#DEN4002
#D4/S2/W11
#OPM

OPM Pharmacology

Key drug classes

• antibiotics
• antifungal
• antiviral
  **Other
• saliva substitutes and stimulants
• antiseptics
• immunosuppresive therapies,

Antibacterials

Each type of antibiotics has a specific mechanism of action

• first introduced in 1940s

• target specific feature to effectively kill bacteria or inhibit their growth

• prolonged courses can facilitate development of drug resistance

• prescription only when clear indication and need

• types

  • beta lactam derivatives (penicillin, cephalosporins)
  • macrolides
  • tetracyclines
  • nitroimidazoles
  • lincosamides

• Penicillins target bacterial cell walls and are effective against gram-positive bacteria.

• Cephalosporins, similar to penicillins, have a broader spectrum of activity.

• Tetracyclines inhibit protein synthesis and are effective against a wide range of bacteria.

• Aminoglycosides also inhibit protein synthesis and are mainly used for severe gram-negative infections.

• Sulfonamides interfere with bacterial metabolism and are used for various infections.

• Fluoroquinolones inhibit DNA replication and are effective against both gram-positive and gram-negative bacteria.

• Macrolides inhibit protein synthesis and are often used for respiratory infections.

• Carbapenems are broad-spectrum antibiotics that target cell walls and are used for severe or high-risk bacterial infections.

• Lincosamides inhibit protein synthesis and are used for severe infections caused by susceptible bacteria.

• Glycopeptides inhibit cell wall synthesis and are primarily used for gram-positive infections.

Beta lactam derivatives

• penicillin G / benzylpenicillin
• beta lactam ring is responsible for inhibition of bacterial cell wall synthesis in susceptible species (gram positive bacteria)
• target
  • bacteria with beta lactamases
• cephalosporins
  • cefalexin
  • ceftriaxone
• ampicillin
  • first derivative of penicillin for extended spectrum including several gram negative bacteria, including Hemophilus influenza, which causes maxillary sinus infection
• amoxicillin
  • identical spectrum of activity of ampicillin, but exhibits greater oral bioavailability, absorption not affected by food, and longer half life
  • usually dose 1.5-3g daily, about 5-7 days typically
• amoxicillin + clavulanic acid
  • severe refractory odontogenic and periodontal infections with spreading cellulitis, sinus infections colonised by penicillin resistant bacteroides and prevotella species or Hemophilus influenza

Macrolides

• binding to 50s ribosomal subunit of susceptible organism, resulting in protein synthesis
• erythromycin
• azithromycin, roxithromycin, clarithromycin
• historically alternatives for penicillin
• associated with increased risk of cardiac arrythmia due to QT prolongation in susceptible patients

Lincosamides

• structurally similar to macrolide with same mode of action
  • binding to 50s ribosomal subunit of susceptible organism, resulting in protein synthesis
• clindamycin
• active against gram positive cocci, many penicillin resistant staphylococci, anaerobic species such as Bacteroides species
• good for abscess resistant to amox and metronidazole
• unfortunately associated with Cdiff colitis
  • avoid if history of colitis/GI/digestive condition

Tetracycline

• bacteriostatic
  • binding to 30s bacterial ribosome to inhibit protein synthesis
• useful adjunct for perio infection, highly active against many microorganisms in perio disease and high bioavailability in gingival sulcus
• tetracycline and minocycline have some anti-inflammatory properties
• doxycycline and minocycline preferred for treatment of perio infection
• hypersensitivity reaction rarely encountered by can cause blue grey pigmentation of skin, oral, dental tissues

Nitroimidazoles

• unremarkable broad spectr5um against parasites, mycobacteria and anaerobic gram positive and negative bacteria
• MOA
  • prodrug which is converted to a toxic radical within anaerobic microbes, radical destroys DNA and components
  • bactericidal against most anaerobic organisms
• metronidazole
• useful alternative to penicillin for treatment of oral infections cause by beta lactamase producing anaerobes
• first choice drug for necrotising ulcerative gingivitis and pericoronitis
• can be used as adjunct to amoxicillin for patients with spreading infection or pyrexia
• avoid with warfarin, causes warfarin to be twice as strong with same dose
  • metronidazole inhibit cytochrome p450 enzyme cyp2c9, which metabolises enantiomer of warfarin

Antiseptics, Salivary Substitutes, Antifungals

Chlorhexidine

• bisguanide antiseptic used in dental and medical treatment
• developed in 1940s, marketed in 1954 for topical antiseptic
  • initially used for endo and presurg disinfection of the mouth
• antimicrobial is dose dependant
  • low dose (0.02-0.06%) is bacteriostatic
  • high dose (>0.12%) is bactericidal
• target
  • broad activity against bacteria
  • mainly gram positive bacteria, fungi and lipophilic viruses (HSV, HIV, CMV, influenza)
  • may be sporicidal at elevated temperatures
• common adverse affect
  • brown discolouration of teeth and tongue
  • temporary taste alteration
• uses
  • CHX gluconate 0.12-0.2% mouthwash 15ml 30s bid
  • spray (0.12-0.2%) or gel (0.12-1%) for appication to teeth, RAS, dental varnish for caries prophylaxis (1%, 10%, 40%)
  • can have good impact on halitosis, especially reducing levels of anaerobic bacteria related with bad breath

Povidone Iodine

• bactericidal, fungicidal, virucidal
• most common form is 10% povidone iodine in water
  • 10% iodine with povidone (organic carrier) to provide controlled release of iodine
• povidone iodine
  • bactericidal effect similar to pure iodine, effective against most bacteria including putative periodontal pathogens, fungi, mycobacteria, viruses, protozoa
• differently from CHX
  • povidone iodine doesn't show cytotoxic effects on human cells
• allergy
  • iodine
  • shellfish??
• complication
  • too much iodine affects thyroid, cause goitre, myxoedema and hyperthyroidism

Sialagogues and saliva replacement

• 0.6L saliva a day
  • 90% major
  • 10% minor
• cause of xerostomia
  • Sjogren
  • t2dm
  • head and neck radiation
  • stress, mental health
• frequent liquid intake can alleviate xerostomia to an acceptable level
• salivary replacement
  • natura lubricants such as olive oil and milk can provide some benefit
  • commercial oral lubricants use chemicals of high viscosity to mimic physical properties of natural saliva
  • combination of lactoferrin, lysozyme, lactoperoxidase incorporates antimicrobials naturally found in human saliva and has been utilised in many products
    • biotene, bioxtra, oral7 etc.
• sialogogue (promotes secretion of saliva, can be topical or systemic)
  • 1% malic acid spray can help, but potentially lead to enamel erosion
  • chewing gum asociated with increase saliva production in majority of those with residual capacity
  • pilocarpine commonly given at doses of 5mg 3x a day
  • cevimaline further cholinergic agent

Antifungals

• 3 main categories
• polyenes
  • nystatin
  • amphotericin B
• ergosterol biosynthesis inhibitors (azoles)
  • imadazole
    • miconazole (synthetic imadzole, also antistaphylococcal)
    • clotrimazole
  • triazole
    • fluconazole (broad spectrum)
    • itraconazole (useful for fluconazole resistant candidal strains)
    • posoconazole (broad spectrum 2nd gen)
    • voriconazole (broad spectrum 2nd gen, for esophageal candidiasis, candidema, invasive fungal infection)
• allylamines, thiocarbamates, morpholines
  • dna analog 5 fluorocytosin
  • caspofungins (IV)

MOA

• polyene
  • target/binding fungal cell membranes which contain ergosterol, forces membrane to form pores which disrupt permeability of fungal cell membrane (lets vital cellular components to leak out)
• imidazole
  • fungistatic, inhibiting ergosterol synthesis in fungal plasma membrane

Antivirals, Corticosteroids, Immunosuppressives

Antivirals

• aims to
  • block viral replication
  • shorten duration of symptoms
  • accelerate healing of lesions
• antivirals for HSV/VZV are either topical or systemic, all target viral DNA replication and theres 3 classes
• acyclic guanosine analogues
  • acyclovir (potent, selectively active against herpes virus group)
  • famcyclovir (prodrug of pencyclovir, useful against HSV)
  • valacyclovir (prodrug of acyclovir, better absorbed/bioavailability +55%)
  • gangcyclovir, pencyclovir, , valgancyclovir
• acyclic nucelotide analogue
  • cidofovir, adefovir, dipivoxil
• pryophosphate analogues
  • foscarnet (IV herpes virus)

Corticosteroids

• 2 types
  • glucocorticoids
  • mineralocorticoids

hpa axis

Glucocorticoids: systemic corticosteroids

• cortisol (natural GC) secreted from arenal glands at 20-30mg a day
• number of synthetic corticosteroids mimic cortisol, can be used for
  • hormone replacement therapy (hypoadrenocorticism)
  • anti inflammatory agents
• systemic glucocorticoids can be used for short or long term therapy
  • 3 weeks short
  • more than 3 weeks long
• some groups at higher risk of side effects
  • osteoporosis
  • weight gain
  • increase blood glucose

dosage considerations

• tapering off not necessary in short term therapy but very important when treatment has lasted longer than a few weeks, to allow for adrenal recovery
• reduce dose too quickly, will trigger corticosteroid withdrawal syndrome
  • arthralgia, myalgia, mood change, fatigue, headache, GI complaint
• osteoporosis most common long term GC therapy side effect
  • occurs in 30-50% of patient that aren't treated with preventative measures

Topical Corticosteroids

• ointment glucocorticoids
• twice or three times daily application usually recommended
• greatest problem of its use in oral cavity is decreased adherence to mucosa for period required
  • adhesive gel such as carboxymethylcellulose or hydoxyethyl cellulose can be employed and mixed in equal parts with topical GC
  • duration of application varies between 4 and 30 mins, custom made tray best for gingival lesions

Intralesional corticosteroids

• used for management of localised lesions in patients with erosive OLP and for lip swelling in patients affected by orofacial granulomatosis
• triamcinolone acetonide 40mg/ml has been mainly used as intralesional GC, appears to represent effective therapeutic strategy to control permanent disfiguring swelling

Immunosuppressive and anti-inflammatory agents

• major goal of management of patients with immunologically mediated diseases is reduction of patients cumulative exposure to systemic corticosteroids
• immunosuppresive in 4 categories
• calcineurin inhibitors
  • cyclosporine
  • tacrolimus
  • pimecrolimus
• inhibitors of purine and pyrimidine synthesis
  • azathioprine
  • mycophenolate mofetil
• alkylating agents
  • cyclophosphamide
• antimetabolites
  • methotrexate
• all have glucocorticoid sparing effects but also affect b cells and t cells
• drugs with anti inflammatory rather than immunosuppressive action
  • colchicine
  • dapsone
  • tetracycline
  • thalidomide

Biologic agents

• monoclonal antibodies with biologic source that includes
  • human -mab
  • humanised -zumab
  • chimeric -ximab (e.g. mouse human)
• or variant fusion proteins -cept
• used in variety of oral diseases
  • behcet, severe RAS, bullous disease, OLP, crohn/OFG, SJS, cGvHD, oral cancer
• but mostly for bullous diseases and oral cancer