Pharmacology Flashcards
1
Q
What are the 3 naturally occurring oestrogen’s?
A
- 17-beta estradiol (most important)
a. Most abundant and potent oestrogen
b. Produced by ovarian granulosa cells - Estrone
a. Produced by ovaries and adrenals
b. Levels increase slightly after menopause - Estriol
a. Placental – only in pregnancy
2
Q
What is common to all endogenous oestrogen’s?
A
- 18 carbon steroids
- transported by SHBG
- Bind estrogen receptors (ER-alpha and ER-beta) in target cells (OH)
3
Q
What are the oestrogen receptors and where are they expressed?
A
ER alpha beta are expressed in reproductive system and breast tissue
ALSO - in CVS, skeleton, CNS, immune system
4
Q
What proportion of breast cancers express ER alpha?
A
70%
5
Q
Action of oestrogen’s
A
Development
• Pubertal breast and genital development
Menstrual cycle regulation
• Modulation of FSH and LH release
• Cyclical changes in uterus and breasts
• Induction of progesterone receptors (PR)
Metabolic
• Increase in bone mass – blocks bone resorption
• Improved TG profile – increases HDL:LDL ratio
• BUT increases coagulability – DVT/PE and stroke risk
6
Q
5 facts about natural progestogens
A
- 21 carbon steroid
- secreted mainly by corpus luteam and placenta
- secreted in the 2nd half of the cycle
- levels decrease before menstruation (unless pregnant)
- transported by albumin and corticosteroid binding globulin (CBG)
7
Q
Where are progestogen receptors located?
A
Female reproductive tract, breast and CNS
8
Q
Actions of progestogen on the endometrium, cervix and myometrium
A
o Endometrium – decrease proliferation and increase secretory changes
o Cervix – thickens and reduced secretions – reduced sperm penetration
o Myometrium – reduced uterine excitability
9
Q
Other effects of progestogens
A
- Breasts – glandular development
- Hypothalamus – reduced LH surge and GnRH release – block ovulation
- CNS – increase in body temperature (0.5’C)
- AR – binds weakly very low pro/anti-androgenic effects
10
Q
What synthetic oestrogen’s are in COCs
A
Ethinylestradiol (EE)
• derivative of estradiol
• addition of ethinyl group has reduced hepatic metabolism
• potent oral activity
• most commonly used
Mestranol
• pro-drug of EE – undergoes demethylation
11
Q
1ST 2ND + 3RD generation progestogens
A
1st generation – ethisterone • significant androgenic effects o Acne o Hirsutism o Weight gain • No longer used
2nd generation – levonorgestrel, norethisterone
• Some androgenic effects
3rd generation – desogestrel, gestodene
• Reduced androgenic and lipid effects
• Increased thromboembolic effects
12
Q
COC mechanism of action
A
Inhibit ovulation prevent release of (estrogen) FSH for follicle development and (progestogen) LF (ovulation)
Also
• Thickened cervical mucous – form barrier to sperm
• Progestogen effect
• Thin endometrial lining reduce endometrial receptivity to inhibit implantation
• Estrogen and progestogen effect
**Decrease the likelihood of pregnancy by inhibiting ovulation, fertilization and implantation
13
Q
What reduces COC effectiveness?
A
- Poor compliance
- Delayed start of next pack - reduced HPO suppression
- Missed pills (47% miss 1 or more per month)
- Vomiting or diarhoea
- Broad spectrum A/B
P450 induction – griseofulvin, anti-epileptics (phenytoin and carbamazepine), TB drugs (rifampicin), St John’s Wort
14
Q
Common side effects of COC
A
- breakthrough bleeding – increase estrogen or progesterone
- nausea – decrease estrogen dose, take at night with food
- fluid retention, breast tenderness – reduce estrogen
- chloasma avoid sun/stop estrogen
- although transient, these are common reasons for stopping COCs
15
Q
Androgenic side effects of COC
A
- Acne
- Weight gain
- Depression
- Irritability, fatigue
- Reduced libido
16
Q
Serious side effects of COC
A
Enhanced coagulation (estrogens) Breast cancer (1.24x) Small increased risk of cervical cancer
17
Q
Contraindications for COC
A
• Pregnancy • History of o DVT, PE stroke o Major elective surgary o Estrogen dependent tumours o Migraine with aura – stroke rsk o Hepatic disease • Breast feeding • > 35 yrs old, smoker, HT and DM
18
Q
Minipill mechanism of action
A
- inhibition of ovulation due to inhibition of LF surge
- thickening and reduction in amount of cervical mucous impedes sperm penetration
- Endmetrium thins reduced implantation rates
- BUT 30-40% of women on progestogen only OCs still ovulate less effective than combined OC
19
Q
Define menopause, peri-menopause and post-menopause
A
Menopause - The final menstrual period (median age 50‐52 years)
Peri‐menopause - The transition to the end of a woman’s reproductive life
menstrual cycle begins to change in length and symptoms may begin to occur (takes about a decade; hormonal swings and heightened symptoms)
Post‐menopause - 12 months after the final menstrual period
20
Q
Symptoms of menopause
A
¥ Central: Hot flushes & night sweats; insomnia; mood and memory changes
¥ Joint aches & muscle pains
¥ Urogenital: Dry vagina/dyspareunia; urinary
frequency, UTI, incontinence
¥ Skin: Dryness, thinning, loss elasticity, crawling under the skin, acne
¥ Hair: increased facial hair, thinning scalp & pubic hair
¥ Loss of libido
¥ Long term consequences: metabolic, cardiovascular, bone & brain
21
Q
Role of oestrogen and progestogen in HRT
A
Oestrogen provides
¥ Relief of menopausal symptoms– flushes, tiredness, moods
¥ Preserves bone density, lowers cardiovascular risk (ifstarted early)
Progestogen
¥ Protects the endometrium from the stimulatory effects of oestrogen
¥ NB for a woman who has no uterus–no progestogen
22
Q
Cyclical and continuous HRT
A
Cyclical HRT ¥ More appropriate for younger women ¥ Produces periods Continuous HRT ¥ NO vaginal bleeding ¥ Popular with older women ¥ Note recent concerns about this
23
Q
Oral oestrogens and the ‘first pass effect’
A
¥ Beneficial effect on HDL – inhibits hepatic lipase activity
¥ Beneficial effect on LDL – induces LDL receptors
¥ Raises TGs
¥ Increases thrombosis risk by effects on coagulation cascade and thrombophilic factors
NOTE: transdermal oestrogen does not increase VTE risk
24
Q
Oral progestogens and the ‘first pass effect’
A
¥ Deleterious effect on HDL – induces hepatic lipase activity
¥ Deleterious to neutral effect on LDL
¥ Neutral effect on TGs
¥ Additive effect on thrombosis risk (MPA)
¥ Dose and androgenicity to be taken into account
25
Which time frame is the embryo most susceptible to damage by medications?
17-70 days
26
Do not prescribe a X class drug to a reproductive age woman unless ______
A pregnancy test is negative and effective contraception is being used
27
NSAIDS category and associated risks
NSAIDs inc. COX-2s (cat. C) – BUT BE CAREFUL!
¬ First trimester use & early pregnancy loss
¬ Small risk of fetal harm from 27-32 weeks until delivery
¥ premature closure of the ductus arteriosis & pulmonary hypertension
¥ necrotising enterocolitis
¥ renal failure
¥ neonatal intracranial haemorrhage
28
Opioids category, risks and recommendations
Opioids (cat C) – BUT BE CAREFUL
¬ Probably safe in early pregnancy but possible potential for long-term behavioural effects
¬ Neonatal respiratory depression at birth
¬ neonatal withdrawal (abstinence syndrome) - 30-90% post-methadone & 50% post-buprenorphine
29
Categories of tramadol, gabapentin, pregabalin and clonidine
Tramadol (cat C) - No good trials or epidemiology so safety not established, but widely used & appears OK
Gabapentin (cat B1)
Pregabalin (cat B3)
• safety not established but used
Clonidine (cat B3) • safe
30
Cardiovascular drugs which are ok to use in pregnant women
¥ methyldopa (cat A)
¥ beta-blockers (labetolol safe; possibly avoid atenolol etc.) (cat C)
¥ calcium channel blockers (cat C)
¥ hydralazine (cat C)
31
Cardiovascular drugs which should be avoided in pregnant women
¥ ACE inhibitors & ARBs (cat D due renal failure/fetal death)
¥ amiodorone (cat C but causes hypothroidism & bradycardia)
¥ thiazide diuretics (cat C but cause neonatal electrolyte derangements)
¥ spironolactone (cat B3 due to feminisation of the male fetus)
32
Diabetes drugs in pregnant women
¥ Sulphonylureas (glibenclamide/gliclazide) cat C but not recommended
¥ Rosiglitazone not recommended
¥ Metformin cat C but probably safe and widely used
Insulin recommended
33
Antidepressants in pregnant women
TCA - cat C - appear safe
Venlafazine, mianserin,
MAOIs - cat B2 - unclear but no increased risk
SSRI - Cat C - appear safe, use in 3rd trimester can lead to neonatal withdrawal syndrome so reduce if possible
34
Prednisolone recommendations in pregnant women
cat C
o AVOID if possible, esp. first trimester high-dose (cleft palate) or later, pre-term delivery
o CONTINUE if needed in lowest effective dose (prefer < 15 mg/day)
35
Hydroxychloroquine reccomendations in pregnant women
cat D
- avoid if possible (neurological disturbance)
36
Azathioprine and cyclosporine recommendations in pregnant women
```
Azathioprine = cat D
Cyclosporine = cat C
```
Usually continue for organ transplant
37
Specific drugs to avoid using in pregnant women
* Cytotoxics
* Retinoids and interferon
* Mycophenolate, danazol
* Statins
* Tetracyclines – after 18 weeks but typically throughout
38
Symptoms of menopause
¥ Central: Hot flushes & night sweats; insomnia; mood and memory changes
¥ Joint aches & muscle pains
¥ Urogenital: Dry vagina/dyspareunia; urinary
frequency, UTI, incontinence
¥ Skin: Dryness, thinning, loss elasticity, crawling under the skin, acne
¥ Hair: increased facial hair, thinning scalp & pubic hair
¥ Loss of libido
¥ Long term consequences: metabolic, cardiovascular, bone & brain
39
Indications for HRT
¥ Relief of menopausal symptoms
¥ Maintenance of bone density and prevention of osteoporotic fracture
40
Preparations of HRT
Oestrogen = basis
- relief of menopausal symptoms, preserves bone density and lowers cardiovascular risk
Progestogen: protects endometrium from stimulatory effects of E, NOT for a woman without a uterus
41
What type of HRT is more appropriate for younger women?
Cyclical - because it produces periods
| - oestrogen always given, cycle in and out of progestogen
42
Continuous HRT
Oestrogen and progestogen continuously given - popular with older women, no vaginal bleeding
43
Oral oestrogen and the first pass effect
¥ Beneficial effect on HDL – inhibits hepatic lipase activity
¥ Beneficial effect on LDL – induces LDL receptors
¥ Raises TGs
¥ Increases thrombosis risk by effects on coagulation cascade and thrombophilic factors
NOTE: transdermal oestrogen does not increase VTE risk
44
Oral progestogen and the first pass effect
¥ Deleterious effect on HDL – induces hepatic lipase activity
¥ Deleterious to neutral effect on LDL
¥ Neutral effect on TGs
¥ Additive effect on thrombosis risk (MPA)
¥ Dose and androgenicity to be taken into account
45
Cardiovascular risk in HRT
Proposed mechanisms for protective oestrogen effect on cardiovascular disease
¥ lipoprotein effects (raised HDL, lowered LDL)
¥ vascular mechanisms
o endothelium dependent
o endothelium independent
¥ antioxidant effects
¥ lowering of insulin resistance
¥ coagulation and fibrinolysis
46
Analgesic recommendations in pregnant women
Use paracetamol (cat A)
```
Low-dose aspirin OK (avoid high-dose)
Codeine OK (cat C)
```
NSAIDs inc. COX-2s (cat. C) – BUT BE CAREFUL!
Opioids (cat C) – BUT BE CAREFUL
Tramadol (cat C) - No good trials or epidemiology so safety not established, but widely used & appears OK
Gabapentin (cat B1)
Pregabalin (cat B3)
• safety not established but used
Clonidine (cat B3) • safe
47
Anti-emetics in pregnant women
• metoclopramide (cat A)
* 5-HT3 antagonists (most cat B1)
* droperidol (cat C)
* promethazine (cat C)
* prochlorperazine (cat C)
48
Antibiotics which are safe to use in pregnant women and which might have possible risk?
Safe
• all penicillins (cat A & some B)
* early generation cephalosporins (cat A or B)
* erythromycin (cat A & other macrolides cat B)
* clindamycin
* metronidazole
Possible risk
¥ sulphonamides (cat C) & nitrofurantoins
¥ aminoglycosides (cat D)
¥ anti-retrovirals (mainly cat B but some D)
49
Cardiovascular drugs which are ok to use in pregnant women
¥ methyldopa (cat A)
¥ beta-blockers (labetolol safe; possibly avoid atenolol etc.) (cat C)
¥ calcium channel blockers (cat C)
¥ hydralazine (cat C)
50
Cardiovascular drugs which should be avoided in pregnant women
¥ ACE inhibitors & ARBs (cat D due renal failure/fetal death)
¥ amiodorone (cat C but causes hypothroidism & bradycardia)
¥ thiazide diuretics (cat C but cause neonatal electrolyte derangements)
¥ spironolactone (cat B3 due to feminisation of the male fetus)
51
Diabetic drugs which carry a risk of macrosomnia, neonatal hypoglycaemia and congenital abnormalities
¥ Sulphonylureas (glibenclamide/gliclazide) cat C but not recommended
¥ Rosiglitazone not recommended
¥ Metformin cat C but probably safe and widely used
--> insulin recommended
52
Endogenous estrogens
Location of production: follicle cells in oocyte
Target tissues: breast, endometrium, bone, liver
Primary effect: proliferation
53
Estrogens and breast cancer
* Oestrogen does not directly induce DNA mutations to cause BC
* It stimulates proliferation of a normal ductal epithelial cells that can then develop mutations
* It stimulates proliferation of ER+ BC cells (2/3 of BC cases)
54
Estrogen and bone health
• ERα & ERβ are expressed in bone and B/M cells
• E2 rise ↑ at puberty triggers long bone growth → growth spurt
• E2 then maintains bone mineral density
• protective effects of E2 are multiple:
o inhibit osteoclasts
o promote osteoblast & osteocyte survival
55
Synthetic oestrogen's action
Agonist ligands (E2) induce LBD conformations that allow the ER to stably interact with co-activator proteins, e.g. SRC-1 or HATs → gene transcription
Antagonist ligands (i.e. “anti-oestrogens") induce a LBD conformation that interacts with co-repressors, e.g. HDACs → chromatin condensation
- some synthetic ligands are agonists in some tissues and antagonists in others (partial agonist)
56
Mechanism of action of selective oestrogen receptor modulators (SERMs)
* ER LBD consists of 12 α-helices → helices 1-11 form a pocket
* and helix 12 forms the lid
* E2 binds LBD of ER → helix 12 (pink) closes over E2
* Exposes amino acids critical for co-activator binding and co-repressor release
* SERMs are often bigger → prevent helix 12 from closing
* Co-activators don’t bind → antagonism
57
SERM uses
• prevention and treatment of BC
* prevention and treatment of osteoporosis
* infertility (Clomiphene)
58
Action of tamoxifen in breast cancer
¥ In BC cells, it antagonises E2’s effects on proliferation
59
Agonist and antagonist effects of tamoxifen
```
Antagonist effects on the breast = anti-estrogen
Partial agonist (estrogenic) effects on:
• Bone maintains bone density = reduced hip fractures
• Blood lipids reduced LDL cholesterol so cardioprotective
• Endometrial epithelium increased endometrial cancer
```
60
Differences between tamoxifen and raloxifene
Raloxifene not as effective as tamoxifen in preventing DCIS
61
What are aromatase inhibitors used for
First line adjuvant therapy in BC in post menopausal women
| - reduces circulating oestrogen levels
62
Australian adjuvant hormone prescription guidelines
• BC prevention in high risk women → tamoxifen
• BC treatment in premenopausal women → tamoxifen (10y)
• BC treatment in postmenopausal women → depends on stage & risk:
High risk of recurrence: treat with A.I's
Low risk: treat with tamoxifen
63
Androgenic and estrogenic effects of testosterone
```
Androgenic – masculinizing
• foetal male sex organ development
• pubertal maturation of male sex organs
• maintenance of male characteristics
• spermatogenesis
```
Anabolic – growth stimulating
• increase in protein synthesis in growing tissues
• increase in muscle and bone mass (+ maintenance)
64
Control of testosterone synthesis at puberty
• GnRH → ALP → LH and FSH
• LH → Leydig cells secrete testosterone
• FSH → Sertoli cells (nurse cells) in seminiferous tubules:
o support spermatogenesis
o secrete androgen binding protein (ABP/SHBG)
• Secreted T binds to ABP
* Intra-testicular T levels >> circulating levels (25-100x)
* T binds AR in Sertoli cells to regulate spermatogenesis
* Circulating T inhibits both GnRH and gonadotrophin production – negative feedback loop
65
Causes of androgen deficiency - male hypogonadism
Testicular (primary hypogonadism)
Hypothalamic-pituitary (Secondary hypogonadism)
66
Androgen replacement therapy
• Testosterone is inactivated by the liver (T1/2 = 10m)
• Testosterone esters given by IM injection
o Bioconverted into testosterone
o Lasts 2-3 weeks
o Safe, effective and easy to monitor
• Newer formulations avoid first pass metabolism
o S.c implants stable levels, long lasting
o Transdermal gels and patches increased compliance
67
When to prescribe ART
1. Testicular or hypothalamic-pituitary disorders with severe androgen deficiency – ART is unquestioned
2. Other conditions may be associated with partial androgen deficiency
68
Adverse effects of misused AAS
1. Masculinisation
- - in women: hirsutism, ↓breast tissue & menstruation
- - female foetuses: during pregnancy
2. Acne
3. Testicular atrophy & ↓ spermatogenesis
a. prolonged use of AAS, ↓ LH & FSH (reversible?)
4. Premature epiphyseal closure (↓stature)
5. Mood disturbance &↑aggression
6. Dyslipidaemia & Hypertension
7. Polycythaemia
8.
Hepatitis & hepatic tumours
- - 2° to 17α-alkylated androgens e.g. stanozolol
- - is not produced by other classes of AAS
69
3 regions of the prostate and their significance in cancer
• Transition zone: surrounding the urethra
o From which benign prostatic hyperplasia and 20% of prostate cancers arise
• Peripheral zone: most of the prostate tissue
o Gives rise to 70% of cancers
• Central zone
70
Androgens and the prostate
* Androgen receptor is expressed in both stromal and epithelial cells
* Development of the prostate is driven by 5alpha dihydrotestosterone (DHT)
* DHT is a metabolite of testosterone, converted in the prostate by 5-alpha reductase (type 2)
* DHT is more potent than testosterone (> 10X) due to higher affinity for the androgen receptor
71
What is benign prostatic hyperplasia?
* Nodular overgrowth of both epithelial and fibromuscular components of the periurethral and transition zone of the prostate
* Androgen dependent
Does not predispose to prostate cancer
72
Incidence of BPH
o Rises with age
o Over 50% of men have microscopic evidence of BPH by 60 years of age
♣ 25% of these will develop symptoms of prostatism
♣ mean age of onset = 65 years
73
Obstructive and irritative symptoms of BPH
```
Obstructive symptoms: due to pressure on urethra from enlarging prostate
• Decreased force of urine stream
• Hesitancy in initiating voiding
• Post-voiding dribble
• Sensation of incomplete emptying
```
```
Irritative symptoms:
• Dysuria
• Frequency
• Urgency
• Nocturia
```
74
Main drugs in the treatment of BPH
1. Alpha adrenergic blockers
2. 5-alpha-reductase inhibition
a. finasteride
b. dutasteride
75
4 examples of alpha-1-adrenergic blockers
* Prazosin – oldest, shorter half life requires multiple daily dosing
* Terazosin – longer half life than prazosin
* Alfuzosin
* Tamsulosin – selective alpha-1-antagonist, some selectivity for the bladder, better tolerated and less postural hypotension
76
Action of alpha 1 adrenergic blockers in BPH
* Rapid symptom reduction
* Improve urinary flow rate (16-25%)
* Do not influence prostate size or disease progression
* 1st line therapy in BPH if prostate volume <30ml and moderate to severe symptoms
* provide symptom relief at 48 hours with maximum effect at weeks 4-6
77
5 alpha reductase inhibitors
* Indicated for use in men with moderate to severe symptoms of BPH
* Most effective in men with larger prostate
* Reduce prostate volume
* Improve symptoms and urine flow
* Reduce disease progression – decrease incidence or acute urinary retention and requirement for prostate surgery
* Evidence for improved quality of life
78
Side effects of alpha 1 adrenergic blockers
* fall in BP
* Postural hypotension, dizziness, syncope
* Tiredness
* Headache
* Ejaculatory dysfunction – tamsulosin
* Interaction with phosphodiesterase-5 inhibitors to potentiate hypotension
79
Dutasteride
* Type 1 + 2, 5-alpha reductase inhibitor
* More effective in combination with alpha blocker than when used alone
* Prostate volume starts to reduce after 1 month
* Maximum effect on symptoms and prostate volume can take up to 6-12 months
80
Finasteride
* Type 2, 5-alpha reductase inhibition
| * Similar effectiveness and safety/side effect profile to dutasteride
81
Sexual adverse effects from dutasteride/finasteride
* Erectile dysfunction
* Ejaculatory disorders
* Reduced libido
* Gynaecomastia
* Sexual dysfunction more common when used in combination with tamsulosin
* Used as a monotherapy most side effects resolve spontaneously with ongoing therapy by 2 years but SE more likely to be ongoing if used in combination with tamsulosin
82
Androgen receptor antagonists used in prostate cancer
flutamide, bicalutamide, nilutamide, cyproterone acetate
83
Androgens and prostate cancer
* Growth and development of the normal prostate is androgen dependent
* Prostate cancer development is dependent on the presence of androgens
* Anti-androgen therapy induces apoptosis and reduced cell proliferation
* Androgen independent growth is inevitable in advanced disease following a period of antiandrogen therapy – tumour recurrence and progression on therapy
84
Inhibitors of androgen production used in hormonal therapy for prostate cancer
GnRH analogues: goserelin + leuprolide
Diethyl-stilboestrol
85
Flutamide action and side effects
* Non-steroidal synthetic androgen receptor antagonist – blocks androgen binding
* Used often in combination with GnRH agonist to prevent an initial flare of disease from GnRH therapy
```
SE:o Gynacomastia
o Hot flushes
o Reduced libido
o Reduced facial hair and body hair
o Diarrhoea
o Abnormal liver functions
```
86
Cyproterone acetate
• A derivative of progesterone
• Dual action:
o Competes with DHT for androgen receptor – partial agonist
o Suppresses hypothalamic GnRH secretion
• May be used in combination with GnRH agonists
• Side effects – reduced libido, gynacomastia, impaired spermatogenesis, tiredness
87
GnRH agonists
* Endogenous GnRH secretion from hypothalamus is pulsatile
* Continuous GnRH agonist inhibits pituitary LH and FSH secretion, thereby decreasing testosterone
* May cause an initial flare of disease due to a transient rise in testosterone levels
* Administered by S.C injections or IM
* Also used for other conditions where suppression of gonadotrophins is indicated
88
Erectile dysfunction prevalence
Prevalence: 52% in men 40-70yrs (minimal to moderate and complete erectile dysfunction)
Prevalence of complete erectile dysfunction increases from 5 15% as age increases from 40 to 70 years
89
Erection development
1. Sexual arousal activated in higher cortical centres which then stimulates the medial preoptic and paraventricular nuclei of the hypothalamus
2. These signals descend to activate sacral parasympathetic nerves (S2-4)
3. Neurovascular events result in release of the NT NO from both nerves and endothelial cells
90
Drugs used for erectile dysfunction
Phosphodiesterase (PDE-5) inhibitors = 1st line
Sildenafil – Viagra
Vardenafil – Levitra
Tadalafil – Cialis
91
Action of PDE-5 inhibitors
* Breaks down cGMP, the 2nd messenger of NO
* Increased response to NO release resulting in increased smooth muscle relaxation and vascular engorgement
* Only acts in the presence of sexual stimulation
* No effect on libido or in men with normal erectile function
92
Side effects of PDE-5 inhibitors
* Headache
* Facial flushing
* Nasal congestion
* Dyspepsia
93
Side effects specific to sildenafil and tadalafil
PDE-6: retina sildenafil = blue vision in 3% of people lasting 2-3 hours
PDE-11: Skeletal muscle tadalafil = back and muscle pain
94
Contraindications for PDE-5 inhibitor
* Men taking nitrate drug for heart disease – have severe risk of hypotension
* Caution in men with severe CVD
* Severe postural hypotension
* Severe aortic stenosis
* Retinitis pigmentosa
* Introduce with caution in men using alpha blockers
95
Adverse effects of intracavernosal alprostadil
penile pain
penile fibrotic changes
priapism = erection > hour
