Pharmacology Flashcards
1
Q
HCQ & CQ ADME
A
- Structure - 4-aminoquinolines
- Absorption
- completely absorbed in the gut
- Distribution
- Bound to organ tissue
- peak 4-5 hours after
- most commonly found in liver, kidneys, spleen
- low amounts in bone, skin, fat and brain
- Metabolism
- HCQ - 2 metabolites
- CQ - 1 metabolite
- Excretion
- HCQ - 20% urine unchanged
- CQ - ~45% urine
- Then also excreted by faeces, sweat, etc
- No evidence to change dose in mild-mod renal impairment
- Steady-state concentration 3-4 months
2
Q
HCQ and CQ MOA
A
Believed to have a few MOAs:
- Anti-inflammatory
- Immunosuppressant
- Acts on Toll-like receptors
- suppresses cytokines
- Reduces UV induced damage
- Gets into lysosomes?
- Reduces thrombus formation
- Reduces lipids and vitamin D
- Inhibits RNA/DNA synthesis
- Anti-viral
3
Q
HCQ and CQ Contraindications
A
- Absolute: hypersensitivity, development of true retinopathy
- Relative:
- pregnancy
- For SLE weigh up benefits and risks
- breast-feeding
- not enough data so not safe to recommend
- neuromuscular issues such as Myaesthenia Gravis
- pregnancy
- Caution:
- G6PD deficiency
4
Q
HCQ and CQ A/E
A
Ocular
1. Retinopathy
1. Clinically - bullseye retinopathy, central scotoma, visual acuity changes
2. Irreversible
3. evidence shows that if on 400 mg/day, no increased risk until 5 years, then risk increases by 1% each year
4. should get baseline check - visual fields + optics, then again at 5 years, then annually
2. Pre-maculopathy
1. Clinically - no blurred vision but VF/fundoscopic changes
2. reversible
3. Corneal deposition
1. Reversible
2. anti-malarial deposits in epithelium of eye
3. asymptomatic, or may complain of halos around lights etc
4. not correlated with retinopathy
4. Accomodation issues
1. associated more with CQ
GIT
- Nausea, vomiting, diarrhoea
- LFT derangements
Cutaneous
- 10-30% develop black/grey - brown pigmentation deposits - shins, arms, palate (well defined line)
- Other: urticaria, EAC, etc
Haematological
- Rarely - agranulocytosis, anaplastic anaemia
Neurological
- stimulated/hypervigilant/anxious
- seizures
- headaches
5
Q
HCQ and CQ monitoring
A
- Baseline eyes and FBC, UEC
- FBC every 1 month for first 3 months then every 6 months
- UEC, 1 month, then 3 months then every 6 months
6
Q
HCQ and CQ treatment
A
- For lupus:
- 400 mg/day or 6.5 mg/kg/day whichever is lower
- onset of action 4-12 weeks
- less effective if smoker
- then reduce 25% every 3-6 months
- For sarcoidosis
- 250 mg/day or 3-4 mg/kg/day whichever is lowe
7
Q
Tetracyclines MOA
A
- Anti-bacterial: inhibit ribosome synthetis as 30s subunit
- Anti-inflammatory:
- inhibit neutrophil chemoattractants
- inhibit neutrophil infiltration
- downregulate cytokines
- inhibit granuloma formation - IL-1
8
Q
Tetracyclines ADME
A
- Absorption
- well in the gut
- food can reduce - 20% doxy and 12 % mino
- metallic ions, particularly in dairy, chelates and reduced absorption
- anti-diarrhoeal - bismuth, binds and reduces
- co-administration with iron supplementation reduces
- Distribution
- Lipophilic
- in skin and nails, likes pilosebaceous unit
- Excretion
- doxycycline excreted hepatic –> beware with severe liver failure
- remainder excreted renally –> adjust dose for renal impairment
9
Q
Tetracycline indications
A
- Acne vulgaris
- can develop resistance
- anti-inflam dose
- usually see improvement at 8-12 weeks
- Rosacea
- again anti-inflam
- Immunobullous
- BP has evidence with nicotinamide
- Infectious
- Works on gram positive > gram negative
- also for parasites, rickettsiae, granulomatous infections
- Non derm: CAP
10
Q
Tetracycline a/e
A
Gastrointestinal
- Nausea, vomiting, diarrhoea
- to alleviate take with food
- ? doxy or mino rarely has this
- enteric coated capsule
- Pill eosophagitis
- sit up 2 hours after swallowing
- lots of food
- Hepatitis and pancreatitis
- really rare
- if on long term can do FBC UEC LFT, however no indication to do baseline, more on clinical judgement
Neurological
- Benign intracranial hypertension
- headaches and blurry vision
- if persistent then permanent blindness, need to be on early
Cutaneous - Dyspigmentation - Type 1 - blue/grey pigmentation to face in scars. Stains positive for melanin and iron - Type 2 - blue/grey pigmentation to lower legs. Stains positive for melanin and iron - Type 3 - muddy brownish pigmentation to upper arms. Stains positive for melanin - Type 4 - really rare, grey pigmentation to back in scars - Can also cause adult teeth staining - Phototoxicity - Dose dependance - ? not with minocycline Hypersensitivities - SJS - DRESS - Induced Sweets, urticaria - Autoimmune hepatitis - Induced lupus - Serum sickness like reactions
11
Q
Tetracyclines in pregnancy
A
- Category D
- do not give in 2nd and 3rd trimester
- can give in first if really necessary –> i.e. rocky mountain spotted fever
- causes issues with foetal teeth, bones, maternal hepatotoxicity
- breastfeeding –> excreted in small amounts, recommend not
12
Q
Tetracycline interactions
A
- OCP - ? controversial
- Retinoids - BIH ? may augment
- metallic ions - inhibits absorption
13
Q
Methotrexate MOA
A
- Immunosuppressant:
- Dihydrofolate reductase inhibitor, which stops dihydrofolate turning into tetrahydrofolate
- In turn, this inhibits purine synthesis, inhibiting cellular proliferation
- Also inhibits thym synthetase
- Anti-inflammatory
- Inhibits something else
- Adenosine accumulation
- Inhibition of T cells
14
Q
MTX Dose
A
- Anti-inflam dose is 0.4 mg/kg/week
- Should supplement with folic acid
- Antidote: folinic acid which bypasses the whole thing
15
Q
MTX ADME
A
- Absorption
- Well absorbed in gut
- Can give IM, intra-thecal (as doesn’t cross BBB), etc however gut most reliable particularly with blood tests
- food reduces absorpiton but assists with nausea
- Distribution
- everywhere except BBB
- triphasic:
- 0.75 hours –> distribution and metabolism
- 3-4 hours —> excretion urinary
- up to 24 hours –> tissue release
- but AJD states that actually takes about 5-6 days, and effect takes 30 days, stable at 5-6 months
- Metabolism
- As above
- intra-cellular metabolism to polyglutamate
- Excretion
- Renal
- Beware in renal disease
16
Q
Drugs that increase MTX toxicity
A
- salicylates
- NSAIDs
- sulfonamides
- dapsone
- bacitratin
17
Q
MTX A/E
A
- Hepatotoxic
- Risk factors for cirrhosis:
- obesity
- diabetes type 2
- pre-existing, past or family history of liver disease
- HBV, HCV
- Alcohol >100 g/week
- renal impairment
- > 60 years of age (renal impairment)
- NAFLD - 25-35% of population have this, 15-20% develop NASH, and then percentage of that develop cirrhosis
- Long-term methotrexate use increases exposure
- Liver biopsy still golden standard, however invasive
- Fibroscan - 85% negative predictive value, however difficult in obese patients
- P3NP also has good negative predictive value, but does not say where the fibrosis is coming from (which organ)
- Promising new tests coming out of US - Fibroplus and another
- Risk factors for cirrhosis:
- Acute pneumonitis
- Idiosyncratic
- CXR if clinically suspect, however nothing can be predicted
- Pancytopaenia
- Folate prevents this
- Monitor bloods
- Increased risk if renal impairment
- Gastrointestinal
- Nausea and vomiting
- Diarrhoea and intractable stomatitis more serious
- cease if intractable stomatitis
- Pregnancy
- Category D
18
Q
MTX monitoring for psoriasis
A
- Baseline FBC, UEC, LFT, fasting lipids, HbA1C, weight, abdominal circumference, BMI
- HBV, HCV, HIV, CXR, Quant Gold, +/- Strongyloides
- FBC - week 2, week 4, then ever 3 months
- UEC - 3 monthly
- LFT - 3 months, then 6 monthly
- Remainder do 6 monthly
- HbA1c strongest predictor of mortality
- When doing bloods - get done 5-6 days after last dose
19
Q
DCP Indications
A
topical contact allergen that can be used in:
- alopecia areata - viral warts - metastatic melanoma/multiple cutaneous/ in-transit mets
20
Q
DCP information and MOA
A
- Not mutagenic itself, but its precursor is mutagenic
- Very sensitive to light so needs to be stored protected from flight
- Can remain stable for at least 2 years, keep in a cool, dark place between 4-8 degrees (so fridge)
- Solvent is acetone because:
- It is a strong UV light absorber
- Dries rapidly
How it works:
- Use it as a sensitiser first
- 2% acetone solution for alopecia areata
- 1-3% for warts
- After 2 weeks can use weekly as elicitation
- 0.0000001-2% acetone for alopecia
- 0.001-2% for warts
21
Q
DCP A/E
A
- Common
- Contact dermatitis/eczema –> can blister, enlargen, id reaction
- Regional adenopathy
- Mutagenicitiy
- Less common
- Fever and chills and flu like symptoms
- Fainting
- Pigmentation changes: vitiligo, leukoderma, dyschromia in confetti (hyper and hypopigmentation)
- EM
- Urticaria
- Infection
22
Q
DCP - managing reactions
A
- GSCM
- deflate large blisters
- white soft paraffin
- topical steroids
- jelonet dressings
- infection treatment
- moral support (for melanomas)
23
Q
DCP in alopecia
A
- should have response by 8-12 weeks
- can go on for weeks ~ 20-30
- in review of 148 patients, 90% had response by 24 months, can go up to 3 years
- use a tenth of strength for eye brows
- response rate is ~ 59% average
- Poor prognostic factors:
- disease severity and duration
- age of onset
- family history
- nail changes
- atopy
24
Q
DCP in melanoma
A
- put on inner arm
- treat weekly, self-application
- costs 5 centre - $1 per week
- well tolerated after first few weeks
- little bit overcooked tend to do better than under cooked
- can trigger systemic response - mets elsewhere
- complete responders - more common with thin lesions than thick
- can use overnight imiquimod:
- immune primer, use while waiting for sensitisation and then can use as primer night before weekly thing
- once clinically resolved, can keep maintenance, reduce maintenance, or cease and monitor
- can give with
25
Cyclosporin ADME
- Absorption:
- forms micro-emulsion in an aqueous environment
- Neoral absorption better than Sandimmune
- Neoral is a pre-digested form of cyclosporin, so it is less dependant on bile, food, diet and the GIT environment
- Metabolism
- Metabolized by CYP450 3A4
- Excreted
- Bile through faeces
- 6% through urine
- Hepatic insufficiency amy prolonge the half life and require dosage adjustment
26
Cyclosporin MoA
- not fully understood
- Main: calcineurin inhibition
1. Inhibit production of IL-2 by inhibiting calcineurin --> this reduces T cell proliferation
2. Calcineurin inhibition reduces activity of the transcription factor NEAT-1
3. Inhibits interferon-gamma production by T lymphocytes --> reduces keratinocyte proliferation and HLA-DR positivity
4. Binds to steroid receptor associated heat shock protein 56 - inhibits transcription of lots of pro inflammatory cytokines
27
Cyclosporin contraindications
- Absolute:
- Decreased renal function
- Uncontrolled hypertension
- Hypersensitivity
- Clinically cured or persistent malignancy except for keratinocyte cancers
- CTCL
- Relative
- <18 years or >64 years
- Controlled hypertension
- Needing to receive live unattenuated vaccination
- On medications that interfere with cyclosporin medication or potentiate renal dysfunction
- Active infection or immunodeficient
- Already receiving another immunosuppressant or phototherapy
- Pregnancy or lactation
- Unreliable patient
28
Cyclosporin A/E
- Pregnancy: excreted in breast mild
- Category C
- Renal
- Keep creatinine within 30% of baseline level.
- Not any evidence that patient will get renal failure of clinically significant damage if they use cyclosporin as per dermatology guidelines
- Cardiovascular
- Hypertension
- Could be secondary to vasoconstrictive effect on vascular smooth muscle, or could be secondary from renal dysfunction
- Develop in 27% of patients
- Usually mild and generally reversible
- If can control hypertension, then can continue
- Treat with calcium channel blockers or ARBs, not hyperkalaemic stuff
- Malignancy risk
- Risk of keratinocyte cancers if long-term treatment --> SCC highest
- Rare reports of CTCL and CBCL --> when treatment was less than a year, it resolved after discontinuation
- Small, but significantly, increased risk of developing malignancy if on in a chronic, lifelong fashion
- No evidence that it increased risk if use maximum dose 5 mg/kg, therapy <2 years and monotherapy (no other immunosuppressant) and in generally health patient
- Neurologic
- Tremor, Headache, Paraesthesiae --> self0limiting
- Mucocutaneous
- Hypertrichosis
- Gingival hyperplasia --> can improve with dental hygiene. Nifedipine can induce this.
- GI
- Nausea, abdominal discomfort, diarrhoea
- MSK
- Myalgia, lethargy, arthralgia
- Lab abnormalities
- Hyperkalaemia --> can respond to reduce potassium diet
- Hyperuricaemia --> not seen in psoriasis doses
- Hypomagnesaemia --> only occurs after ~ 4 months duration
- Hyperlipidaemia
- Relatively common
- lifestyle changes, get GP to manage
- potential drug interaction between lovastatin and other statins --> increases risk of rhabdomyolysis. Rosuvastatin is safe, as it doesn't use CYP3A4
29
Cyclosporin drug interactions
- Increase cyclosporin drug levels - CYP3A4 inhibition:
- Abx: macrolides, ciprofloxacin and norfloxacin, cephalosporins, doxycycline
- Anti-fungals: the azoles
- HIV inhibitors (shouldn't be on this anyway)
- Calcium channel blockers
- Anti-histamines - cimetidine
- Steroids - methylpred
- Diuretics - thiazides, frusemide
- Allopurinol, warfarin, OCP
- Grapefruit juice
- Reduce drug levels - CYP3A4 induction
- Anti-convulsants
- Anti-Tb: rifampicin
- Potentiate renal toxicity:
- Abx: aminoglycosides, trimethoprim, vancomycin
- Amphotericin
- NSAIDs
- Anti-histamines
- Tacrolimus
- Occasionally interact:
- Lovastatin: reduces renal clearance
- Pred: reduces renal clearance
- ACEI, potassium sparing diuretics: increase risk of hyperkalaemia
- Digoxin: reduces renal clearance
30
Cyclosporin uses
- Psoriasis:
- 51-79% of patients in a dose titration trial achieve at least a 75% improvement from baseline after 8 and then 16 weeks
- gets there quicker, and actually has better evidence for clearing up than MTX by 16 weeks (71% versus 60%)
- Only try to give for 3-6 months ideally, or 12 at the most
- Off label:
- Eczema
- PG
- Urticaria
- Start as clearing phase, then transititonal phase, then maintenance phase
- Dose on ideal body weight
31
Monitoring cyclosporin
- Baseline assessment: history and physical, 2 BP at least a day apart, baseline UEC (creatinine at least 2 a day a part), FBC, LFT, fasting lipids, CMP, uric acid if have gout
- Re-evaluate every 2 weeks for 1-2 months, then every 4-6 weeks. Check BP at each visit
- Bloods ever 2 weeks for first 1-2 months, then monthly while on it
- You can do trough cyclosporin if you think they're not taking it or something
32
Managing renal complications with cyclosporin
Renal: if >30% above patient's baseline creatinine level then re-check in 2 weeks --> if sustained then reduce by at least 1 mg/kg daily for at least 2-4 weeks. If creatinine decreases, then can continue, if not reduce the dose again or cease. If creatinine rises to 50% or more then cease medication
33
Ceasing cyclosporin
- If insufficient response after 3 months on 5 mg/kg then cease
- When ceasing - gradually taper while an alternative therapy is trialled, if stop cold turkey can have re-bound disease
34
Terbinafine pharmacokinetics
- Bioavailability of 40%
- Metabolised by the liver
- In cirrhosis - clearance reduced by 50%
- Renal insufficiency, clearance is decreased
- Skin:
- diffuses through the dermis and epidermis to stratum corneum --> through sebum and incorporates into migrating basal keratinocytes
- can reach the stratum corneum within hours of starting - within 2 days have high levels in the sebum
- Elimination half life 3-5 days
- Don't detect in sweat
- Nails
- In distal nail within 1 week --> diffuses into nail plate via nail matrix and bed
- Hair --> may become incorporated into hair by hair matrix cells. May be more effective against tinea capitis caused by endothrix than against ectothrix as accumulates preferentially in the hair shaft
35
Terbinafine MOA
- inhibits squalene epoxidase leading to accumulation of squalene and subsequent deficiency of ergosterol --> fungistatic
- accumulation of squalene --> fungicidal
36
Terbinafine - getting kids to take it
- terbinafine you can crush it up or sprinkle on food
37
Terbinafine contraindications
- Hypersensitivity
- Chronic or active liver disease
- Renal impairment --> reduced by 50% renal failure
- CYP2D6 inhibitor: may interaction with drugs
38
Terbinafine A/E
- Gastrointestinal - diarrhoea, dyspepsia, pain, nausea
- Dermatology - rash, pruritis, urticaria, rarely EM, TEN, SJS, serum sickness-like reaction, exacerbates lupus
- Sensory: taste disturbance, visual disturbance
- Hepatic: idiosyncratic hepatobiliary dysfunction. Hepatitis develops within 4-6 weeks --> has features of both hepatocellular necrosis and cholestatic injury
- Psych - ?depressive symptoms
- Pregnancy - category B. No effects on testosterone
- Drug interactions: relatively few drug interactions. Inhibits CYP2D6 - careful with tricyclic antidepressants
39
Terbinafine monitoring
- assess pre-existing liver damage
| - monitor blood counts in those with suspected immunodeficiency if >6 weeks of use
40
Azole pharmacokinetics
- Fluconazole has bioavailability of >90%, itraconazole is 55%
- Fluconazole has little hepatic metabolism and its steady state is within 5-10 days, but this can be increased quicker by doubling the dose on the first day
- Itraconazole is metabolised by the liver, when there is cirrhosis the half life has a 2 fold increase
- Renally excreted
- Metabolism by CYP450 --> enzyme provides potential for interactions
- Itraconazole:
- passive diffusion to skin, detectable in sweat within 24 hours, may persist for 3-4 weeks
- Nails: is in the distal fingernail by 1 week, and toenail by 2 weeks
- incorporates into hair follicle - detectable 1 week after therapy
- Fluconazole
- drug accumulates in stratum corneum through sweat
- has a rapid uptake to the nail
- not too much literature of it in the hair, but believed to linger there
41
Azole MOA
inhibits CYP-dependant enzyme lanosterol 14 alpha demethylase --> inhibition of the conversion of lanosterol to ergosterol --> fungistatic
42
Taking itraconazole
- itraconazole can be opened and mixed with fatty foods such as peanut butter
43
Itraconazole CI
- Hypersensitivity
- Ventricular dysfunction
- Active liver disease, elevated abnormal liver enzymes, previous experience of liver toxicity with other drugs
- CYP3A4 drug interactions
44
Fluconazole CI
- Coadministration with drugs that prolong QT and are metabolised through CYP3A4
- Hypersensitivity
45
Itraconazole A/E
- GIT: as above
- Neuro: headache
- Derm: as above, rarely oedema, EM, SJS
- Liver: LFT derangement, serious adverse effects 3-4 per 100 000
- Pregnancy C: no effect on androgen, but ketoconazole does
- Malignancy: in rats saw increased risk of pancreatic adenocarcinoma but this hasn't translated over to humans?
46
Fluconazole A/E
- More favourable
- GIT: nausea, vomiting, abdominal pain, diarrhoea
- Derm: TEN, SJS, EM
- Liver: none, voriconazole and posaconazole have these issues. Fluconazole has self limiting hepatic and biliary abnormalities in 0.5%. With chronic use can have elevated LFTs
- Pregnancy: Category D
- Importantly: voriconazole can increase melanomas and SCCs
47
Azole drug interactions
- Azoles are contraindicated with anti-arrhythmics (quinidine), antipsychotics (pimozide) and antihistamines (terfenadine and astemizole) --> can cause QT prolongation, torsades de pointes, VT, etc
- Azoles interfere with CYP3A4
- Can lead to increases in INR values and excessive coagulation when given with warfarin
- Also be careful of using azoles with cyclosporin, hypoglycaemics and phenytoin
48
Ketaconazole MOA
interfere with ergosterol which is a crucial component of the fungal cell membrane --> resulting in arrest in cell growth which if fungicidal and fungistatic
49
Lichenoid drug eruption causes
```
hotodistributed or looks like idiopathic lichen planus
ACE inhibitors
Thiazide diuretics
Antimalarials
TNF alpha
Anti PD1- nivolumab, pembro
Quinidine
Gold
*note many in the list are sulfonamides- is sulfamethoxazole, furosemide, thiazide
```
50
Botox structure and serotypes
- C botulinum produces 7 known neurotoxins: A-G. C&D are not effective on humans. A is the most potent.
- Produce inhibition of acetylcholine neurotransmitter release from the NMJ leading to flaccid muscle paralysis
- Has a small neurotoxin protein which protects agains the gut so it doesn't get degraded by intestinal proteases
- When it reaches the blood stream, it dissociates and exerts its toxic effect
51
Botox MOA
- Action potential triggers a calcium influx --> this results in vesicles moving towards the plasma cell membrane where they dock and fuse via SNARE proteins, and release their contents into the synaptic cleft
- The ACH binds to the receptors on the post-synaptic muscle which initiates muscular contraction
- Botox light chains target the SNARE proteins --> resulting in postsynaptic cellular paralysis
- A, C and E target SNARE
- The others target VAMP
52
Botox recover of mm function
- Mm weakness within 2-4 days, and maximal paralysis in 7-10 days
- 1 month --> nerves begin to sprout new, smaller, unmyelinated nerve endings --> by 3 months a functional connection is re-established in the original nerve terimal
- Can get muscular atrophy with each injection
53
Botox contraindications
- Absolute
- Allergy
- Infection at injection site
- Relative
- Psych
- Pregnancy or lactation
- Known neuromuscular disease
- Inflammation at the injection site
- >65 years
- Concurrent use of aminoglycosides, cholinesterase inhibitors, succinylcholine, magnesium sulfate, quinidine, calcium channel blockers, lincosamides, polymyxins
54
Botox A/E
- Local
- Pain, swelling, erythema, bruising
- Ptosis
- Lip --> lasts 6 weeks
- Eyelid --> 2-14 days to show, and lasts 2-12 weeks. Can use alpha-adrenergic eye drops until it resolves
- Brow --> can last 3 months
- If cervical --> dysphagia
- Systemic
- muscular weakness, paralysis
- Resistance (antibody development) --> lack of effect
55
Botox - tricks for injection sites
- Forehead
- keep injections at least 1 cm above the orbital rim to avoid ptosis
- keeping injections 3 cm above the brow will lessen the risk of diminished expressiveness
- Ptosis: give adrenergic agonist drops to stimulate Muller's muscle
- Glabella
- Lateral canthus
- Inject >1 cm lateral to the orbital rim to avoid diplopia and lid ptosis
- injections close to the inferior margin of the zygomatic arch risks weakening the lip elevator muscles, causing lasting lip ptosis
- Neck injections
- Hyperhydrosis
- dilute concentrations, 1-1.5 cm apart
- can go straight into the subcutaneous fat in axillae
- in palmoplantar skin --> usually requires ice or local block
- inject into the dermis to avoid dispersion in the hands and feet as otherwise you cause intrinsic hand muscle and resulting weakness --> mild and lasts several weeks
56
Generations of systemic retinoids
- First generation
- Tretinoin
- Isotretinoin - half life 10-20 hours
- Second generation
- Etretinate - half life 80-160 days
- Acitretin - half life 50 hours
- Third generation
- Bexarotene
- Only one excreted hepatobiliary
57
Vitamin A physiology
- Acquired through diet
- Exists in body as interconvertible forms:
- retinol (vitamin A alcohol): for reproduction
- retinal (vitamin A aldehyde): for visual function, epithelial differentiation and growth
- retinoic acid (vitamin A acid)
- Precursor: beta-carotene --> these are synthesized by plants and function as photosensitive structures
- Primary form of dietary vitamin A is retinyl ester - meat, animal products such as eggs and milk
- In gut: retinyl esters are hydrolyzed to retinol --> this is absorbed and initially stored in the ester form in the liver
- retinol and retinal can easily turn into each other, but retinol is irreversibly metabolised to retinoic acid
- Retinal: important for visual function
- Retinol: for reproduction
- Retinal and RA: essential for epithelial differentiation and normal growth
58
Vitamin A structure
- manipulation of polar end group and polyene side chain of vitamin A --> forms first generation retinoids
- Second generation are monoaromatic - replaces cyclic end group of vitamin A with various substituted and non-subtituted ring systems
- Third generation: also include tazarotene, adapalene --> much more potent, however increased toxicity
59
Absorption and distribution of synthetic retinoids
- Absorption improved with food intake, acitretin and bexarotene fatty meals particularly
- Accumulates in liver, when exceeds liver storage results in hypervitaminosis A
- Isot and acit are water soluble, but etretinate is 50X more lipophilic --> slowly releases from adipose over several years
- For water solubles, undetectable in serum within 1 month after stopping therapy
- Breast: drug consumed ~1.5% so contraindicated
- Semen: 1/200 000 of a single 25 mg capsule
60
Systemic retinoid metabolism and excretion
- Metabolised: via oxidation and chain shortening to biologically inactive, water-soluble products in the liver
- Isotretinoin is oxidated, acitretin is isomerized
- Excretion: eliminated in bile as beta-glucuronide or through the kidneys as soluble metabolites with shorter side chains --> so urine and faeces
- Half lives: tretinoin 40-60 mins, bexarotene 7-9 hours, isot 10-20 hours, acit 50 hours, etretinate 80-160
61
Acitretin re-esterification
- alcohol indirectly enhances the re-esterification of acitretin to etretinate
- therefore, don't fall pregnant for 3 years after ceasing acitretin
- its also difficult to detect plasma etretinate so don't know if there or not
- etretinate hangs out in the subcutaneous fat
62
Systemic retinoids MOA
- Small-molecule hormones that elicit their biologic effects by activating nuclear receptors and regulating gene transcription
- Transport of retinoids
- predominantly in all-trans form, transport is by albumin
- CRABP (cytosolic retinoic acid-binding protein) transports the RA to cell nucleus - present in high levels in the epidermis, and particularly high in psoriasis, lamellar ichthyosis, lesional Darier's, PRP, KP --> so maybe more sensitive to retinoids
- Mechanism at nuclear level
- bind to nuclear receptors: retinoic acid receptor and retinoid X receptor - each have 3 isoforms - alpha, beta and gamma
- RAR always with RXR, where as RXR can be homodimer or heterodimer with other receptors like vitamin D3 receptor
- acitretin activates but does not bind to multiple RAR
- upon binding of a ligand, the RAR-RXR heterodimer acts as a transcription factor --> resulting in expression of a number of proteins involved in growth and regulation
- clinical effects: ability to affect pathways involved in inflammation, cellular differentiation, apoptosis and sebaceous gland activity
63
Systemic retinoids practical considerations
- don't take vitamin A over >5000 IU
- take with milk and fatty foods as it enhances absorption
- avoid an excessively fatty diet
- don't drink alcohol during and up to 2 months after cessation of neotigason
64
Systemic retinoids indications
- Neotigason - psoriasis
- of 385 cases, 84% had response compared to 76% with MTX, 71% CsA and 46% PUVA
- using with phototherapy obviously more effective --> if doing start the acitretin 2 weeks prior to the initiation
- can be taken with MTX or cyclosporin but be super careful --> adverse liver effects with neotigason and methotrexate combination and possible elevation in trigs
- only trial with neotigason and etanercept seemed fine but need more research
- Roaccy --> acne
- higher relapse rate with lower doses --> 82% relapsed on 120 mg/kg as opposed to 30% on 150 mg/kg
- worsens in first 4-6 weeks
- Bexarotene --> MF
- overall response rate of 48%, with complete response of 4% --> these were patients who were refractory to at least one previous systemic treatment
- is believed to cause apoptosis of malignant cells
65
Systemic retinoids off label indication
- Rosacea --> microdoses after low doses of daily 10 mg may prevent relapses
- HS and dissecting cellulitis of the scalp --> about 50% of HS improved with 0.7-1.2 mg/kg daily, more successful with milder forms of HS. For cellulitis - can administer with rifampicin
- Darier's
- PRP --> improvement in 70% of patients
- Ichthyosiform dermatoses
- Chemoprevention of malignancy
- transplant patients: one study supported reduction in SCCs, another said no but there was a reduction in the number of AKs
- histology showed: decrease in epidermal thickness, increase in differentiation marker K10, however markers of apoptosis, epidermal proliferation, inflammation and keratinocyte epidermal neoplasia was unchanged. all of the trials were limited by the small number of patients studied
- XP and naevoid BCC syndrome: effective in reducing numbers but as soon as you stop acitretin then the effect is lost
- Lupus - not as good as plaquenil
- Lichen planus --> with 30 mg daily, 64% of patients showed remission or marked improvement, and then in the 8 week open phase, 83% responded favourably to neotigason
- Chronic hand eczema
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Systemic retinoids and pregnancy
- Teratogenicity ----> retinoic acid embryopathy and spontaneous abortions
- Defects: cranium, face, cardiovascular defects, thymic abnormalities, CNS malformations --> 50%
- 1/3 spontaneous abortion
- General requirements: negative pregnancy test, try and start taking on period or on proof of negative pregnancy, must be on 2 forms of contraception, and need 1 month wash out, effective contraception 1 month prior to starting
- Neotigason: can't fall pregnant for 3 years afterwards --> don't drink alcohol during to minimize re-esterification
- Teratogenicity in males: there is little, if any risk, of retinoid embryopathy with fathers
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Systemic retinoids A/E
- Mucocutaneous
- Dry mucous membranes and skin
- Acitretin: 'sticky skin' sensation
- palmoplantar desquamation
- retinoid dermatitis
- photosensitivity
- pyogenic granulomas
- Staph infection
- Granulation tissue around nail fold and at sites of trauma
- Acne fulminans --> abruot onset of ulcerating acne lesions with associated arthralgias, myalgias, fever, leukocytosis --> discontinue plus systemic steroids
- Epistaxis
- Hair
- Telogen effluvium
- Abnormal hair texture, dryness
- Nails
- Fragility with nail softening, paronychia, onycholysis
- Ocular
- Reduced night vision
- Persistent dry eyes
- Staph infections
- Dry eyes with visual blurring
- Photophobia
- Blepharoconjunctivitis
- Bone
- Diffuse skeletal hyperostosis
- Osteophyte formation
- Premature epiphyseal closure
- Lipids
- Hypercholesterolaemia
- Hypertriglyceridaemia
- Gastrointestinal
- IBD flare
- Pancreatitis --> primarily a risk with bexarotene
- Nausea, diarrhoea, abdominal pain
- Hepatic
- Transaminase elevation
- Toxic hepatitis (rarely)
- Endo
- Hypothyroidism
- Diabetes mellitus?
- Haem
- Leukopaenia
- Agranulocytosis
- Neurologic
- Pseudotumour cerebri
- Depression
- Headache
- Muscle
- Myopathy
- Arthralgias, myalgias, fatigue, tendinitis
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Dapsone absorption and availability
- lipid soluble and water insoluble
- Well absorbed in gut: 70-80% in gut
- Peak concentration 2-8 hours after administration, elimination half life 10-50 hours (so can have once daily dosing)
- Crosses the placenta and into breast milk --> have seen haemolysis in infants
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Dapsone metabolism
- 1. Acetylation
- In the liver --> to MADDS, then deacetylated back
- Inter-variability in rates of this with people
- 2. Hydroxylation by CYP450 (different types of CYP)
- This is responsible for methemoglobulinaemia and haemolytic anaemia
- Can be inhibited by cimetidine
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Dapsone excretion
- Conjugated to more water soluble --> excreted in kidneys
- Has significant enterohepatic recirculation
- Okay to use in liver failure, don't have info on renal failure
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Dapsone MOA
- Anti-neutrophilic
- Inhibits neutrophil myeloperoxidase and impairs neutrophil chemotaxis
- Inhibits folic acid pathway
- important for leprosy
- Anti-eosinophilic
- Inhibits eosinophil myeloperoxidase
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Dapsone CI
- Absolute: hypersensitivity
- Relative:
- G6PD deficiency
- Sulfonamide allergy --> cross-reactivity is quite rare
- Significant cardiopulmonary disease
- Significant liver or renal impairment
- Pre-existing peripheral neuropathy
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Dapsone haem A/E
- Haemolytic anaemia (pharmacologic)
- Dose related, and occurs to some degree in everyone
- The metabolites formed in the liver are potent oxidants
- Red blood cells tolerance of oxidative stress decreases with age --> so older cells are damage and sequestered
- Patients initially have a decrease in Hb, then increase in RCC by bone marrow
- Causes falsely low HbA1c as it has lots of new red blood cells
- Those with G6PD deficiency are more at risk of haemolysis --> African, Middle Eastern, Asian
- Methemoglobinaemia
- Dose related
- Related to the metabolites as well
- Results in decreased oxygen carrying capacity and hence total Hb and clinical status of the patient's cardiopulmonary system
- % of methemoglobin may not accurately reflect the clinical significance as can have varying Hb
- Can worsen intra-operatively
- How to treat?
- Treat when levels over 30%
- Vitamin E - 800 IU daily has demonstrated small protection against haemolysis and methemoglobin
- Cimetidine --> inhibits metabolites of dapsone
- Emergency: methylene blue 100-300 mg daily to reduce methemoglobin, but this is contraindicated in those with G6PD deficiency
- Can also do plasma exchange
- Leukopenia
- Agranulocytosis
- Mechanism unknown
- Occurs mostly within the first 12 weeks of therapy
- Clinically: fever, pharyngitis, sepsis
- Recover quickly with cessation
- Can use G-CSF to treat
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Dapsone non-haem a/e
Hepatic
- Hepatitis --> resolve when discontinue
- Infectious mononucleosis like syndrome
- Cholestatic jaundice
- Hypoalbuminaemia --> rare
Cutaneous
- Morbilliform eruption
- Exfoliative erythroderma
- TEN
- Photosensitivity
Hypersensitivity
- Dapsone syndrome
- fever, generalised cutaneous eruption and hepatitis
- cutaneous: maculopapular to TEN
- Hepatitis: mixed picture
- Peripheral eosinophilia
- Rx: steroids
- Cross-reactivity with sulfonamide antibiotics
- not really been widely observed
- slight increase
- if previous SJS to sulfonamide, obviously withhold
GIT
- Gastric irritation with nausea
- self-limited
- take with meals
- Anorexia
Neurologic
- Psychosis
- vast majority in leprosy patients
- resolves are dapsone discontinuation
- Peripheral neuropathy
- Most common neurologic a/e, mechanism unknown
- Distal motor neuropathy with some degree of sensory involvement --> weakness of hands and legs, wasting of hand muscles
- Shown axonal degeneration
- Discontinuation --> complete recovery, can take up to 2 years
- Other neurologic effects
- possibly all due to hypoxia --> like retinal damage
Carcinogenesis
- weak carcinogen, observed in animals
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Dapsone and pregnancy and lactation
Pregnancy and lactation
- Category C
- Can be secreted in breast milk, and rarely causes haemolytic anaemia
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Dapsone drug interactions
- Drugs that induce CYP3A4 result in reduced dapsone levels: rifampicin, anticonvulsants, antifungals
- Drugs that reduce GI absorption reduce dapsone levels: antacids, HIV drugs
- Drugs that increase serum levels of dapsone: anti-emetics, probenicid
- Drugs that inhibit folate production pathway and increase haematologic risk: sulfonamide antibiotics, methotrexate, trimethoprim
- Drugs that increase oxidative stress to red cells resulting in haemaolysis: sulfonamide antibacterials, local anaesthetics benzocaine and prolocaine, plaquenil
- Also careful with HIV drugs
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Dapsone monitoring
- Baseline history and exam
- Cardiopulmonary, gastrointestinal, neurologic, renal
- Lab: FBC, LFT, UEC, urinalysis, G6PD
- G6PD can be falsely normal in a patient who has an elevated reticulocyte count or has a variant of the enzyme that is less capable of handling oxidative stresses
- there is genetic variability in response
- Consider B12, iron and folate --> those with deficiency won't be able to mount as good a bone marrow response
- Follow-up
- Peripheral motor neurologic exam (peripheral motor), cardiopulmonary
- Lab:
- FBC every week for 4 weeks, then ever 2 weeks until week 12, then every 3-4 months
- Reticulocyte count as needed
- If not mounted, may be due to underlying anaemia from something else --> iron, folate, B12
- Liver function tests every 3-4 months
- Renal function tests and UA every 3-4 months
- Methemoglobin levels as clinically indicated --> excessive fatigue, headaches, increasing cardiac or pulmonary symptoms
- Increase frequency if high risk
- Advise if prolonged febrile illness --> stop to see if helps
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Which penicillins to take with food
Amoxicillin and amp
| Rest on empty stomach
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Which penicillins have best staph coverage
Penicillinase resistant: methicillin, dicloxacillin
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Dosage of dicloxacillin
125-500 mg QID - adult
| 12.5-50 mg/kg/day QID - child
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Dosage of amoxicillin
25-50 mg/kg/day TDS - child
| 250-500 mg BD - adult
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Dosage of augmentin
20-40 mg/kg/day of amoxicilllin TDS or BD
| 500-875 mg BD - adult
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Percentaage of cross reaction with penicillin and cephalosporins
10-15% of adults
| 2 % children
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The risk of developing a morbilliform reaction when taking amp or amoxi when you have EBV is increased with what
Lymphocytic leukaemia
| Concomitant allopurinol
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A/E of penicillins
Hypersensitivity in 5-15%: anaphylaxis, urticaria, angioedema
Cutaneous: morbilliform, SJS/TEN, DRESS, pustular, serum sickness like illness
GIT: diarrhoea, pseudomembranous colitis, hepatic dysfunction
Renal: acute interstitial nephritis - proteinuria, haematuria, renal casts, eosinophilia, fever, arthralgias
Haem: prolonged use: pancytopaenia, agranulocytosis, platelet dysfunction
Infections: candida in 10% of patients
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Penicillin drug interactions
Probenicid: increases duration of action of penicillin (acts at distal renal tubules)
Allopurinol: increases risk of morbilliform reaction
Tetracyclines: reduces bacteriacidal effect
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Cephalexin dosage
25-100 mg/kg/day q6hourly or BD - children
| 250-500 mg QID - adults
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Ceftriaxone dosage
50 mg/kg IM max 1 g - child
| 1-4 g IM daily, or 250 mg IM stat for uncomplicated gonorrhoea
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% of those who have allergy to cephalosporin that have it with penicillin
2%
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Cephalosporin a/e
Cutaneous: morbilliform, urticaria, AGEP
Haem: neutropenia, thrombocytopaenia, Coombs poisitive haemolytic anaemia (particularly when renal insufficiency)
GIT: nausea, diarrheoa, pseudomembranous coliits
Certain subset: cefotetan, cefoperazone - disulfiram like effect with ETOH and anti vitamin K (bleeding)
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Cephalosporin interactions
Aminoglycosides: incr risk of nephrotoxicity
Probenicid: renal
Impair absorption: antacids, PPIs
