Lecture Lecture 1- Intro Intro Intro • Yo dawg, I heard you liked intros, so I put an intro, in your intro. • One part of our job requirements is to be able to compound extemporaneous compounds • Extemporaneously compounded dermatological products are rather common (especially if i t has coal
tar) • And we need to remember that there are standards associated with compounding ○ Equipment Clean Accurate (and certified) Dedicated for compounding use only (i.e. don't eat off them) Certified ingredients ○ Paperwork and good record keeping Expiry dates ○ 1-3 months for external products
Extemporaneous compounding of dermatological compounds • A galenical is
A simple cure based on plants ○ Named after Galen ○ Examples include salicylates and even coal tar (wut) • Examples of subsidised bases are Aqueous cream ○ ○ White soft parafin Hydrocortisone creams ○ • We need to be comfortable in using this diagram (from the schedule) to determine subsidy requirements: ○
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• What does it mean? ○
Need to have at least one galenical Glycerol isn't a glaenical, and it also isn't funded for external use Therefore, 10% glycerol in aq cream isn't funded at all, because it's got no galenical Need to have at least one o ne subsidised base If those conditions are met: The non-subsidised parts (e.g. glycerol) isn't funded, but the rest of the product is This is why some pharmacists will make a 0.1% coal tar in glycerol and aqueous cream to make it cheap for patients (the 0.1% coal tar won't have any effects, so it's a cheap form of glycerol in aqueous cream) Finally, the corticosteroid creams are special We can dilute them with another base BUT only if the prescription is given by a specialist For non-specialists, then the product isn't subsidised at all
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Lecture 2- Superficial skin conditions (immune system) Intro • The skin is a barrier which keeps pathogens out of the body to prevent them from causing harm
The stratum corneum will keep them out o ut • The barrier function is especially important once you realise the skin is covered in commensal bacteria E.g. staph species ○ They will be shed as the outer layer of the skin is shed ○ But let's not forget their role in keeping us safe as well, as they outcompete some nastier ○ pathogens and they stimulate our immune system to keep it on its toes • Even if they manage to get past the skin's barrier, they will wil l encounter the strong immune presence in the skin ○ Langerhans cells in the epidermis ○ Monocytes in the dermis • Superficial skin conditions tend to be ○ Opportunistic fungal infections Viral infections ○ ○ Immune-mediated inflammatory conditions ○
Fungi • Eukaryotic organisms
They have a nucleus ○ Tend not to have extrachromosomal extrachro mosomal DNA (i.e. they don't carry any extra DNA outside the chromosomes as plasmids) Debatable, some may carry plasmid-like structures ○ Have a cell wall made of chitin Large cells (100 microns across) ○ ○ Can be either multicellular (mushrooms) or unicellular (candida) ○ Carries out mitotic division with cell checkpoints like us (causes less mutations) ○ Can have sexual reproduction as well (releasing highly-resistant spores) • Low resistance patterns Don't reproduce or mutate as quickly (so there's less chance of producing cells with resistance) ○ Can't pass on resistance with plasmids ○ ○ BUT there are forms which are slowly becoming multi drug resistant Changes in drug entry/efflux Metabolised once it gets into the cell Loss of target (i.e. the enzyme mutates, and the drug can't bind anymore) ○ Resistance is being countered with: New drugs (not happening much) New delivery systems (liposomal amphotericin B as an example) Combination therapy (prevents resistance from forming) • Tend to be opportunistic infections ○ Only superficial skin infections in most people Systemic infections in immunocompromised people ○ ○
Drug targets for fungi • Ergosterol ○ ○ ○
Sterol used to reinforce the cell membrane For reference, humans use cholesterol instead This difference means we can exploit its synthesis as a drug target (and it will have a wide therapeutic index because it's so different)
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Azoles and allylamines will bind to egosterol • Glucan synthesis ○ Glucans make up part of the wall of fungi (crosslinking in the wall) ○ A glucan synthase enzyme sits in the cell membrane to produce the glucans, which are then secreted out into the wall ○ Echinocandins will inhibit this enzyme ○ This causes the wall to lose strength, and the cell will lyse due to osmotic stress • DNA Flucytosine acts just like 5-FU ○ Except it's quite specific to fungi, because it's taken up via cytosine permease ○ So it will inhibit thymidylate synthase AND be incorporated as a false metabolite The effect of these two processes is to prevent DNA and RNA synthesis ○ But there are more side effects associated with this, because it will be broken brok en down to 5-FU by bacteria in the gut ○
Fungal infections • Can be diagnosed from clinical appearance
But the problem is they are very similar in appearance when compared to other inflammatory skin conditions • Wood's light can be used ○ Long wave UV light ○ Some fungi will fluoresce (glow) under UV light ○ A positive result is good, because we definitely know it's a fungal infection ○ But a negative result means it could still be a fungal infection, but it could also be anything else • Microscopic examination Can see parts from the infection (e.g. ( e.g. hyphae or spores) ○ ○ So it can be used to make a definite diagnosis as well • Culturing ○ Rarely used Takes several days ○ Only good to check susceptibility patterns when choosing an antifungal ○ ○
Tinea pedis (athletes foot) • Very common infection ○
Especially in younger males
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RARE in children under 12 (refer?) Tends to be a chronic condition Caused by Trichophyton rubum ○ T. mentagrophytes ○ ○ Epidermophyton floccosum Can be spread via spores ○ Hard to spread though However, spores can survive in places for months ○ Therefore, very hard to eradicate (e.g. it stays in the socks for a long time) ○ Prefers warm, moist environments ○ As presented in shoes Risk factors ○ Poor hygiene ○ Poor circulation (immune cells can't reach the foot) ○ Immunodeficiency Symptoms Dry, scaly, red itchy skin either between toes or around the heels or o r sides ○ ○ Scaling or splitting between toes ○ Blistering Complications Secondary bacterial infection, which requires antibiotic treatment ○ Treatment ○ OTC preparations (see workshop) ○
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Picture is in the public domain Tinea corporis (ringworm) • Common in children • Can be an acute or chronic infection • Can be different fungi from tinea pedis
T. rubum (as seen in tinea pedis) Microsporum canis (seen in dogs?) ○ ○ T. verrucosum • As implied above, it can be a zoonotic infection (i.e. from animals) ○ But it also can be caused via self-inoculation from the feet (T. rubum) • Symptoms Inflamed red patches ○ White healing middle (leads to a ring shape) ○ ○ Itchy • Diagnosis is difficult ○ Similar to other conditions like impetigo, dermatitis etc. Using Wood's light is recommended reco mmended for diagnosis ○ ○
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Picture is in the public domain Tinea capitis • Common in children as well • Also zoonotic
From infected felines ○ And other animals • Person to person transmission is difficult, but possible e.g. sharing hairbrushes which have spores on them • Treatment is with OTC ointments and shampoos (and treat asympto matic contacts) ○
Image is licensed under the Creative Commons Attribution-Share Alike 3.0 Unported license. Author :Grook Da Oger Warts • Common infection, especially in younger people • Caused by human papilloma viruses • Spread via human to human contact
Auto-inoculation is possible, e.g. picking at the wart • Diagnosis is straightforward, because it's quite distinct Only worried about elderly or immunocompromised i mmunocompromised patients ○ • Treatment ○ Not generally needed (self limiting) They will just disappear after a few years after the immune system acts against them All the warts will disappear suddenly ○ Can be removed Freezing Chemical Laser Immune stimulation ○ Imiquimod cream (not common) Just by freezing it or cutting it stimulates inflammation to help remove it ○
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Image is in the public domain Cold sores • Caused by herpes simplex virus type 1 (HSV-1) ( HSV-1)
Genital is HSV-2 • Cannot be removed, it remains latent in nerve endings ○ Primary infection Usually occurs in childhood 7 day incubation period Widespread sores (red bump, blister, crusting) Usually doesn't form scars Recurrence ○ Not as severe Prodromal period can be felt by the person e.g. itching or burning feeling • Can be triggered by certain things like sunlight, menstruation, immune suppression etc. • Treatment is with acyclovir ○
Image is in the public domain Inflammatory skin diseases • These are caused by immune dysfunction • Not by pathogens
Dermatitis • • • •
Superficial inflammation of the skin There are many forms of it Can be acute or chronic Atopic/allergic forms are dose independent, while irritant induced dermatitis has a specific cause and dose-response ○ Both are related to genetics though But there are some other differences ○ The allergic forms require prior exposure, because they need that initial exposure to build up an immune reaction Once the immune reaction is set up, it can spread to other sites of the body (e.g. exposed at
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foot, still see the same reaction in the arms) This is because it's a systemic condition, compared to irritant induced dermatitis which is only a local response (so it doesn't spread, or need prior immune activation)
Contact dermatitis • Irritant dermatitis • Many different agents (depends on the person
Light, heat, chemicals etc. • Can be acute or chronic/recurrent • Can be mild or severe • Treatments ○ Find out what's causing it, and prevent exposure ○ If that's not possible, limi limitt exposure via protective clothes/gloves etc ○ Medication ○
Nappy rash • Irritant dermatitis • Triggered by
Ammonia from urine Proteolytic enzymes from faeces ○ ○ Friction and dampness Can be acute or chronic Symptoms ○ Redness ○ Swelling ○ Initially scaly and can erode the skin in later stages ○ Clearly defined areas, because the nappy limits the irritants to that region only Can become complicated ○ Secondary bacterial or fungal infection Uncomplicated cases can be treated via OTC Barrier creams to prevent contact with skin ○ ○ Regular nappy changes Careful cleaning ○ ○
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Atopic dermatitis/eczema • Chronic allergic hypersensitivity
Immune mediated Common in children (incidence is increasing) ○ Hygiene hypothesis (being in a too to o clean environment when young means the immune system gets bored and attacks the host instead) 'Dirt' (more siblings, on a farm, daycare, pets) was protective against eczema ○ Broad spectrum antibiotic use is a risk factor for eczema ○ Tends to resolve spontaneously by adolescence at the latest Symptoms ○ Dry, red, cracked skin Itchy ○ Complications are again possible ○ Secondary fungal or bacterial infections Treatments ○ Phototherapy Sometimes, outbreaks occur during winter, so shining light actually works ○ Medications Antifungals/antibiotics for secondary infections ○
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Topical corticosteroids to reduce symptoms Avoid irritants Perfumes tend to be irritant So are surfactants used in detergents Don't scratch the areas Probiotics? Some evidence for use
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Cradle cap • • • • •
Occurs within the first 6 weeks of life Self-limiting Caused by overactive sebum (sweat) production caused by mat ernal hormones Yellow scaly patches on the scalp Soften with mild shampoo and carefully take flakes off
Psoriasis • T cell mediated inflammation
Might be an autoimmune disease, but we haven't identified the target yet • Symptoms ○ Red lesions with a well marked border Scaly ○ ○ May blister with friction or sweat ○ Can be widespread • Treatment (hit and miss here, try everything and see what works) Phototherapy may work here as well ○ ○ Baths and moisturisers Lifestyle factors ○ Weight reduction Smoking cessation Reduce alcohol intake Topical creams or ointments ○ Keratolytics Corticosteroids Coal tar Vitamin D analogues ○ Systemic treatment Corticosteroids Cyclosporin (immune suppression) Retinoids ○ Biologicals Infliximab Anti-TNF-alpha mouse antibody □ IV □ □ Every 6-8 weeks Ustekinumab □ Anti IL-12/23 SC □ □ Every 8-12 weeks Better than infliximab (safer and more efficacious) □ Expensive as hell, and will cause c ause marked immunosuppression in the host ○
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Lecture Lecture 5- Bacterial Bacterial infections infections of the skin NOTE: lecture 3 and 4 can be found after this (I wanted to keep the two micro lectures together) Intro • This lecture deals with the more mo re serious infections of the skin
Can be deeper or systemic • Mostly bacterial infections • Bacteria involved usually are: ○ Staph species Especially S. aureus, which is aerobic and toxin producing And it tends to be resistant to antibiotics (remember MRSA?) ○ Strep species Group A, beta haemolytic □ S. pyogenes Facultative anaerobe, so it can survive both on the surface of skin, and in deep parts of the skin However, they still tend to be sensitive to antibiotics (penicillin) ○ Propionibacteria species Can tolerate anaerobic conditions as well ○ Mycobacteria leprae Clostridium perfrigens ○ ○
Acne • Not an infection
Because the bacteria don't actually invade the tissues, they just happen to be in the sweat gland But you do have to recognise the bacteria are a part of the problem though (see below) ○ Occurs mostly around the face, where sebaceous glands are common Forehead ○ ○ Around the nose and mouth The main reason why acne forms is due to blockage of these sebaceous glands Blockage means the sebum is kept in the gland ○ ○ The commensal bacteria present in the gland will multiply ○ They produce lipases, which break down fats (as triglycerides) into free fatty acids ac ids (reduces pH) Pimples will form around the site ○ Whiteheads- sebum is unexposed to the air, so it appears white as it applies pressure against the skin Blackheads- sebum is exposed to the air, so it appears black as the topmost part turns black with exposure ○ They stimulate the production of inflammatory chemokines to c ause inflammation Bacteria involved are: ○ Staph epidermis ○ Propionibacteria acne, P. granulosum, P. parvum Risk factors are: ○ Major factor: hormones, the androgens Androgen receptors on the sebaceous glands will be activated to stimulate growth and production of sebum The 5-alpha reductase enzyme will convert the androgens to more active forms (testosterone to dihydrotestosterone) The conversion rate to the active form happen much more often in the skin of people suffering from acne During puberty, a lot of hormones tend to be released, which leads to an increase in acne ○
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Or abusing anabolic steroids will cause acne as well (weightlifter's acne) ○ Genetics Polygenic causes (see the other's below) Sebaceous glands ○ High sebum production is linked to increased risk But Parkinson's disease patients have overactive sebum production, but they don't tend to suffer from acne, so it's not the major factor Bacteria ○ Involved in inflammatory processes But they aren't important, as pretty much muc h everyone has bacteria present, so it's not no t a major risk factor Abnormalities ○ Abnormal gland reaction and keratinisation (i.e. having skin grow over the gland to cover it to form the pimple) is more common in people suffering from acne • Major risk factors are NOT Diet- some evidence, but eating eating healthy isn't likely to remove acne ○ DirtDirt- Nope. Nope. ○ ○ Stress- doesn't cause acne, but can cause exacerbation of acne • Treatment ○ For mild cases, they will resolve spontaneously, so the intention of treatment is to prevent scarring Generally topical treatments of retinoids or antibiotics For severe cases, they need to treat the cause of acne ○ Antimicrobials (tend to be oral) Hormonal therapy Oral retinoids (tend to cause atrophy atr ophy of sebaceous glands) Peeling or keratolytic agents to remove skin ○ Rule of thumb is to not pop the pimples, as popping them can break down the barrier function of the skin and introduce potentially nasty bacteria (leading to deeper infections or systemic infections)
Hair follicle infections • Different from acne, because this is a true tr ue infection, where the bacteria will infect tissues
Could also be fungal or viral ○ But usually it's S. aureus again, so empirical treatment with antibiotics is recommended It could be a complication from acne, where the bacteria are able to invade into the tissues Occurs in the follicles with conditions of high humidity ○ Groin ○ Arm pits ○ Scalp Folliculitis is a more superficial infection ○ Small inflamed pustules ○ Plenty of pus ○ Can be itchy or painful Boils are more deep ○ Central yellow plug ○ Bigger lesions Occurs where friction is common (joints) ○ ○ Will drain themselves ○ Systemic symptoms are possible Carbuncles are the worst ○ Several boils joined together ○ Massive amount of damage and necrosis ○ Needs to be drained surgically ○ Systemic symptoms will be present, antibiotic therapy is required ○
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• One important complication of deep infections is endocarditis
If bacteria reach the blood (bacteraemia), then they can reach the heart, where they will hang around on the heart valves. ○ The immune response against them will cause endocarditis and sinus thrombosis ○ Therefore, early treatment before these complications is recommended, especially in parts of New Zealand where it's common (e.g. Northland) • But more superficial forms can be left l eft alone ○
This file is licensed under the Creative Commons Com mons Attribution 1.0 Generic license. Author: Mahdouch Impetigo • Looks very serious, with redness with a honey coloured crust around the face
But it's a very superficial infection, so no systemic symptoms are seen ○ Tends to heal without scarring Caused by Staphococus aureus or Streptococci pyogenes Very common in school age children ○ Especially because it's highly contagious ○ Autoinoculation is possible as well, e.g. picking nose and then picking at a sore on the face Starts off as blisters, which then rupture Then the golden crust will form ○ Treatment is mainly to reduce bacterial load to prevent it from being contagious ○ Child can return to school 24 hours after oral antibiotics, because the bacterial load drops Is associated with complications ○ Can breach deeper tissues to cause systemic infection (especially ( especially if immunocompromised) ○ Glomerulonephritis can occur ○ Scarlet fever (systemic infection) is rare ○
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This file is licensed under the Creative Commons Com mons Attribution-Share Alike 3.0 Unported license. Author: Åsa Thörn
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Cellulitis • Very deep infection
All the way down to the muscles and tendons ○ S. pyogenes, S. aureus, S. pneumoniae, H. influenzae They must have breached the skin barrier somehow som ehow ○ Tends to be a cut, abrasion, burns, bites etc. which allows entry ○ Tends to occur in the legs and face Periorbital (around the eyes) cellulitis can occur in children due to a sinus infection Risk factors are Immune suppression ○ If they can't fight off the initial infection, it's unlikely they can get rid of all the bacteria Diabetes ○ Tend to be slightly immunosuppressed and they have poor circulation ○ Surgery Provides entry, and they tend to be resistant bacteria ○ Poor circulation Immune cells can't reach site properly Symptoms are ○ Ill defined regions (diffuse) ○ Red, painful and swollen sites ○ Can rapidly spread Area affected is usually marked, and checked to see the rate of spread ○ Systemic symptoms (fever, chills etc.) Treatment ○ Uncomplicated No systemic spread (just local infection) Small area No risk factors Just give oral antibiotics ○ Complicated Systemic involvement IV antibiotics Debridement (i.e. slough away dead skin, because the c irculation is damaged, so the antibiotics won't reach that site anyway) ○
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This file is licensed under the Creative Commons Com mons Attribution-Share Alike 3.0 Unported license. Author: Pshawnoah Invasive Group A Streptococcal infection (toxic shock) • Bacteria gain systemic access and cause havoc ○
Organ failure and amputation
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Death Risk factors ○ Skin lesions (so this is a complication from skin lesions) ○ Very young or elderly Immunocompromised patients ○ Early symptoms are ○ Redness ○ Swelling and pain ○ Usually around the site of the wound (bacteria need to gain deep access) NEED to treat early (to prevent what happens below) ○ Some bacteria can release 'superantigens' ○ S. pyogenes (as seen from cellulitis and impetigo) is one such species ○ The superantigens will cause a cytokine cyto kine storm, which is where the immune reaction reactio n to the bacteria is so intense that it i t causes severe hypotension, organ damage and death Treatment Aggressive supportive care (ICU ward) ○ ○ Keep blood pressure up (IV fluids etc.) Antibiotics ○ ○ Wound care Drainage of site Debridement ○ IV immunoglobulins, which will bind to t o the superantigens to try and reduce the immune response Very expensive and rarely used, only used as a last line measure ○
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Necrotising Fasciitis • Tissue infection which leads to gangrene
Destruction of deep and superficial structures Includes muscle, vasculature, skin etc. ○ • Also called flesh eating bacteria for a reason ○
• Caused by strep. Pyogenes (again…) • Again, like toxic shock, the bacteria need to get into the tissue via a wound • Risk factors
Age Vascular disease ○ ○ Diabetes (causes vascular disease) ○ Immunosuppression Early symptoms Trauma ○ Discomfort in the area ○ Malaise (feel unwell) ○ Headache Fever Joint and muscle pain Advanced symptoms ○ Severe pain ○ Visible blisters ○ Skin appears dead Critical symptoms ○ Less pain (nerves dead) ○ More systemic symptoms (toxic shock from superantigens) ○ Coma and death ○ Gas pockets can be felt/seen Treatment Early treatment to prevent morbidity (especially amputation) ○ Treatment important for people with risk factors ○
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IV antibiotics Intensive care unit Keep blood pressure up as well Debridement Amputation (tissue damage is just so severe that there's no point in keeping it) Skin grafts, because lots of skin will be lost
[Debridement picture omitted] This file is licensed under the Creative Commons Com mons Attribution 2.0 Generic license. Authors: Piotr Smuszkiewicz, Iwona Trojanowska and Hanna Tomczak Gangrene • Similar to necrotising fasciitis, because of massive soft tissue necrosis • But the causative agent here is Clostridium perfringens
Anaerobic organism, can infect deep tissues as well • Pretty much the same as above, but it's even faster ○ And produce more gas • Changes are visible in the magnitude of minutes • At least the treatments are the same as above ○
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Chronic infection Caused by Mycobacterium leprae Very long incubation time as it's slow growing Invasion of the skin, mucosal membranes and nerve endings ○ Nerve damage leads to peripheral neuropathy, which leads to more tissue damage Can infect any age group Strong social stigma against lepers Exact transmission patterns are unknown ○ Person to person? Insects? Airborne? Minimally contagious ○ Tuberculoid leprosy Not infectious (only a few bacteria bact eria present) ○ ○ Small, dry and scaly lesions Grows slowly ○ ○ Hair loss Systemic nerve damage, leading to peripheral neuropathy ○ Lepromatous leprosy Contagious (but still pretty hard to infect others) ○ ○ Usually involves the face, earlobes and nose Chronic nasal discharge ○ ○ Systemic nerve damage as well Treatment is simple and effective today
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Needs to be given for a long time, because it is slow growing Up to two years in the case of lepromatous leprosy Since treatment time is very long, resistance can occur, so a multi-drug approach is needed Dapsone, rifampicin and clofamizine Surgical reconstruction is recommended recom mended to restore appearance
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Lecture Lecture 4- Adverse Adverse Drug Drug Reactions Reactions Intro • Adverse drug reactions (ADRs) can be described as a noxious, unintended effect of a drug which occurs
at normal therapeutic doses (adapted from WHO) • It is also considered to be a subset of adverse drug events Adverse drug events encompasses all of prescribing errors (wro ng drug, dose etc.), medications ○ errors (e.g. dispensing and compliance) and ADRs • Some people in the population will for some reason will experience an ADR while others o thers won't ○ It's our job to make to minimize ADRs, because ADRs are not a part of safe and effective use of drugs Types of ADRs • Type A (Augmented)
Predictable due to the drug's pharmacology ○ Shows a dose dependent effect The severity and chance of an ADR increases with increasing dose Therefore, can respond to dose reduction/adjustment ○ Can be a minor reaction (e.g. nausea) or major (e.g. haemorrhage) Examples: ○ Warfarin can cause bleeding as an ADR as it's an anticoagulant Opioids such as morphine can cause ca use respiratory depression Notice how each ADR tends to be linked to overdoses • Type B (Bizarre) ○ Unpredictable, random people will have ADRs Mostly due to immunological causes ○ Can occur at any dose, where tiny doses can cause effects Tend to be rare ○ ○ But they also tend to be serious Stopping the drug is the usual course of action due to severe effects ○ ○ Examples: Penicillin allergies can occur ○
Pathogenesis of type A ADRs • Since the reason for ADRs in type A reactions is due to pharmacology, pharmacolo gy, we need to consider:
Pharmacokinetics ○ Pharmacodynamics • The pharmacokinetics is quite easy to understand: ○ The main reason for ADRs is due to a decrease in clearance Age is one of the main reasons, as it leads to hepatic and renal function decreases Poor metabolisers (enzyme polymorphs) will see a reduced r educed CL Addition of an enzyme inhibitor does the same thing (i.e. drug interactions) Saturable kinetics is also something which needs to consider, as the clearance stops increasing with the plasma concentration ○ A reduction in clearance, leads to an increase in plasma levels, because they are inversely proportional (see formula) A higher plasma level is then associated with ADRs ○ ○ Also, an increase CL can be seen in some patients (not an ADR as such, but are ADEs) Increased CL = reduced plasma levels (see formula) This will lead to therapeutic failure due to underdose Could be due to enzyme induction, enzyme polymorphs polymo rphs (rapid metabolizer) or poor ○
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compliance (not related to CL)
• His explanation for the pharmacodynamics was:
Top part: Emax represents occupancy, so more m ore occupying = more effect ○ Bottom part: represents the potency (potency represents how easily the drug binds, and how much of an effect it has) • Consequences ○ Disease states: Myasthenia Gravis is exacerbated by aminoglycoside use, because aminoglycosides reduce ACh release (remember: myasthenia gravis patients don't have enough ACh receptor activation) Pharmacogenetic: people with VKORC1 polymorphisms can produce less vitamin K epox ide ○ reductase, so warfarin will affect them more, mo re, because they have less VKER to begin with ○ Drug interactions: Fluoxetine and sumatriptan both i ncreases serotonin in the brain, which can lead to serotonin syndrome ○
Pathogenesis of type B reactions
They can be: • Immunologic Allergic response (i.e. an unwanted immune response against a drug) ○ ○ Therefore, requires prior exposure before immunological response ○ Four different mechanisms • Idiosyncratic ○ Unknown cause ○ But we know most are immune im mune responses (of unknown mechanism) • Pseudoallergy ○ Produces symptoms which are like the ones o nes seen in allergies ○ But they don't have an immune component Types of allergic reactions
Has been covered last year, summary below: Type
Mediator
Target cell
Mechanism
I
IgE (true allergy)
Mast Mast cells cells • Histam Histamine ine releas releasee once once IgE binds binds to antigen • Note: drugs by themselves are not
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Onset
Outcome
Immediate
• Anaphylaxis • Uricartia (hives) • Angioedema
antigenic (too small), they become antigenic once covalently bound to a protein II
III
• Antibodies attack cells which have been Rapi Antibodies Many Rapid d or or del delay ayeed (blood coated in drug cells • i.e. recognised as foreign Liver etc.)
• Bloo Blood d dys dyscras crasia iass • (haemolytic
IgG, IgM
1-2 weeks (delayed)
• Glomerunephritis • Serum sickness • Tissue damage
Delayed
• Contact dermatitis • Most delayed
M an y
• Immune complexes (antigen with
antibody) are in the blood • They settle (usually filtration membranes like in the kidney) and cause inflammatory damage IV
T cells
T cells
• T cells come into contact with antigens,
and that causes release of cytokines
anaemia)
hypersensitivity reactions • Pseudoallergies aren't true allergies, because it's not mediated by the immune system
Instead they cause the symptoms by directly triggering the reaction ○ For example, NSAIDs increase leukotriene production (which are inflammato ry mediators) This causes asthma ○ There is some cross sensitivity, where drugs of o f the same action will cause the same allergy symptoms, regardless of their chemical structure. • DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) and SJS (Stevens-Johnson syndrome) are likely to be the same thing, with different effects: ○ Both involve a T cell response (probably against toxic and antigenic metabolites) ○ DRESS causes rash, fever, eosinophilia and hepatitis Allopurinol and aromatic anticonvulsants While SJS causes skin, GI tract and respiratory tract illnesses, where the epidermis can come off ○ the dermis Allopurinol (again), sulphonamides and NSAIDs ○
Prevention and management • Type A can be managed/prevented by:
Identify what's causing the ADR (or identify potential ADRs and remove them) Taking a good drug history and checking compliance is a good idea Changing kinetics means a change in dose is necessary with age Taking multiple drugs increases the chances of an interaction (and ADR) Reduce the dose ○ Good for overdoses (especially if caused due to decreased clearance with age) Plus the ADR tends to be dose-dependent do se-dependent Consider alternative routes ○ Alendronates can cause oesophageal burning if taken incorrectly Therefore, injections can be considered to prevent this ADR But the best thing to do is to replace the drug if it's possible ○ e.g. metoprolol is a better choice compared to atenolol if renal function is impaired • Type B is quite simple DON'T use the drug again ○ ○ Immune reactions can be potentially lethal (e.g. DRESS and SJS) ○ Watch out for cross for cross reactivity ○
Cross reactivity/allergy • Cross reactivity is common within a chemical group, which share similarities ○
Most commonly given example is penicillin, which shows a high chance of cross reactivity within penicillins
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• Cross reactivity is uncommon between chemical groups
For example, very little cross reactivity between penicillin and erythromycin ○ This is why people can be given erythromycin if they have a known allergy to penicillin • Cross reactivity MIGHT occur between similar chemical groups Both penicillins and cephalosporins share the beta-lactam moiety ○ ○ But the chance of cross reactivity is surprisingly low ○
Reporting ADRs • NZ is good at it • Good for
Detecting ADRs which weren't detected during trials (i.e. pharmacovigilance), because rare ADRs don't tend to be picked up as the trials are only 1000's of people (not everyone) Allows us to predict who will get ADRs (and prevent use) ○ OR even disprove that some people get ADRs, so we can get them to use certain drugs ○ Safety, so drugs can be pulled off the market if harm is shown • Communicating ADRs is tricky ○ Patients have the right to informed consent (so they need to know about what the possible harmful effects are) But at the same time, it could freak them out, as they can ignore the benefits ○ ○ So use absolute risk, not relative risk 10x increased risk sounds horrible Saying it changes your chances from 1 in 10,000 to 1 in 1,000 doesn't sound so bad Just hope they can't do headmath ○
Bonus: extra pharmacodynamics which doesn't make sense • Pharmacodynamics rely on several things: ○ ○ ○
Affinity Efficacy (Emax) These two gives rise to potency (EC50), as potency is proportional to both affinity and efficacy (but they are not the only parameters which chance potency)
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Affinity is a measure of how easily a drug binds to the receptor Shouldn't change much, it's a property of the drug and the receptor/enzyme i.e. the dissolution constant Efficacy is the maximum response which is able to be produced from the drug (i.e. even if you have the drug at unlimited concentration, it won't have any more effect) Can be related to the number of receptors/enzymes expressed by the person Both are proportional to potency. A potent drug will bind easily to its receptor AND give a strong response Strictly speaking, the EC50 represents the concentration which is required to achieve 50% of the response, and a lower number means a drug is more mor e potent This means a more potent drug will need a lower concentration to achieve 50% effect But there are other factors which can determine the EC50 (see below) Notice how the plasma concentration is also expressed at the top An increase in concentration should increase the occupancy (how much % of the receptors are bound) Lastly, if two drugs exert the same effect, but with different mechanisms, then effect is increased So some examples of how this works (note: this is just a guess from me) Disease states- Myasthenia Gravis sufferers sufferers already have low ACh receptor activity. Aminoglycosides will reduce ACh release, so the level o f activation at the ACh receptor will be reduced, exacerbating symptoms.
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i.e. the disease and drug had additive effects Pharmacogenetic- VKORC1 encodes for for a part of the Vitamin K epoxide epoxide reductase enzyme, a target for warfarin. Some people with VKORC1 polymorphisms will produce less of the enzyme component, so warfarin has more effect Affinity can't have changed if the enzymes are still functionally identical (i.e. their □ binding affinities/dissociation constant won't have changed) BUT due to the reduced concentration of enzymes, the overall concentrations at equilibrium would have changed so a reduced concentration of warfarin is required. (stab in the dark here) Efficacy can't have changed, the extent of o f effect (i.e. inhibiting every single enzyme in □ the body) would be the same, so Emax shouldn't change The relative potency (I'm sure that's not even a proper term, just making it up on the □ spot) would increase, because less warfarin would be r equired to cause a large response because less enzymes are present (EC50 is reduced) Drug interactions- fluoxetine and sumatriptan when taken together can cause serotonin syndrome, which is having too much serotonin Additive effects, both release serotonin □ • Note: I probably went WAY too deep. ○ This is why lecturers should be careful when using formulae... □
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All workshops Note: I can't use images from DermNet here (copyright issues), just go visit their their website instead Parts of the body and its associated conditions Part
Immune related?
Head (scalp)
• Psoriasis
Face
• Dermatitis
Bacterial
Other
• Dandruff • Tinea capitis • Seborrhoeic dermatitis • Cradle cap • Impetigo • Seborrhoeic dermatitis • Cold sores (viral) • Acne • Tinea faciei • Sunburns • Shingles (viral) • Drug sensitivity
(all types)
Neck and ears
Fungal
• Dermatitis
• Sunburn • Photosensitivty
Esp. contact Trunk
• Tinea corporus • Drug sensitivity • Seborrhoeic dermatitis • Chicken pox (viral) (in hairy patches) • Measles (viral) • Tinea versicolor • Scabies (viral) • Viral rash (flu)
Hand Hands, s, wris wrists ts and and arms arms • Psori Psorias asis is (Palms) (elbow) • Eczema (inside of elbow) • Contact dermatitis (both types)
• Tinea corporus • Tinea unguium (nails)
Groin
• Tinea cruris (jock itch)
Legs
• Psoriasis
• Tinea corporus
• Waxing • Sunburn • Photosensitivity
• Tinea pedis • Tinea unguium
• Corns and callouses
(front of knee) • Eczema (flexure of knee) • Asteatotic dermatitis (winter itch) Feet
• Psoriasis • Dermatitis
• Warts (viral) • Sunburn • Photosensitivity
(all types)
Note: title colour gives an idea about how much each column is complete (red = mostly missing, green = mostly finished) Note 2: Psoriasis can occur pretty much anywhere, but the listed ones are the common sites Note 3: Eczema (atopic dermatitis), allergic contact dermatitis, irritant contact dermatitis = 'all types'
Conditions (diagnosis and treatments) Dermatitis Contact dermatitis • Two forms:
Allergic contact dermatitis Irritant contact dermatitis ○ • Allergic contact dermatitis: ○
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Takes several hours after exposure to a small amount of allergen If it appears in minutes, it's urticaria ○ Settles down over a few days (5-7) ○ True allergic reaction Redness, swelling and itchiness Can spread away from initial contact area Doesn't have clear red borders ○ Try to ask about changes in behaviour (e.g. switched laundry powder, started a new job, eating something new etc.) as that could help to identify the culprit • Irritant contact dermatitis ○ Takes a long time to develop, need to have a long term exposure to mild irritants (or a short one if it's particularly irritant, like strong acids) So taking a good history is very important to try and help to find the cause ○ Isn't an allergic immune reaction (but can occur in conjunction with allergic contact dermatitis) Tends to have clearer red borders ○ ○ Still itchy (and red) matt er if you can't tell the difference, the treatments are the same anyway, • Personal opinion: it doesn't matter but do take a history to see if you can detect an allergen/irritant (and tell them to avoid it) ○
• Treatments: ○
Avoid contact with the irritant/allergen If avoiding contact is impossible, i mpossible, minimise exposure Protective equipment (e.g. gloves or clothes) Barrier ointments (e.g. zinc oxide or dimethicone) to prevent contact of water-based irritants/allergens with skin Emollients Very, very important to keep the skin healthy (dried out skin will be much more prone to dermatitis) Therefore, they need to be applied regularly Not essential for people who already have healthy skin though, for example, with □ allergic contact dermatitis to something they rarely touch, an emollient isn't vital, but still recommended. Emollients include: fatty creams, non-ionic (cetomacragol) cream Note: aqueous cream isn't recommended due to one of its ingredients (sodium lauryl □ sulphate, a surfactant) Surprisingly, urea (10%) is also used as an emollient □ They also come in two variants: Creams- better tolerated, but less effective, as they don't form form a greasy layer over the □ skin like ointments do. But because people are more likely to use it, it's a good idea to try a cream first Ointments- less tolerated due to their greasy greasy feel. Recommended if a cream doesn't □ work, or at night where they can't feel it as much. Should be applied at least twice daily, up to 4 times daily (doctor would have to prescribe a decent amount for patients), but really, they can and should apply it as often as needed Tar based products Pine tar or coal tar has anti-pruritic properties Comes in ointments, creams, soaps and bath oils etc. Calamine lotion Good for a range of itchy conditions (including dermatitis, chicken pox, bites etc.) Mixture of zinc oxide and iron oxide Antiseptic- helps to prevent secondary infection Anti-pruri Anti-pruritictic- prevents prevents itchiness itchiness AstringentAstringent- helps to close up open sores Corticosteroids Should be considered as first line treatment t reatment for flare ups Topical hydrocortisone as 0.5% and 1% are available in pharmacies 0.5% is good for sensitive areas like the eyelids and face □
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1% is good everywhere else 0.5% is pharmacy only, but 1% is pharmacist only (so we need to take their details □ down) We only sell 30g 1% creams, as they shouldn't need too much, because we're only □ interested in treating minor cases (major cases should be referred) 0.05% clobetasone is also available (but not for use here, see eczema) Antihistamines First generation antihistamines (e.g. diphenhydramine) is recommended to reduce the itchiness, and to help people get to sleep Plus it's one of the few antihistamines we can give for pregnant women □ Second generation antihistamines (e.g. loratadine) can be used during the day Topical antihistamines are not recommended, because the creams could m ake the skin worse (especially if they contain ionic surfactants) □
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• Advice: ○ ○
After showering, do not rub dry, pat dry. Then apply emollients Baths with bath oils, such as Pinetarsol is recommended Oils have an emollient effect Contains pine tar, which has anti-inflammatory and anti-pruritic(itch) effect Normal soaps should not be used, they have some detrimental effects: Strips the skin of its oils, which are important in maintaining skin moisture They are alkaline. The problem with this is the skin is normally slightly acidic to help keep bacteria under control. They can contain fragrances, which can aggravate skin conditions They may contain lanolin (wool fat), which some people have have an allergy to So a mild soap substitute should be used, as they keep oils in, and they are pH neutral to prevent pH changes on the skin The QV range is good because it's pH neutral, don't contain fragrances etc. Wear cotton clothing Synthetics or wool can exacerbate skin conditions, or they can make the area itchy, which can lead to secondary infections Can wear thin cotton undergarments under other clothing to prevent contact Avoid lotions and alcohol wipes with a passion They tend to dry the skin Alcohol hurts like crazy on broken skin
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• Referral symptoms ○ ○
Affected area is extensive, or it is spreading Infection (by bacteria or fungi or viruses), tends to be more common in children, as they will scratch the site more Broken skin with weeping sores Crusting Pus Systemic symptoms (e.g. fever, malaise) Be aware of shingles Rash follows lines on the skin Blisters can be seen Commonly around the eyes Refer if a medication is suspected to cause the reaction For example, allopurinol Can develop DRESS or SJS
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Atopic (eczema) • Caused by an immune reaction to something (we're still not sure) • Tends to occur commonly in children, less common in adults • Symptoms
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Red, itchy areas Tends to occur on the insides of the joints (e.g. elbow and and knee) ○ • Treatments are pretty much the same ○ Again, really, really need emollients 0.05% clobetasone is available for these patients, which is classified as a potent corticosteroid, ○ which is used for flare ups This is pharmacist only as well, need to take down their details ○ And another note is we shouldn't annotate prescriptions with 'apply sparingly', because it's important to apply enough so that there's enough steroid to calm down the immune system ○
Asetatotic • Cobblestone appearance, with red raised areas
Tends to occur on the legs Also called winter itch, because winter is associated with: Lower humidity ○ People sitting next to fires/heaters/sources of dry heat ○ All these factors cause the skin to dry out, which causes dermatitis ○ Especially in older people, as their skin is normally drier Treatments as above, emollients are vital, because this conditio n is caused by dry skin Other advice is: ○ Avoid baths if possible, and try to keep showers short. Using warm water instead i nstead of hot water is recommended ○ Avoid using external sources of heat to warm up as it can dry skin further Wear cotton undergarments as they cause the least amount of irritation Then wear something warm over that ○
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Seborrhoeic • Although it's labelled as dermatitis, it's a skin reaction to the compounds fungi release • See the fungal section instead
Fungal infections Seborrhoeic dermatitis • Skin reaction from fungal products, the fungi tend to grow due to an increase in sebum • Scaling appears to be greasy (yellow) in colour
The skin can appear red and inflamed under the scales ○ Occurs on the scalp, face and hairy areas of the chest Can be itchy ○ ○ Infantile seborrhoeic dermatitis is cradle cap (see below) Important: the scaling occurs throughout the scalp ○ Distinguishes it from tinea capitis, as it tends to occur in a few focalised areas And there is no ring pattern ○ Tinea capitis has a relatively clear (and bald) centre ○ May or may not cause balding Tinea capitis tends to leave a round patch of bald hair • Need to treat with a product with antifungal, keratolytic (break down skin) and antipruritic (anti-itch) ○ Coco-scalp contains: ○ Coal tar Antipruritic Sulphur ○ Fungistatic Keratolytic ○ Salicylic acid ○
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Keratolytic ○ Plus, since it's an ointment, it will help to keep the scalp moist (reduce itchiness?) ○ Rub into affected areas twice daily, wash hair with shampoo (preferably something with antifungal and keratolytic effects) 1 hour after each application. Wash hands immediately i mmediately after application, as this product can stain • Coal tar shampoo can be used as well (and maybe one of the antifungal shampoos, see below) • But it's important to use these shampoos regularly to prevent flareups • If it occurs on the face, an antifungal cream, such as ketoconazole cream can be used ○ Use it for 2 weeks, continue for 2 weeks after symptoms have disappeared ○ BD to TID ○ Avoid the eyes ○ See below on how to use fungal creams
Cradle cap • Also called infantile seborrhoeic dermatitis • Not itchy, the babies don't seem to care about this condition • Tends to occur, because maternal hormones will increase sebum production, which then attracts fungal
growth • Treatment is simple: ○ Baby oil, almond oil or peach oil (but not olive oil, because it can cause the yeast to get pissed off) it should be applied at night and left overnight to soften up the scales for easy brushing ○ Salicylic acid (in oil) lotion should be applied nightly to the scaled areas only to help remove the scales. If possible, avoid washing for a few days and wash with a baby shampoo to remove the scales If it spreads, then we can refer them to a doctor so they can get a ketoconazole shampoo and ○ possibly hydrocortisone to prevent inflammation ○ Warning: do not forcefully take the scales off, just use a soft brush • The condition should resolve within a few weeks, and can continue up to about 9 months of age Tinea capitis • Fungal infection which causes round patches
Patches tend to be bald ○ Flaky skin (like dandruff) can be seen as a ring with a healing centre ○ Tends to be itchy May glow under Wood's light (UV), glowing means it's definitely fungal ○ ○ Can be transmitted between people, or some can be from animals Treat contacts as well • Best to refer, as the fungal infection tends to be quite deep, so oral or al antifungals are recommended ○ 4-6 week treatment with itraconazole, fluconazole or terbinafine • But while waiting for the doctor, we can give them an antifungal shampoo (see below) ○
Dandruff • Flakes can be seen being shed from the scalp, can also be itchy • This is caused by fungi as well • Treatment is with an antifungal shampoo ○
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For shampoos, they should be applied and left on for about 3 minutes and then washed off. This is to increase the contact of medication with the scalp Coal tar shampoos Can also contain salicylic acid, which is a keratolytic Can also contain sulfur, which is fungistatic and keratolytic Coal tar itself is anti-pruritic and anti-inflammatory Zinc pyrithione Found in head and shoulders Use at least twice a week (can be used more often)
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Should see improvement in 2-3 washes Use regularly to prevent dandruff Selenium disulfide Caution: alters hair colour and perms are lost As above Ketoconazole 1% and 2% shampoos are also available Also use at least twice weekly Use the stronger formulation for more severe cases, and that should be used about twice twic e a week (other times, they should use their normal shampoo)
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Pityriasis (tinea) versicolor • Causes a change in skin colour
Lighter skin can produce darker patches ○ Darker skin can produce lighter patches Produces patches which won't tan with surrounding skin, making light patches ○ Mildly itchy ○ ○ May glow under Wood's light • Treatment ○ At night, have a shower, then apply an azole cream ○ Do not shower for a few hours after application (preferably leave on overnight) o vernight) ○ Will take up to two weeks for resolution (continue treatment even if symptoms disappear with azole creams, see below) • Advice: ○ Try to avoid activities activiti es which cause excessive sweating and heat ○ Tends to occur commonly around summer for this reason ○ Skin should return to its original colour over time Try tanning again ○
Tinea corporus • Also called ringworm • Occurs commonly around the arms, legs and torso • Characteristic red ring with clearer inside
Can also form pustules • This will be itchy • Infection can be zoonotic (from animals), or from self-inoculation from other parts of the body ○ Generally from cats ○
Tinea cruris • Also known as jock itch • Occurs in the groin region • As its name implies, it's itchy
Area can also be red and inflamed • Auto-inoculation is common ○ Socks before jocks, stop tinea pedis spreading to the groin region Avoid sharing towels to prevent spread as well ○ • Treatment Miconazole and hydrocortisone lotion initially ○ ○ Apply BD after washing the affected area Should resolve within 2 weeks, but continue co ntinue for another 2 weeks (see below for a reason) ○ ○ Note: Some formulations require refrigeration, others don't ○ Note: Normally, you wouldn't use hydrocortisone during a fungal infection, because that would dampen down the immune system. But the lotion also contains miconazole to fight off the ○
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infection, while the hydrocortisone will sooth the area to reduce symptoms After resolution, using an antifungal powder is recommended to prevent recurrence Plus it keeps the area dry to prevent recurrence as well
Tinea pedis • Infection of the foot • Very itchy
Tends to get worse at night Can be uni or bilateral Can occur at different parts of the foot ○ Cracked, red or white macerated skin between the toes ○ Dry areas which appear like tinea corporus at the top of the foot Small pustules on the side or bottom of the feet ○ ○ All over the bottom and sides (moccasin type) Can also have nail involvement invol vement (tinea unguium) ○ People with diabetes tend to be predisposed, referring is recommended Treatment Topical antifungal cream/ointment ○ Miconazole/azoles in general : Apply BD after washing and drying feet Should see improvement within 2 weeks Continue for 2 weeks after resolution This is because it takes 2 weeks for the skin lining to shed □ Spores tend to remain on the skin, and they are resistant to treatment □ Therefore, it's important to continue treatment for at least 2 weeks to prevent □ recurrence Make sure you tell your patients this to improve compliance (they'll think we're trying □ to rip them off by overselling ov erselling them products) Terbinafine: 1 spray daily (after washing and drying the affected area) 7 day treatment Continuous treatment not essential, terbinafine is fungicidal Antifungal spray ○ As above BUT they need proper technique, as they need to pry apart the toes to really get the medication between the toes ○ Powders e.g. Gran's remedy Mild antifungal action But it helps with the condition, because it will dry out the shoes as well (preventing fungal growth) Apply a spoonful into each shoe and leave overnight, then tip out powder It's recommended to have two pairs of o f shoes, and alternate use between them Advice: ○ Can be picked up at the pool, wear jandals Change socks every day ○ ○ Be careful in drying feet, they need to be dry to prevent growth Consider cotton socks, they tend to absorb moisture well ○ ○
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Tinea unguium • Fungal infection of the nails (either on the hands or feet)
It may be discoloured (black, yellow, white etc.) ○ The nail may be damaged or destroyed • Treatments are: ○
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Oral: terbinafine for several months (review every 3 months when writing out a new script) Takes a few months to treat, as the levels of terbinafine need to build up over time within the nail Because the terbinafine will be in the nail, it will prevent recurrence for quite some time Very good for treatment where many nails are ar e affected as it's systemic Topical Ciclopirox lacquer Sell a nail file with it, as using it will help to get the antifungal deeper into the nail Also sell nail polish remover and alcohol swabs so they can clean up the area as well Good where only one or two nail has minor infection
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Quick mention of formulations • Creams- best for hairless areas which have red, inflamed skin. Well tolerated as it is absorbed well into
the skin. • Ointments- best for dry, scaly areas which require moisture. Not as well tolerated as it can feel greasy, and will sit on the surface of the skin. • Lotions- best for hairy areas, but to be avoided on dry skin, as it may cause drying out of the skin.
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