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    Summary for UKPID




    Alfuzosin




    Helen Seymour, BPharm (Hons)

    National Poisons Information Service (Newcastle Centre)
    Regional Drug & Therapeutics Centre
    Wolfson Building
    Claremont Place
    Newcastle upon Tyne
    NE1 4LP
    UK


    This monograph has been produced by staff of a National Poisons
    Information Service Centre in the United Kingdom.  The work was
    commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review group: Directors of the UK National Poisons Information
    Service.


    SUMMARY

    Type of product

         Selective alpha-blocker used to relax smooth muscle in benign
         prostatic hyperplasia

    Ingredients

         Tablets 2.5mg, 5mg SR

    Presentation/packaging

         60 or 90 tablets

    Toxicokinetics

         Peak plasma levels reached in 0.5 to 3 hours in therapeutic doses
         Plasma half life range 3-5 hours
         Volume of distribution 2.5L/kg
         Extensively liver metabolised, metabolites pharmacologically
         inactive

    Features of toxicity

         Flushing postural hypotension and tachycardia are common.
         Tachycardia may be associated with signs and symptoms of angina
         and myocardial infarction. Effects more pronounced in patients
         with preexisting hypovolemia.
         Dizziness CNS stimulation and seizures may occur
         Vomiting abdominal pain and diarrhoea may occur following large
         oral doses

    Management

         Administer activated charcoal if presentation within 2 hours
         Hypotension will usually be corrected by lifting the feet 15 cm
         above the trunk or by administering intravenous fluids.
         Control convulsions with IV diazepam, 10mg.
         Routine chemistry and pH monitoring are not required unless
         otherwise indicated.
         ECG

    SUBSTANCE

         Alfuzosin hydrochloride

    NAME

         Brand name          Xatral
         Generic name        alfuzosin

    CHEMICAL GROUP/FAMILY

         selective alpha-blocker
         BNF 7.4.1
         a quinazoline derivative with structural similarities to prazosin

    REFERENCE NUMBER

         CAS
              81403-80-7 (alfuzosin)
              81403-68-1 (alfuzosin HCl)

         PRODUCT LICENCE NUMBER
              Xatral 2.5mg 4969/0010
              Xatral SR 5mg 4969/0018

         MANUFACTURER/SUPPLIER
              Lorex
              Lorex Synthelabo Ltd
              Lunar House
              Globe Park
              Marlow
              Bucks
              SL7 1LW

              Tel: 01628 488011
              Fax 01628 471435

    PRESENTATION

         Form
              tablets alfuzosin 2.5mg, SR 5mg

         Pack size
              60, 90

    PHYSICO-CHEMICAL PROPERTIES (Martindale)

    Chemical structure
          N-19H27N5O4

    Physical structure at room temperature
         Solid

    Colour
         NIF

    Odour
         NIF

    Viscosity
         NA

    pH
         NA

    Solubility
         NA

    USES

    Indication

         Relaxation of smooth muscle in benign prostatic hyperplasia
         producing an increase in urinary flow-rate and an improvement in
         obstructive symptoms.

    Therapeutic Dosage (BNF)

         Adults 2.5mg three times daily, max 10mg daily, elderly 2.5mg
         twice daily initially.
         First dose may cause collapse due to hypotensive effect
         (therefore should be taken on retiring to bed). Patients should
         be warned to lie down if symptoms such as dizziness, fatigue or
         sweating develop, and to remain lying down until they abate
         completely.

    Contraindications (Data sheet)

         Hypersensitivity to alfuzosin
         History of orthostatic hypotension
         Hepatic insufficiency
         Concurrent use with other alpha-blockers

    Abuses
         NIF

    HAZARD/RISK CLASSIFICATION

         NIF

    PHARMACOKINETICS

    Absorption (Data sheet)

         Oral - 64%

    Distribution

         (Micromedex - Drug evaluation monograph):
         Volume of distribution (healthy subjects)2.5L/kg

    Metabolism

         Extensively liver metabolised
         Metabolites pharmacologically inactive

    Elimination

         11% excreted unchanged in urine
         Up to 30% of a dose is excreted renally as metabolites
         Most of a dose of alfuzosin is excreted via the faeces

    Half-life (Data Sheet)

         Plasma half life    range 3 - 5 hr

    Special Populations (Micromedex - Drug evaluation
    monographs)

         Elderly - More rapid and complete oral absorption and higher
         plasma levels of alfuzosin have been reported in elderly subjects
         (>75 years) who may be more sensitive to alfuzosin-induced
         vasodilation. Dose reduction may be necessary. For patients over
         65 with benign prostatic hyperplasia, initial doses of 2.5mg
         twice daily are recommended, increasing to 10mg daily, based on
         clinical response.

         Renal failure - dosage adjustments are not necessary

         Hepatic disease- reduced doses are recommended in hepatic
         disease, although specific guidelines are unavailable

    BREAST MILK

         NIF

    TOXICOKINETICS

         NIF

    EPIDEMIOLOGY OF POISONING

         NIF

    ADVERSE EFFECTS

         Most frequently observed: vertigo, dizziness, malaise, headache,
         minor gastro-intestinal disorders (nausea, gastralgia, diarrhoea
         or vomiting).

         Less frequently reported: hypotension (postural), syncope,
         tachycardia, palpitations, chest pain, fatigue, drowsiness, rash,
         pruritis, flushes and oedema

    INTERACTIONS - alpha blockers (BNF)

         ACE Inhibitors:enhanced hypotensive effect
         Aldesleukin:enhanced hypotensive effect
         Anaesthetics:enhanced hypotensive effect
         Analgesics:NSAIDs antagonise hypotensive effect
         Antidepressants:enhanced hypotensive effect; manufacturer of
         indoramin advises avoid MAOIs
         Other antihypertensives: additive hypotensive effect
         Antipsychotics:enhanced hypotensive effect
         Anxiolytics and Hypnotics:enhanced hypotensive and sedative
         effect
         Beta-blockers:enhanced hypotensive effect; increased risk of
         first-dose hypotensive effect of post-synaptic alpha-blockers
         such as prazosin
         Calcium-channel blockers:enhanced hypotensive effect, increased
         risk of first-dose hypotensive effect
         Corticosteroids:antagonism of hypotensive effect
         Diuretics:enhanced hypotensive effect; increased risk of first-
         dose hypotensive effect
         Dopaminergics:levodopa enhances hypotensive effect
         Muscle relaxants:enhanced hypotensive effect
         Oestrogens and Progestogens:antagonise hypotensive effect
         Ulcer-healing drugs: carbenoxolone antagonises hypotensive effect

    MECHANISM OF ACTION:

         Alfuzosin is a selective alpha-1 adrenoceptor antagonist, with
         structural similarities to prazosin. In vitro and in vivo studies
         have demonstrated potent and selective alpha-1 adrenoceptor
         antagonistic effects of alfuzosin on the genitourinary tract
         (proximal urethral, bladder base, prostatic and prostatic capsule
         smooth muscle. Studies suggest that alfuzosin is more selective
         for alpha-1 receptors in the genitourinary tract compared to the
         vasculature than prazosin or terazosin and may reduce urethral
         resistance at doses not affecting blood pressure.

    FEATURES OF POISONING

         Acute - Ingestion

         CARDIOVASCULAR
         Postural hypotension and tachycardia are common. Tachycardia may
         be associated with signs and symptoms of angina and cardiac
         infarction. Effects are more pronounced in patients with
         preexisting hypovolemia, or states associated with increased
         catecholamine secretion.

         NEUROLOGICAL
         Dizziness, CNS stimulation, and seizures may occur.

         GASTROINTESTINAL
         Vomiting, abdominal pain, and diarrhoea may occur following large
         oral doses

         DERMATOLOGICAL
         Flushing is common

    CHRONIC TOXICITY
         NIF

    MANAGEMENT (Micromedex - Poisindex - Alpha adrenergic
    blockers)
         6th March 1995

    Decontamination

         Administer activated charcoal if presentation within 2 hours

    Supportive care

         Seizures
         Administer diazepam, 10mg by slow intravenous injection.

         Hypotension
         Administer IV fluids and place in Trendleburg position.
         Alpha agonist agents may only be effective at very high dose.
         Adrenaline stimulates both alpha and beta receptors. In the
         presence of alpha blockade, the net effect is vasodilation and
         worsening of hypotension.
         Similarly dopamine is primarily a beta-adrenergic agent and has
         produced fatal cardiac arrest secondary to hypotension when given
         with tolazoline
         Noradrenaline primarily stimulates alpha receptors and is
         preferable (Prod info Dibenyline 1993)

         Suggested initial dose of noradrenaline
         Adults:                  8 to 12 mcg/ minute
         Adult and child:         0.1 to 0.2 mcg/kg/minute. Titrate to
                                  maintain adequate blood pressure
         Maintenance dose
         2 to 4 mcg / minute

    Monitoring (Micromedex -Poisindex)

         Blood levels of alpha blockers are not clinically useful
         following acute overdose. No specific laboratory measurements are
         necessary unless otherwise indicated.
         (From Micromedex - drug evaluation monographs)
         Blood pressure and heart rate
         ECG monitoring in patients with coronary artery disease

    Antidotes

         None

    Elimination techniques

         None

    Investigations

         Routine chemistry
         ECG

    Management controversies

         None

    CASE DATA

         None

    OTHER TOXICOLOGICAL DATA

         None

    ENVIRONMENTAL DATA

         No info on LC50

    Author

    Helen Seymour, BPharm (Hons)

    National Poisons Information Service (Newcastle Centre)
    Regional Drug & Therapeutics Centre
    Wolfson Building
    Claremont Place
    Newcastle upon Tyne
    NE1 4LP
    UK

    This monograph was produced by the staff of the Newcastle Centre of
    the National Poisons Information Service in the United Kingdom. The
    work was commissioned and funded by the UK Departments of Health, and
    was designed as a source of detailed information for use by poisons
    information centres.

    Peer review was undertaken by the Directors of the UK National Poisons
    Information Service.

    Last updated January 1997

    REFERENCES

    British National Formulary, Number 30 (September 1995) London. British
    Medical Association and The Pharmaceutical Press 1995

    Drug Evaluation Monographs(R) Micromedex Inc, Denver Colorado, Edition
    expires 31/3/96

    Martindale The Extra Pharmacopeia 13th Ed, London The Pharmaceutical
    Press 1993

    Poisindex System(R) Micromedex Inc, Denver Colorado, Edition expires
    31/3/96