FINALSSSSS Flashcards
IC1-3, IC7-9, IC14-19 wo yao feng le
hOW MANY CDR PER ANTIBODYYYYY
12
3 each light/heavy chain
2 Fab arm
how many CDR per TCR and where is it found
6
3 in V alpha
3 in V beta
Name the CD3 dimer pairs part of the octameric complex of TCR
CD3εγ
CD3εδ
CD3ζζ
What does IFN alpha, beta and gamma respectively help in for cytokine therapy?
alpha - used to upregulate immune system for antiviral/anticancer therapy
beta - effective treatment for multiple sclerosis (slows down ifn gamma activity and slows growth of attacking immune cells)
gamma - activate resting macrophages and monocytes to phagocytosise more (stimulate immune response)
What does IL2 and IL11 respectively help in for cytokine therapy?
IL2 - T cell growth factor. stimulates growth, differentiation and activation of T cells, B cells and NK cells
IL11 - stimulates differentiation of hematopoietic stem cells and induced megakaryocyte maturation (platelets formation)
Difference between the 4 generations of CAR
1st generation → 1 intracellular signalling domain (CD3ζ)
2nd generation → 2 intracellular signalling domains for stronger signalling (CD3ζ + co-stimulatory CD28 or 4-1BB)
3rd generation → 3 signalling domains (CD3ζ + CD28 + 4-1BB)
4th generation → 3 signalling domains + transgene → activated upon binding to tumour cells to express cytokine (e.g IL12) → exerts autocrine and paracrine effect to activate more T cells to eliminate cancer cells
modifications in rapid acting insulin & what’s the purpose
Lispro
B28 & B29 reverse
Pro-Lys –> Lys-Pro (THATS WHY ITS CALLED LISPROOOO)
Aspart
ProB28 –> AspB28 (THATS WHY ITS ASPART COS IT CHANGED TO ASPARTAME)
Glulisine
B29 –> GluB29
B3 –> LysB3 (AND THATS WHY ITS GLU-LIS-INE)
Aim to reduce association between insulin molecules and remain as monomers
modifications in long acting insulin & what’s the purpose
Glargine
AsnA21 –> GlyA21
Add on 2 Arg residues to beta chain
–> change pI of glargine to 6.7 compared to regular insulin @ 5.4 to dissolve slower
Detemir
Remove Thr30, covalently attach C14 fatty acid chain to B29
–> more lipophilic, dissolve slower and slow down diffusion
Where can proteolysis occur?
- ECF present in organs/tissues - with immune cells lying in ambush and take part in phagocytosis and proteolysis
- on cell surface
- intracellular by lysosomes and proteasome degradation
Where does diffusion and convection drain to?
Diffusion: blood and lymphatic capillaries
Convection: Lymphatic capillaries only
2 functions of FcRn
- cellular recycling of IgG and albumin
- transcytosis of IgG and albumin
How does FcRn help in cellular recycling of IgG and albumin?
FcRn can bind to both IgG and albumin. When the cell pinocytosised, the acidic pH in the endosomes cause IgG and/or albumin to bind to FcRn. Rest of the endosome undergoes lysosomal degradation and the FcRn-IgG or FcRn-albumin complex goes back to the cell surface, where pH is neutral and IgG/albumin unbinds from FcRn.
Cut off MW for glomerular filtration of proteins
50kDa
How does charge affect renal elimination of protein?
Glomerular basement membrane and reabsorption tubular epithelium are negatively charged.
Positively charged proteins will be filtered through glomerulus more but also reabsorbed more.
3 strategies to improve PK profile of proteins
- glycosylation of protein
- PEGylation of protein
- increase in size of protein by fusion proteins
Should vaccines by PEGylated?
NO
Once PEGylated, the vaccine protein/peptides will avoid immunosurveillance, which defeats its purpose. We want the vaccines to trigger immune response in the host and develop antibodies against the vaccinated protein/peptide.
Lipid soluble hormones
tyrosine derivative - T3, T4
tryptophan derivative - melatonin
steroid hormones - androgens, estrogen, progestins, glucocorticoids, calcitriol, aldosterone, cortisol
examples of glycoprotein peptide hormones
TSH, LH, FSH
EPO
inhibin
Hormones that bind to cell membrane receptors
- protein hormones
- catecholamines
Hormones that bind to intracellular receptors
- steroid hormones
- thyroid hormones
What does thyroperoxidase (TPO) do?
- Convert inactive iodine to active iodine
- Attach active iodide to tyrosine backbone (organification)
- Coupling of MIT/DIT
physiological effects of T3,T4
- controls rate of metabolism
- cardiovascular effect (increase CO)
- sympathomimetic effect (feel pulse in throat, BP rise, shaking)
- essential for normal bone growth and maturation
- crucial in normal development of nervous system, especially in brain during childhood and normal CNS activity in adults
- increased synthesis and degradation of proteins, lipids, carbohydrates
Why does a patient present with low TSH levels in primary hyperthyroidism?
Stimulation of the TSH receptor by TSI results in increased secretion of T4 and T3 into the blood stream. [T3, T4] signals the pituitary to reduce secretion of TSH in order to reduce secretion of T3,T4 in negative feedback loop.
How does pregnancy affect levels of T3 and T4 in the blood?
More thyroxine binding globulin (TBG) is present in pregnant women, causing more thyroid hormones to bind to it due to high affinity. This causes the amount of free thyroid hormones in the blood to decrease, causing more TSH to be released to tell thyroid gland to secrete more hormones to return to normal levels of T3,T4.
Potentially hypothyroid if thyroid gland cannot keep up.
Routine screening needed for which group of patients?
- paediatrics (affects brain development)
- pregnant women (affects mother and child thyroid levels)
Medications that can cause thyroid disease?
amiodarone & lithium
Primary cause and secondary causes of hypothyroidism
Primary: failure of thyroid gland itself
Secondary: Insufficiency/deficiency of TRH, TSH or both
Inadequate supply of iodine in diet
Cardiac complications of hypothyroidism
- increased total cholesterol, LDL and triglycerides
- increased atherosclerosis and MI risk
When should thyroid levels be measured again after starting on / modifying levothyroxine sodium?
in 4-8weeks for clinical effect to be visible
DDI and DFI to levothyroxine sodium
Affected by gastric pH and potential for chelation
DDI: antacid, PPIs, H2RA, etc that will alter gastric pH & Ca supplements and Fe supplements, etc cations that will chelate with negatively charged levothyroxine
DFI: food that alters gastric pH like milk
Initial dosing for levothyroxine sodium
Start with 100mcg (usually)
If 50-60 years old with no cardiac issues: 50mcg
If CVD: 25mcg and uptitrate
Adverse effects of levothyroxine sodium AND contraindications
- reduced appetite
- anxiety
- diarrhea (increased bowel motility)
- difficulty sleeping
- hair loss
RARE - heart issues (high BP, arrhythmia)
- seizures
HENCE: contraindicated in patients with severe heart conditions & epilepsy
General TSH target
0.4-5mIU/L
(around there, some is 0.4-4 some is 0.5-5, see lab ranges)
After achieving euthyroid status, how often should TFTs be checked for nonpregnant adult patients?
every 6 months to yearly
Why is liothyronine not recommended for hypothyroidism?
- high incidence of adverse effects
- hard to regulate and monitor
- hard to get & expensive
Target TSH for 1st, 2nd and 3rd trimester
1st: <2.5 mIU/L
2nd: <3.0 mIU/L
3rd: <3.5 mIU/L
What is subclinical hypothyroidism?
Elevated TSH with normal T4
What are the risks involved with high TSH levels
Older adults with TSH > 7mIU/L –> higher risk of HF
TSH > 10mIU/L –> higher risk of coronary heart disease
When to treat for subclinical hypothyroidism and if dont treat, whats the follow up plan?
Treat when TSH > 10 OR
symptomatic/history of CVD/HF/risk factors/TPO(+) with TSH 4.5-10
if dont treat, check every 6month-1year to monitor for overt hypothyroidism
Primary cause and secondary causes of hyperthyroidism
Primary: stimulation of TSH receptor by Thyroid stimulating immunoglobulin (TSI)
Secondary:
- excess of TRH, TSH or both
- hypersecreting thyroid tumour (MAYBE CANCEr??? GG)
- subacute thyroiditis, may be sign of early Hashimoto’s thyroiditis (release of stored hormone)
Why is carbimazole first line compared to PTU?
PTU has boxed warning for hepatotoxicity, so generally carbimazole is first line
time for Clinical response when using carbimazole
3-6weeks (considering long half life of t4)
2 main signs of hyperthyroidism in pregnancy
- failure to gain weight despite good appetite
- tachycardia
What thionamides should pregnant women use and why?
1st trimester: use PTU due to carbimazole having higher risk of congenital malformations
2nd and 3rd trimester: use carbimazole due to PTU having higher risk of toxicity
When should Lugol’s solution be used? (Place in therapy)
- before surgery (7-10days) to shrink the gland
- after ablative therapy (3-7 days) to inhibit thyroiditis-mediated release of stored hormone
- preventing thyroid storm
What is subclinical hyperthyroidism?
Low/undetectable levels of TSH but normal T4
Treatment for subclinical hyperthyroidism & if dont treat, what is the follow up plan?
- similar to hyperthyroidism (PO therapy is alternative to ablative therapy in YOUNG patients)
- more compelling if TSH < 0.10 mIU/L
- start BB especially if patient has AF
if no treat: screen 6months-1 year for overt hyperthyroidism
How does continuous exposure to GnRH affect release of LH and FSH?
Continuous exposure to GnRH desensitises the GnRH receptors and end up reducing LH and FSH secretion by the anterior pituitary.
Effects of testosterone
- internal male genitalia differentiation
- pubertal growth spurt
- penis growth
- deepening of voice
- spermatogenesis
- libido
- muscle mass
Effects of dihydrotestosterone (DHT)
- external male genitalia differentiation
- sebaceous glands, etc (pimples!)
- prostate growth
- male hair pattern - body and facial hair growth promoter (just not the head hair..)
- male pattern baldness
Cholesterol is converted to testosterone in the _______________ and testosterone is converted to DHT in the _________________ by ______________
Leydig cells
Sertoli cells
5alpha-reductase
Where does LH and FSH bind to in the follicle?
LH binds to theca cell (start conversion of cholesterol to intermediate molecule)
FSH binds to granulosa cell (converts intermediate molecule to estradiol [estrogen] via aromatase)
When estrogen levels are moderate, how are LH and FSH affected?
rising moderate levels of estrogen
- act on hypothalamus to inhibit GnRH secretion –> lowers FSH and LH
- act on pituitary to selectively inhibit FSH secretion
developing follicle releases inhibin to selectively inhibit FSH secretion as well.
results in accumulation of LH
When estrogen levels are high, how are LH and FSH affected?
Rising high levels of estrogen
- act on hypothalamus to increase GnRH secretion (more FSH and LH)
- act on pituitary to selectively stimulate LH secretion
Inhibin still inhibiting FSH secretion
results in surge of LH (trigger ovulation)
How does estrogen affect endometrium?
Estrogen causes thickening of endometrium
How does progesterone affect endometrium?
Progesterone increases number of blood vessels and secretory glands in endometrium to nourish fetus (prepare for pregnancy)
Signs of puberty in females
- thelarche - development of breasts
- pubarche - growth of pubic and axillary hair
- menarche - first menstrual period
- others (growth of secondary sex organs, fat deposition, rapid increase in height)
signs of menopause
- cessation of menstrual cycle (12months since last menstrual period)
- gradual atrophy in genital organs
- vasomotor changes (blood vessel dilation/constriction –> hot flushes)
- skin changes
- psychological and emotional (feeling irritable)
- increase in cholesterol level (not converting to estrogen/progesterone –> CVD risk factor)
- risk of osteoporosis (lack of estrogen –> lower bone mass)
selective alpha1A blockers
tamsulosin, alfuzosin, silodosin
Risk factors for prostate cancer?
- age (men > 70 common)
- family hx (brother > father)
- ethnicity (chinese > malay/indian)
- diet high in fat
Diagnosis of prostate cancer ?
- DRE and PSA (if results are low/slightly elevated, put on hold, might be BPH)
- if results high^, proceed with biopsy to get gleason scoring
- MRI/CT/PET scan for metastasis
4 ways to achieve androgen deprivation (for androgen sensitive cancers)
- inhibition of pituitary gonadotropin release (GnRH analogues) –> lower FSH & LH –> lower testosterone –> lower DHT
- Inhibit androgen synthesis –> 5ARI prevent conversion of testosterone to DHT
- inhibit androgen binding - androgen receptor blocker
- surgical extirpation of glands (castration and adrenalectomy)
Monitoring for leuprorelin
- PSA in first few weeks of therapy (measure growth of prostate tissue)
- LH, FSH and testosterone levels after 4 weeks of therapy
Bicalutamide primary use and why cant it be used as monotherapy of prostate cancer?
Primary use in conjunction with GnRH to alleviate effects of testosterone surge (tumour flare) resulting from the GnRH analogue in treatment for metastatic prostate cancer.
Cannot use as monotherapy as it will result in high serum testosterone levels
Barrier techniques for contraception
- external condom
- internal condom
- diaphragm with spermicide
- cervical cap
% failure rate for barrier contraception vs hormonal contraception (% pregnancy)
Barrier contraception: 13-21%
Hormonal: 1-7%
Role of progestin in oral contraceptives
- thicken cervical mucus to prevent sperm penetration and slow tubal motility
- arresting glandular proliferation in endometrium –> endometrial atrophy in long term use
- prevent ovulation (progestin inhibit FSH and LH release –> stops follicular development and ovulation, no peak/changes no hypothalamus feedback no induction of LH production –> inhibits LH surge)
Role of estrogen in oral contraceptives
Stabilise endometrial lining and provide cycle control
Why do we tend to avoid high dose estrogen
High dose estrogen is associated with vascular, embolism events and significant adverse effects
Which groups of patients favour low dose estrogen?
- adolescence
- underweight (<50kg)
- age >35
- perimenopausal
in which groups of patients is higher dose of estrogen favoured?
- obesity / weight > 70.5kg
- early to mid cycle breakthrough spotting
- tendency to be non adherent
Androgenic side effects from progesterone
Acne, Oily skin, hirsutism
Which progestin/progesterone has the lowest/no androgenic side effects? What are its side effects?
Drosperinone - analogue of spirinolactone
–> expect mild diuresis
–> can cause hyperkalemia, thromboembolism and bone loss
3 ways to start COC
- First Day Start (first day of period, no need back up contraceptive)
- Sunday Start (start on first sunday of period - backup contraceptive for at least 7 days)
- Quick Start (any time start, back up contraceptive for at least 7 days)
How does estrogen predispose a patient to VTE risk??
Estrogen increases hepatic production of factor VII & X and fibrinogen of the coagulation cascade –> increase risk of clots
Do old or new generation of progestin have higher risk of VTE?
New
Risk factors for VTE
- > 35yo
- obesity
- smoker
- immobilisation
- cancer
- hereditary thrombophilia (higher risk for clots)
How to manage breakthrough bleeding from COC?
- if early/mid cycle, increase estrogen (stabilise endometrium well)
- if late cycle, increase progestin to stabilise endometrium
How to manage acne from COC?
Use less androgenic progestin (drosperinone)
Consider adding/increasing estrogen
How to manage bloating from COC?
- reduce estrogen
- use progestin with mildly diuretic effect (drosperinone)
How to manage N/V from COC?
Reduce estrogen
Take at night/change to POP
How to manage headache from COC?
- exclude migraine with aura
- switch to extended cycle/continuous cycle
How to handle menstrual cramps from COC?
Increase progestin (stops PG production)
Can estrogen or progesterone be used in breastfeeding?
Progesterone - good for breastfeeding
Estrogen - should be used in breastfeeding & <21days postpartum
–> estrogen downregulates milk production >:(
Contraindication in POP
Current/history of breast cancer
Ways to start POP
- within 5 days of menstruation (no need back up)
- other days: back up for at least 2 days / 7 days for drosperinone POP
Missing dose for COC what to do?
<48 hours
>48 hours
<48 hours take missed dose ASAP and continue as per normal
> 48 hours take missed dose asap &
- abstain/use barrier for at least 7 days of consecutive COC
- if miss during last week –> skip placebo pills and start new pack directly (if cannot then abstain/barrier for at least 7 days of consecutive COC)
- if miss during first week and unprotected sexual intercourse occurred in past 5 days –> EMERGENCY CONTRACEPTION
Missing dose for POP what to do?
Drosperinone POP
<3h
>3h
Drosperinone POP same as COC missing dose
<3h : take missed dose asap
> 3h: Abstain/barrier for at least 2 days consecutive POP
- if have had unprotected sexual intercourse, use EMERGENCY CONTRACEPTION
Non oral hormonal contraceptives and frequency of administration
- transdermal contraceptive - once weekly for 3 weeks then 1 week free
- vaginal ring - 3 weeks then discard
- progestin injection - IM inj every 12 weeks
- subdermal progestin implants - 3 years
- copper iud - 10 years
- levonorgestrel iud - 5 years
Contraindications of progestin injection
Short term bone loss which decreases bone mineral density (Black box warning)
(avoid)
–> contraindicated in older women, osteoporosis risk factors (e.g long term steroids)
Features of copper iud
- Heavier bleeding
- Ideal if concomitant menorrhoea
- Lasts 10 years
- Can use as emergency contraception
Features of levonorgestrel iud
- lesser menstrual bleeding
- typically spotting, can cause amenorrhea
- ideal if concomitant menorrhagia
- lasts 5 years
emergency contraception options
- copper iud, insert within 5 days
- ella (ulipristal tablet), take 1 tab within 120h (5 days) –> cannot be on POP/ can only continue POP after 5 days
- Postinor (levonorgestrel), take 2 tab asap within 12h best but not later than 72h (3days) –> less effective in morbidly obese patients
In HRT why do we need to add progestin to estrogen if there is a working uterus?
Reduce the risk of endometrial cancer (estrogen promotes the proliferation of endometrium)
Monitoring for HRT in menopausal women
- annual mammography for breast cancer surveillance
- endometrial surveillance for:
unopposed estrogen: vaginal bleeding
continuous-cyclic: if bleeding occurs when progesterone is still on
continuous-combined: if bleeding is prolonged, heavier than normal, frequent, persistent after 10 months of treatment
medication that can potentially cause BPH/urinary retention
- anticholinergics (antihistamines, TCAs - amitriptyline, etc)
- a1 adrenergic agonist (decongestants)
- opioid analgesics
- diuretics (increase urinary frequency)
- testosterone
Nonpharmacological lifestyle modifications for BPH
- limit fluid intake in the evening (esp no caffeine after 3pm)
- minimise caffeine or alcohol intake (alcohol have diuretic effect)
- educate patients to take time to empty bladder completely and often (schedule voiding every 3-4h)
- avoid/remove medications that can exacerbate symptoms (let patient know since many of them are OTC)
Alpha adrenergic antagonist is indicated for:
affect prostate size/PSA/none?
onset:
moderate-severe LUTS with small prostate size (<40g)
no effect on PSA/prostate size (clinical effect based on symptoms)
onset: days-weeks (quick)
5ARI is indicated for:
affect prostate size/PSA/none?
onset:
moderate-severe LUTS with large prostate (>40g) & patients who want to avoid surgery/intolerant to alpha adrenergic antagonist
reduces prostate size & PSA levels
onset: 6-12months (slow)
PDE5i is indicated for:
affect prostate size/PSA/none?
onset:
add on therapy for patients with concomitant ED
does not affect prostate size
onset: days-weeks
(only tadalafil is indicated for BPH)
