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tension and more profound hypokalaemia if any. Less
common types of PA include familial forms (types I to IV),
unilateral hyperplasia, adrenocortical carcinoma, and ectopic aldosterone-producing tumours [48].
Early screening and detection of PA enable targeted
treatments which potentiate improved BP control and
reduction or cessation of antihypertensive medications
[49]. Beyond BP control, early detecting and targeted treatment is demonstrably ameliorates the risk of
hyperaldosteronism- associated organ damage (cardiac,
renal, vascular) and mortality [42, 50].
Screening for PA is recommended in patients with:
1. sustained blood pressure elevation >150/100mm Hg on
each of three measurements obtained on different days,
2. resistant hypertension
3. hypertension accompanied by spontaneous or diuretic-
induced hypokalaemia
4. hypertension and adrenal incidentaloma
5. hypertension and family history of early onset hyperten-
sion and/or premature (< 40years) cerebrovascular event
6. hypertension and rst-degree relatives with conrmed PA
7. hypertension and sleep apnoea
The Endocrine Society through an extensive review of the
literature, has devised an algorithm for detection, conrmation, subtyping, and treatment of PA (Fig.22.2).
Screening
The aldosterone: renin ratio (ARR) is the preferred screening test for PA. Notwithstanding its screening utility and
wide availability, there are several limitations which underscore the need to exercise diligence in interpreting its
results. ARR may be elevated as a function of very low
renin levels, giving false impression of a positive test, this
in spite of a concurrent relatively low plasma aldosterone
concentration (PAC). Some centres attempt to overcome
this by considering a PAC threshold >410pmol/L (15ng/
dL) in their diagnostic algorithms. This however may come
at the cost of a missed diagnosis (and consequently missed
therapeutic opportunity), considering that both forms of PA
(BAH to a greater extent) can be associated with modest
elevations in PAC [43, 51].
It should therefore be performed under ‘ideal’ testing
conditions that enhance the test’s sensitivity and specicity;
these include:
1. normal serum potassium (with supplementation if
required)
2. unrestricted salt diet
3. patient is ambulant for at least 2h, and seated for 5–15min
prior to testing
4. non-interfering antihypertensive medications as required
to maintain acceptable control of BP:
Fig. 22.2 Algorithm for the
detection, conrmation,
subtype testing, and treatment
of PA. [Adapted from J.W.
Funder etal.: Case detection,
diagnosis, and treatment of
patients with primary
aldosteronism: an Endocrine
Society Clinical Practice
Guideline. J Clin Endocrinol
Metab.2016;101(5):1889–
1916, with permission. ©
Endocrine Society.] Crosslled circles indicate the
quality of the evidence, such
that ⊕○○○ denotes very
low-quality evidence;
⊕⊕○○, low quality;
⊕⊕⊕○, moderate quality;
and ⊕⊕⊕⊕, high quality
[47]
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• non-dihydropyridine calcium antagonist (e.g.,
Verapamil)
• alpha blocker (e.g., Prazosin)
• vasodilator (e.g., Hydralazine)
• alpha-2/imidazoline receptor antagonist (Moxonidine)
5. where feasible (safe), a washout of interfering antihypertensive medications for at least 2weeks, and preferably
4weeks in the case of mineralocorticoid receptor antagonists (MRAs)
Conrmation
Conrmatory testing is performed following a positive ARR
to denitively conrm or exclude the diagnosis of PA, and
consequently rationalise the decision to proceed with subtyping into unilateral or adrenal forms. International guidelines recommend performing one of four tests: oral sodium
loading, intravenous saline suppression, udrocortisone suppression, or a captopril challenge test [52]. Fludrocortisone
suppression is the most reliable of all four, however it is
expensive and time consuming. Saline suppression test is the
most widely utilised conrmatory test and can be performed
with the patient either seated or recumbent. The seated SST
has been shown to have a sensitivity of 88%, far more superior than that of the recumbent SST, and ideal specicity of
94%. It is the therefore the preferred conrmatory test [53].
PA is essentially excluded if PAC fails to suppress to
<170 pmol/L after a 4-h infusion of 2 L of 0.9% normal
saline. It is critical that the patient assumes the seated position for at least 30min prior commencement of SST.
Subtype Classication—CT andAdrenal
Venous Sampling (AVS)
Unilateral PA (adenoma, or less commonly, unilateral hyperplasia) is treated with laparoscopic adrenalectomy, which
universally results in normalization of hypokalaemia, and
may effect cure of hypertension in 30–60%. Conversely,
adrenalectomy seldom corrects hypertension in bilateral
forms of PA, where treatment is primarily with MRAs [42,
48]. This nal step in the diagnostic algorithm is therefore
crucial in guiding treatment decisions. Subtyping is comprised of adrenal CT imaging, and/or performance of adrenal
venous sampling (AVS) by an experienced interventional
radiologist.
CT may provide important radiological clues as to the
subtype of PA, including visible nodules, hyperplasia and
other features. Moreover, CT can detect features consistent
with adrenal adenocarcinoma, which tend to exceed 4cm in
size.
Younger patients (<35years) with conrmed PA, hypokalaemia, and CT features of a unilateral adenoma may not
require AVS to proceed with an adrenalectomy, although
most centres prefer conrmation by AVS prior to surgery.
Otherwise, where adrenalectomy is feasible and desired by
the patient, AVS is strongly recommended to distinguish
(and localise) unilateral PA from bilateral forms [54].
CT, while useful in providing valuable additive subtyping
information, has its limitations. Functioning microadenomas
(≤1cm) can be easily missed, and conversely, detected macroadenomas (>1cm) might represent non-functioning nodularity. It is therefore almost universally advisable to proceed
with AVS following a CT evaluation. AVS is the gold standard for the detection and sub-classication of PA with a
sensitivity and specicity of 95 and 100%, respectively, for
detecting unilateral PA [47].
Most patients with unilateral PA have adrenal-to-adrenal
aldosterone-to-cortisol ratios of >4. Ratios of <3 suggest
hyperplasia, and values of 3–4 are considered indeterminate
results. However, like any test, using diagnostic thresholds
that enhance specicity might come at a cost of reduced sensitivity, and therefore, potentially a missed opportunity to
identify and denitively treat patients with unilateral PA
[55]. This is an area of great diagnostic challenge that often
necessitates repeated AVS, with or without Synacthen
(Corticotropin) stimulation, and the involvement of an experienced endocrinologist.
Cushing’s Syndrome
Cushing’s syndrome (CS) is dened as excessive production
of cortisol, either from autonomous ACTH-independent
adrenal secretion, or secondary to excessive ACTH secretion
from pituitary or non-pituitary source. ACTH-dependent CS
accounts roughly for 80–85% of case of CS [56]. While it is
a rare endocrine cause of secondary hypertension, the overwhelming majority (~80%) of patients with CS develop
hypertension that is often difcult to control without denitive treatment of CS [57]. Some of the classical symptoms
and signs that point to possibility of CS in a hypertensive
patient include obesity, plethoric facies, buffalo hump, hirsutism, and striae [58].
Screening forCS
Screening includes the performance of one or a combination of 1mg overnight or 2mg 48-h dexamethasone suppression test, late-night salivary cortisol, and 24-h urinary
free cortisol (UFC). It is advisable that, where possible,
these tests are performed away from clinical settings asso-
Cushing’s syndrome suspected
ely)
(Suggest additional
Cushing’s syndrome
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ciated with physiological hypercortisolaemic states such as
hospitalisation, illness or peri-operative periods, and that
results are interpreted with caution in these and other states
associated with increased endogenous cortisol secretion
such as untreated obstructive sleep apnea, pregnancy,
intense exercise, alcohol excess, or major depression [59].
Diagnostic criteria that suggest Cushing’s syndrome are
UFC greater than the normal range for the assay, serum cortisol greater than 1.8 μg/dl (50nmol/L) after 1 mg dexamethasone (1-mg DST), and late-night salivary cortisol
greater than 145ng/dL (4nmol/L). An abnormal test should
be repeated for conrmation before undergoing testing for
the underlying cause of CS [58].
Determining theSubtype ofCS
Once hypercortisolism is established through screening, it is
critical that the subtype of CS is determined to guide tailored
therapeutic decisions. The rst step involves the measurement of corticotropin (ACTH), which should be performed
twice, on 2 separate days given the episodic secretion of
ACTH in all forms of CS.A suppressed ACTH [<5pg/mL
(1.1 pmol/L)] suggests primary CS, i.e., adrenal adenoma/
hyperplasia, while an unsuppressed ACTH [>20 pg/mL
(4.4 pmol/L)] suggests ACTH-dependent CS. ACTHdependent CS is known as Cushing’s disease in the case of
pituitary corticotroph adenoma. Cushing’s disease makes up
the majority of ACTH-dependent CS, while a minority are
due to ectopic secretion of ACTH. Rarely, ectopic
corticotropin- releasing hormone (CRH) secretion may be the
cause of Cushing’s syndrome.
In the case of ACTH-independent CS, CT or MRI imaging may demonstrate a unilateral adrenal adenoma (~90% of
cases) or hyperplasia, which may be unilateral of bilateral
[60]. If ACTH-dependent hypercortisolism is suspected or
conrmed, specialised biochemical testing (corticotropinreleasing hormone stimulation test, desmopressin stimulation test, high-dose 8mg dexamethasone suppression test),
imaging (pituitary MRI), and nally petrosal venous sinus
catheterisation will help differentiate pituitary from ectopic
sources of excess ACTH production. Choice(s) of testing is/
are best guided by an endocrinologist, and beyond the scope
of this chapter. In 2008, The Endocrine Society devised a
diagnostic algorithm for patients suspected of having
Cushing’s syndrome (Fig.22.3) [58].
Fig. 22.3 Algorithm for
testing patients suspected of
having Cushing’s syndrome
(CS). All statements are
recommendations except for
those prefaced by “suggest”.
Diagnostic criteria that
suggest Cushing’s syndrome
are UFC greater than the
normal range for the assay,
serum cortisol greater than
1.8g/dL (50nmol/L) after
1mg dexamethasone (1-mg
DST), and late-night salivary
cortisol greater than 145ng/
dL (4nmol/L). [Adapted from
Nieman LK, etal. The
diagnosis of Cushing’s
syndrome: an Endocrine
Society Clinical Practice
Guideline. J Clin Endocrinol
Metab. 2008;93(5):1526–40.
With permission. ©
Endocrine Society.] [58]
(consider endocrinologist consultation)
Exclude exogenous glucocorticoid exposure
Perform one of the following tests
24-h UFC (> 2 tests)
Consider caveats for each test (see text)
Use 48-h, 2-mg DST in certain populations (see text)
Exclude physiologic causes of hypercortisolism (Table 2)
Perform 1 or 2 other studies shown above
Suggest consider or repeating the abnormal study
Suggest Dex-CRH or midnight serum cortisol in
Discrepant
evaluation)
certain populations (see text)
Overnight
1-mg DST
ANY ABNORMAL RESULT
Consult endocrinologist
ABNORMAL
Late night salivary
cortisol (> 2 tests)
Normal (CS unlik
Normal (CS unlikely)
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Phaeochromocytoma/Paraganglioma (PPGL)
Catecholamine-secreting tumours are rare, and are estimated to account for <0.2% of cases of hypertension,
although this may be an underestimate. Those located in
the chromaffin cells of the adrenal medulla are referred to
a phaeochromocytomas and account for around 90%,
while the remaining 10% are located somewhere along
the sympathetic chain, most commonly in the abdomen
[61]. Catecholamine- secreting tumours are collectively
referred to as pheochromocytomas and paragangliomas
(PPGLs) [62]. While most cases are sporadic, a significant proportion are part of a familial disorder. Therefore,
there should be a strong suspicion and lower threshold
for screening when a relative of a hypertensive patient is
affected by a familial disorder predisposing to
PPGL.Familial disorders associated with adrenal phaeochromocytoma are of autosomal dominant inheritance
pattern and include von Hippel-Lindau syndrome, multiple endocrine neoplasia type 2, and less commonly, neurofibromatosis type 1 [63]. Genetic testing is
recommended, including in all patients with sporadic
PPGL as roughly one-third of these patients will have
germline mutations, and this would allow detection of
genotypes associated with higher risk of malignant/metastatic disease, in addition to allowing early diagnosis and
treatment of PPGLs in relatives [62]. PPGL presentations
are quite varied, ranging from an asymptomatic incidental finding of an adrenal tumour on abdominal imaging
through to severe and life-threatening emergencies.
Screening Tests
The 2014 Endocrine Society Clinical Practice Guidelines recommend either test can be used when PPGL is suspected [62]:
• 24-h urine fractionated metanephrines and catecholamine
• Plasma fractionated metanephrines
Plasma fractionated metanephrines are technically easier
to perform, and a negative test reliably excludes pheochromocytoma except in patients with early preclinical disease
and those with strictly dopamine-secreting neoplasms [65].
While highly sensitive, one disadvantage is the higher rates
of false positives (specicity 77–89%) which might lead to
additional unnecessary testing and the associated excessive
costs [66]. Ideally, testing should be performed on a sample
withdrawn from a cannula with the patient in supine position
for at least 30min [62]. It is the generally considered the test
of choice when there is a higher index of suspicion for PPGL
(e.g. family history of PPGL, high-risk genetic syndrome,
typical imaging features).
24-h urine fractionated metanephrines and catecholamine, while more time-consuming, are both highly sensi-
tive and specic, and is adopted by some institutions as the
preferable initial screening test, especially when the clinical
index of suspicion is relatively lower (e.g. resistant hypertension, hyperadrenergic spells) [67].
Imaging
When toScreen?
Phaeochromocytoma/Paraganglioma should be suspected
and screened for in patients with hypertension in the following settings [64]:
• classic triad of episodic headache, sweating, and
tachycardia
• presence of the ‘ve P’: paroxysmal hypertension, palpitations, perspiration, pallor, pounding headache
• onset of hypertension at a young age (<20years)
• resistant hypertension
• familial syndrome predisposing to catecholaminesecreting tumour
• family history of PPGL
• adrenal mass on imaging characteristic of a
pheochromocytoma
The overwhelming catecholamine-secreting tumours, be
they adrenal or extra-adrenal, are located within the abdominal cavity.
CT imaging is highly sensitive, with features of typical
lesion being an attenuation >10HU on unenhanced CT, and
marked enhancement with intravenous contrast medium CT.
MRI distinguishes a pheochromocytoma from other
adrenal tumours by the characteristic hyper-intensity on
T2-weighted imaging, as other tumours tend to be isointense.
However, MRI provides lower spatial resolution compared
to CT.
I-123 MIBG scintigraphy might be of diagnostic value
where CT and/or MRI has failed to identify a PPGL when
biochemical screening was positive and the clinical index of
suspicion high. They are particularly useful for identifying
metastatic disease, especially when the primary lesion is
large (>10cm in diameter), but are less reliable for sporadic
forms of pheochromocytoma [68].
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FDG-PET and 68-Ga DOTATATE PET are mainly utilised in the diagnosis of metastatic PPGLs. They are less sensitive in detecting the primary tumour in non-metastatic
settings where they are superseded by CT/MRI [69].
Parenchymal Renal Disease
The relationship between renal disease and hypertension is
bidirectional and could be described as a pathophysiologic
vicious cycle. Several renal pathologies can cause and
exacerbate hypertension, and hypertension itself is a major
cause of chronic kidney disease [70, 71]. Moreover, there
is a positive correlation between chronic kidney disease
(CKD) progression and hypertension, with prevalence rising as glomerular ltration rate declines [72]. IgA nephropathy, the most common form of primary glomerulonephritis,
is often associated with emergence of hypertension at
some stage through the disease course, and infrequently
presents with malignant hypertension [57]. The mechanisms that underpin the pathogenesis of renal hypertension
include, but are not limited to: sodium retention, increased
activity of the RAS, enhanced sympathetic nerve activation and secondary hyperparathyroidism [73, 74].
Erythropoietin-stimulating agents used to treat CKDassociated anaemia are also established as a cause of
hypertension in this cohort [75].
The usual rst sign of renal hypertension is the nding of
an elevated creatinine and correspondingly reduced glomerular ltration rate on baseline biochemical screening. The
most useful step in evaluation that follows is an assessment
of the urine sediment with particular attention to presence of
pathological levels of albuminuria/proteinuria, and/or microhaematuria. This is usually followed by a renal tract ultrasound study, and were indicated, a renal biopsy to determine
the form of suspected primary glomerulonephritis.
Obstructive Sleep Apnoea
Obstructive sleep apnea (OSA) is characterised by repetitive
apnea or hypopnea due to obstruction of the upper airway
during sleep, and is a common and often underappreciated
cause of secondary hypertension. There is strong correlation
between severity of OSA and the risk for hypertension, a
stronger correlation with diastolic than systolic hypertension
[76, 77] and with resistant HTN [78] OSA is associated with
increased sympathetic nervous system activity evidenced by
elevated catecholamines and increased muscle sympathetic
nerve activity [79, 80]. Diagnosing OSA guides the appropriate initiation of continuous positive airway pressure which
has additive BP-lowering effects to antihypertensives and
weight loss [81].
The presence of hypertension, or indeed resistant hypertension, in an overweight or obese patient should prompt
screening for OSA, especially when accompanied by a history of daytime sleepiness. Other symptoms that raise suspicion include snoring and/or choking during sleep, and
morning headaches. In clinic, screening begins with performance of an evaluation tool such as the Epworth sleepiness
scale or the STOP-Bang questionnaire which predict the
high likelihood of OSA [82]. However, none of these tools
should replace formal sleep apnea testing. They should be
supplemented with a physical examination assessing for
obesity, a crowded oropharynx, craniofacial abnormalities,
and increased neck and/or waist circumference. The gold
standard for conrmation and grading of severity of OSA is
in-laboratory polysomnography, although unattended home
sleep apnea testing is a reasonable alternative.
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Drug Adherence inHypertension
https://t.me/medicina_free
Management
DanLane, MichelBurnier, andPankajGupta
23
Non-adherence inHypertension
Hypertension is one of the leading causes of mortality worldwide. It is estimated to account for 1.16 million deaths in
2019 [1], and over 1.28 billion people are affected by the
disease [2]. Yet, 79% of those are estimated to have uncontrolled hypertension [2]. For those with diagnosed and
treated hypertension, non-adherence is recognized as a frequent contributor to uncontrolled blood pressure (BP)
together with medical inertia and poor access to drug therapies [3]. A 2017 systematic review of 28 studies involving
12,603 patients determined that 45.2% of hypertensive
patients were non-adherent [4]. Further still, 83.7% of
patients with uncontrolled BP were non-adherent. Nonadherence to antihypertensive medications has major clinical
consequences [5]. Indeed, non-adherent patients have a
higher risk of mortality and or developing cardiovascular
complications such as stroke, heart failure or myocardial
infarction. The main contributors to non-adherence are classied by: patient mannerisms (e.g., treatment misconceptions, forgetfulness etc.), physician conduct (e.g., poor
communication, lack of monitoring etc.), society and environment (e.g., media, transportation links, etc.), and health
care provisions (e.g., symptoms from poorly tolerated medications, medication cost, etc.) [5]. Adherence, therefore, can
be thought of as a complex problem not only because of the
high number of potential causes but also because it is a
dynamic process that varies over time.
D. Lane ∙ P. Gupta (*)
The Department of Chemical Pathology and Metabolic Diseases,
Leicester Royal Inrmary, Leicester, UK
Department of Cardiovascular Sciences, University of Leicester,
Cardiovascular Research Centre, Gleneld Hospital, Leicester, UK
e-mail: Pankaj.gupta@uhl-tr.nhs.uk
M. Burnier
Service of Nephrology and Hypertension, University Hospital,
Lausanne, Switzerland
Measuring Drug Adherence: Methods
andConsiderations
Although most physicians tend to recognize that medication adherence is an important issue in the management of
patients with chronic asymptomatic diseases such as hypertension or dyslipidaemia, their major concern relies in their
ability to detect poorly adherent patients. As shown in
Fig.23.1, simple methods tend to be relatively unreliable,
and methods providing the best information tend to be
more expensive and demanding in terms of infrastructures.
The ideal method to assess drug adherence should “provide
a reliable capture, storage, analysis, and communication of
dosing history data in ways that make it difcult or impossible for patients or trial staff to censor or otherwise
manipulate the data” [6]. Interestingly, the prevalence of
poor adherence to medications varies depending on the
method used to measure it. Thus, self-reports, questionnaires (like the widely used Morisky Scale [7]) and pill
counts overestimate adherence and are prone to bias.
Systematic reviews have shown that non-adherence rates
are typically higher in studies that use chemical adherence
tests (CAT) [8, 9] or electronic monitoring [10]. In recent
years, several new objective ways of measuring drug adherence have been developed including CAT or digital medicines with ingestible sensors inserted in pills [5]. The
ability to assess medication adherence accurately is crucial
as it leads to a better understanding of the issues. Yet, large
clinical trials have been slow to adopt some of these new
technologies, except perhaps for the Medication Event
Monitoring System, which has been the gold-standard to
measure medication adherence in real-time in new drug
developments and was recognized by the Food and Drug
Association. In recent years, much emphasize has been
focused on the detection of non-adherence in patients with
apparent resistant hypertension, a clinical situation in
which partial or complete non- adherence has been found to
be particularly high [11, 12].
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
R. R. Heuser et al. (eds.), Renal Denervation, https://doi.org/10.1007/978-3-031-38934-4_23
229
230
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Fig. 23.1 Objective and subjective adherence testing measures
D. Lane et al.
Introduction toChemical Adherence Testing
inHypertension
CAT has fast become an important tool in the clinician’s
arsenal to differentiate those with true resistant hypertension
from those who are non-adherent. Adherence, dened as participating with the agreed upon treatment prescription [13],
can be objectively and accurately determined by
CAT.Essentially, a patient’s urine, blood, or other biomatrix,
are analysed to determine medication presence, and therefore determine whether the medication has been ingested.
These techniques were researched on in the early 2010s [11,
14, 15], and were known to be used in clinics from 2014in
the UK. The basis of these methods typically involves
hyphenated mass spectrometry [16], which include a separation system (e.g., liquid chromatography (LC), gas chromatography (GC)) and a detection system (e.g., tandem mass
spectrometry (MS/MS), high-resolution mass spectrometry
(HRMS). The most common of these combinations are
LC-MS/MS, which have been steadfast in clinical laboratories over the last 20years and are capable of exquisite sensitivity, specicity, and selectivity over a large dynamic range
of compounds (from small drugs like metformin to large proteins like haemoglobin).
The overhaul to these platforms has seen CAT recommended in the recent European Society of Cardiology (ESC)
and European Society of Hypertension (ESH) 2018 clinical
guidelines [3]. By involving the techniques both clinically
and in research, undue procedures and treatment escalation
may be avoided.
The evolution of adherence testing by hyphenated mass
spectrometry has been rapid and continuous. The following
sections will discuss the technical and clinical aspects, as
well as limitations and where the technology will likely
progress to.
Determination ofDrug Levels Using Mass
Spectrometry
The only measures that conrm medicine consumption are
direct observed therapy (DOT), digital pills (which are both
more expensive and labour intensive), and CAT using blood
or urine. As urine and blood samples (among others) may
be sent via the post, CAT may be absorbed into the service
of a centralised laboratory like any other pathology test.
Burns et al (2019) showed most antihypertensive drugs
were suitably stable in urine so that postal delivery under
no special conditions (e.g., on dry ice) and delivery under
3-days had no impact on the ability to detect by LC-MS/
MS [17]. In brief, nifedipine, hydralazine, bendroumethiazide, and captopril are known to be unstable at room temperature [17, 18]. Long-term freezer stability has been
demonstrated for antihypertensive drugs in blood [18],
though little data exists on room temperature storage. It is
thought the blood delivery through existing framework
(i.e., room temperature if on- site, on ice if by courier)
between the clinic and laboratory is suitable. With the
advent of dry blood sampling for adherence testing [19], no
special conditions would be required [20].
Mass spectrometry is a powerful instrument. Picograms
−12
(10
grams) of medications may be detected in human biomatrices (sampling typically needs <1.5mL), allowing the
sensitive resolution of adherence. Hyphenated approaches
differ in terms of their ion separation mechanisms, though
the generic process is similar—molecules are introduced
Der
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231
into an ionisation source where they pick up a charge. Ions
are transferred through the mass spectrometer where they are
separated (resolved) by their mass to charge ratio (m/z); the
separated ions collide with the detector, transferring their
charge, which may be measured. To increase the power of
mass spectrometry, chromatography is used to aid separation
before the molecules are introduced into the ionisation
source. The separation is dependent on a molecule’s chemistry and therefore afnity to either stationary phase or mobile
phase. For example, a polar compound (e.g., atenolol) exhibits greater retention on a polar stationary phase and thus is
separated form a non-polar species. In most chemical adherence tests, reverse phase LC is used (a non-polar stationary
phase e.g., a hydrocarbon chain like C18, and a polar mobile
phase e.g., water). This is often used in conjunction with an
electrospray ionisation (ESI) source—a solvent containing
molecules is sprayed across a eld with a differential charge
and at high temperature, where desolvation occurs, molecules become charged, and are transferred into the MS inlet.
As mentioned before, hyphenated MS techniques differ
by their ion separation mechanisms. Between MS/MS and
HRMS, the two key systems in adherence testing are LC-MS/
MS (e.g., triple quadrupole, approx. £250,000/$339,611
circa Oct-21) and quadrupole time-of-ight (QTOF)-MS
(approx. £400,000/$543,502 circa Oct-21). LC-MS/MS is
capable at resolving m/z to 10−1units (m/z>0.1) and is the
most widespread. The system is pictured in Fig. 23.2. In
brief, cylindrical metal rods are organised symmetrically,
each pair charged similarly – negative opposite negative,
positive opposite positive. Applying a small radio frequency
voltage to the metal rods may stabilise the ight path of an
ion travelling through the centre of the rods. The ions’ m/z is
intrinsically proportional to the applied voltage, so each set
of rods (4 being quadrupole, 8 being octupole, and so on) can
scan for specic ions to either stabilise or destabilise trajectories towards the detector. These are essentially mass lters.
Between each lter situates a collision cell. Depending on
the system, energy is introduced (e.g., collision with an inert
gas), and ions are fragmented into small pieces which are
indicative of their larger pieces. These are known as the par-
ent and daughter ions, or the precursor and product ions. The
transition from parent to daughter is generally unique to a
given ion, and multiple transitions may be monitored simultaneously in a mode known as multiple reaction monitoring
(MRM). This increases resolution between ions and increases
condence in differentiating ions that could have the same
parent ions. If the fragmentation does not match the expected
pattern, an analyst may conrm interference.
QTOF-MS offers high resolution, being capable of resolving m/z of 10−3 (m/z>0.001). The schematic of QTOF-MS is
outlined in Fig.23.3. Briey, like in MS/MS, a quadrupole
and collision cell select and fragment parent ions. The nal
MS system is the main difference. Daughter ions are entered
into a pulser, which applies a constant energy to accelerate
the ions along a ight path. As force is proportional to mass
and acceleration, ions with small mass move with higher
velocity and reach the detector in less time—vice versa for
high mass ions. These platforms can be operated in an untargeted mode where continual data is collected—the main
benet of using these instruments. Data sets may be sifted
through to identify compounds outside the original scope
i.e., additional research questions may be asked where sufcient consent is given. In the context of adherence testing,
where consent is necessary, this untargeted mode may be
unnecessary (at least in the current state of consenting).
Perhaps in opt-out systems, like organ donation is in many
countries, the power of QTOF-MS and other HRMS platforms may be increased. At present, QTOF-MS and LC-MS/
MS offer similar sensitivity and specicity, so cost is often
the main decision point for acquiring a platform.
In terms of detecting common antihypertensive drugs,
most are good candidates by mass spectrometry. Depending
on the matrix (urine or blood), different compounds may be
better detected. For example, extensively metabolised drugs
like ACE inhibitors may be seen primarily as their metabolite
in urine (e.g., ramiprilat, enalaprilat) and primarily as their
prodrug in blood (e.g., ramipril, enalapril). Some medications are scarcely renally excreted (e.g., spironolactone),
hence, either blood should be used, or metabolites must be
targeted. These medications make up the minority. With the
Fig. 23.2 Triple quadrupole
mass spectrometry (MS/MS)
schematic. The red arrows
track the movement of the
analyte/ion path. Reused with
permission from Gupta etal.
[39]
ivitised
Analyte
ESI; API
Ionisation source
First MS
Selection of
parent lon
Collision cell
Fragmentation
Second MS
Selection of
daughter ion
Detector
(electron
multiplier)
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