Cardiovascular risk factors

Drugs for hypertension treatment

October 13th, 2015

 Cardiovascular risk factors

Hypertension
Cigarette smoking
Obesity (BMI>30)
Physical inactivity
Dyslipidemia
Diabetes mellitus
Age (>55 male; >65 female)

Family history of cardiovascular

disease
Multiple risk factors markedly increase
individual cardiovascular risk

Risk shown here is compared with the baseline risk for a 40-year-old male non-
smoker with TC of 185 mg/dL, SBP of 120 mm Hg, no glucose intolerance, ECG-LVH
negative, and a probability of developing CVD of 15/1000 (or 1.5%) in eight years.

Addapted from Kannel WB. Hypertension:Physiopathology and Treatment.1997

Fig.1 ISS chart for cardiovascular risk in non-diabetic women (10 years)

Risk Risk
Risk Risk
Risk Risk
No smoking Smoking
Cholesterolemia

Age

Age

Age
Fig.2 ISS chart for cardiovascular risk in non-diabetic men (10 years)

Risk Risk
Risk Risk
Risk Risk

No smoking Smoking

Cholesterolemia

Age

Age

Age
 The mediocre physician treats severe disease

The average physician treats symptoms of disease

The superior physician prevents disease

Huang Dee, Nai Ching

2600 B.C.
ABC prevention
Each year, more than 2 million Americans have a heart attack or
stroke, and more than 800,000 of them die; cardiovascular
disease is the leading cause of death in the United States and the
largest cause of lower life expectancy among blancks.
Aspirin therapy, Blood pressure control, Cholesterol management,
and support for Smoking cessation.
In Italy, about 15 million people have
hypertension with a mortality rate of 240,000
fatal events, 40% of all deaths

VI Global Symposium against hypertension

Why is hypertension management needed?

The Rule of Halves

Only 1/2 have been diagnosed
Only 1/2 of those diagnosed have been
treated
Only 1/2 of those treated are adequately
controlled
Thus, only 12.5% overall are adequately
controlled
...it has been estimated that better
adherence to antihypertensive
treatment alone could prevent
89,000 premature deaths in the
United States annually.
 What is adherence?

Adherence (or compliance):

The extent to which a persons behaviour, taking a
medication, following a diet and/or executing lifestyle
changes, corresponds with agreed recommendations from a
healthcare provider
Persistence: Refers to the overall duration of the
treatment, from a specific diagnosis to the end of treatment
 Factors that affect adherence

40-75% in >65 years old

Memory disorders

Treatment of asymptomatic disease

Faith in the physician or medicines

Lifestyle

Number of prescribers

Number of concomitant medicines

Disability

Adverse events
Mojtabai R, et al. Health Affair 2003;22:220-29
Osterberg L, et al. N Engl J Med 2005;353:487-97
Definitions and classification of blood pressure levels (mmHg)a
 When to initiate antihypertensive drug treatment?

Summary of recommendations on initiation of antihypertensive drug treatment

Stratification of total CV risk in categories of low, moderate, high and very high risk
according to SBP and DBP and prevalence of RFs, asymptomatic OD, diabetes, CKD
stage or symptomatic CVD
 Choice of antihypertensive drugs
The main benefits of antihypertensive treatment are due to lowering of BP per se and
are largely independent of the drugs employed.
The following five classes of drugs are all suitable for the initiation and maintenance
of antihypertensive treatment, either as monotherapy or in some combinations:
Diuretics (thiazides)
Adrenergic antagonists
Calcium antagonists
Angiotensin-converting enzyme (ACE) inhibitors
Angiotensin receptor antagonists

Centrally active agents, -receptor antagonists and direct inhibitors of the Renin-
Angiotensin System can be used for antihypertensive therapy in particular clinical
conditions.
Legend:
Green continuous lines: preferred combinations;
Green dashed line: useful combination (with some limitations);
Black dashed lines: possible but less well tested combinations;
Red continuous line: not recommended combination.
 Advantages of combination therapy

-a prompter response in a larger number of patients (potentially beneficial in high-risk

patients),
-a greater probability of achieving the target BP in patients with higher BP values,
-a lower probability of discouraging patient adherence with many treatment changes.
-patients receiving combination therapy have a lower drop-out rate than patients given any
monotherapy.
-a further advantage is that there are physiological and pharmacological synergies between
different classes of agents, that may not only justify a greater BP reduction but also cause
fewer side-effects and may provide larger benefits than those offered by a single agent.
 Fixed-dose or single-pill combinations
The 2013 ESH/ESC Guidelines favors the use of combinations of two
antihypertensive drugs at fixed doses in a single tablet, because reducing the number
of pills to be taken daily improves adherence, which is unfortunately low in
hypertension, and increases the rate of BP control. This approach is now facilitated by
the availability of different fixed-dose combinations of the same two drugs, which
minimizes one of its inconveniences, namely the inability to increase the dose of one
drug independently of the other. This holds also for fixed- dose combinations of three
drugs, which are increasingly becoming available. Availability extends to the so-called
polypill (i.e. a fixed-dose combination of several antihypertensive drugs with a statin
and a low-dose aspirin), with the rationale that hypertensive patients often present
with dyslipidemia and not infrequently have a high CV risk.
 Diuretics
Drugs affecting renal
and cardiovascular function

October 13th, 2015

Classification of diuretics

- Thiazide diuretics

- Loop diuretics

- K+-sparing diuretics

- Osmotic diuretics

- Inhibitors of carbonic anhydrase

 Renal Physiology

DCT
5%
60% 20% 5%
65%
PCT
AA afferent arterioles EA

EA efferent arterioles
H2O AA

PCT proximal convoluted tubule

CT

TAL thick ascending limb Na+

TAL
tDL
tDL thin descending limb
DCT distal convoluted tubule 20% 15-25%

CT collecting tubule
Sites of action
 Thiazide Diuretics
mechanism of action in the distal convoluted tubule

Na+-Cl- symport inhibitors in distal convoluted tubule

Increased Na+ and Cl- excretion

Hydrochlorothiazide
Chlorthalidone
Indapamide
 Therapeutic uses Side effects
hypertension hypercalcemia

congestive heart failure hypokalemia

hypercalciuria: prevent hyperglycemia

excess Ca2+ excretion to
form stones in ducts hyponatremia

osteoperosis hyperuricemia

nephrogenic diabetes
insipidus

treatment of Li+ toxicity

 Loop Diuretics
mechanism of action in thick ascending limb
Na+-K+-2Cl- symport inhibitors in thick ascending loop of Henle

Furosemide
Bumetanide
Torsemide
 Therapeutic uses Side effects

congestive heart failure hypocalcemia

hypertension hypokalemia

pulmonary oedema metabolic alkalosis

chronic renal failure or hyponatremia

nephrosis
hyperuricemia
acute and chronic
hyperkalemia
 K+ Sparing Diuretics
mechanism of action in distal convoluted tubule and collecting tubule
inhibitors of renal epithelial Na+ channels

Triamterene
Amiloride

inhibits apical Na+ channels

Spironolactone
Canrenone
Potassium Canrenoate

competitively antagonizes
aldosterone receptors preventing
Na+ renal reabsorbion
 Osmotic Diuretics
These drugs are not reabsorbed, they promote H2O and Na+
excretion by increasing osmotic pressure in the proximal tubule and
loop of Henle

Mannitol
Endovenous treatment, used in acute renal
failure prevention, it reduces cerebral oedema
and intraocular pressure

Glycerin and isosorbide

Oral treatment, used for ophatmic
procedures and corneal oedema.
 Carbonic Anhydrase Inhibitors
mechanism of action in renal proximal tubule
Carbonic anhydrase catalyzes formation of HCO 3- and H+ from H2O and CO2

The inhibition of carbonic anhydrase decreases [H +] in tubule lumen,

reducing Na + reabsorption

Acetazolamide
Methazolamide
used for intraocular pressure reduction
in glaucoma treatment
 Location 2
Location 1 Thick ascending loop of Henle
Proximal tubule
CARBONIC ANHYDRASE LOOP DIURETICS
Inhibitors of carbonic anhydrase Inhibitors of Na+-K+/2Cl- symport
Acetazolamide Furosemide, Bumetamide

4
3

Location 5 1
EX
Loop of Henle CO
RT
A
LL
E DU
M
Osmotic diuretics 2
Mannitol 5

Location 4
Location 3
Distal tubule
Distal tubule
Inhibitors of ephitelial channel of Na +
Inhibitors of Na+-Cl- symport Antagonist aldosterone
Idrochlorothiazide , Chlorthalidone
Reduction of reabsorption of Na+
Loss of K+ at location 4
 Mechanism of action of main diuretics

Inhibitors of carbonic anhydrase (acetazolamide): inhibition of H+

production which in the proximal tubule exchanges with Na+ (antiport)
Osmotic diuretics (mannitol): they increase the osmolarity inside the
lumen, filtered but not reabsorbed
Loop diuretics (furosemide, bumetanide, etacrinic acid): they inhibit
the reabsorption of Na+ and K+ cotransported with 2Cl- (symport)
Thiazidic diuretics (chlorthalidone, idrochlorthiazide): they inhibit
the reabsorption of Na+ cotransported with Cl- (symport); Na+ is
exchange with K+ at basal membrane level (ATPase)
K+-sparing diuretics (amiloride, triamterene): they inhibit the renal
ephitelial channel of Na+; spironolactone: antagonist of aldosterone
(aldosterone induces syntesis of Na+ channel); K+ is not excreted because
Na+ does not enter.
Pharmacokinetics
Differences between diuretic classes
Differences between loop diuretics and thiazides
 Diuretics side effects

Hypovolemia

Loss of K+ (except K+-sparing diuretics) with

consequent hypokalemia;

Hyperuricemia

Hyperglycemia (thiazide) in diabetics or pre-

diabetics
Factors that contribute to diuretic resistance

Diet rich in Na+

Patients non-compliance

Diminished renal function

FANS
 Drug interactions

Drug Mechanism

Li+ Li+ excretion (thiazides) Li+ toxicity

Aminoglycosides Ototoxicity (Loop d.)
ACE-I Hyperkalemia (K sparing)

Digoxin Digoxin GFR and tubular Dig toxicity

excretion (K-sparing)
Hypokalemia-associated
arrhythmias
Quinidine Hypokalemia-associated
arrhythmias