13 Desember 1980
`
`SA MEDIESE TYDSKRIF
`
`955
`
`Hypertension in General Practice
`
`Part I. Examination and Investigation of a Patient with Hypertension
`
`L. H. OPIE
`
`SUMMARY
`During the history taking and physical examination.
`several
`important diseases should be searched for be(cid:173)
`fore diagnosing essential hypertension. A critical
`in(cid:173)
`vestigation is repetitive abdominal auscultation for a
`bruit.
`In young patients with significant hypertension.
`coarctation of
`the aorta must be excluded by clinical
`examination.
`Investigations will especially be aimed at
`uncovering renal artery disease (relatively common)
`or a phaeochromocytoma (relatively rare). The initial
`assessment must also diagnose associated diseases
`which will
`influence the type of
`therapy chosen. Thus
`asthma and heart
`failure contraindicate ,a-blockers.
`liver disease contraindicates methyldopa. severe de(cid:173)
`pression
`contraindicates
`reserpine, methyldopa and
`,a-blockade, while diabetes or gout may be precipitated
`or aggravated by thiazide diuretics.
`
`S. Afr. med. l., 58, 955 (1980).
`
`tarts with
`Investigation of a patient with hypertension
`In general,
`the history and clinical examination.
`the
`younger the patient or the more severe the hypertension,
`the more active should one be in searching for remediable
`causes of hypertension (Fig. 1). In children, there is more
`frequently an underlying cause for
`the hypertension;
`especially, coarctation of the aorta must be considered.
`In the elderly,
`the diagnosis of hypertension needs to be
`made with some reserve, especially when it is the systolic
`value which is elevated. In perhaps lout of 10 patients
`the hypertension will have a remediable cause, usually a
`renovascular one, but occasionally a less familiar cause
`
`Hypertension Clinic, Groote 8chuur Hospital, and MRC
`Ischaemic Heart Disease Research Unit, Department of
`Medicine, University of Cape Town
`L. H. OPIE, M.D., F.R.C.P., Director, Hypertension Clinic and
`Professor
`
`Date received: 27 August 1980. Modified from a series of talks given to
`general practitioners
`in Oranjemund, S\VA/ Tarnibia.
`
`such as phaeochromocytoma or Cushing's syndrome or
`primary aldosteronism (Conn's disease)..The purpose. of
`this article is to give the general practitIOner a practl.cal
`approach to the distinction between primary (essential)
`and 120+ mmHg -
`severe hypertension (Table I).
`
`DOES THE PATIENT HAVE HYPERTENSION
`REQUIRING TREATMENT?
`Normal values for most South African populations are
`not known. A number of limited population surveys sug(cid:173)
`that populations such as Natal Indians, Zulus, ~nd
`gest
`Cape Coloureds have a marked incidence of hypertensIOn
`(see below). In American adults (aged say 40 - 60 years),
`sustained diastolic values (phase V Korotkoff sounds) can
`follows: ' 90 - 104 mmHg - mild
`be differentiated as
`hypertension; 105 - 120 mmHg - moderate hypertension;
`and ] 20+ mmHg -
`severe hypertension (Table I).
`In addition, high diastolic pressures (130 - 140 ~mHg)
`plus
`papilloedema
`are
`taken
`to
`indicate ma.lignant
`to su:nPh~y
`hypertension. Systolic values
`are omitted,
`and also because treatment of systolic hypertensIOn IS
`controversial. Other definitions of the severity of hyper(cid:173)
`tension are also available (Table I).
`The treatment of mild hypertension remains contro(cid:173)
`therapy
`versial with increasing evidence in favour of
`if ther~ is a sustained diastolic level of 95 - ]00 mmHg.'
`The argument
`for
`treatment of mild hypertension is
`strongest
`if there is associated sy tolic hypertension,
`if
`there are other risk factors for ischaemic heart disease,
`if there is end-organ damage, and especially if the patient
`is likely to be compliant and co-operative.
`In adolescence, lower values are taken: about 5 mmHg
`less for boys below 20 years of age, and in adolescent
`girls, ]0 mmHg less (Table II).3
`In the elderl)', there are as yet no clear guidelines for
`the levels of blood pressure requiring treatment. Up to
`the age of 70,
`raised systolic or diastolic ~ressures ~re
`associated with increased mortality, but
`III otherWise
`healthy people above 70,
`there is some doubt
`that
`there
`
`TABLE I. SOME DEFINITIONS OF SEVERITY OF HYPERTENSION ACCORDING TO SUSTAINED DIASTOllC BLOOD
`PRESSURE LEVELS
`
`Diastolic blood pressure (mmHg)
`
`Mild
`Moderate
`Severe
`
`Joint American
`Committee'
`90 - 104
`105 - 119
`120+
`
`NIH Study21
`90 -104
`105 -114
`115+
`
`• With syslol,c of
`
`less
`
`than 200 mmHg.
`
`Australian multi(cid:173)
`centre triol 22
`95 - 110'
`
`McMahon 23
`90 -115
`115-130
`130+
`
`J
`
`-
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1029-1
`IPR2016-00379
`
`

`
`956
`
`SA MEDICAL JOURNAL
`
`13 December 1980
`
`IN A JUVENILE
`TABLE 11. BLOOD PRESSURE (MEAN)
`AMERICAN POPULATION
`Age group
`
`Male
`90th percentile
`95th percentile
`Female
`90th percentile
`95th percentile
`
`14
`114/64
`130178
`133/82
`
`124/80
`128/83
`
`111/68 }
`
`15
`117/67
`133/81
`138/86
`
`16 -18
`120170
`136/84
`140/87
`
`All groups
`
`Hypertension may be defined as values
`percentile (see Goldnng et al. 3 ).
`
`sustained above the 95th
`
`is any relation between the blood pressure and survival.
`On the other hand,
`the Framingham study suggests that
`even isolated systolic hypertension (systolic exceeding
`160 mmHg, diastolic below 95 mmHg) i hazardous even
`in people over 55 years of age! A conservative point of
`to tteat elderly patients with systolic hyper(cid:173)
`view is not
`tension unless there is target organ damage. In practice,
`many physicians are now more aggressive: I support a
`recommendation to aim at a systolic value of
`recent
`180 mmHg in asymptomatic patients over 60: Diastolic
`pressures are frequently unreliable in the elderly. What
`is clear
`is that,
`in the elderly, over-vigorous treatment
`may oause cerebral
`ischaemia and postural hypo'tension
`is serious.
`Hypertension in females is said to be less serious th~n
`in males'
`in White American females,
`therapy of mild
`hyperten;ion produced no benefit,
`in contrast
`to White
`male
`and Black males
`and females
`(all populations
`American).7 But
`in Cape Coloured females, not only is
`there a very high incidence of severe hypertension, but
`there are correspondingly severe ECG changes to show
`that the disease is not benign in this group."
`In urbanized South African Blacks, values tend to be
`about 10 mmHg higher
`than in age-matched London
`Whites;'
`hypertension
`is probably very common in
`South African Blacks, with an incidence of 25% in
`urbanized Zulus.'· Of Durban Indians, 19% are hyper(cid:173)
`that
`these
`tensive. 1l There is no evidence whatsoever
`Indian populations
`can 'tolerate'
`Black, Coloured or
`hypertension better than Whites.
`The important point
`is that
`there is no strict cut-off
`point; for example, malignant hypertension is not neces(cid:173)
`sarily present when there is papilloedema and the diastolic
`value is 131 mmHg, or necessarily absent when the
`diastolic value is 129 mmHg.
`To assess the significance of hypertension,
`three simple
`rules are:
`(i) hypertension with end-organ damage is by
`definition serious and warrants therapy; (ii) in the absence
`of end-organ damage, blood pressure readings should be
`taken on three occasions with the patient relaxed, recum(cid:173)
`bent and warm before deciding what
`the true value is;
`if still
`in doubt, obtain a
`elf-reading machine for
`(iii)
`the patient to take home readings. Then,
`taking age, sex
`and race into account, decide whether there is significant
`hypertension or not. If there i's significant hypertension, a
`full history and examination must precede the institution
`of therapy.
`
`mSTORY
`The majority of patients with hypertension will have
`essential hypertension, but remediable causes must always
`be considered (Table Ill). In all patients, a famil)' histOf)'
`of hypertension, strokes or diabetes must be enquired
`into; when this is present,
`the argument
`for
`treatment
`becomes
`stronger. Essential hypertension more usually
`has a familial basis, but even renal arterial disease .can
`
`PHYSICAL
`HISTORY,
`SUMMARY OF
`Ill.
`TABLE
`EXAMINATION AND INVESTIGATIONS IN SIGNIFICANT
`HYPERTENSION
`
`General assessment
`Age and sex: special assessment of adolescents, elderly
`patients, pregnant patients.
`is she pregnant? Does she take the contracep(cid:173)
`Female -
`tive pill?'
`is it endocrine? Con weight be reduced? Is
`Obesity -
`there spurious hypertension?
`History and physical examination: search for specific con(cid:173)
`ditions
`Renal artery stenosis -
`epigastric bruit (listen repeatedly)!
`Coarctation -
`usually in younger patients; decreased
`leg blocd pressure lower; may present
`femoral pulses',
`rupture of aorta, bacterial endocar(cid:173)
`with heart failure,
`ditis or intracranial haemorrhage.
`Phaeochromocytama -
`fluctuating clinical course, usual(cid:173)
`ly with headache, sweating and palpitations;
`in con(cid:173)
`in about half
`the patients the hypertension is
`trast,
`sustained. A rare condition.
`low plasma potas(cid:173)
`Primary aldosteronism - weakness,
`sium (see below). Another rare condition.
`Cushing's syndrcme -
`diabetes, characteristic pattern of
`obesity", hirsutism.
`papilloedema of malignant hypertension
`Retinopathy'
`-
`or haemorrhage and exudates of premalignant hyper(cid:173)
`tension; micro-aneurysms of diabetes.
`Arteritis -
`unequal pulses, elevated ESR.
`Diseases not directly causing hypertension but associa(cid:173)
`ted with it include obesity and gout.
`Side-room investigations
`1. Urinalysis
`(proteinuria, glycosuria",
`micro-organisms).
`2. Blood haemoglobin (polycythaemia) and ESR·,
`Special
`investigations
`(rib notching in coarctation; heart
`1. Chest
`radiography"
`enlargement ar failure).
`ventricular
`(left
`2. Electrocardiography'
`silent
`ischaemic heart disease).
`.3. Rapid sequence intravenous pyelographyt especially
`in younger patients' or those with serious hypertension;
`occasionally isotopic renography and renal arterio(cid:173)
`IVP negative.
`graphy even if
`4. Urine aliquot: biochemical determination of cathecho(cid:173)
`lamine metabalitest (VMA and metanephrines).
`potassium (Icw in primary aldo(cid:173)
`5. Blood chemistry·:
`steronism). creatinine (high in renal
`failure). glucose
`(suspected diabetes). uric acid (suspected gout).
`
`spun deposit
`
`for
`
`hypertrophy;
`
`• Routine in significant hypertension.
`t In selected patients.
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1029-2
`IPR2016-00379
`
`

`
`13 Desember 1980
`
`SA MEDIESE TYDSKRIF
`
`957
`
`occur in families. A family history of diabetes mellitus
`requires a search for micro-aneurysms in the fundi and
`for glycosuria, and indicates the need for care in giving
`thiazide diuretics, which may precipitate overt diabetes.
`Familial
`gout
`argues
`against
`therapy with
`thiazide
`diuretics.
`In females, a history of amenorrhoea may indicate
`pregnancy, which can either cause or complicate hyper(cid:173)
`tension; contraceptive pill-takers are unlikely to be preg(cid:173)
`nant, but may have diastolic pressures 5 - 10 mmHg
`higher than their baseline. Frequent pregnancies predis(cid:173)
`pose to repetitive attacks of
`renal
`infection and renal
`hypertension.
`A history of smoking is important; more patients with
`malignant hypertension smoke than those with ordinary
`hypertension" and smoking is also associated with renal
`artery stenosis. Smoking acts in part by promoting arterial
`disease,
`thereby aggravating the hypertension; additional
`harmful effects are also possible (increase of cardiac out(cid:173)
`put; arrhythmias).
`Episodic symptoms of catecholamine discharge (sweat(cid:173)
`tachycardia, headache) may indicate phaeochromo(cid:173)
`ing,
`cytoma or strong emotional factors. Muscular weakness
`is rare but suggests primary aldosteronism. The occupa(cid:173)
`tional histoiy is important in the overall evaluation of the
`patient. A young patient in a stressful occupation is usually
`a good candidate for ,B-blockade therapy, both to reduce
`the effects of sympathetic discharge and to avoid the
`drowsiness sometimes associated with methyldopa therapy.
`'Stress' is not limited- to the young male executive. Male
`doctors frequently forget that running a home with young
`children is an extremely stressful occupation.
`The history should also probe into the complications of
`h)'pertension. Is there a story of left ve'ntricular failure or
`renal
`impairment? Is there evidence of cerebral vascular
`insufficiency or stroke? These complications will govern
`treatment;
`cerebral vascular
`insufficiency in particular
`indicates the need for gradual and smooth antihyperten(cid:173)
`sive treatment.
`
`PHYSICAL EXAMINATION
`
`General Assessment
`General assessment frequently reveals endocrine causes
`of hypertension, such as obesity. Rarely, endocrine causes
`of hypertension such as Cushing's syndrome or acro(cid:173)
`megaly are found (Table Ill, Fig. 1). The rash of lupus
`erythematosus is also rare. Gouty tophi
`in the ears or
`the joints might
`indicate renal disease. Pregnancy is not
`always evident from the history and may need careful ex(cid:173)
`clusion, but usually pre-eclamptic toxaemia occurs in the
`last trimester when pregnancy is obvious. Severe psycho(cid:173)
`logical depression is
`a
`contraindication to reserpine
`and
`,B-blockers
`therapy,
`as well
`as
`to methyldopa
`(especially propranolol),
`
`Taking the Blood Pressme
`
`Especially in young subjects, hypertension may be
`labile (sometimes above 140/90 mmHg and sometimes
`
`-
`
`Cushingoid facies
`Buffalo hump
`Truncal obesity..~
`Obese arm
`/
`false
`,
`hypertension
`'
`(wide cuff)
`"
`Palpable kidneys -r-....,..".-.>
`(polycystic disease;
`obstructive
`uropathy)
`
`Femoral pulses
`(coarctation)
`
`Polycythaemic facies
`
`Renal artery.bruit
`
`--+-,r+- Female
`pregnancy?
`pill?
`Evidence of collagen
`disease (Raynaud's,
`finger tips, arthritis)
`
`i urine
`
`-diabetes?
`- VMA collection
`- culture for organisms
`
`Fig. 1. H)'Pertension: looking for a cause.
`
`below). Repeated measurements in relaxed warm condi(cid:173)
`tion
`are useful;
`it
`is important that
`the doctor should
`also be relaxed and not rushed. The patient's ann should
`be resting and the muscles relaxed, because isometric
`tension increases the blood pressure. The diastolic pressure
`is best
`taken as phase V,
`to allow comparison with
`American and Australian surveys. If phase IV is taken,
`as is customary in the UK,
`then 10 mm must be sub(cid:173)
`tracted from the diastolic reading."
`
`Assessment of Obesity
`Three important questions as regards obese hyperten(cid:173)
`sive patients are:
`Is this simple obesity or an endocrine obesity such as
`Cushing's
`s)'Ddrome? Obesity,
`diabetes mellitus,
`and
`hypertension are all common diseases and may occur
`together by random association or because obesity We(cid:173)
`disposes
`to diabetes and hence
`to hypertension. Not
`every patient with the
`triple
`combination will have
`Cushing's syndrome.
`Is there true hypertension? If an ordinary cuff is used,
`likely to be
`the degree of blood pressure recorded is
`(Table IV) can be
`falsely elevated. Correction tables
`
`TABLE IV. CORRECTION TABLE FOR ARM CIRCUM(cid:173)
`FERENCE USING A CUFF 13 cm BROAD AND 30 cm LONG
`(PICKERING24)
`
`Arm circumference
`(to nearest cm)
`15 - 20
`21·26
`27 - 31
`32 - 37
`38 - 43
`44 - 47
`
`Diastolic pressure
`(mmHg)
`No correction
`-5
`-10
`-15
`-20
`-25
`
`NB.: These corrections are only approximate.
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1029-3
`IPR2016-00379
`
`

`
`958
`
`SA MEDICAL JOUR AL
`
`13 December 1980
`
`used if a special large cuff is not available to give an idea
`of the true blood pressure reading. If an ordinary sized
`the
`cuff is used on a patient with a really obese arm,
`apparent diastolic blood pressure can be as much as
`25 mmHg above normal; normotension can sometimes
`falsely become 'dangerous hypertension'.
`Is the hypertension likely to respond to weight reduc(cid:173)
`tion? Once simple obesity plus hypertension i diagnosed,
`the practitioner must assess the patient's personality. Is a
`weight-reducing programme really feasible? If it
`is,
`the
`patient should receive sustained advice and encourage(cid:173)
`ment which will make it easier to lose weight and thereby
`to control
`the hypertension."'"
`
`we investigated further by renography and angiography;
`both revealed renal artery tenosis, which was curable.)
`Abdominal palpation is required to exclude hepato(cid:173)
`megaly
`(consider
`cardiac
`failure,
`avoid methyldopa
`therapy) and splenomegaly (consider collagen disease,
`polycythaemia vera). Occasionally,
`enlarged polycystic
`kidneys or a unilateral enlargement of
`the kidney will
`be
`discovered. Rarely,
`during
`abdominal
`palpation,
`patients with phaeochromocytoma will develop a hyper(cid:173)
`tensive episode because palpation stimulates the tumour
`to liberate catecholamines.
`If there are any signs of liver disease, methyldopa must
`not be used as an antihypertensive agent.'·
`
`Retinopathy
`
`retinopathy of malignant hypertension
`classic
`The
`(papilloedema) and of premalignant hypertension (haemor(cid:173)
`rhages and exudates must be searched for. Nowadays
`with increa ed awareness of hypertension and earlier
`treatment, severe retinopathy is rare. But papilloedema,
`if found in a patient with a severe diastolic hyperten(cid:173)
`in
`excess
`of
`130 - 140 mmHg),
`indi(cid:173)
`sion
`(usually
`cates malignant hypertension and special care in therapy;
`such patients run the danger of hypertensive encephalo(cid:173)
`pathy, and here the differential diagnosis from a cerebral
`tumour is not always easy.
`
`Examination of the Cardiovascular System
`
`Cardiac features of hypertension include cardiomegaly
`and extra heart sounds. If there i heart failure,
`therapy
`is directed towards 'unloading'
`the heart and ,B-blockers
`are avoided (see Part III later).
`The classic feature of c()arctation of the aorta is the
`in some patients
`delayed and decreased femoral pulse;
`there are visible collateral vessels and
`with coarctation,
`Cln audible bruit down the back.
`In cases of doubt,
`the leg pressure (which also needs a
`measurement of
`large cuff) is very useful
`(the leg pressure i
`decreased
`in coarctation).
`the pulses and pressures in
`Sometimes a check of all
`each leg and arm confirms a widespread arteritis; such
`patients are rare, but may present with a severe renal
`hypertension.
`
`Examination of the Abdomen
`
`in establishing the aetiological diag(cid:173)
`This can be vital
`nosis and merits much care. Specifically, a renal arteI1'
`bruit must be listened for repetitively, as it may be the
`only sign of renal artery stenosis; especially important is
`a
`high-pitched
`systolic
`or
`diastolic
`bruit
`radiating
`laterally. The bruit
`is usually best heard anteriorly be(cid:173)
`tween the umbilicLls and the flank;
`its intensity may vary
`from day to day.
`auscultation was
`abdominal
`(The clinical value of
`hown by the recent presentation at our Hypertension
`Clinic of a young female patient with severe hypertension.
`An intermittent abdominal bruit was heard. Hence, even
`though the intravenous pyelogram showed no abnormality,
`
`Urine Examination
`Proteinuria is usually a rather nonspecific finding except
`in hypertensive pregnant women in whom pre-eclampsia
`must be suspected and the hypertension treated vigorously.
`Occasionally there is a heavy proteinuria; a nephrotic
`syndrome with an added nephritic element must be
`sLlspected. Sometimes features of chronic renal
`failure
`are detected or the diagnosis of porphyria is made. An
`occult urin3I"J'
`tract
`infection should always be
`con(cid:173)
`sidered (microscopy of spun deposit; urine culture and
`sensitivity testing of any organisms found).
`In practice
`the yield is disappointing, unless there is a suggestive
`history.
`
`Blood Count and Erythrocyte Sedimentation Rate
`A high ESR may be caused by an arteritis (whether
`reflecting an
`and of obscure origin, or
`'idiopathic'
`underlying collagen vascular disorder
`such
`as
`lupus
`erythematosus). Rarely, polycythaemia can be a mani(cid:173)
`festation of unilateral renal disease, or part of a 'stress
`to
`polycythaemia'
`(reduced
`blood
`volume
`responds
`,B-blockers rather than to diuretics).
`
`SPECIAL INVESTIGATIONS
`Biochemical Investigations
`in a patient with
`The single most useful blood test
`hypertension is measurement of serum creatinine. If the
`it
`is relatively simple to undertake a
`value is elevated,
`creatinine clearance test which is a good reflection of
`overall
`renal
`function.
`Impaired renal function indicates
`either a renal cause of the hypertension or the involve(cid:173)
`ment of the kidneys as a secondary event; it is frequently
`not possible to separate these two possibilities. The degree
`of elevation of the serum creatinine level
`indicates the
`severity and stage of the hypertension. Less usually,
`the
`is high for other reasons, such as
`serum creatinine level
`haemoconcentration
`following
`a
`furosemide
`(Lasix)(cid:173)
`induced diuresis.
`The plasma potassium value is a very useful measure(cid:173)
`ment, acting as a screening test for primary aldosteron(cid:173)
`ism." In a patient who has not been receiving diuretic
`therapy, a low plasma K+ level (below 3,5 mm011I) sug(cid:173)
`gests excess aldosterone secretion or excess renal K+ loss
`(Cushing's syndrome usually has other diagnostic fea-
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1029-4
`IPR2016-00379
`
`

`
`13 Desember 1980
`
`SA MEDIESE TYDSKRIF
`
`959
`
`tures). Further very specialized investigations at a special(cid:173)
`ist hospital are required to differentiate renal di ease from
`an
`aldosterone-secreting
`tumour.
`In
`principle,
`renal
`disease causes a high peripheral blood renin activity which
`calls
`forth the
`aldosterone
`secretion;
`in contrast,
`in
`renin activity is
`primary aldosteronism the peripheral
`suppressed by the aldosterone secretion. Thus unilateral
`renal artery stenosis may sometimes present with hypo(cid:173)
`kalaemia, a result of secondary hyperaldosteronism.
`
`Investigation of Renal Function
`
`Intravenous pyelography with a rapid sequence ex(cid:173)
`amination is a very important special
`investigation that
`can readily be undertaken even in a peripheral hospital
`or clinic. The patients selected for pyelography should be
`either young or have severe hypertension, or (especially)
`the combination of these.
`The intravenous pyelogram (IVP) can be normal even
`when there is significant renal artery stenosi . Therefore,
`if the IVP is negative in a young patient with severe
`further
`investigations should be arranged
`hypertension,
`at a specialized centre. The higher the diastolic mlue,
`The greater The chance of an underlying renal artery
`stenosis, because renovascular hypertension is
`found in
`20 - 30°{, of patients (average age 44 years) with grade
`III or grade IV retinopathy. IS In a British female popula(cid:173)
`tion under 45 with established hypertension and angina,
`over half had renal artery stenosis."
`investi(cid:173)
`Renography and renal arteriography. Further
`gations include renal
`isotopic scanning (renography) and
`renal arteriography;
`the latter
`is critical
`in diagnosing
`renal artery stenosis. This renogram and the arteriogram
`the reno(cid:173)
`types of information,
`basically give different
`gram indicating the degree of perfusion of the kidney
`renal
`there is
`and the arteriogram indicating whether
`artery stenosis or not. Hence the surgeon is more inter(cid:173)
`ested in the results of the arteriogram. As a practical
`rule,
`if severe hypertension is caused by unilateral renal
`arterial disease, the renin output from that kidney should
`be one and a half times thut of the other side.
`In phaeochromocytoma the IVP may show downward
`the kidney and the
`angiogram may
`displacement of
`delineate the blood supply to the adrenals, thereby usually
`identifying any adrenal tumour.
`Urinae)' vanillymandelic acid (VMA) and associated
`of VMA and
`associated
`metabolites. Assessment
`metabolites such as metanephrine should probably be
`undertaken routinely in any young patient with signifi(cid:173)
`cant hypertension. Some patients with phaeochromocy(cid:173)
`toma present with a sustained hypertension and without
`the classic features of phaeochromocytoma such as tachy(cid:173)
`It is
`loss.
`relatively easy
`cardia, arrhythmias or weight
`to send urine for VMA estimation from an outlying
`that is required is an
`centre to a specialist hospital -
`all
`aliquot of a 24-hour urine specimen collected into 10 ml
`of concentrated hydrochloric acid in a dark container.
`The well-known 'diet' before an estimation of VMA
`really means 3 days of avoiding vanilla-containing com(cid:173)
`pounds (ice cream and custard), bananas, grain cereals,
`tea, coffee and chocolate. There are a host of drugs
`
`the metabolism of catecholamine
`which may alter
`or
`interfere with the assay;
`these include methyldopa, quini(cid:173)
`dine,
`tetracycline, chlorpromazine, bronchodilators,
`levo(cid:173)
`lithium and nitroglycerine. The simple rule is to
`dopa,
`avoid all drugs for the week before the assay.
`If values
`for VMA and associated metabolites are
`can
`be
`excluded with
`normal,
`phaeochromocytoma
`reasonable certainty, especially if urine has been collected
`the plasma
`during a hypertensive episode. In rare cases,
`catecholamine levels are elevated when the urine values
`are normal. The techniques for collection and analysis of
`plasma for catecholamine assay require the facilities of
`a specialist hospital.
`
`The Electrocardiogram
`in differentiation between
`The ECG is not
`important
`primary and secondary hypertension, but is of value from
`the following points of view. Firstly, definite left ventricu(cid:173)
`lar hypertrophy (high voltage plus ST depression in the
`absence of digitalis) may provide proof of target organ
`involvement before clinical signs are present;
`treatment
`must correspondingly be more vigorous and the electro(cid:173)
`cardiographic abnormalities will frequently return to nor(cid:173)
`mal. Secondly,
`left ventricular hypertrophy may indicate
`past hypertension, now 'burnt out'. Thirdly, in the middle(cid:173)
`ischaemic heart disea e may be
`aged or elderly, silent
`detected (Q waves of old infarction,
`left bundle-branch
`block),
`thereby pointing to a more limited prognosis. In
`such patients, better control of the blood pressure should
`the evidence is not
`theoretically prevent reinfarction, but
`yet firm. w
`
`Chest Radiography
`is more useful to
`like the ECG,
`The chest radiograph,
`assess the cardiac effects of hypertension than to distin(cid:173)
`guish between primary and secondary hypertension. Only
`one cause of secondary hypertension can be diagnosed
`
`Malignant hYRertension
`--......
`Avoid too rapid
`pressure reduction
`
`BronchosRasm
`Avoid B-blockers
`
`Liver disease
`Avoid methyldopa
`
`failure
`Renal
`Generally reduce doses~
`Beware of digitalis toxicity
`
`CVA
`Avoid hypotension
`E:§ychological assessment·
`~Qression
`Avoid methyldopa
`reserpine
`clonidlne
`
`B§ynaud·s Rhenomenon
`Avoid B- blockers
`
`\S.L.E. Avoid hydralazln8
`
`Gout
`Avoid thiazide diuretics. or
`reserpine-thiazide
`
`PenRheral vascular disease
`A Old B-blockers
`
`Fig. 2. Hypertension: some factors governing treatment.
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1029-5
`IPR2016-00379
`
`

`
`960
`
`SA MEDICAL JOUR AL
`
`13 December 1980
`
`on the chest radiograph: coarctation of the aorta and its
`rib notching. (Palpation of the femoral pulse and measur(cid:173)
`ing blood pressure in the leg will
`in general already have
`diagnosed coarctation.)
`Chest
`radiography is extremely valuable in detecting
`cardiomegaly or early left ventricular failure, both contra(cid:173)
`indications to therapy with /3-blockers.
`
`DRUG THERAPY
`The drug chosen for therapy will
`in part be governed by
`various complications or associated conditions, as shown
`in Fig. 2. For example, /3-blockers are contraindicated by
`heart failure, marked bradycardia or heart block, asthma
`or symptomatic peripheral vascular disease.
`
`1 thank Professors Y. K. Seedat and H. C. Seftel for advice.
`and the South African Medical Research Council for support:
`REFERENCES
`1. Moser, M. et al.
`J. Amer. med. Ass., 237, 255.
`(1977):
`2. Leading Article (1980): Brit. med. J., 280, 1062.
`et al.
`3. Goldring, D., Hemandez, A., Choi, S.
`95, 298.
`
`J. Pediat.,
`
`(1979):
`
`(1980): Circula-
`
`(1978):
`
`Ibid., 53,
`
`Ibid., 54,' 10.
`(1979): Brit.
`
`J.
`
`et al.
`
`(19;78):
`
`4. Kannel, W. B., Dawber, T. R. and McGee, D. L.
`tion, 61, 1179.
`5. Editorial (1977): Lancet, I, 684.
`Ibid., 1, 1391.
`6. Editorial (1980):
`7. Relman, A. S.
`(1980): New Eng!. J. Med., 302, 293.
`8. Settel, H. C., Jobnson, S. and Muller, E. A.
`(19 0): S. Air. med.
`J., 57, 313.
`Ibid., 45, 634.
`9. Schrire, V. (l97l):
`10. Seedat, Y. K., Seedat, M. A. and Nkomo, M. N.
`923.
`11. Seedat, Y. K., Seedat, M. A. and Reddy, K.
`(1978):
`12. Bloxham,. C. A., Beevers, D. G. and Walker, 1. M.
`med. J., I, 581.
`13. Editorial (1980): Lancet, I, 1283.
`14. R":-,,,say, L. E., Ramsay, M. H., Heltiarachchi,
`Bm. med. J.. 2, 244.
`15. Reisin, E., Abel, R., Modan, M. et al.
`298.
`I.
`16. Seggie, J., Saunders, S. J., Kirsch, R. E. et al.
`J., I, 75
`17. Leading Article (1980): Brit. med. J., 280, 667.
`18. Davis, B. A., Crook, J. E., Vestal, R. E. et al.
`J. Med., 301, 1273.
`19. MacKay, A., Cumming, A. M. M., Brown,
`Brit. Heart J., 43, MO.
`(1978): The Treatmellt of Cardio(cid:173)
`ill Gross, F., ed.
`20. Doyle, A. E.
`vascular Diseases, p. 240. Berne: Hans Huber.
`21. Hypertension Detection and Follow-Up Program Cooperative Group
`(1979): J. Amer. med. Ass., 242, 2562.
`•
`22. Reader, R. et al. (1980): Lancet, 1, 1261.
`23. McMabon, F. G. (1978): Management of Essential Hyp.rtension, p ..2
`New York: Futura.
`(1968): High Blood Pressure, 2nd ed., p. 11. London:
`24. Pickering, G.
`J. & A. Churchill.
`
`(1978):
`
`ew Eng!. J. Med.,
`
`(1979): S. Afr. med.
`
`(1979): New Engl.
`
`J.
`
`J.
`
`et al.
`
`(1980):
`
`NUUS EN KOM/MENTAAR
`
`NEWS AND COM/MENT
`
`KORTIKOSTEROi'EDE VIR ASMA
`
`THYROXINE REPLACEMENT THERAPY
`
`Trembath, van die Respiratoriese Eenheid, Austin-bospi(cid:173)
`taal, Melbourne, Australie, gee 'n goeie, beknopte opsom(cid:173)
`ming van die gebruik van kortikosterolede vir asma (New
`Erhicals, 1980, 17, 43). Hy se orale kortikcsteroiede moet
`oorweeg word vir die behandeling van akute, ernstige
`asma-aanvalle en moet moontlik ook voorafgegaan word
`deur parenterale toediening daarvan. Vir pasiente met
`minder ernstige aanvalle en wat weinig respons toon op
`brongodilators het orale kortikosteroiede ook 'n plek; dit
`kan moontlik opgevolg word deur beklometasoon-toe(cid:173)
`'n Derde groep pasiente is die wat al om die
`diening.
`ander dag lae dosisse kortikosteroiede gebruik en by wie
`beklometasoon nie effektief is rue.
`Beklometasoon moet vir drie tipes pasiente gebruik
`word. Eerstens diegene wat nie goed respondeer op alter(cid:173)
`natiewe terapie soos /3,-simpatomimetiese middels d.m.v.
`teofillien en natriumcromoglikaat nie. Twee(cid:173)
`aerosolle,
`dens kan dit
`lae dosisse orale kortikosteroiede vervang
`wanneer die instandhoudingsdosis laag is. Die vervanging
`moet geleidelik geskied en die toediening van orale korti(cid:173)
`kosteroiede moet dadeiik vermeerder word as die simp(cid:173)
`tome vcrerger. Dit help rue om die aerosoltoediening
`onder sulke omstandighede te vermeerder nie. Laastens
`kan pasiente wat beide orale steroiede en aerosolle gebruik
`moontlik die orale dosis verminder weens die gebruik van
`die aerosol.
`
`therapy re(cid:173)
`Are your patients on thyroxine replacement
`ceiving the correct dose? This question was studied in
`Scotland recently by analysis of 2710 computer-held
`follow-up records containing information about
`patient
`nearly 3000 prescriptions for
`thyroxine. Although the
`average dose of thyroxine required to
`uppress concen(cid:173)
`trations of thyrotrophin is now known to be about 160
`,ug/d, 27 prescriptions were for less than 100 J-l-g/d and
`for 300 - 500 .,ug/d. Patients involved in this
`204 (7%)
`study are followed up annually by general practitioners,
`results are
`and biochemical analyses and reporting of
`performed by a central registry with laboratory and com(cid:173)
`puting facilities. When undertreatment was detected at
`follow-up examinations, an attempt was made to deter(cid:173)
`mine whether it was due to inadequate prescription or to
`irregular use of medication. As a result of this study a
`treat(cid:173)
`total of 217 adjustments was made to replacement
`ment.
`
`this report (Brit. med. J.,
`The group responsible for
`1980, 281, 969) offer a decision-tree as a guide to thy(cid:173)
`therapy. They also emphasize that
`roxine replacement
`methods used in a follow-up system for detecting under(cid:173)
`treatment should include the use of serum thyrotrophin
`estimations to improve the sensitivity and specificity of
`the screening tests.
`
`LOWER DRUG PRICES FOR CONSUMERS, LLC
`Exhibit 1029-6
`IPR2016-00379