.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Gender differences in the effects of
cardiovascular drugs
J. Tamargo
1,2
*, G. Rosano
3,4
, T. Walther
5
, J. Duarte
2,6
, A. Niessner
7
, J.C. Kaski
8
,
C . Ceconi
9
,H.Drexel
10
, K. Kjeldsen
11,12
, G. Savarese
13
, C. Torp-Pedersen
14
,
D. Atar
15
, B.S. Lewis
16
, and S. Agewall
17
1
Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain;
2
CIBERCV, Madrid, Spain;
3
Cardiology Clinical Academic Group, St George’s
University Hospitals, NHS Foundation Trust, London SW17 0QT, Great Britain;
4
IRCCS San Raffaele Hospital, Department of Medical Sciences, Via Della Pisana 235, 00163
Rome, Italy;
5
Department of Pharmacology and Therapeutics, Western Gateway Building, University College Cork, Cork, Ireland;
6
Departamento de Farmacolog
ıa, Facultad de
Farmacia, Universidad de Granada, Granada 18071, Spain;
7
Division of Cardiology, Department of Internal Medicine II, Medical University of Vienna, Waehringer Guertel 18-20,
A-1090 Vienna, Austria;
8
Cardiovascular Sciences Research Centre at St George’s, University of London, Cranmer Terrace, London SW17 0RE, Great Britain;
9
University
Hospital of Ferrara, U.O. Cardiologia, Post Degree School in Cardiology, Heart Failure and Cardiovascular Prevention Unit, Via Aldo Moro 8, 44124 Cona, Ferrara, Italy;
10
Department of Medicine and Cardiology, Academic Teaching Hospital and VIVIT Institute Carinagasse 47, 6800 Feldkirch, Austria;
11
Division of Cardiology, Department of
Medicine, Copenhagen University Hospital (Holbaek Hospital), Holbaek, Denmark;
12
Department of Health Science and Technology, The Faculty of Medicine, Aalborg
University, Aalborg, Denmark;
13
Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital , 171 76 Stockholm, Sweden;
14
Institute of
Health Science and Technology, Aalborg University, Niels Jernes Vej 12, A5-208, 9220 Aalborg, Denmark;
15
Department of Cardiology B, Oslo University Hospital and Institute
of Clinical Sciences, University of Oslo, Kirkeveien 166, N - 0407 Oslo, Norway;
16
Cardiovascular Clinical Research Institute, Lady Davis Carmel Medical Center, The Ruth and
Bruce Rappaport School of Medicine, Technion-Israel Institute of Technology, Haifa, Israel; and
17
Oslo University Hospital Ulleva˚l and Institute of Clinical Sciences, University of
Oslo, Kirkeveien 166, N - 0407 Oslo, Norway
Received 28 September 2016; revised 14 November 2016; editorial decision 16 November 2016; acc epted 5 December 2016; online publish-ahead-of-print 28 February 2017
Although sex-specific differences in cardiovascular medicine are well known, the exact influences of sex on the effect of cardiovascular drugs
remain unclear. Women and men differ in body composition and physiology (hormonal influences during the menstrual cycle, menopause, and
pregnancy) and they present differences in drug pharmacokinetics (absorption, distribution, metabolism, and excretion) and pharmacodynamics,
so that is not rare that they may respond differently to cardiovascular drugs. Furthermore, women are also less often treated with evidence-
based drugs thereby preventing optimization of therapeutics for women of all ages, experience more relevant adverse drug reactions than
men, and remain underrepresented in most clinical trials. Thus, current guidelines for prevention, diagnosis, and medical treatment for cardio-
vascular diseases are based on trials conducted predominantly in middle-aged men. A better understanding of these sex-related differences is
fundamental to improve the safety and efficacy of cardiovascular drugs and for developing proper individualized cardiovascular therapeutic strat-
egies both in men and women. This review briefly summarizes gender differences in the pharmacokinetics and pharmacodynamics of cardiovas-
cular drugs and provides recommendations to close the gaps in our understanding of sex-specific differences in drug efficacy and safety.
............................ .......................... ............................... .......................... ............................... ............................... ............. .........
Keywords
Pharmacokinetics
•
Pharmacodynamics
•
Sex
•
Gender
•
Cardiovascular drugs
Introduction
Cardiovascular diseases (CVD) are the leading cause of morbidity
and mortality in both sexes.
1–6
In the past, the risk of CVD was
underestimated in women due to a misperception that females were
protected against CVD.
1–6
Furthermore, women develop coronary
artery disease (CAD) around 10 years later than men and at that
time present a higher prevalence of cardiovascular risk factors, so
they were more likely to be excluded from clinical trials.
5–9
Even
nowadays CVD are commonly perceived to be a health problem
only for men, leaving women with an inadequate prevention vulner-
able to CVD. However, even when women during the fertile period
have a lower risk of cardiovascular events, this protection decreases
after menopause, so that CVD is the major cause of death in women
older than 65 years of age.
1–10
In Europe, CVD cause a greater pro-
portion of deaths among women (51%) than men (42%) overall, i.e.
they kill twice as many women as all forms of cancer combined.
1,2
Men and women differ in the anatomy and physiology of the cardi-
ovascular system (body composition, role of hormonal changes dur-
ing menstrual cycle/pregnancy/menopause) and in risk factors,
prevalence, symptoms, management, and outcomes of CVD.
11–22
There are also gender-related differences in the pharmacokinetics
(PK) (i.e. the way drugs are absorbed, distributed, biotransformed,
and excreted) and pharmacodynamics (PD) (the relationship
between drug effect and drug concentration at the site of action) of
some widely used cardiovascular drugs
12,13
(Figure 1). Thus, it would
*Corresponding author. Tel:/Fax: þ34 91 3941472, Email: jtamargo@med.ucm.es
Published on behalf of the European Society of Cardiology. All rights reserved.
V
C
The Author 2017. For Permissions, please email: journals.permissions@oup.com.
European Heart Journal - Cardiovascular Pharmacotherapy (2017) 3, 163–182
REVIEW
doi:10.1093/ehjcvp/pvw042
Downloaded from https://academic.oup.com/ehjcvp/article/3/3/163/3058007 by guest on 16 August 2022
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
not be a surprise that efficacy and safety of these drugs can differ
between men and woman.
13–21
However, the reported clinical rele-
vance of these differences in PK/PD is moderate or remains uncer-
tain, mainly because women are underrepresented in clinical trials.
14
Thus, current guidelines for CVD are based on studies conducted
predominantly on middle-aged men. As expected, the lack of evi-
dence on the gender difference in the efficacy and safety of cardiovas-
cular therapeutic interventions leads to poor appropriateness.
For these reasons, there has been growing attention of the European
Society of Cardiology on the gender-related differences in the effects
of cardiovascular drugs.
1,2,4,13,20
Taking into account these issues,
the aims of this review are to summarize the effects of gender on PK/
PD of cardiovascular drugs; to identify the scientific gaps that exist
regarding to cardiovascular therapy in women; and to improve
the treatment of CVD from a gender perspective. Throughout the
text the terms ‘sex’, which is genetically determined, and ‘gender’,
which refers to the socially constructed characteristics of women
and men (such as norms, roles and relationships of and between
groups of women and men), will be used as synonyms.
Gender differences in
pharmacokinetics
Sex-based differences in PK may arise from differences in body com-
position, drug absorption, plasma and tissue distribution, metaboliz-
ing enzymes and transporters, and drug excretion
12–19,23–29
(Table 1).
Oral drug absorption is influenced by gastric pH, gastrointestinal
transit times, blood flow and presystemic gut, and hepatic metabo-
lism. Gastric acid secretion is lower and gastrointestinal transit times
are slower in women, whereas gut metabolism does not consistently
vary by sex.
15–19,23–30
A prolonged gastrointestinal transit can
decrease the absorption of metoprolol or verapamil and drugs
requiring an acidic environment for absorption may have lower oral
bioavailability in women and they should wait longer after eating
before taking drugs that should be administered on an empty stom-
ach.
27
Formulations designed to be absorbed in the duodenum
(i.e. enteric-coated aspirin) may exhibit reduced/delayed absorption
in women, particularly after a meal.
31
However, transdermal absorp-
tion is similar in both sexes.
12,15,29
Drug distribution depends on body composition, plasma volume,
organ blood flow, and tissue and plasma protein binding.
15,18,24,25
Sex
hormones modulate drug plasma protein binding but limited data sup-
port that these gender differences significantly affect pharmacological
effects. Women have higher percent of body fat and lower body
weight, plasma volume and organ size, and blood flow. This explains
the faster onset, higher volume of distribution (Vd), and longer effects
of lipophilic drugs (anaesthetics, benzodiazepines, neuromuscular
blockers) (Table 2), while the Vd of hydrophilic drugs is smaller, reach-
ing higher peak plasma levels (C
max
)andgreatereffectsascompared
with men.
15–18,24,25
Therefore, drugs requiring loading-dosages [i.e.
some antiarrhythmics (amiodarone, lidocaine, procainamide), digoxin,
heparin, thrombolytics] can reach higher C
max
and produce a higher
risk of adverse drug reactions (ADRs) in women.
27,29
In patients with
obesity or marked increases in extracellular volume (e.g. heart failure),
differences in body composition may alter drug distribution.
29,32
Drug elimination from the body occurs by two processes: biotrans-
formation and excretion. Hepatic clearance is a function of cardiac
outputandliverbloodflow,whicharelowerinwomen,andsex-
based differences in drug-metabolizing enzymes and transporters
(Table 1),whichplayagreaterroleinPKvariabilitythananyofthe
other parameter.
15–19,23–25,33–39
CYP3A and the transporter P-glyco-
protein (P-gp) present appreciable substrate overlap so that the
increased clearance of CYP3A4 substrates in women might be the
result of their lower hepatic P-gp activity.
12,15,17,35–39
Renal clearance
depends on glomerular filtration rate (GFR) and tubular secretion and
reabsorption. GFR is 10–25% lower in women, mostly older women,
and drugs primarily excreted unchanged in the urine are cleared more
slowly in women, but sex-related differences in renal excretion disap-
pear after normalization for body weight or GFR.
12,17,18,26,40
Differences in body composition and PK parameters may affect drug
disposition leading to differences in drug efficacy and safety. However,
only a few sex-based differences in PKs may lead to clinically relevant
changes in drug efficacy or safety as most of the differences disappear
after adjusting drug dosages for total body weight/size or GFR.
29
Sex-
based differences in PK and weight-dosing recommendations may be
warranted for drugs with a narrow therapeutic margin (e.g. antiarrhyth-
mics, digoxin, anticoagulants, antithrombotics, and thrombolytics) to
avoid an increase in the incidence of ADRs.
12,15–21,23–26
Gender differences in
pharmacodynamics
Prospective and mainly retrospective analysis of clinical trials
revealed sex-related differences in the efficacy and safety of sev-
eral widely used cardiovascular drugs (Tables 3 and 4).
1,12,15–20,23–
29,41
PD differences have not been studied as extensively as the PK
differences and can be difficult to quantify as women are often
underrepresented in trials and differences can be partly modu-
lated by sex hormones [e.g. oral contraceptives (OCs) and hor-
mone replacement therapy (HRT)].
41
This explains why
differences in clinical outcomes are still uncertain for some
Drug Administration
Absorption
Distribution
Intra/Extravascular space
Plasma protein binding
Tissue stores
Excretion
Renal, Billary, Fecal
Metabolism
Phase I and II
reactions
Metabolites
Drug concentration at
the site of action
Clinical responses
Effectiveness Toxicit y
PHARMACOKINETICS
PHARMACODYNAMICS
Figure 1 Schematic representation of the interrelationship of the
absorption, distribution, metabolism, and excretion of a drug (phar-
macokinetics) and its concentration at the site of action
(pharmacodynamics).
164 J. Tamargo et al.
Downloaded from https://academic.oup.com/ehjcvp/article/3/3/163/3058007 by guest on 16 August 2022
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
cardiovascular drugs routinely used in clinical practice. Next, we
shall review several sex-related PD differences.
Antithrombotic drugs
Antithrombotic therapy, including anticoagulants and antiplatelet
drugs, is the cornerstone for prevention and treatment of arterial
thrombosis (e.g. myocardial infarction and stroke), venous
thromboembolic disorders, and the complications of atrial fibrillation
(AF).
42
Women with acute coronary syndromes (ACS) have a higher
risk of major bleedings than men, probably due to their smaller body,
older age, reduced creatinine clearance, higher prevalence of comor-
bidities (hypertension, diabetes, renal dysfunction), higher risk of
antithrombotics overdosing, and, perhaps, differences in response to
antithrombotics between women and men.
42–45
................................................................... .......................................................................... ............ ...........................................................
Table 1 Gender differences in absorption, distribution, metabolism, and excretion
Parameter Sex differences
Drug bioavailability
Absorption M > W
Gastric acid secretion M > W > P. Decreases absorption of weak acids but increases absorption of
weak bases in M
Gastric emptying M > W > P. E inhibit gastric empting
Gastrointestinal transit times
Gut metabolism M = W
Body composition
Body surface area M > P > W. Absorption increases when body surface is larger
Organ (heart) size M > W
Organ blood flow Greater blood flow to skeletal muscle and liver in M; greater to adipose tissue in W.
Blood flow increases during P
Total body water M > P > W
Plasma volume P > M > W. Varies during the menstrual cycle and P
Body fat content W > M
Cardiac output M > P > W. Increase rate of distribution in M
Pulmonary function M > P > W. Increase pulmonary elimination in M
Drug distribution
Volume of distribution W > M. Higher Vd for lipophilic drugs in W
M > W. Higher Vd for hydrophilic drugs in M
Plasma protein binding to
Albumin M = W. P and OCP reduce plasma albumin and increases free drug plasma levels
a1-acid glycoprotein M > W. E, OC and P decrease its plasma levels
Globulins E increase sex-hormone binding, corticosteroid-binding and thyroxine-binding globulins
Drug transporters
Hepatic P-glycoprotein M > W
OCT2 M > W. E downregulates OCT2
OATP1B1-3 M > W
Drug metabolizing enzymes and transporters
Phase I metabolic reactions
(hydrolysis, oxidation, reduction)
mediated via cytochrome P450 (CYP) isoforms
CYP1A2: M > W. Decreased in pregnancy and by OCP
CYP2B6: W > M
CYP2C9: M = W
CYP2C19: M = W
Decreases in pregnancy and by OCP
CYP3A4: W > M. Increases by OCP
CYP2D6: M > W. E induces and OCP decreases CYP2D6 activity
CYP2E1: M > W. Increases by OCP
Phase II metabolism
Uridine diphosphate glucuronosyltransferases (UGTs 1/2) M > W. Increase by OCP and E and during pregnancy
N-Acetyltransferases M = W
Catechol-O-methyltransferase M > W
Acetyl-/Butyryl-cholinesterase M > W
Xantine-oxidase W > M
Gastric alcohol dehydrogenase M > W. Higher alcohol plasma levels in W
Drug excretion
Renal blood flow
Glomerular filtration rate
Tubular secretion/reabsorption
M > W. Renal Cl increases during P
Drugs actively secreted by the kidney may show sex differences in renal excretion
References are presented in Supplementary material online, Table S1.
Cl, clearance; E, oestrogens; GFR, glomerular filtration rate; GI, gastrointestinal; M, men; OCP, oral contraceptives; OATP, organic anion-transporter polypeptide; OCT, organic
cationic transporter; P, pregnancy; P-gp, P-glycoprotein; Vd, volume of distribution; W, women.
Gender differences in effects of cardiovascular drugs 165
Downloaded from https://academic.oup.com/ehjcvp/article/3/3/163/3058007 by guest on 16 August 2022
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
Anticoagulants
Indirect thrombin inhibitors
In men, unfractioned heparin (UFH) distributes into plasma volume,
which is proportional to body weight, and is eliminated more rapidly;
so, higher doses are required in heavy patients
46,47
Women treated
with UFH for acute myocardial infarction (AMI) achieve higher acti-
vated partial thromboplastin time than men, a finding associated with
an increasing bleeding risk, even after weight-adjusted dosing.
48
The
main suggested risk factors for bleeding included a smaller body size,
older age, reduced creatinine clearance, higher prevalence of comor-
bidities, and an increased sensitivity to heparin.
46,48,49
A post hoc analysis of the TIMI 11A study showed similar PK/PD
profiles of enoxaparin in men and women with non-ST-segment ele-
vation ACS (NSTEMI-ACS).
50,51
The meta-analysis of two large trials
.............................................................. ................... ................................................................................. ..................................................
Table 2 Sex-related differences in drug pharmacokinetic parameters
Drug class Outcomes in females
Anaesthetics: propofol Plasma propofol levels decline more rapidly in W at the end of infusion
Alcohol Lower gastric alcohol dehydrogenase activity in W. Higher plasma concentrations in W as compared with
M following an equivalent drink
Antidepressants Higher AUC and C
max
in W
H1-antihistamines Slower metabolism and elimination in W
Antipsychotic drugs
a
Higher plasma levels and Vd and lower Cl in W. Reduce the dosage in W or increase dosage in M.
Olanzapine is more rapidly eliminated in M than in W
Aspirin Bioavailability and plasma levels of aspirin and salicylate are higher in W possibly due to lower activity of
aspirin esterase, larger Vd and lower Cl in W than in M. Differences disappear with OCP
Benzodiazepines Lower initial plasma levels due to larger Vd, and possibly higher Cl, in W. OC reduce their Cl. Higher
plasma levels of free diazepam in W
Beta-receptor agonists W are less sensitive
Beta blockers: metoprolol, propranolol W have higher plasma levels due to a smaller Vd and slower Cl. Drug exposure to metoprolol increases by
OC
Renal Cl of atenolol and metoprolol increases during P due to enhanced hepatic metabolism
Calcium channel blockers Faster Cl of verapamil, and nifedipine in W. Increased bioavailability and decreased clearance of oral vera-
pamil in W compared with M
Digoxin W have higher serum digoxin concentrations due to reduced Vd and lower Cl. Drug Cl increases during P
Glucocorticoids Oral Cl and Vd of prednisolone are higher in M. Prednisolone clearance was reduced by OC
Heparin W had higher plasma levels and APTT values than M due to a lower Cl
Iron Oral absorption of iron is greater in W than in M
Isosorbide mononitrate W had significantly higher serum plasma concentrations compared with men, probably due to the lower
body weights in females
Labetalol Labetalol concentrations are 80% higher in W
Lidocaine W has a larger Vd and may require a higher i.v. bolus dose than M. Higher free plasma levels in W receiving
OCP, as alpha 1-acid glycoprotein levels are reduced by oestrogens
l-opioid (OP3) receptor agonists
b
Slower onset and offset of action in W
Neuromuscular blocking drugs
c
Lower Vd, higher plasma levels, faster onset and prolonged duration in W due to the higher body fat and
lower Vd
Paracetamol Lower plasma levels and higher Cl in M due to increased activity of the glucuronidation pathway. OCP
increase drug clearance
Procainamide Plasma levels are higher (30%) in W due to a lower BMI and Vd
Quinidine Plasma protein binding decreases during P
Selective serotonin reuptake inhibitors
d
W present higher plasma levels, probably related to sex-related activity of various CYP enzymes
Statins Higher plasma levels of lovastatin and simvastatin in W
Theophylline Metabolism is faster and half-life is shorter in W than in M. Plasma protein binding decreases and the Vd
increases during P
Torasemide Higher C
max
and lower Cl in W than in M
Tricyclic antidepressants Free plasma concentrations of imipramine, clomipramine, and nortriptyline are higher during pregnancy
Verapamil W display faster Cl of verapamil after i.v. administration probably due to the higher activity of CYP3A4 or
lower activity of P-gp; lower Cl in W after oral administration
Vorapaxar C
max
and AUC are 30% higher in women but no dose adjustment is required
Warfarin Higher free plasma levels in W
Zolpidem Plasma levels and AUC are higher, and Cl is lower in W
References are presented in Supplementary material online, Table S2.
AUC, area under the curve; BMI, body mass index; Cl, clearance; C
max
, peak plasma drug concentrations; CYP, cytochrome P450 isoforms; i.v., intravenous; M, men; OC, oral
contraceptives; P, pregnancy; P-gp, P-glycoprotein; Vd, volume of distribution; W, women.
a
Olanzapine, clozapine, pimozide, haloperidol.
b
Fentanyl, morphine, pentazocine, ramifentanil.
c
Atracurium, pancuronium, rocuronium vecuronium.
d
Citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline.
166 J. Tamargo et al.
Downloaded from https://academic.oup.com/ehjcvp/article/3/3/163/3058007 by guest on 16 August 2022
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
(ESSENCE and TIMI 11B) reported that enoxaparin was more effec-
tive than intravenous (i.v.) dose-adjusted UFH in reducing the risk of
death, MI, or recurrent angina prompting urgent revascularization,
but the benefit was greater in women.
52
In the FRISC study, dalte-
parin reduced the risk of death and MI in patients with ACS, but
women showed larger absolute and relative reduction of the primary
endpoint compared with men.
53
However, minor bleeding was more
frequent and anti-Xa activity during the acute phase treatment was
higher in women.
54
The ExTRACT-TIMI 25 study randomized ST-
segment elevation MI (STEMI) patients with planned fibrinolysis to
enoxaparin or UFH. Women had a similar relative benefit and greater
absolute benefit than men when treated with enoxaparin, despite
they presented higher baseline risk and increased short term mortal-
ity.
55
In the SYNERGY study, enoxaparin was not superior but also
non-inferior to UFH across multiple subgroups, including those strati-
fied by sex, with a modest increase in the risk of major bleeding.
56
Direct thrombin inhibitors
Clearance of argatroban is faster in women, but no sex-related differ-
ences in anticoagulant response were reported.
57,58
In the pooled
analysis of REPLACE-2, ACUITY, and HORIZONS-AMI trials men
and women undergoing percutaneous coronary interventions (PCI)
experience similar safety benefits of bivalirudin in reducing bleeding
complications, but women experienced a more pronounced benefit
of bivalirudin in reducing 12-month mortality than men.
59,60
In the
ACUITY trial, no differences were observed in rates of 1-year com-
posite ischaemia or mortality in women who received bivalirudin vs.
heparin plus GPI.
61
Bleeding complications were higher in women,
likely because of comorbidities, as they were older and had more dia-
betes, hypertension, and renal impairment.
59,60,62–64
In the
REPLACE-2 trial, female gender was associated with higher rates of
death and bleeding complications in univariate analyses, but multivari-
ate analyses eliminated nearly all outcome differences between
sexes.
60,65,66
Similar results were observed in another study.
67
Parenteral anti-factor Xa inhibitors
In the OASIS-5 trial, fondaparinux and enoxaparin showed similar
efficacy in reducing the composite endpoint (death, MI, or refractory
ischaemia at 9 days) or major bleeding in men and women with
.............................................................. ................... ................................................................................. ..................................................
Table 3 Sex differences in drug pharmacodynamics
Drug class Outcomes
Alcohol Higher vulnerability of W to acute and chronic complications of alcoholism
Anaesthetics: propofol W are less sensitive to propofol. W wake up faster and require higher doses than M for the same
effect
ACEIs No mortality benefit in W with asymptomatic LV systolic dysfunction
Antidepressants W respond better to selective serotonin/noradrenaline uptake inhibitors. M respond better to
TCA and MAO inhibitors than W
Antipsychotic drugs More effective in W. They require lower doses to control symptoms
Aspirin Higher protective effect against stroke in W and against MI in M. Aspirin is more active in male pla-
telets. Aspirin resistance is more frequent in W
Benzodiazepines Diazepam impairs psychomotor skills to a greater extent in W. They should be initiated at lower
dosages in W
Beta blockers Greater reduction in blood pressure and heart rate in W treated with metoprolol and propranolol
Digoxin W with HF have an increased risk of mortality on digoxin therapy. W require lower doses and
lower plasma levels (< 0.8 ng/mL)
Glucocortioids Females are more sensitive to the effects of methylprednisolone
Heparin W had increased partial thromboplastin time, even after weight-adjusted dosing, suggesting an
increased sensitivity
Ibuprofen Less effective in W
Lidocaine W may require a higher i.v. bolus doses to achieve the same plasma levels
l-opioid (OP3) and j* (OP2) receptor agonists
a
W experience more pain and are more sensitive to opioid receptor agonists. M require 30–60%
greater dose of morphine and j receptor agonists for the same pain relief
Neuromuscular blocking drugs
b
W are more sensitive and require lower (20–30%) doses than M due to a smaller Vd. If a rapid
onset of action is required the dose should be increased in M
Paracetamol W displayed lower Cl and Vd compared with M. OCP increase drug Cl
rt-PA W with acute ischaemic stroke obtain more benefit from rt-PA than M
SSRIs
c
W respond better than M, being the preferred therapy
Verapamil Greater reduction in blood pressure and heart rate in W
Warfarin W need less warfarin per week than M. Doses should be modified to reduce the risk of excessive
anticoagulation in W
Zolpidem The recommended initial dose is lower in W
References are presented in Supplementary material online, Table S3.
ACEIs, angiotensin-converting enzyme inhibitors; Cl, clearance; E, oestrogens; HF, heart failure; i.v., intravenous; LV, left ventricular; M, men; MAO, monoamine oxidase; MI,
myocardial infarction; OCP, oral contraceptives; rt-PA, recombinant tissue plasminogen activator; SSRIs, selective serotonin reuptake inhibitors; TCA, tricyclic antidepressants;
Vd, volume of distribution; W, women.
a
Alfentanyl, butorphanol*, fentanyl, morphine, nalbuphine* pentazocine*, remifentanyl.
b
Atracurium, pancuronium, rocuronium and vecuronium.
c
Citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline.
*refers to j (OP2) receptor agonists.
Gender differences in effects of cardiovascular drugs 167
Downloaded from https://academic.oup.com/ehjcvp/article/3/3/163/3058007 by guest on 16 August 2022