oder
verringert werden können.

Materialien und Methoden: Es handelte sich um eine systematische Übersicht, die


Übersichtsarbeiten von Fall-Kontroll-Studien, Fallberichtsstudien und retrospektiven
Fallfolgestudien berücksichtigt, in denen die Komplikationen dieser in der Zahnmedizin
weit verbreiteten Medikamente evaluiert werden. Wir berücksichtigen auch alle Studien,
die Nebenwirkungen dieser Medikamente in der Zahnmedizin und in dieser Meta-
Analyse beinhalten; 15 Studien wurden aufgenommen, davon waren 9 prospektive
Studien und 6 Fall-Kontroll-Studien.

Ergebnisse: NSAR können zusätzlich zu zahlreichen Symptomen des oberen und


unteren Gastrointestinaltrakts orale Ulzerationen verursachen. Zahnfleischhyperplasie
ist mit der Verwendung von Cyclosporin verbunden. Osteonekrose des Kiefers,
ulzerative Läsionen und dicke Blasen werden als orale Komplikationen bei
Bisphosphonaten berichtet. Die Zahnfleischvergrößerung war die am häufigsten
berichtete Läsion, die hauptsächlich durch Cyclosporin A und Nifedipin induziert
wurde. Zahnverfärbung war die zweithäufigste Läsion, die hauptsächlich durch
Tetracyclin induziert wurde. Es wurde dokumentiert, dass orale Kontrazeptiva eine
hypertrophe Gingivitis und ein ausgeprägtes gingivales Erythem verursachen.

Schlussfolgerung: Diese Studie untersucht die zahlreichen medikamentös induzierten


oralen Reaktionen, um das Bewusstsein von Zahnärzten und Zahnärztinnen für eine
verbesserte Diagnose und Therapie zu schärfen.

Stichwörter: Unerwünschte Arzneimittelwirkungen, Gingiva, eine systematische


Übersicht, Gingivavergrößerung.

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Abstract

Background: Adverse drug reactions (ADRs) are a main cause of development of oral
lesions that can be misdiagnosed with underlying diseases.

Aim and objectives: The study aimed to describe the effects of some medications on oral
health, the recommendations when using these medications, and how these side effects
could be eliminated or reduced.

Subjects and methods: This was a systematic review, which considered reviews of
case-control studies, case report studies, and retrospective case follow-up evaluating the
complications of these common drugs in dental medicine. We also considered all
studies that involved side effects of these medications in dental medicine, and in this
meta-analysis; 15 studies were enrolled, nine of them were prospective studies and six
were case-control studies.

Results: NSAIDs can cause oral ulceration, in addition to numerous upper and lower
gastrointestinal symptoms. Gingival hyperplasia is associated with Cyclosporine usage.
Osteonecrosis of the jaw, ulcerative lesions and thick bullae are reported as oral
complications for bisphosphonates. Gingival enlargement was the most common
reported lesion, induced mainly by Cyclosporine A and Nifedipine. Teeth discoloration
was the second most common lesion, induced mainly by Tetracycline. Oral contraceptives
have been documented to cause hypertrophic gingivitis, marked gingival erythema.

Conclusion: This study reviewed the numerous oral drug-induced reactions to improve
the awareness amongst dentists and oral health practitioners for better diagnosis and
management.

Keywords: Adverse drug reactions, gingival, a systematic review, gingival enlargement.

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Table of Contents

List of abbreviations
Table of figures
Index of tables

1 INTRODUCTION ............................................................................................................................ 8
2 MATERIAL AND METHODS ....................................................................................................... 9
3 RESULTS....................................................................................................................................... 14
3.1 Non-steroidal anti-inflammatory drugs (NSAIDs) ................................................................. 14
3.2 Cyclosporine........................................................................................................................... 17
3.3 Bisphosphonates ..................................................................................................................... 21
3.4 Nifedipine ............................................................................................................................... 27
3.5 Tetracycline ............................................................................................................................ 30
3.6 Oral Contraceptive Pills ......................................................................................................... 31
4 DISCUSSION ................................................................................................................................ 35
5 BIBLIOGRAPHY .......................................................................................................................... 40

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List of Abbreviations
ADRs Adverse drug reactions
ASAs Aspirins
BPP Bisphosphonate
COX Cyclooxygenase
COXIBs COX-2 inhibitors
CsA Cyclosporine A
CSF Cerebro-spinal fluid
DMFS Decayed, missing, and filled surfaces
DVT Deep venous thrombosis
FSH Follicle-stimulating hormone
GCF Gingival crevicular fluid
GI Gastrointestinal
GvHD Graft-versus-Host-Disease
HSCT Hematopoietic stem cell transplantation
IMAGE test International Multicenter Angina
Exercise test
LH luteinizing hormone
LP Lichen planus
MS Mutans streptococci
NSAIDs Non-steroidal anti-inflammatory drugs
OCP’s Oral Contraceptive Pills
ONJ Osteonecrosis of the jaw
PB Papilla bleeding
PDL Periodontal ligament
PMNL Polymorphonuclear leukocytes
PPI Proton pump inhibitors
PRISMA Preferred Reporting Items for Systematic
Reviews and Meta-Analyses
tNSAIDs Traditional NSAIDs

WHO World Health Organization

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Table of figures

Title

Figure 1 Distribution according to the type of study

Figure 2 Distribution of the studies according to the site of lesions

Figure 3 Distribution of the studies according to the drug used and


number of cases

Figure 4 Specific structure of the bisphosphonate

Figure 5 Ulcerations in the mouth floor following administration of


alendronate

Index of Tables

Title

Table 1 Distribution according to the type of study

Table 2 Distribution of studies according to the number of cases


included with oral complications

Table 3 Distribution of the studies according to the drug used and


oral lesion found

Table 4 Cyclosporine Pharmacokinetics

Table 5 Cyclosporine Side Effects

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1 INTRODUCTION

Some drugs can have adverse effects, even when administered in normal doses and for appropriate
indications. (1) Adverse effects can take place in any organ. In the oral cavity, adverse reactions
could affect any part of the oral mucosa, and could result from medications taken either locally or
systematically. (2) Interestingly, adverse drug reactions might occur after the drug has been used
once or after a few years of persistent drug use. (3) Oral adverse reactions to medications might be
uncommon and often challenging to detect. (2) The systemic side effects include hyposalivation,
burning oral sensation, oral ulcers, erythema multiforme, gingival hyperplasia, lichenoid, and
angioedema. (4)

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2 MATERIAL AND METHODS

An exploratory study had been conducted using data from many scientific publications. The data
had been collected, analysed, and marked with information cross in order to extract the results.

Criteria for considering studies for this review:

x Type of study: Case-control studies, case report studies, and retrospective case follow-up
were considered, to evaluate the complications of these common drugs in dental medicine.
x Types of participants: All researches analysing the side effects of the common drugs in
dental medicine were considered.
x Types of intervention: Interventions of interest included those linked to the side effects of
these medications in dental medicine.
x Search strategy for identification of studies: The search approach was planned to include
both manual and electronic data. The research was built based on the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines (PRISMA Group,
2009) to provide a systematic overview and conduct a meta-analysis. Potential studies were
found in the initial search were expected to meet the inclusion criteria; observational
randomized controlled trials for a dental implant or dental extraction for common drugs and
complications in dentistry.

Electronic searches included searching collections of electronic and manual literature reviews
separately of many repositories, including PubMed, MEDLINE, EMBASE, Cochrane Oral Health
Group Trials Register (Cochrane Library), and Web of Science. Studies conducted up to 2020 have
been considered. Wherever possible, the PubMed library has used combinations of controlled terms
(MeSH and EMTREE), and keywords and other terms not indexed as MeSH and filters were also
used. The quest technique used was "drugs" OR "medication" OR "pharmacological agents" (MeSH
Terms)) AND "dental effects, (MeSH Terms) OR 'NSAIDs' (MeSH Terms) OR 'anti-inflammatory
drugs, non- steroidal agents' (MeSH Terms) OR 'adrenergic cyclosporine' (MeSH Terms) OR
'bisphosphonate' (MeSH Terms) OR 'tetracycline' (MeSH Terms) OR 'nifedipine' (MeSH Terms)
OR 'liquid contraceptive pills' (MeSH Terms) OR 'nifedipine' AND Classical Research (ptyp) OR
Scientific Study (ptyp) OR Scientific Trial (ptyp). Besides, a less precise test using non-MeSH index
words was carried out to assess the papers to be evaluated. The screening technique has been as the
following: (Medication-related (Title/Abstract) OR drug-related (Title/Abstract) OR variations of
'medication-related' OR 'drug-related' OR 'dental complication' AND 'failure' OR 'survival' restricted
to names and abstracts. Full copies of articles of available medical journals and other published
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studies were found by the quest, interviews with a variety of field investigators and published case
reports deemed to meet the requirements for inclusion. Based on their description, abstract and
subject descriptors were also collected for data synthesis. Our study was restricted to studies in the
English language.

Methods of the review

Locating and selecting studies: Abstracts of the articles found using the search technique referred to
above were viewed and articles that tended to fulfill the inclusion requirements were retrieved in
full. Information on at least one outcome variable were included in the analysis.

Data extraction: Data were extracted from each sample by the reviewer (the researcher)
independently based on the pre-specified selection criteria. Disagreements during screening and
quality assurance have been settled by debate.

Table 1. Distribution according to the type of study

Study Type
Aleid, (103) prospective
Kharazmi et al., (105) prospective
Krishnan et al., (106) prospective
Clayton et al., (90) prospective
Sabnis et al., (98) case-control
Helenius-Hietala et al.,( 99) case-control
Lin et al., (100) prospective
Tilakaratne et al., (126) prospective
Mullaly et al., (121) case-control
Shaker et al., (122) prospective
Vennila et al., (119) case-control
Ruan et al., (125) Prospective
Faus-Matoses et al., (120) case-control
Sunil et al., (110) case-control
Sousa et al., (111) prospective

15 studies were enrolled, nine of them were prospective studies and six were case-control
studies.

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Figure 1. Distribution according type of study

type of studies

10

5
type of studies

0
type of studies
prospective
case control

Table 2. Distribution of studies according to the number of cases included with oral
complications

Study Number
Aleid, (103) 1
Aleid, (103) 1
Kharazmi et al., (105) 13
Krishnan et al., (106) 106
Clayton et al., (90) 1
Sabnis et al., (98) 84
Helenius-Hietala et al., (99) 25
Liny et al., (100) 32
Tilakaratne et al., (126) 42
Mullaly et al., (121) 40
Shaker et al., (122) 4
Vennila et al., (119) 142
Ruan et al., (125) 1
Faus-Matoses et al., (120) 1
Sunil et al., (110) 35

The total numbers of cases included were 528 cases.

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Table 3. Distribution of the studies according to drug used and oral lesion found.

Study N drug used site Lesion

Krishnan et al., (106) 106 NSAIDs Mucosa Lichen planus


Clayton et al., (90) 1 Cyclosporine A Gingiva Gingival enlargement

Sabnis et al., (98) 84 Cyclosporine A Gingiva Gingival enlargement

Helenius-Hietala et al., (99) 25 Cyclosporine A Gingiva Gingival enlargement

Aleid, (103) 1 Bisphosphonates Tongue Ulcerative lesions

Kharazmi et al., (105) 13 Bisphosphonates Tongue Thick bullae

Faus-Matoses et al., (120) 1 Nifedipine Gingiva Gingival enlargement


Sunil et al., (110) 35 Nifedipine Gingiva Gingival enlargement

Shaker et al., (122) 4 Tetracycline Teeth Teeth discoloration

Vennila et al., (119) 142 Tetracycline Teeth Teeth discoloration

Ruan et al., (125) 1 Tetracycline Teeth Teeth discoloration

Lin et al., (108) 32 Oral contraceptives Gingiva Gingivitis


Mullally et al., (90) 40 Oral contraceptives Gingiva Gingivitis
Tilakaratne et al., (126) 42 Oral contraceptives Oral cavity Periodontitis

This table shows that gingival enlargement was the most common lesion, being reported in
146 cases in five studies. In addition, it was induced mainly by Cyclosporine A and
Nifedipine.

Furthermore, teeth discoloration was the second most common lesion, found amongst 147
cases in three studies. It was induced mainly by Tetracyclines.

Being linked mainly to NSAIDs, Lichen planus was reported in 106 cases in only one study.

Gingivitis was reported amongst 72 cases in two studies, and was attributed mainly to oral
contraceptive pills. Another study suggested that oral contraceptive pills might be linked to
periodontitis, in about 42 cases.

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Moreover, Bisphosphonates were suggested to be linked to thick bullae in one study amongst
13 cases, and to ulcerative lesions in other two studies among two cases.

Figure 2. Distribution of the studies according to the site of lesions

number of cases

250
200
150
100
50 number of cases
0

tongue mucosa
gingiva oral
teeth
cavity

Figure 3. Distribution of the studies according to the drug used and number of cases

160

140

120
NSAIDs
100
Cyclosporine A

80 Bisphosponates
Nifedipine
60
Tetracyclines

40 Oral contraceptives

20

0
Number of cases

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3 RESULTS

3.1 Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs are among the most widely used medications globally; their use is more prevalent
among old women, probably due to musculoskeletal disorders . In addition, more than 90% of
prescriptions for NSAIDs are issued to people > 65 years of age. (5)

Mechanisms of gastrointestinal (GI) injury

NSAIDs can affect the intestine by causing topical mucosal disruption and systemic effects
associated with COX-1 depletion of mucosal prostaglandins. (6) Moreover, the cumulative
effects of NSAIDs continue to play a leading role. Due to the systemic effects, unfortunately,
the usage of enteric-coated aspirin preparations and the parenteral or rectal administration of
NSAIDs to avoid topical mucosal injury, failed to prevent the occurrence of ulcers. (7)

x Systemic effects

NSAIDs suppress cyclooxygenase (COX), a precursor to the biosynthesis of


prostaglandins. There are two available isoforms, COX 1 and COX 2. Present NSAIDs
(tNSAIDs) and ASA suppress both isoforms, however, selective NSAIDs (COXIBs) are
COX 1-sparing and mainly inhibit COX 2. (8) COX 1 isoform is expressed in most tissues,
releasing prostaglandins that might protect the intestine by inducing synthesis and
secretion of mucus and bicarbonate, increasing mucosal perfusion, and promoting
epithelial proliferation. When the enzyme is blocked by the NSAIDs, it makes the gastric
mucosa more vulnerable to topical affection due to endogenous and exogenous causes. (9)
In addition, inhibition of COX 1 prevents the production of thromboxane in platelets,
which increases bleeding when an active GI bleeding site is present. (10) On the other
hand, COX 2 isoform is found in most tissues to respond to inflammatory stimuli. COX-
2-derived prostaglandins at the ulcer margin appear to play a crucial role in ulcer healing
by inducing cell proliferation, stimulating angiogenesis, and restoring mucosal integrity.
This isoform is the primary target for anti-inflammatory drugs. Selective COX-2
NSAIDs, therefore, despite having little or no effect on COX-1, might lead to effective
pain relief with a decline in adverse GI effects. However, this 'COX 2 hypothesis' was
challenged by evidence from animal studies. (11)

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x Topical injury:

The acidic properties of most ASAs can cause mucosal disruption. In the highly acidic
gastric environment, these weak acids remain in their non-ionized lipophilic form. These
conditions facilitate their migration to the surface epithelial cells, where the NSAIDs
become disassociated to the ionized form, which absorbs hydrogen ions causing mucosal
injury. (12)

Upper gastrointestinal effects of NSAIDs

NSAIDs can have adverse effects on both the upper and lower gastrointestinal tract. Clinical
impact and frequency of adverse reactions with NSAIDs in the lower GI tract have been
increasingly identified, but are less distinguishable than in the upper GI tract. (13)

Upper GI adverse events of NSAIDs can be categorized in different types: (14)

̶ Features of gastritis including dyspepsia, nausea, vomiting, stomach pain, and heartburn.

̶ NSAIDs-linked gastroduodenal injury with uncertain clinical significance. The disease


involves a combination of subepithelial haemorrhage, erosion, and ulceration.

̶ Symptomatic ulcers and GI-complications (GI-leakage, ulcer perforation and obstruction)

̶ NSAIDs-caused oral ulceration. (15) NSAIDs can cause mucosal ulceration due to local
vasoconstriction. (16)

Adverse reactions of NSAIDs and aspirin are usually non-allergic, with the inhibition of
cyclooxygenase leading to significant alterations in arachidonic acid metabolism, such as
angioedema mediated by overproduction of cysteinyl leukotriene. (2) Additionally, it has also
been documented that NSAIDs and ACE inhibitors can cause lichenoid reactions in the oral
cavity. (2)

Management

A main aim in the treatment of patients receiving NSAIDs is to prevent their GI affection.
Those goals include the treatment of GI mucosal lesions and the detection and prevention of
NSAID-induced dyspepsia. (17) In addition, due to the association of NSAIDs and Coxib use
with cardiovascular risk, this factor should also be taken into consideration in the
management of patients in need of NSAIDs. (18)

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x Prevention strategies:
Preventive approaches should be implemented for patients with one or more risk factors from
a cost- effective perspective. There are many ways to accomplish this goal. (19)

x General Rules: (20)

̶ Using "safer" NSAIDs (coxibs, diclofenac, aceclofenac, ibuprofen).


̶ The lowest effective dosage should be chosen, for the shortest period of time.
̶ Less use of NSAIDs with significant gastrointestinal risk (ketorolac, piroxicam,
ketoprofen).
̶ Discontinuing concomitant treatment with anticoagulants, corticosteroids, low-dose
aspirin or antiplatelet agents.
̶ Eradication of infection with Helicobacter pylori in patients with a previous history of
ulcers.
̶ In case of absent cardiovascular and gastrointestinal risk factors: tNSAID can be used,
(no preventive strategy required).
̶ If one or more gastrointestinal risk factors are present: coxib (standard dose) alone or
tNSAID, proton pump inhibitors or misoprostol can be prescribed.
̶ Experience of inflammation or bleeding of the ulcer: stop tNSAID and coxib, give PPI
and eradicate the infection of Helicobacter pylori.
̶ In case of low-dose aspirin prophylaxis for cardiac patients, if there is one or more
gastrointestinal risk factors: low-dose tNSAID can be used. Throughout Europe, the
use of coxibs is contraindicated by the EMA if there is a prior cardiovascular event.

Targeting modifiable risk factors:

There are certain risk factors (e.g., age) that cannot be modified. Nonetheless, most of the
other risk factors could be adjusted. The best way to avoid mucosal harm is to restrict the use
of NSAIDS and to use a less harmful agent such as acetaminophen instead. (21) Instead,
gastro-protective agents such as H2-receptor antagonists or Proton Pump Inhibitors (PPI) can
be added to NSAIDs in patients with GI risk factors requiring anti-inflammatory medications.
(22)

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3.2 Cyclosporine

Uses:
Pancytopenia associated with lymphoblastic leukaemia. (23)

Contraindications:
History of hypersensitivity reactions to cyclosporine or polyoxyethylated castor oil used in the
intravenous formulation. (24, 25)

Mechanism of Action:

Cyclosporine is a metabolite derived from tolypocladium fungi. It is a potent suppressor of the


immune system, particularly T- lymphocytes. (26) Cyclosporine binds to intracellular
receptor called cyclophilin, thus inhibiting the production of cytokines, including interleukin-
2 and interleukin 4, tumour necrosis factor-alpha and interferon-gamma, leading to impaired
normal lymphoid cell activation. (27) In addition, Cyclosporine is effective due to specific
and reversible inhibition of immunocompetent lymphocytes in the G0- and G1-phase of the
cell cycle. (28, 29)

Pharmacokinetics:
Table 4: Cyclosporine Pharmacokinetics: (30, 31)

Oral
Absorption Significant inter- and intra-patient variability

Highly lipophilic; high concentrations of body fat, with accumulation in the


liver, pancreas, lungs, kidneys, adrenal glands, spleen and lymph nodes;
multi-compartmental activity with potential overload of the peripheral area.

Distribution
Cross blood-brain yes; very low levels detected in brain and
barrier? cerebrospinal fluid

Volume of distribution 3.5-9 L/kg

Plasma protein binding 90-98%, mostly to lipoproteins and


erythrocytes

Extensively biotransformed by cytochrome P450; no single major


metabolic pathway
Metabolism
Active metabolite(s) AM1, AM9, AM4N

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Inactive metabolite(s) no information was found

Primarily biliary; renal excretion is a minor pathway

Urine 6%; 0.1% as unchanged drug

Faeces metabolites (44%) and unchanged drug


Excretion (<1%) in bile

Terminal half-life highly variable; approximately 18 h


(range 7.7-26.9 h)

Clearance 5-7 mL/min/kg; highly variable; impaired


in liver disease

More likely to have serum creatinine ≥50 percent higher than normal
Elderly after 3-4 months of treatment; more likely to have systolic hypertension.

More frequent and higher doses can be needed to achieve therapeutic blood
Children levels; greater clearance than adults, vary by age.

Side Effects:
Table 5: Cyclosporine Side Effects: (30, 31)

Organ Site Side Effect


Allergic reactions, including anaphylaxis (1- 3%)
Anaphylactoid reactions, due to polyoxyethylated castor oil
Allergy/Immunology in IV formulation; see paragraph following Side Effects
table
Angioedema (1-3%)
Hearing loss (1-3%)
Auditory/Hearing Tinnitus (1-3%)
Vestibular disorder (1-3%)
Anaemia (1-3%)
Blood/Bone Marrow/ Febrile Leukopenia (1-3%)
Neutropenia
Thrombocytopenia (1-3%)
Abnormal heart sounds (1-3%)
Cardiovascular (Arrhythmia)
Arrhythmia (5%)
Cardiac failure (1-3%)
Hypertension (26-50%); see paragraph following
Cardiovascular (General) Side Effects table
Myocardial infarction (1-3%)
Peripheral ischemia (1-3%)

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Bleeding (1-3%)
Coagulation Clotting disorders (1-3%)
Nose bleed (1-3%)
Fatigue (1-10%)
Fever (1-3%)
Constitutional Symptoms
Influenza-like symptoms (6-10%), weight
changes (1-3%)
Extravasation hazard: none
Abnormal pigmentation (1-3%)
Acne (1-3%)
Alopecia (4%)
Brittle nails, abnormal nail growth (1-3%)
Dermatitis (1-3%)
Dry skin (1-3%)
Flushing (1-5%)
Dermatology/Skin
Folliculitis (1-3%)
Hirsutism (21-45%); see paragraph following Side Effects
table
Hypertrichosis (1-19%)
Keratosis (1-3%)
Pruritus (1-3%)
Rash (1-12%)
Urticarial (1-3%)
Endocrine Hot flushes (1-3%)
Emetogenic potential: low13
Abdominal distention (1-3%)
Anorexia (1-10%)
Appetite increase (1-3%)
Belching (1-3%)
Constipation (1-3%)
Gastrointestinal Diarrhoea (1-13%)4,6
Dysphagia (1-3%)
Dyspepsia (2-12%)
Esophagitis (1-3%)
Flatulence (5%)
Gastritis, gastroenteritis (1-3%)
Gingival bleeding (1-3%)
Gingival hyperplasia (1-35%); see paragraph following
Side Effects table
Gingivitis (4%)
Glossitis (1-3%)

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Nausea (1-23%)
Salivary gland enlargement (1-3%)
Stomatitis (7%)
Ulcer; gastric (1-3%), peptic (1-3%)
Vomiting (1-10%)
Haemorrhage Rectal haemorrhage (3%)

Some adverse gastrointestinal effects have been documented, including diarrhoea, nausea,
vomiting, anorexia, and abdominal pain. Gastritis, hiccough, and peptic ulcers are less
common, and constipation, trouble swallowing, and upper GI ulcers are rare. Gingival
cyclosporine-mediated hyperplasia is clinically similar to that caused by phenytoin. (32) This
can occur more frequently in adolescents. Risk can be reduced by ensuring proper oral
hygiene. Resolution typically occurs 1- 2 months after cessation of treatment, and in severe
cases gingivectomy might be indicated. For some patients, metronidazole and azithromycin
have been used to treat gingival hyperplasia. (33)

Decreasing Cyclosporine Side Effects

It has been suggested that the use of antioxidants might be beneficial to prevent the adverse
effects of Cyclosporine A (CsA). (34) Low-dose CsA tends to have a detrimental effect on
conditions such as hyper- reactivity and autoimmune diseases. However, low-dose CsA has
been shown to be effective in cases such as allogeneic HSCT and GvHD prophylaxis. There
are important arguments in favour of low-dose CsA as a potential tool against cancer, either
as monotherapy or in combination with medications. (35)

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3.3 Bisphosphonates

General Aspects

Bisphosphonates (BPP) are non-metabolized pyrophosphate analogues capable of binding to


the bone and inhibiting osteoclast activity by reducing bone turnover and successfully
reshaping in areas where excessive bone resorption occurs. (36) They have been used as an
anti-plate toothpaste and as a Tc 99 conveyor in diagnostic studies. (37) The first BPP was in
the form of low-powered etidronate with a tendency to develop osteomalacia. For this reason,
more active compounds with less adverse effects were developed, including the second
(alendronate, pamidronate, ibandronate, tiludronate) and the third generation BPP
(risedronate, zoledronic acid, mildronate). (38)

The BPP are composed of two groups of phosphates bound to a carbon atom (P-C-P). Unlike
pyrophosphates, BPP strongly binds to hydroxyapatite, explaining their pharmacological
activity in bone R1 radicals. Furthermore, the hydroxyl (OH) groups increase fixation while
Cl groups decrease it. This might explain why BPP with OH groups (alendronate,
pamidronate ...) bind more than just clodronate. (38) BPP is released as bone reabsorption
occurs, and this might explain their long half-life, and their long-lasting bone impact. (38)

Figure 4: Specific structure of the bisphosphonate (39)

Mechanism of Action

BPP prevents bone absorption by reducing reabsorptive osteoclast activity, promoting their
apoptosis, preventing the development of their hematopoietic precursors, or influencing
osteoblasts. When in the osteoclast, the R2 chain determines the potency and efficacy of the
medication. Clodronate (Cl in R2) and etidronate (CH3 in R2) function to metabolize toxic
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ATP analogues that induces osteoclastic apoptosis. (39) These drugs induce osteoclast
apoptosis by inhibiting the biosynthesis of cholesterol and the mevalonate pathway due to
inhibition of farnesilpiro phosphate synthesis. (40) These disturbances affect the structure of
the cytoskeleton, the vesicle traffic, and the composition of the osteoclast boundary of the
tree. BPP also has a certain impact on osteoblasts, which is not yet entirely clear, decreasing
their apoptosis, and facilitating the secretion of inhibitors in the recruitment of osteoclasts. An
antiangiogenic effect of BPP has also been documented by inhibiting endothelial cells,
reducing their proliferation and inducing apoptosis. (41)

Therapeutic Indications

The BPP indications have undergone substantial development as they have been used to treat
a lot of bone and calcium metabolic disorders. The major indications of BPP nowadays are:
(42)

̶ Osteoporosis, especially in postmenopausal women and with corticosteroids use. In these


situations, the most commonly used BPP is alendronate, which prevents pathological
fractures from occurring.
̶ Paget's disease, in which BPP are used to improve bone morphology and reduce pain.
̶ In the case of hypercalcemia of malignancy, its role is to try to control hypercalcemia,
minimize pain and prevent the development of osteolytic lesions and fractures.
̶ In patients of breast and prostate bone metastases, BPP are used for pain relief, fracture
prevention, and reduction of hypercalcemia.
̶ In multiple myeloma, BPP have been shown to decrease associated bone disorders such
as vertebral dysfunction, fractures, and pain.

Oral BPP are potent inhibitors of osteoclasts but are less effective in the treatment of bone
processes associated with malignancies. Thus, they are specifically recommended for
treating of osteoporosis. On the other hand, systemic BPP are used in cases with metastatic
breast cancer, multiple myeloma, hypercalcemia malignancy, Paget disease and bone
metastases of solid tumours (prostate, lung, etc.)

General Adverse Effects

BPP are generally well tolerated. However, some adverse effects and complications
associated with their use have been reported.

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In the case of oral BPP, the most commonly recorded GI effects are gastric ulcers,
oesophagitis, and oesophageal stenosis. Recently, isolated cases of uveitis have been reported
in patients treated with alendronate, pamidronate and zoledronic acid. (43, 44)

In addition, several experimental models have suggested that inhibition of bone remodelling
caused by BBP may lead to a reduction in bone resistance, although there is no strong clinical
evidence, at least concerning oral BPP. (39) General adverse reactions of intravenous BPP are
similar to oral ones, in addition to some reported cases of phlebitis and kidney failure.

Oral Adverse Effects

There are a few cases of chronic oral mucosal ulceration associated with alendronate in
osteoarthritis patients. (38) Oral ulcerations in the mucosa were suggested to be secondary to
inadequate treatment with corticosteroids. Many cases of oral ulceration are typically
associated with inappropriate administration. (45)

Over the last years, publications have been published recording different cases of a special
form of osteomyelitis of the jaws (ONJ) in patients with myeloma or breast cancer and in
treatment with BPP, in particular pamidronate and zoledronic acid and more rarely with
teriflunomide. (46) There are also some reported cases of hypocalcemia following high doses
of BPP, although most patients are unaffected due to the compensated rise in parathyroid
hormone. (39)

Figure 5: Ulcerations in the mouth floor following administration of alendronate (39)

Two hypotheses are suggested to clarify the emergence of the ONJ. One is referred to the role
of BPP in bone retention and the other is related to their anti-angiogenic activity. (47) The
main theory suggests that ONJ is caused by the termination of bone remodelling and

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osteoclast inhibiting effects. BPP is especially concentrated in the jaws because there is a
higher blood flow than in other bones and a faster bone turnover due to their high growth and
presence of teeth. This disorder, along with the frequent presence of dental pathologies, dental
hygiene, and thin mucosa over the maxillary bone explains why osteonecrosis is especially
apparent in these bones. Maintenance of bone turnover is important to maintain bone viability.
If osteoclast function is substantially reduced, osteocytes are not replaced and the capillary
bone network is not established, resulting in avascular bone necrosis. (48)

The weakening of the oral mucosa, caused by traumatic ulceration or surgery, causes local
bone necrosis that occurs when healing fails. The risk of ONJ increases with dental neglect
and poor hygiene, because the bone is exposed to oral microbiota, which induces pain,
tumefaction, suppuration, and progressive bone necrosis. (38) The other etiopathogenic
hypothesis focuses on experimental evidence that most active BPP also inhibits capillary
neoangiogenesis, reduces capillary production, and inhibits endothelial growth factors leading
to avascular necrosis. This is not the only explanation, however, as it is not associated with
more potent anti-angiogenic drugs. (39) ONJ cases associated with BPP have been identified
in patients who have been on treatment for years or weeks. Nonetheless, a study of several
patients with myeloma showed that the risk of ONJ was time-dependent and was only
significant after 12 to 36 months. (49)

Prevention of BPP Associated Osteonecrosis of the Jaws

Like in every prophylactic approach, preventive action for osteonecrosis of the jaws is taken
prior to the initiation of BPP therapy.
a) Measures before initiating BPP therapy
The patient should be referred to the dentist for an urgent oral examination, consisting
of a complete clinical and radiographic examination, as soon as the oncologist
consider that BPP is indicated.
Oral therapy is intended to minimize infections and the need for unnecessary dental
procedures shortly; thus, preventive care should be successful and should include tooth
removal, periodontal surgery, root canal therapy, tooth decay prevention, dental
rehabilitation and prosthesis if needed. These patients are not recommended for dental
implants due to the risk factors involved. (38) A month before initiation of BPP
therapy, the removal of large mandibular tori or palatal tori with thin overlying
mucosa is recommended to reduce the risk of ulceration. Patients with no cardiac

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disease do not need prophylactic antibiotic treatment for semi-invasive procedures, but
for invasive procedures; antibiotic prophylaxis might be indicated.

Combination treatment with quinolones and metronidazole is effective in individuals


with penicillin allergy. Clindamycin alone is not recommended because it is
ineffective against actinomycin, Eikenella corrodens and related species, which also
colonize exposed bones in the oral cavity. (50) If the patient only needs non-invasive
dental treatment, BPP therapy is not delayed. However, if the patient needs intensive
care, BPP therapy should be delayed for one month to allow for bone recovery and
good healing. A monitoring schedule with plaque control and strict hygienic
procedures is recommended every four months.

b) Measures during BPP therapy


The dentist can examine the oral cavity closely to assess the extent of bone damage in
the areas most frequently affected, for example, the posterior and lingual areas of the
mandible. For signs of osteolysis, osteosclerosis, swollen periodontal spaces, and
furcation, a full radiographic examination should be performed. Careful dental hygiene
and safe use of fluorine and chlorhexidine as well as strict hygienic procedures should
be considered. (50) All procedures required to protect the teeth and avoid infections
should be performed as early as possible. When the tooth is not remediable, removal
of the root canal and decapitation of the crown are preferable to extraction. Root canal
treatment can be done with minimal disruption to the middle and apical periodontal
tissues. (39) In the case of periodontal disease, teeth can only be removed if they have
three or more mobility grades or related periodontal abscesses. Adequate antibiotic
treatment, as previously suggested, is crucial in these cases. (38)

Surgical techniques have been contraindicated. Nonetheless, in patients who require


surgery, BPP discontinuation is advised in the event of a poor recovery. Nevertheless,
it is not clear whether the discontinuation of BPP will preclude ONJ from appearing
because of their half-life. (51) Special steps such as completely aseptic procedures,
atraumatic surgery, and, if possible, first-line closure should be taken when oral
surgery is needed in a patient with BPP therapy. (39) If a prosthesis is required, it
should ideally be fixed and well performed to prevent secondary traumatic ulcers from

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occurring; if possible. For patients undergoing BPP treatment, a regular monitoring
schedule with plaque management and strict hygienic steps is prescribed every 3 to 4
months. (39)

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3.4 Nifedipine

Indications – FDA Approved Indications (52)

Nifedipine is a calcium channel blocker that is part of the dihydropyridine group. This is
mainly used as an antihypertensive and anti-anginal medication.

̶ Chronic stable and vasospastic angina


Nifedipine decreases the severity of angina and increases the mean workout time during
the International Multicenter Angina Exercise (IMAGE) test. Reflex tachycardia can
restrict its efficacy; however, the addition of a beta-blocker can overcome this restriction.
Long-acting formulation (extended-release) is preferred.
̶ Hypertension
This may be used as monotherapy or in conjunction with many different drugs to control
hypertension (such as angiotensinogen converting enzyme inhibitors or diuretic thiazide)

Off-label uses (53)

̶ Raynaud's phenomenon.
̶ Severe gestational and postpartum hypertension
̶ High-altitude pulmonary oedema
̶ Pulmonary hypertension
̶ Oesophageal achalasia
̶ Distal ureteric calculi
̶ Tocolysis

Mechanism of Action

Nifedipine prevents calcium ions from reaching the vascular smooth muscle and myocardial
cells by blocking the voltage-dependent calcium L-type channels, preventing calcium inflow,
supressing the depolarization process. (54) Decreased intracellular calcium results in reduced
systemic blood pressure and increased myocardial oxygen supply. Thus, Nifedipine has
hypotensive and anti-anginal properties. (54)

Administration: (55)

Nifedipine is essential for both immediate and extended-release plans. Its initial marketing
was in a short-acting, immediate-release formulation that required several daily doses. Such
preparations triggered rapid vasodilation, resulting in side effects such as headache,

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palpitation, and flushing. Such side effects led to the introduction of extended-release
formulations, which have been shown to have a consistent 24-hour anti-hypertensive effect
and fewer side effects. Extended-release preparations are available on tablets of 30, 60, and 90
mg. ideally; dose changes will be made at 7-to 14-day intervals.

Immediate-release preparations shall have an onset of action within 20 minutes with a plasma
half-life of approximately 4 to 7 hours. Extended- release preparations have an average time
of action of about 24 hours. Hepatic metabolism occurs through the CYP3A4 pathway.
Extended- release formulations have a bioavailability of up to 89% compared to the
immediate-release formulation. Bioavailability dramatically rises in patients with liver failure
requiring dose modification (due to decreased drug clearance).

Recommended Dosages: (55)

̶ Chronic stable angina


Immediate-release: 10 to 20 mg three times daily; average daily dose of 180 mg
Extended-release: 30 or 60 mg daily; maximum daily dose of 120 mg daily
̶ Vasospastic Angina:
Extended-release: 30 or 60 mg daily; maximum 120 mg daily
̶ Hypertension:
Extended-release: 30 or 60 mg daily; maximum 120 mg daily
̶ Hypertensive emergency during pregnancy or postpartum period:
Immediate-release: 10 mg; can be repeated with a 20 mg dose in 20 minutes.

Adverse Effects: (55)

Adverse effects are present in around 20-30% of patients who have received Nifedipine.
These are largely attributed to its vasodilatory effects. The most common adverse reactions
include flushing, peripheral oedema, dizziness, and headache. Tolerance with extended-
release preparations is greater than with immediate-release preparations. (56) Hypersensitivity
reactions, such as pruritus, hives, and bronchospasms, are fairly rare. Abrupt discontinuation
of the medication after extended use can lead to a rebound in hypertension or angina. (57)

Nifedipine-induced gingival enlargements

Nifedipine-induced enlargement of the gingiva was first reported in 1984. (58) Various
factors were reported, including high plaque index (poor oral hygiene), high drug dosage,
genetic factors, human sensitivity, and interaction between drugs and metabolites with gingiva

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fibroblasts (59).

It has been reported a 15 to 316-fold increase in Nifedipine in the cervical gingival fluid
relative to plasma. Researchers also found that higher concentrations of Nifedipine in the
gingival cervical fluid could increase the risk of gingival enlargement. (60; 61) Gingival
hyperplasia can be significantly reduced by using the appropriate prophylactic procedures,
followed by plate control steps. (62) It is concluded that Nifedipine-induced gingival
enlargement can be prevented by periodontal treatment with anti-inflammatory medications
such as anti-IL-I β (interleukin-I beta). (63)

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3.5 Tetracycline

Uses (64)
̶ Chronic Bronchitis, Acute Exacerbation
̶ Mild to Severe Acne
̶ Brucellosis
̶ Gonorrhoea
̶ Uncomplicated urethral, endocervical or rectal infections

Adverse Effects

̶ Gastrointestinal: anorexia, nausea, epigastric pain, vomiting, diarrhoea, glossitis,


oesophageal ulceration, black hairy tongue, dysphagia, enterocolitis, and inflammatory
lesions (with Candida overgrowth) in the anogenital area. (65)
̶ Teeth: persistent discoloration of teeth, hypoplasia of enamel. (66)
̶ Skin: maculopapular and erythematous rashes, exfoliative dermatitis, onycholysis
discoloration of the skin, and photosensitivity. (67)
̶ Renal toxicity (dose-related). (67)
̶ Liver: hepatotoxicity, failure of the liver. (68)
̶ Hypersensitivity reactions: urticaria, angioneurotic edema, anaphylaxis, anaphylactoid
purpura, pericarditis, exacerbation of systemic lupus erythematosus, and serum disease
reactions such as fever, rash, and arthralgia. (69)
̶ Blood: haemolytic anaemia, thrombocytopenia, thrombocytopenic purpura, neutropenia,
and eosinophilia. (70)

Pharmacology

̶ Mechanism of Action: Tetracycline inhibits bacterial protein synthesis by binding to 30S


and possibly 50S ribosomal subunits. (71)
̶ Absorption: Absorption: 75% (PO), Peak plasma time: 2-4 hr (PO). (68,72)
̶ Distribution: Tiny amount occurs in bile; relative diffusion from blood to CSF: fine even
with inflammation (exceeds to normal MICs) CSF: blood volume ratio: swollen
meninges: 25 %. Bound protein: 65 %. (68,72)
̶ Elimination: Half-life: 8-11 hr (normal renal function); 57-108 hr (end-stage renal
disease). (68)
̶ Excretion: Urine (60% as unchanged drug); faeces (as an active form). (68)

Minimizing the side effects of Tetracycline (68)

̶ Through avoidance of direct exposure to sunlight or tanning devices to reduce


photosensitivity.
̶ Reduce the dosage of the drug or taking the drug with adequate water to avoid the renal
failure

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̶ Prevent irreversible discoloration of the teeth by not using tetracycline during dental
growth
̶ Do not use obsolete tetracyclines to avoid Fanconi-like syndrome.

3.6 Oral Contraceptive Pills

Indications

There are actually three types of oral contraceptive drugs: combination


estrogen-progesterone, progesterone-only, and regular or extended-use drugs.

The birth control pill is the most widely prescribed form of contraception in the United States.
Approximately 25% of women aged 15-44 who are currently using contraception reported
using a pill as their preferred form. The most widely prescribed drug is a hybrid synthetic
drug containing oestrogen and progesterone. Progesterone is a hormone that prevents
pregnancy, and the oestrogen portion is used to regulate menstrual bleeding. (73) Birth control
drugs are used mainly to avoid pregnancy. The effectiveness of this type of birth control is
referred to as normal and ideal use. Typical usage, meaning that the procedure will not always
be used regularly or correctly, results in a failure rate of 9 out of 100 pregnant women within
the first year of use of this procedure. Good usage ensures that every time the system is used
regularly and correctly, less than one woman out of 100 will become pregnant in the first year
of usage. OCP can be used to treat other health conditions, especially menstrual-related
disorders such as menstrual pain, prolonged menstruation, fibroids, endometriosis-related
pain, and menstrual-related migraines. (74, 75)

Mechanism of Action

Progesterone is largely responsible for the prevention of pregnancy. The main mechanism of
action is inhibition of ovarian growth, and suppression of ovulation. (75) Progestogen
negative feedback acts on Hypothalamus to reduce gonadotropin pulse rate releases hormone.
It simply increases follicle-stimulating hormone (FSH) secretion and decreases luteinizing
hormone (LH) secretion. If the follicle does not grow, the estradiol levels do not increase (the
follicle contains estradiol). The mid-cycle LH surge may be stopped by progestogen negative
feedback and a lack of oestrogen positive feedback on LH secretion. Oestrogen can inhibit
follicular production due to its negative feedback on the anterior pituitary with the slow
secretion of FSH; however, it is not as prominent as the progesterone effect. Another primary
mechanism of action is the capacity of progesterone to prevent sperm from entering the cervix
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and upper genital tract by making the cervical mucosa unfriendly. (75)

Contraindications

There are a few absolute and relative contraindications to oral contraceptive use. People with
uncontrolled hypertension should not begin using oral contraceptive until their blood pressure
is controlled; diabetics can experience some hyperglycaemia while starting OCs, but these are
problems that can be resolved. (75) Nevertheless, OCPs are contraindicated in smokers over
35 years of age due to a greater risk of cardiovascular problems and, specifically, deep vein
thromboembolism (DVT).

The risk of venous thromboembolism increases among OCPs users 3-9/10,000 female-year-
olds relative to non-pregnant and non-hormonal users (1-5/10,000 female-year-olds), the risk
is even greater for those over 35 years of age and smoking. (76) Women with a history of
DVT, documented ischemic heart disease, aura migraines, active or history of breast or
endometrial cancer and valve heart disease should not take OC because these conditions
might possess unnecessary health risks. (76)

Oral contraceptives and oral health

There is ample evidence that gingival tissue produces oestrogen receptors, and that gingival
tissues metabolize sex hormones. Oestrogen receptors on periosteal fibroblasts, broken lamina
Propria fibroblasts, periodontal fibroblasts, and osteoblasts are also present. (77) There has
been a detailed study of the effects of oestrogen and progesterone on the oral mucosa and
periodontal tissue. The effects on periodontal tissue by oestrogen and progesterone are
summarized as follows: (78)
Effects of oestrogen on the periodontal tissues: (78)

̶ Stimulates gingival fibroblast development


̶ Encourages the growth and maturation of gingival connective tissues.
̶ Raises gingival inflammation.
̶ Increases blood vessel cell proliferation.
̶ Reduces keratinization while improving epithelial glycogen, improving the
efficacy of the epithelial barrier. (79)
̶ Changes in the acid content of mucopolysaccharide of connective tissue in human oral
mucosa.
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̶ Reduces inflammation mediated by T-cells.
̶ Disable the development of leukocytes from the bone marrow.
̶ Induces phagocytosis by PMNL.
̶ Inhibits the chemotaxis of PMNL.
̶ Inhibits pro-inflammatory cytokines generated by human marrow cells. (78)

Effects of progesterone on the periodontal tissues. (80)

̶ Inhibits the synthesis of collagen in PDL fibroblasts.


̶ Inhibits the proliferation of human gingival fibroblasts
̶ Alters the rate and pattern of development of collagen in gingiva, resulting in decreased
repair and maintenance capacity.
̶ Increases vascular dilation, thereby increasing permeability and increasing amount of
gingival fluid and GCF.
̶ Increases in gingival cervical fluid (GCF), polymorphonuclear leukocytes and
prostaglandin E2.
̶ Decreases the anti-inflammatory activity of glucocorticoids.
̶ Increases the metabolic breakdown of the folate needed to sustain and repair tissues. (80)

Oral side effects of OCPs:

Several studies documented hyperplastic oedematous gingivitis after oral contraceptive use,
which is resolved when the drugs are discontinued. (81) Oral contraceptives have been
documented to cause hypertrophic gingivitis, marked gingival erythema, and epulis of the
form of bleeding and pregnancy, especially in higher doses. Gingivitis may occur under
normal doses with an increase in gingival exudate and an increase in the number of inflamed
papillae. (82) It is noticed that OCP users usually have greater probing range, more serious
connection loss, and more check bleeding sites than controls. Women using OCPs might show
about a 16-fold rise in species of Bacteroides. (83) In OCP users, greater numbers of
prevotella species were detected in oral microflora. This increase is most likely due to
increased female sex hormones that replace naphthoquinones released by certain prevotella
species. (84)

Adverse Effects

The most common adverse reaction of combined oral contraceptive pills is bleeding. Females
often complain of nausea, fatigue, stomach cramping, breast tenderness, and increased vaginal

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discharge or reduced libido. Nausea can be prevented by taking medications the night before
sleep. Most of the other effects can be overcome with time or by moving to another
preparation of OCPs. (75)

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4 DISCUSSION

Adverse drug reactions (ADRs) are one of the main contributors to the development of oral
lesions that can be mistaken for underlying diseases. Oral ADRs can have a broad variety of
clinical symptoms, including xerostomia/hyposalivation, ulcerative lesions, vesicular lesions,
red/white and pigmented lesions, and dental abnormalities. (85) The WHO defines an adverse
drug reaction as 'a response to a medication that is harmful and undesirable and occurs at
doses widely used in humans for prophylaxis, diagnosis, disease therapy or alteration of
physiological function'. (86)

Fortunately, several disease patterns have been established, and they may help the clinician
develop a possible correlation of cause and effect with a particular drug or group of drugs. It
contains the clinical features of the oral reactions caused by medications. Due to the aging of
the population and the widespread and growing use of medicines, anti-drugs, and herbal
remedies, dentists may expect their patients to experience oral side effects due to the use of
these medicines. Since many patients take prescription and non-prescription medications,
dentists should take a thorough medical history and be aware of opioid-related conditions and
their potential impact on diagnosis and recovery planning. (87)

Any drug can lead to adverse reactions, even when used in standard doses and in the
appropriate mode of use. Within the oral cavity, adverse reactions can affect any part of the
oral mucosa and can be caused by medications taken either locally or systemically. Adverse
drug reactions can develop after a drug has been used once or after a few years of continuous
drug use. Oral adverse reactions to medications are not common and are thus often difficult to
detect. (88) The aim of the present study was to describe the side effects of some medications
on oral health and control while using these drugs, and how these side effects could be
avoided or reduced. This was a systematic review of case-control reports, case-report reports,
and a retrospective follow-up of cases examining the risks of these specific drugs in dentistry,
We also included all research concerning side effects of these medications in dental medicine
and in this meta-analysis; 15 trials were registered, nine of them were prospective research
and six were case-control trials.

Numerous medications can cause toxic effects in the oral cavity. Drugs have the ability to
induce symptoms such as inflammation of the salivary gland, oral ulceration and changes in
taste, discoloration of the teeth, mucosal pigmentation, white spots, swelling, and oral
malodour. Such side effects interfere with patient function and increase the risk of infection,
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pain, and potential tooth loss. Xerostomia, altered taste, and stomatitis have been reported as
the most common side effects of drugs. (89)

The present study stated that Lichen's plans identified a prospective study in 106 cases in one
of the studies induced by the NSAIDs. (90) Lichen planus (LP) is an inflammatory condition
that may include the skin, oral and genital mucous membranes, scalp, and hair. LP is known
to be idiopathic, but there are sporadic accounts of different drugs associated with it. Those
include β- blockers, non-steroidal anti-inflammatory drugs (NSAIDs), methyldopa,
penicillamine, quinidine, and angiotensin-converting enzyme (ACE) inhibitors. (90)

LP is a fairly common disease. Mucosal lesions include oral and genital lesions, which are
less common in males. Oral lesions are the only symptom of LP in 15–35 % of patients but up
to 65 % of patients with the classical cutaneous disease having oral involvement. (91) There
are relatively few literature studies evaluating the prevalence of vulva LP, although this is
probably more normal than previously believed. An Italian study found a prevalence of 3.7 %
in a dedicated vulvar clinic (92) and recorded that 51 % of women with cutaneous LP had
vulvar lesions. (93) It is found that the use of NSAIDs in oral LP patients was substantially
higher than in controls (P < 0.03); 17 percent of their LP patients were taking NSAIDs. (94) It
has been found that the ingestion of NSAIDs is almost ten times more prevalent in those with
erosion than in those with non-erosive LP (P = 0.01). (95) All papers indicate that, since
NSAIDs are known to cause mucosal ulceration in other parts of the gastrointestinal tract,
they may cause erosion at other mucosal sites. Many of our patients had mucosal degradation.

Cyclosporine A was suggested to alter the metabolic activity of gingival fibroblasts by


increasing the secretion of interleukin-6, which improves collagen and glycosaminoglycan
synthesis and decreases collagen breakdown. It also affects T lymphocytes, which play a key
role in the immune response to periodontal antibacterial. (96) The extent of gingival
enlargement is associated with the degree of oral hygiene and concomitant use of drugs such
as calcium channel blocker, nifedipine. However, there are conflicting results concerning the
length of therapy or drug serum levels. (97)

In our study, both the Sabnis et al. (98) and Helenius-Hietala et al. (99) case-control and
prospective studies of Lin and Yang (100) suggested that gingival enlargement of these
children caused by cyclosporine is not statistically associated with age, gender, gingival
inflammation or cyclosporine serum (P > 0.05). The gingival enlargement was found to be
significantly associated with the plaque index at any time up to 12 months after liver
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transplantation (P < 0.05). Several reasons for gingival overgrowth caused by cyclosporine
have been studied, with a particular focus on cyclosporine treatment and oral hygiene. It has
been concluded that there is a dose- dependent relationship of gingival overgrowth caused by
cyclosporine by analysing gingival measurements and histopathological findings in rats (101),
both Sabnis et al. (98) and Helenius-Hietala et al. (99) concluded that gingival enlargement is
statistically more related to plate scores than other variables such as age, gender, gingival
inflammation, and cyclosporine serum.

Bisphosphonates are a group of medications that avoid bone resorption and are used to treat a
variety of pathologies including Paget's disease, osteoporosis, multiple myeloma, and cancer-
related metastases in the breast or prostate. The most common complication in patients with
bisphosphonate therapy is osteonecrosis of the jaw (ONJ) that can occur after any surgical
dental procedure, and the risk of developing osteonecrosis of the jaw is higher in patients
receiving intravenous bisphosphonate therapy than in those receiving oral bisphosphonate
therapy. Typical appearance is in the form of non-extraction socket, exposed bone
involvement, gingival swelling, or purulent discharge where local debridement and antibiotics
are ineffective. (102) In the present study, there are three studies of Aleid and Sidebottom
(103), Kharazmi et al., (104), and Kharazmi et al., (105) These were retrospective studies and
included 15 Bisphosphonate treatment cases. We found that one study reported 13 cases of
one Bisphosphonate-induced condition, the other Bisphosphonate-induced complication in the
other two studies was ulcerative lesions reported amongst two patients. Accumulation of high
concentrations of Bisphosphonates in bone tissue decreases endothelial proliferation and
enhances capillary development, which leads to the anti-angiogenic properties of
bisphosphonates. Caution should be taken as excessive accumulation of bisphosphonates in
the alveolar bone can predispose to avascular necrosis due to decreased capillary and
endothelial necrosis. (106)

It is stated that the most common complication in patients undergoing bisphosphonate


therapy, osteonecrosis of the jaw occurs after any dental surgery. (107) Although spontaneous
cases of osteonecrosis have been reported, but in most cases (68.8%) patients have a history
of dental disease or treatment, the risk of developing osteonecrosis of the bisphosphonate-
associated jaw is higher in patients with IV bisphosphonate therapy than in patients with oral
bisphosphonate because oral osteonecrosis is low. (108).

Drug-induced gingival overgrowth is known to be associated with three types of medications:

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phenytoin, antiepileptic; cyclosporine A, immunosuppressive; and calcium channel blockers,
such as dihydropyridines, nifedipine, diltiazem, and verapamil commonly used for the
treatment of various cardiovascular diseases. It is characterized by the accumulation of the
extracellular matrix in the gingival connective tissue with varying degrees of chronic
inflammation, particularly the collagen component. (109) As regards the impact of nifedipine
on the oral cavity, our meta-analysis revealed that both the Sunil et al., (110) case- control and
prospective studies of Sousa et al., (111) suggested that gingival inflammation measured by
the gingival index and PB did not differ significantly between the study and control groups.
However, the correlation test showed a combination of both the gingival index and the
bleeding on probing with the degree of gingival overgrowth frequency, and this relationship
was greater for the test group.

This outcome can clarify the effect of these periodontal variables on gingival overgrowth.
Gingival inflammation is known to be a significant risk factor in the presentation of gingival
overgrowth associated with the use of nifedipine. (112) The gingival index found in this study
showed similar findings to those reported by King et al., (113), Barclay et al., (114), Miranda
et al., (115) and ̈ Guncu et al., (116), with bleeding on probing similar to those reported by
Tavassoli et al., (117), while Margiotta et al., (118) did not find a correlation between
bleeding on probing and gingival overgrowth. Cyclosporine A, an immunosuppressant of the
calcineurin inhibitor class, is an important factor in the treatment of aplastic anaemia.
Important side effects of chronic cyclosporine therapy include nephrotoxicity, hypertension,
hyperglycaemia, seizures, and opportunistic infections. (97)

Also, the current literature review found that dental discoloration was the second most
common lesion found in 147 cases in 2 studies that were induced by tetracycline. (119, 120)
Tetracyclines are a broad- spectrum antibiotic community originally found in Streptomyces
bacteria and used to treat many serious infections. The antibiotic can accumulate in the
forming teeth and can result in intestinal staining. (120) As seen in this study, the adverse
drug reactions (ADRs) are one of the major contributors to the development of oral lesions
that may be misdiagnosed with underlying diseases. This study found that the most common
oral ADR is the gingival enlargement, that was identified in 146 cases in 5 studies involving
cyclosporine A and nifedipine. These results reinforce the idea that dentists should be aware
of potential oral ADRs. Indeed, the analysis of the medical history of patients allows dentists
to improve their therapeutic modalities.

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In the study of Mullaly et al., 50 women aged 20 to 35 years had to undergo a comprehensive
periodontal examination. (121) The periodontal health of current pill users contrasted with
that of women who did not take a pill. The results indicated that 42% of the subjects took a
contraceptive pill at the time of periodontal examination. Current pill consumers had greater
mean probing depths compared to non-users and more extreme attachment failure, Pill
consumers had more sites with probing bleeding (44.0 percent versus 31.1 percent ; P =
0.017).

Two more studies of Shaker et al., (122) assessed the side effects of contraceptive pills and
stated that the Gingival index was substantially higher among oral contraceptive users than
non-users (P<0.01), consistent with the length of use (r=0.50). It is concluded that long-term
use of contraceptive pills raises the risk of gingival inflammation and substantially raises the
degree of sIgA, so that daily use of oral contraceptives tends to improve mucosal immune
function in the study subjects. The prevalence of dental caries and the number of colonies of
Streptococci was higher in OC-consuming women than in non- consuming women. The MS
colony increased with the rise in length of use, but the DMFS had no association with
duration. Our findings are not consistent with other studies by Saadet and Kenneth (123)
which found no significant variation between groups. It was estimated that one-fourth of
women of reproductive age had dental caries, a disease in which dietary carbohydrates are
fermented into acid by oral demineralizing enamel bacteria. (124)

Numerous medicines can cause toxic effects in the oral cavity. Drugs can cause symptoms
such as inflammation of the salivary gland, oral ulceration, changes in taste, discoloration of
the teeth, mucosal pigmentation, white spots, swelling, and oral malodour. Such side effects
interfere with the function of the patient and increase the risk of infection, discomfort, and
possible teeth loss. It has been claimed that gingival enlargement, dental discoloration, and
gingivitis are the most common side effects of medications. Health care professionals must
consider the impact medications can have on the oral health of their patients. A
comprehensive medical history including prescribed medications, counter-drugs, and dietary
supplements must be recorded to properly identify and treat patients, enabling the health team
to recognize the causative agents.

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