1
Q
a blocker eg
A
- Alfuzosin
- Tamsulosin
- Silodosin
non-selective: doxazosin, terazosin, prazosin
2
Q
prostate physiology
A
1) prostate smooth muscle maintained by noradrenaline (from adrenergic nerves)
2) Stimulate post-junctional a1-adrenoceptor
3) Prostate and LUT tissue exhibit
a) High proportion of a1A receptors
3
Q
a1 receptor antagonist MOA
A
- Antagonist of a1A receptor = relax smooth muscle of bladder (int. sphincter) & urethra
○ improve urine flow - Reversible antagonist
○ Inhibit vasoconstrict by endogenous catecholamines
○ Block a1-adrenoceptors on smooth muscle of
§ Prostate, prostatic urethra, bladder neck
○ Decr muscle tone, reduce bladder obstruction
○ Relax prostate smooth muscle
○ Improve urodynamics
§ Max urinary flow (less tension in muscle)
§ Less obstruction
4
Q
a1 receptor antagonist reduce symptoms of
A
*Bladder instability
*Tension in smooth muscle of LUT
Improve urinary flow rate (after few hrs/ days)
5
Q
PK of a1 receptor antagonist
A
A: well absorbed orally (0.4 mg OD)
D: highly bound to plasma proteins (90-99%)
Small Vd (0.2L/kg)
M: CYP (3A4, 2D6)
T1/2: ~10-15h
E: urine
6
Q
ADR OF a1 receptor antagonist
A
- Abnormal ejaculation
- Backpain
7
Q
when is a1 receptor antagonist used
A
- Moderate-severe symptomatic BPH regardless of prostate size
- Selective for a1A (prostate, blood vessels) > a1B (blood vessel, heart)
- less effect on BP- LT therapy to maintain effect of urinary storage, voiding symptoms
*Delay surgery, catheterisation
- LT therapy to maintain effect of urinary storage, voiding symptoms
8
Q
CI of a1 receptor antagonist
A
Concurrent use of another a1-adrenoceptor antagonist
- prazosin, epinephrine
9
Q
5a reductase inhibitor eg
A
Finasteride, dutasteride
10
Q
5a reductase in normal physiology
A
- Testosterone –> dihydrotestosterone (DHT)
○ Prostate to grow
○ Male pattern hair loss (androgenetic alopecia)
11
Q
5a reductase inhibitor MOA
A
- Competitive, 5a-inhibitor (no affinity for androgen receptor)
- Inhibit conversion of Testosterone –> dihydrotestosterone (DHT)
○ In male external genetelia - Decr prostate size
○ Inr urine flow
○ Reduce freq of ACUTE retention of urine - Decr need for surgical procedures for prostate transurethral resection, prostatectomy
- Inhibit conversion of Testosterone –> dihydrotestosterone (DHT)
12
Q
symptom relieve of 5a reductase inhibitor
A
inhibit 5a-reductase enzyme action
* Decr prostate size
*Incr hair growth
take up to 6mnth to see BPH clinical effect
PSA decr over time
13
Q
PK of 5a reductase inhibitor
A
A: well absorbed orally (5mg OD)
f~0.65
No dosage adj for renal insuff/ liver failure/ elderly pt
D: highly bound to plasma proteins (90%)
M: CYP (3A4, 2D6)
T1/2: ~6h
E: 50% unchanged in feces
Metabolites in feces, urine
14
Q
ADR of 5a reductase inhibitor
A
- Loss of libido, sexual potency
- Gynecomastia (rare)
15
Q
clinical efficacy 5a reductase inhibitor
A
Take up to 6mnths to see BPH clinical effect after initiate
Lower dose used for male pattern baldness
Used for female hirsutism
16
Q
CI 5a reductase inhibitor
A
Women and children
Preg
17
Q
ED risk factors
A
alcohol
enlarged prostate BPH
psychological factors
sleep disorders
stress
18
Q
PDE5 inhibitor
A
Tadalafil (can be used for BPH)
sildenafil, vardenafil, avanafil
19
Q
PDE5I MOA
A
- Inhibit phosphodiesterase type 5 (PDE5) in penis
- Sexual stimulation, release NO
- Incr convert GTP –> cGMP levels
○ Decr Ca levels
○ Less cGMP —> 5’ GMP (by PDE5)
- Smooth muscle relaxation
- Incr blood flow to corpora cavernosa
○Produce erection
20
Q
PDE5 normal physiology
A
- PDE5: highly expressed in corpora cavernosa (of penis, vasculature)
- Poorly in myocardium
*Tissue specificity to compound
- Poorly in myocardium
21
Q
PK of PDE5I
A
A: well absorbed orally (5mg OD/ PRN)
f~0.4
No dosage adj for renal insuff/ liver failure/ elderly pt
Onset 30-60min
Duration ~12h (uncomfortable)
D: widely distributed
M: CYP (3A4, 2C9 -minor) T1/2: ~4h
E: metabolites largely excreted in feces
22
Q
ADR of PDE5i
A
- Headache
- Flushing
- Dyspepsia
- Dizzy
- Back pain, muscle pain (PDE11 affinity)
- Blur vision
(inhibit retinal PDE6, blue-green tint of vision)
7.Priapism (prolonged erection
23
Q
initiate PDE5i
A
Start Dose: at lowest conc
- esp for >65yrs old
1) Check for cardiac 2) Check dose
24
Q
CI for PDE5i
A
- Cardiac pt on GTN (nitroglycerin)
Potentiate vasodil effect of GTN (via incr cGMP) due to incr inhibition of cGMP degradation) - marked vasodilation, hypotension
25
Ethinyl estradiol
Estrogen receptor agonist
Synthetic estrogen (birth control pills, oral contraceptives)
26
MOA of estrogen agonist
* Inhibits FSH release from anterior pituitary
* Suppress development of ovarian follicle
* Make endometrium unsuitable for implantation of ovum
27
PK of estrogen agonist
A: well absorbed orally (OD)
f~0.45
IV, transdermal, TOP too
Onset 30-60min
D: highly plasma protein bound (~98% albumin)
M: metabolised by liver (T1/2 13-27hrs)
E: excreted in feces, urine
28
metabolism of estrogen agonist
Phase 1: EE hydroxylation (CYP3A4)
Phase 2: conjugation (to inert)
- Glucuronide(ethinylestradiol glucuronides
- sulfation (ethinylestradiol sulfate)
Enterohepatic recirc** (liver, bile, SI, ab by enterocyte, back to LIVER)
29
ADR of estrogen agonist
1) Breast tenderness
2) Headache
3) Fluid retention (bloat)
4) NV
5) Dizzy
6) Weight gain
* Venous thromboembolism (VTE)
* MI/ stroke
*Liver damage
30
CI for estrogen agonist
* History/ susceptibility to arterial/ venous thrombosis (VTE)
* Advanced DM with vascular disease
* Hypertension >160/100
* Avoid breastfeeding (21 days postpartum)
* Breast cancer women
31
indication for ethinyl estradiol
menopausal sx
gynecological disorders
hormone-sensitive cancers
32
progestin
Norethindrone
33
progestin uses
* Synthetic progesterone (birth control pill, oral contraceptives)
* treat endometriosis
* abnormal periods of bleeding, for a normal menstrual cycle
34
progestin MOA
* Inhibit luteinizing hormone release
* Prevent ovulation
* Make endometrium unsuitable for implantation of ovum
* Act as progesterone receptor AGONIST
35
PK of progestin
A: well absorbed orally (OD)
f~64%
D: highly plasma protein bound (albumin)
M: metabolised by liver (T1/2 8hr)
Phase 1: reduction
Phase 2: conjugation (to inert)
Glucuronide
sulfation
Some % norethindrone metabolised --> EE
E: excreted in feces, urine
36
ADR of progestin
1) Headache
2) bloat
3) NV
4) Dizzy
5) Weight gain
6) Unpredicted spot/ bleed (initial)
7) Amenorrhea (stop)
partial conversion of norethindrone -->EE*
* Venous thromboembolism (VTE)
* MI/ stroke
* Liver damage
37
CI for progestin
Not for women planning preg soon after cessation of therapy
- ovulation suppressed may persist for as long as 1.5yrs
38
structure of estrogen agonist and progestin
estrogen agonist
(from estrogen CH3 ----> Alkynes : allow PO)
progestin
(alter from estrogen agonist, OH --> C=O)
39
Hypertensive disorders of preg
* Common causes of mortality in pregnancy
○ HTN: 140/90 mmHg
§ Based on >1 measurement, 4hrs apart
§ Start treatment
* Severe HTN: >160/110 mmHg (after 2 measurements)
40
Chronic HTN
Preexisting HTN / New onset HTN
Before 20wks gestation
41
Gestational HTN
New onset HTN
w/o proteinuria after 20 wks of gestation
42
Preeclampsia
New onset HTN after 20 wks of gestation w/ any of new onset
1) Proteinuria
2) Sign of end organ dysfunction
3) Uteroplacental dysfunction
43
Chronic HTN with superimposed preeclampsia
New onset proteinuria in women with chronic HTN, no proteinuria
Before 20 wks gestation
44
Preeclampsia
complex multisystem disease. Not understood pathophysiology, multifactorial and varied
1) proteinuria
2) signs of end organ damage
45
Proteinuria
* 24h urinary protein UTP > 300mg
* Dipstick protein > 2 +
* Urine protein:
- creatinine ratio (uPCR) > 0.3 mg/dL
46
Signs of end organ damage
* PLT platelet < 100
* LFT > 2X ULN
* Double SCr, absence of other renal disease
* Pul oedema
* Neurological complications **
□ Altered mental status
□ Visual disturbances
□ Seizure
□Headache
47
eclampsia
new onset tonic-clonic, focal, multifocal seizure superimposed on preeclampsia
§ Medical emergency --> risk to both maternal & fetal
§ Complications of eclampsia
48
Prevention of preeclampsia
Low dose aspirin
□ *high risk pt :
□ Dose: 100mg or more daily (low dose)
□ Started from 12-16wks. Continue till delivery
49
high risk HTN preg pt
HTN on previous preg
multifetal gestation (twins, triplets)
autoimmune disease
DM
CKD
50
MOA of aspirin
□ MOA: improve utero-placenta blood flow
-Inhibit thromboxane A2, precursor of preeclampsia
51
Treatment of HTN in preg
1) Labetalol (BB)
i. Preferred over the other BB due to less ADR on uteroplacental blood flow, fetal growth
ii. ADR: broncho-constrictive effects, bradycardia
2) Nifedipine ER (CCB)
i. Most studied, widely used CCB in preg
ii. ADR: pedal oedema, flush, headache
3) Methyldopa
i. Extensive safety data
ii. ** LOW POTENCY
iii. ADR: sedation, dizziness
4) Hydrochlorothiazide
i. 2nd, 3rd line. Potential interference with normal blood vol expansion during preg --> diuretic
5) Hydralazine
i.ADR: similar sx as severe preeclampsia --> eclampsia. NV, palpitation, flush, headache, tremor
52
Contraception
1. Inhibit viable sperm from coming into contact with mature ovum
- Barriers
- Prevent ovulation
2. Prevent fertilised ovum from successfully implanting in endometrium
- Unfavioural uterine environment
53
Barrier techniques
(typical use) 13-21% of preg vs OHC 1-7%
condom (M,F)
diaphragm w/ spermicide
cervical cap
54
male condom
CI: Allergy to latex or rubber
ADV: STD protection
DISADV:
*High user failure rate
* Poor acceptance
* Breakage possibility
55
female condom
CI: Allergy to polyurethane
TSS
- overgrowth of staph aureus bact
ADV: STD protection. inserted ahead of time
DISADV:
*High user failure rate
* Dislike ring hanging outside vagina
56
Diaphragm with spermicide/ cervical cap
CI:
* Allergy to latex, rubber or the spermicide
* Recurrent UTI
* Hist of TSS
*abnormal gynecologic anat
ADV: Low cost, Reusable
DISADV:
* High user failure rate
* Low protection against STD
* Incr risk of UTI
* Cervical irritation
57
Hormonal contraceptives benefits
* Prevent preg
* Other health benefits
○ Menstrual regularity, flow, cramp
○ Manage perimenopause
○ Manage other conditions -- PCOS, acne, PMS, iron-deficient anemia
○ Reduce risk from
§ Ovarian, endometrial cancers
§ Ovarian cysts, ectopic preg, pelvic inflamm disease, endometriosis, uterine fibroids, benign breast disease
58
Combi of estrogen/ progestin
COC (combined oral contracep)
progestin + estrogen
59
progestin MOA
thickens cervical mucus to
* prevent sperm penetration
* Slow tubal motility (delay sperm transport)
* Induce endometrial atrophy
* Block LH surge (prevent ovulation)
Most of contraceptive effect
60
estrogen uses
stabilize, growth of endometrial lining, provide cycle control
Suppress FSH release
61
eg of estrogen
○ Ethinyl estradiol (EE)
○ Estradiol valerate
○ Esterol
○ Mestranol
62
dose of estrogen
Mod, standard 30-35
Low dose: 15-20ug
High dose: 50ug
63
low dose 20-25mcg favoured for
○ Adolescene
○ Underweight <50kg
○ Age > 35yrs
○ Peri-menopause
○ Fewer ADR
64
high dose 50 mcg favoured for
○ Obese, >70.5kg
○ Early-mid cycle breakthrough bleed, spotting
○ Non adherence
risk of ADR: vascular embolic events, Cancers
65
CI for COC
* Breast cancer
* Ischemic stroke, MI
(E > P)
* Venous thromboembolism (VTE)
* Estrogen
* Progestins (4th gen DROS, CRYPRO, desogestrel)
66
Breast cancer risk
* Ok for healthy young
* CI: >40 yrs
* Fam hist, risk factor of BC
* Current/ recent PMH (5yr)
- risk incr with duration and age >40yrs
- after discontinuation, risk returns to same lvl as those who never used COC
67
Ischemic stroke, MI
- ESTROGEN > PROGESTINS
* Risk factor:
○ Age
○ HTN
○ Migraine with aura !!!!
○ Obese
○ Dyslipidemia
○ Smoke
○ Prothrombotic mutation
* Change to
○ Prog only, barrier, low dose estrogen
68
MIGRAINE WITH AURA
SENSORY DISTURBANCES
flashing lights, halo vision, blind spot, tingling sensation
69
Venous thromboembolism (VTE)
* Estrogen incr hepatic prod of factor VII, X, fibrinogen of coagulation cascade
* Progestins (4th gen dros, cypro, desogestrel)
* Risk factors (promote stasis)
○ >35yr
○ Obese
○ Smoker
○ cancer
○ Fam history
○ Immobilization
* Consider change:
○ Low dose estrogen, older progestins
○ Prog only
○ Barrier method
70
incr estrogen when
Breakthrough bleed early
Acne
71
Reduce estrogen when
Bloat
NV
Breast tender, weight gain
72
ADR of estrogen
1. Breakthrough bleed
2. Acne
3. Bloat
4. NV
5. Headache
6. Menstrual cramp
a. Extended cycle, continuous, less pill free
7. Breast tender, weight gain
73
DDI of COC
* Rifampicin
* theoretical that AB alter gut flora, alter M, less active drug
* Additional contracep (7 days) after discontinue
* Incr dose
* Anticonvulsants
* Phenytoin, carbamazepine, barbiturates, topiramate, oxcarbazepine, lamotrigine
* Reduce free serum conc of Estro, prog
* HIV antiretrovirals
* Ritonavir, darunavir
* Reduce both effectiveness of COC, antiretrovirals
74
absolute contraindications for COC (12)
- current breast CA/ recent hist in 5yrs
- hist of DVT/PE, acute, pts with & on anticoagulant therapy
- thrombogenic mutations
- major surg with prolonged immobilisation
- current/ hist of IHD
- HTN with vascular disease
- HTN > 160/100 mmHg
- cardiomyopathy
- <21 days post partum
- hist of cerebrovascular disease
- migraine with aura
- smoke >15sticks/ days & age > 35 yo
75
progestin activity
* Vary in pregestational activity
* Androgenic effects
* Androgen-to-progesterone activity ratio
* Acne, oily skin, hirsutism
* Pregestational activity prevent
* late cycle breakthrough bleeding
*Painful menstrual cramps
* CI: BREAST CANCER
76
Progestin 4th
Cyproterone
drospirenone
77
drospirenone
* Spironolactone analogue, anti androgenic action, diuretic (less bloat) , less acne
Hyperkalemia
Thromboembolism
Bone loss
78
Cyproterone
* Anti-androgenic, antigonadotrophic
* Treat excessive androgen related conditions (severe acne, hirsutism)
* not solely as contraceptive
Thromboembolism
79
POP -- norethisterone
* Good for breastfeed, those that cannot take estrogen (NV)/ conditions that preclude estrogen
CI: current/ recent hx of breast cancer
80
POP initiate
* 28 active pills
* Continuous
○ Start: within 5d of menstrual cycle (no need backup)
* Any other day: back up 2 d
* late dose > 3hr = BACK UP 2 DAYS
81
Incr progestin when
* Late breakthrough bleed
* Menstrual cramp
* Bloat (drospi -- mild diuretic)
82
change progestin to COC
* Acne (less androgenic)
Stop POP --> COC
83
decr progestin when
Breast tender, weight gain
84
Monophasic COC
Same amt of estrogen & progestin in every pill
Less confusing
Less complicated missed dose instruction
85
Multiphasic COC
Variable amt of estrogen and progestin
4 phases (higher estrogen at start, higher prog at end)
* Less overall prog
* Less ADR
* Mimics physiologic menstrual cycle
but expensive
86
Conventional cycle COC schedule
21 days active pill
7 day placebo
= 28 days
24 days active pill
4 day placebo
= 28 days
87
Extended cycle/ continuous COC schedule
84 days
7days placebo
0 placebo (continuous)
88
Conventional cycle COC ADV
Period triggered when pill stop
Shorter pill free interval
- Reduce hormone fluctuation b. cycle (less SE
89
Extended cycle/ continuous COC ADV, DISADV
Convenient
Less periods
DISADV: breakthrough bleeding
90
3 ways initiate COC
* 1st day of menstrual cycle
○ No need backup contraceptives
○ First 5-6 days not likely to get preg
* Sunday start after menstrual cycle begins
○ Backup for 7 days
○ So that weekends free of menstrual periods
* Quick start, any day
○ Backup for 7 days// until next menstrual cycle begins
91
factors to select COC
hormone content required
convenience
adherence lvl
tendency for oily skin, acne, hirsutism
medical conditions (PMS)
92
Hormonal content required
○ More/ less estrogen
§ (pt weight, adherence, early bleed)
○ More prog
§ Late bleeding
93
Convenience
No periods? Placebo?
94
Adherence level
Low = Higher estrogen
Monophasic
95
Tendency for oily skin, acne hirsutism
Less prog (androgenic ADR)
change to 4th gen
96
Medical conditions like PMS, dysmenorrhea (how to counter)
PMS (incr prog)
Dysmenorrhea (extended cycle 84 days active)
- decr hormone free interval
97
ADR for COC SHOULD ....
Persevere on COC for 2-3 mnths
* Usually 3-4 cycles of cycle before stabilsie
* Unless serious ADR
- VTE, stroke, migraine with aura, MI
98
MISSED DOSE: 1 dose missed (less than 48hrs)
1) Take pill immediate
2) Continue rest as usal
– 2 pills on same day
No additional contraceptives required
99
2 or more consecutive dose missed (more than 48hrs)
1) Take missed dose immediate
2) Discard rest of missed dose
3) Continue rest as usual
– (2 pill on same day)
Backup contraceptive required for 1 week
100
Pills missed on last week of hormonal tablet (day 15-21)
1) Finish remaining active pills in current pack
2) SKIP hormone free interval
– Treat missed dose as the hormone free period
3) Start new pack next day
Backup contraceptive required for 1 week
101
dont want period coming in the next week
Ignore placebo pills, start new pack of active pill to delay period
Continue as per usual until next placebo pill (skip 1 menstrual cycle)
102
COC also available in:
1) Transdermal contraceptives
2) Vaginal rings
103
transdermal contraceptives
○ Both estrogen and progestin component
○ Failure rate ~ 7% (COC)
○ Applied once wkly for 3wks -- 1 patch free week
§ Not effective in pts weighing > 90kg
○ SE: similar to COC + application side rxn
104
vaginal ring
○ Both estrogen and progestin component
○ Failure rate ~ 7% (COC)
○ Used for 3wks then discarded -- 1wk free
§ Unlike diaphragms/ cervical caps
§ No need precise placement as hormones are absorbed (less user error)
○ SE: similar to COC + risk expulsion
105
transdermal patch/ ring
continuous, higher exposure to estrogen --> risk of VTE
106
Other progestin only contraceptives
1) prog inj
2) LARC -- IUD, implants
107
Progestin inj
○ Depot-Provera (medroxyprogesterone 1st gen), IM inj every 12wks
Good for adherence issues, need regular doctor visit
§ Good for postpartum, not to get preg soon after giving birth
§ Incr breastmilk
Failure rate ~ 4% <<<(COC)
108
ADR, CI of prog inj
○ ADR: return to fertility delayed. Depot, need to wait for the progestin to be released
§ Variable breakthrough bleeding (first 9mnths)
§ Amenorrhea after 12mnths --> 2yrs
§ Weight gain
§ Short term bone loss (Bone mineral density decr)
○ CI:
§ Avoid in older women
§ Avoid in osteoporosis risk factors, LT steroid use
§>2 yrs use, evaluate other options (bone loss incr with duration of use)
109
2) Long acting reversible contraception (LARC)
Intrauterine devices IUD, implants MOA
1) Inhibit sperm migration
2) Damage ovum
3) Damage/ disrupt transport of fertilised ovum
4) w/ progestin (thicken mucus, endometrial suppression)
110
2 types of IUD
LEVONORGESTREL (2nd) IUD
* Cause decr flow, ideal for menorrhagia
* 5 years
COPPER IUD
* Cause heavier menses, ideal for amenorrhea
* 10yrs
*Emergency use
111
IUD CI in
○ Preg
○ Current STI
○ Undiagnosed vaginal bleeding
○ Malignancy of genital tract
○ Uterine anomalies
○ Uterine fibroids
112
IUD adv
○ Typical use = perfect use (need to be inserted)
○ Effects reversible quickly after removal
113
IUD disadv
* Invasiveness
* Uterine perforation
* Expulsion
* Pelvic infection
114
LARC: subdermal progestin implants
4cm long implant.
68mg of etonogestrel (3rd)
used for 3yrs
115
LARC: subdermal progestin implants ADR
* Irregular bleeding pattern (continued use)
* Amenorrhea
* Prolonged bleeding
* Spotting
* Freq bleeding
116
breakthrough bleed
early/mid = incr estrogen
late = incr progestin
117
acne
less androgenic prog
incr estrogen
POP --> COC
118
BLOAT
reduce estrogen
change to prog, mild diuretic effect (4th drospirenone)
119
NV
reduce estrogen
take at night
change to POP
120
headache
exclude migraine with aura
usually in pill-free week --> extended/continuous/ shorter pill free interval
121
menstrual cramps
incr progestins
switch to extended cycle/ continuous
122
breast tender/ weight gain
keep both estrogen, prog LOW
3152 finals
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