DRUGS THERAPY IN BPH

Datten Bangun - Tri Widyawati Bagian Farmakologi dan Terapeutik, Fakultas Kedokteran Universitas Sumatera Utara

prostate gland a gland found in men between the bladder and the urethra.

* Secretes semen which carries sperm * During orgasm, prostate muscles contract and propel ejaculate out of the penis
* As men age prostate gland slowly grows bigger (enlarges) may press on the urethra and cause:

Hyperplasia: enlargement Benign : not caused by cancer or infection

What is Benign Prostatic Hyperplasia?

Peripheral zone Transition zone Urethra

Peripheral zone Transition zone Urethra

Complications
Urethral Occlusion Urinary retention Uremia Irreversible bladder dysfunction Hydronephrosis Hematuria UTI

Risk of Complications Increased By:

Antihistamines atropine beta blockers CCB muscle relaxants Smoking damp weather Cold Alcohol emotional stress

The goal of therapy in 1.To improve the urinary flow BPH:

2.To decrease the symptoms 3.To delay or prevent the progression of BPH

HOW? I. Pharmacological approach II. Surgical approach

Medical Treatment

If there is no evidence of complications:

measure severity of symptoms with AUA score index:International Prostate Symptoms Score ( IPSS ) - Mild : 7 Moderate : 8-19 Severe: 20-35 If mild and patient wants no treatment : Monitor annually Encourage lifestyle changes

Lifestyle modification
Reduce

fluid intake Stop diuretics if possible Avoid exercise night time,fluid intake/caffeine /alcohol Empty bladder before longtrips or meetings - Treat co-morbid contributing conditions: -Diabetes -UTI

Medical Intervention
First line of treatment for: - men >60 and - IPSS : 8-19

C lasses of medicines:

1. Antiandrogens 5 -reductase inhibitors (ARIs) 2. Long-acting selective 1-blockers 3. Muscarinic receptor antagonists 4.- Alternative Therapy / Phytochemicals

 Slows the rate of prostate enlargement by regulating the amount of available androgen (prostatic differentiation and growth depend on dihydrotestosteron)

Mechanism of action:
In the prostate,and male hair follicles dihydrotestosterone (DHT) is the essential androgen. testosterone testosterone
+

Dihydrotestosterone

5-alpha Reductase

Finasteri Finasde

teride

Serum testosterone (T)

T
5AR (1 and 2) Growth factors DHT

Serum Dihydrotestosterone (DHT)

Prostate cell

DHT-androgen receptor complex Cell death

Increased Unbalance Cell growth d

2 type : 5-alpha Reductase I and II (5-ARI) = 5-alpha Reductase I: - predominant in sebaceous glands in skin, scalp and liver - responsible in about 1/3 of circulating DHT = 5-alpha Reductase II -primarily found in prostate, seminal vesicles, epididymides, hair follicles and liver. -responsible for about 2/3 of circulating DHT Finasteride preferential inhibition of type II isozyme

Pharmacokinetic : Absorption: = orally active = produces a reduction in DHT levels within 8 hours after administration = the effect lasts for about 24 hours Metabolism: = finasteride will be reduced dihydrofinasteride: - Type I complex t = 14 days - Type II complex t = 30 days

So: - no androgenic - no antiandrogenic - no estrogenic - no antiestrogenic - no progestational effect In men with male pattern hair loss (androgenic alopecia) in that part: - miniaturized hair follicles - increased amount of DHT compared to hairy scalp.

= Scalp DHT = Serum DHT

Rambut tumbuh

Given to women 1mg/day with hirsutism

It helps in some women.

erectile dysfunction abnormal ejaculation decrease of libido decreased of semen released during sex = rarely; breast swelling Drug Interaction = Almost none
Dosage -

= = = =

Finasteride tablet 5mg, once daily - Proscar - Dutasteride, inhibitor of type I and II, 0,5 mg,OD - Duprost - Avodart

= allergic to finasteride = women and children

Pregnant or would be pregnant women not to be exposed to Finasteride; - either by handling broken or crushed tablet - sexual contact with a man taking F

Why? normal development of sex orga of male baby could be affected

Alpha adrenergic receptors : - found at bladder neck and prostate

Prostate smooth muscle tone is mediated via 1-adrenergic receptor Blockage of the receptor leads to improvement of flow rate and LUTS1 Central -receptors and the effect of agents on these receptors likely play an additional role Density of adrenergic receptors changes with Schwinn DA. BJU Int. 2000;86(suppl 2):11-22. prostate size and age

Alpha blockers relax smooth muscle in prostate and bladder neck without affecting bladder contractility = 2 week onset of action = 93% response rate = 44% mean improvement in urinary flow = Tolerance to therapy develops
-

Nonselective

Phenoxybenzamine Prazosin, Alfuzosin

Short-acting selective 1-blocker

Long-acting selective 1-blockers

Terazosin Doxazosin (Cardura) Alfuzosin-SR

All currently available 1-blockers induce fast improvement in LUTS and flow rate parameters with similar efficacy They are all well tolerated; however, the adverse event spectrum differs between the agents Terazosin and doxazosin induce more dizziness, fatigue, and asthenia Tamsulosin ( Flomax) induces more ejaculatory disturbances None of the 1-blockers alter urodynamic parameters, prostate volume or serum PSA None have been shown to alter the

Doxazosin: = well established

This finding suggests that 1A subtype may be the most important subtype mediating prostate smooth muscle contraction

Tamsulosin: = relatively newer,but studied extensively. = has higher affinity for 1A and 1D than

1B selective
for prostate = less orthostatic hypotension

Muscarinic Receptor Antagonists

Effective alone or in combination with alpha blockers Symptomatic relief of frequency, urgency or urge incontinence in patients with normal renal function Careful with : =narrow angle glaucoma, = impaired liver function or = in the presence of anti-fungals or macrolides Ex. - Tolterodine - Trospium .

Results: 1. Combination of F and D delayed the clinical progression of symptomatic BPH, compared to: - single drug - placebo 2. Combination therapy reduced significantly F= Finasterid the risk D=Doxazosin of invasive by 67 % = F only by 64% = D only by 3%

Describe to your patients = the benefits = the risks

How about F and prostate cancer? = MTOPS was not designed to test cancer, but, it was found out that in 18.000 men, F reduced Ca by 25%

Medication
Benefits

Disadvantages

Convenient

Drug Interactions Must be taken every day Manages the problem instead of fixing it

No loss of work time Minimal risk

Alternative Therapies Saw Palmetto Reduces 5 reductase activity 160 mg po bid decreases lower urinary tract symptoms in double blind studies Pygeum africanum tree bark Contains 3 anti-inflammatory sterols

Source -- Serenoa repens Bartram. --

Native to the Southern Atlantic coast through the Gulf coast from South Carolina through Texas. The Palm achieves a height of 6-10 feet. Fruit are irregularly spherical to oblong, ranging in length from 1/2 to 1 inches and 1/2 inch diametre, are deep red-brown and wrinkled.

Active Part

Berry

Inhibition of 5-alpha reductase (in vitro) Antagonism of DHT at androgen receptors Some evidence exists for
Anti-inflammatory actions (MOA unknown) Inhibition of prolactin (MOA unknown) Inhibition of prostatic cell proliferation

Source -- Cucurbitace family, Cucurbita pepo L., C. moschata., widely cultivated in North America and Australia. Active Parts -- Seeds

The current lay recommendations for the use of pumpkin is in the treatment of benign prostatic hypertrophy. Historically, pumpkin has been used to treat tape and other intestinal parasitic helminthic infections.

Pumpkin Pharmacology

Cucurbitin exhibits anthelminthic activity against pinworms and tapeworms in mice. It has also been shown to inhibit the growth of immature Schistosoma. The beneficial effects in BPH are purported to be due to the fatty acids and phytosterols, however this claim has not been

Combination therapy with doxazosin and finasteride was safe and reduced the risk of overall clinical progression more than each drug alone. Finasteride containing regimens reduced the long-term risk of AUR (Acute Urinary retention) and need for invasive therapy.

McConnell et al, N Engl J Med 2003.

Single arm therapy with alpha blocker Improve symptoms and prevent symptom progression Does not alter natural history or cross over to invasive therapy Single arm therapy with 5 ARI Treats symptoms only when LUTS associated with BPH (ie enlargement or high PSA) Alters natural history in pts at risk (large gland, high PSA) Combination (doxazosin+finasteride) therapy is the most effective form of treatment for LUTS and BPH Improve symptoms and flow rate Prevent AUR and/or surgery Alter the natural history of the disease

TREATMENT IN ERECTILE DYSFUNCTION

Datten Bangun - Tri Widyawati

Bagian Farmakologi dan Terapeutik, Fakultas Kedokteran USU,

Universitas Sumatera Utara

RECTILE DYSFUNCTION (ED)

the inability to achieve or maintain a pen erection sufficient to permit satisfactory sexual intercourse.

ncidence :

- over 100 million men wordwide

Prevalence : 39 % in men over 40 years.

DE
52% 92%

Tidak 40%
8% Diagnosa

60% Ya

Prevalensi Total Pria 40-70 th

Tidak terdiagnosa

Diterapi

Why study sexology ?

s:

no doctors can diagnose /treat illness that the know nothing about. no doctors can diagnose a sickness that a patient is afraid of asking.

Tolstoy:

men can endure earthquake and every form of orment, but most dreadful tragedy is the ragedy of the bedroom.

h dear,..

e were born together, lived and stayed togeth aised together, grown up together but: why should you die in front of me.

Nowadays : Quality of Life is important

Physiology of erection

Ereksi terjadi sebagai hasil interaksi dari :

CNS autonomic receptors diotot polos penis psychological and tactile stimuli are importa

2. Neuronal signalling 5. Erection 1. Sexual stimulus

4. Smooth muscle relaxation in penile tissue

cGMP

3. Cellular activation

Click here to advance to next slide

Mekanisme Ereksi di Penis

Flacid

Ereksi

mmon Causes of E.D M V. diseases rgery ugs bstance abuse ormonal imbalance eurological disease - multiple sclerosis - epilepsy - Alzheimers disease inal cord injury ychological (20 % as a primary cause, ore commonly : Secondary to physical problem

Drugs 25 %
anti depressants (SSRI and TCA) phenothiazine cyproterone acetate fibrates levodopa histamin H2 receptors blockers phenitoin carbamazepine allopurinol indomethazine beta adrenoceptor blocker thiazide

DRUGS THAT COMMONLY CAUSE MALE SEXUAL DYFUNcTION

Drugs Anti hypertensives

Beta - Blockers Alfa - blockers Methyldopa

Ejaculatory Erectile Loss dysfunction dysfunction Of libido

+ + + + + + + + + + + + + + +

Psychotropic
Phenothiazines Benzodiazepines TCA SSRIs

Drugs Others
Spironolactones Digoxin Cimetidine Ranitidine Metoclopramide Carbamazepine

Ejaculatory Erectile Loss dysfunction dysfunction Of libido

+ + + + + + + + + + + + + + + + + + + +

Recreational drugs
alcohol Marijuana Cocaine Amphetamine Anabolic Steroids

William Shakespeare: -alcohol my friend, provokes the desire,

but it takes away the performance. ( - Macbeth,Act 2,Scene 3 )

Faktor Risiko :

Diabetes

Martin-Morales et al. J. Urol 2001; 166:569-575

Obesita s

Hipertensi

Dislipidemia

agement of E.D ent and physician perspective = 74 % are embarassed. = 25 % believed E.D is, a normal part of ageing = 5 % do not think it is important

easons why patients do not seek treatment:

Datten dkk ( 2002 ) mendapati bahwa : - dari 50 penderita E.D : = 60 % kedukun tradisional = 32 % membeli obat sendiri (dari iklan

Setelah tidak berhasil baru kedokter. Alasannya: segan / malu

ine : assessment and treatment of any

underlying psychological or physical disease.

psychological psychotherapy hypogonadism testosterone hyperprolactinaemia (mis.o.k. phenothiazine) responds to oral bromocriptine. 2nd line therapy: - treatment of underlying disease: = DM = hypertension = etc.

If 1 st & 2nd line fail: Dulu: - mechanical aids: vacuum erection device - intracavernous injection of vasodilators. - topical glyceryl trinitrate - surgical treatments Penile Prosthetic implant

Nowadays

Vasodilators :
1 Papaverine: = phosphodiesterase inhibitor ----- c AMP intra cell = 50 % success rate = bisa terjadi fibrosis = inconvenient
2. Alprostadil

injection MUSE : Medicated Urethral System for Erection

Adalah prostaglandin E2 analog. - hati-hati bila isteri hamil kontraksi - dapat terjadi priapismus

3. Alpha adrenoceptor blockers 4. Phosphodiesterase, inhibitor - sildenafil - vardenafil - Tadalafil

PDE 1 Heart, lung, brain, vascular smooth muscle 1 PDE 2 Adrenal cortex, brain, heart, olfactory neurons 1 PDE 3 Pancreas, smooth muscle, platelets, heart, adipose 1,2 PDE 4 Brain, lung, lymphocytes1,2 PDE 5 CORPUS CAVERNOSUM, platelets, bladder, urethra, heart, leg muscle, lung, brain, kidney, liver1,2 PDE 6 Retina1 PDE 7 Pancreas, brain, heart, thyroid, skeletal muscle, eye, epididymus, and liver3 PDE 8 Testis, eye, liver, skeletal muscle, heart4 PDE 9 Kidney2 PDE 10 Testis, brain5 PDE 11 Testis, skeletal muscle, prostate, kidney, liver, pituitary,and salivary glands6
Francis SH et al. Cyclic Nucleotide phosphodiesterases: relating structure and function. Prog Nucleic Acid Res Mol Biol 2001; 65: 1-52

= orally active drug = marketed in USA on 1998 = acts by selectively inhibiting PDE5 and enhancing NO action in corpus cavernosum = has no effect if no sexual Pharmacokinetic: desire/activity = peak blood level ;after 1-2 hr = half life in men < 65 yrs 4 hrs = dose recommended 50 mg - men < 65 yrs----- 25 mg

NO is an important regulator of pulmonary vascular resistance----- sildenafil will lower pulmonary arterialpressure------ sildenafil is now become the drug of Side-effects: choice for = vasodilatation- headache,nasal congestion, pulmonary hypertension

flushing,dizziness,BP , = inhibition of PDE-6---- vision impairment,esp blue-green discrimination

Tadalafil - more potent and longer acting than sildenafil - t 18 hrs, duration of action 24-36 hours - lower affinity to PDE-6------ vision disturbances is <<< Vardenafil: - same with sildenafil - prolong Q-T interval------ avoid in patients with = hyperkalemia = long Q-T interval = using class IA or class III antiarhytmia