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
Q
Cyclosporin ADME
A
- 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
Q
Cyclosporin MoA
A
- 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
Q
Cyclosporin contraindications
A
- 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
Q
Cyclosporin A/E
A
- 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
- Hypertension
- 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
Q
Cyclosporin drug interactions
A
- 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
Q
Cyclosporin uses
A
- 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
Q
Monitoring cyclosporin
A
- 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
Q
Managing renal complications with cyclosporin
A
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
Q
Ceasing cyclosporin
A
- 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
Q
Terbinafine pharmacokinetics
A
- 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
Q
Terbinafine MOA
A
- inhibits squalene epoxidase leading to accumulation of squalene and subsequent deficiency of ergosterol –> fungistatic
- accumulation of squalene –> fungicidal
36
Q
Terbinafine - getting kids to take it
A
- terbinafine you can crush it up or sprinkle on food
