Antihypertensive drugs.pdf

Slides about the pharmacology of hypertension.

1. ANTIHYPERTENSIVE
DRUGS
Dr. DivyaG.Krishnan
KMCT Medical College

2. Introduction
 Hypertension is a very common disorder
particularly past middle age.
 Hypertension is defined as a BP more than
140mm Hg systolic and 90mm Hg diastolic.
(JNC 7 guidelines).

3. Introduction
Types of
Hypertension
Essential Secondary
A disorder of unknown origin affecting the
Blood Pressure regulating mechanisms
Secondary to other disease processes

4. Introduction
Outcomes of Hypertension :-
Atherosclerosis
Ischemic heart disease & cerebrovascular
accidents (CVA)
Nephropathy
Congestive heart failure
“Hence early detection &treatment of htnwith
antihypertensive drugs is very important”

5. Normal Blood Pressure Regulation
1. Blood Pressure= Cardiac output (CO)X TPR.
Physiologically CO and PVR is maintained by arterioles ,
postcapillaryvenules& Heart .
2. Baroreflex: Baroreceptorsregulate BP. Central sympathetic neurones
in vasomotor area are tonicallyactive. When there is stretch in the
vessel wall brought about by rise in pressure, baroreceptorstimulation
occurs and inhibits sympathetic discharge. When there is fall in BP,
there is reduction in stretch leading to increased baroreceptoractivity
leading to increase in TPR and CO thereby restoring normal blood
pressure.
3. Renin-angiotensin-aldosteronesystem (RAAS)(role of kidney)
4. Local agents like Nitric oxide
All antihypertensivesact via interfering with one or more of the
normal mechanisms

6. Expected Questions
Classification of antihypertensives. Write
the Mechanism of antihypertensive action,
desirable properties and drawbacks of use of
Diuretics/ ACEI/ARBs/CCB/Beta blockers in
HTN.
Drugs for HTN in pregnancy
Drugs for Hypertensive emergencies
Selection of first line antihypertensives

7. Classification of Antihypertensive Drugs
1. Diuretics:
Thiazides: Hydrochlorothiazide, Chlorthalidone,
Indapamide
High ceiling: Furosemide
K+ sparing: Spironolactone, Triamterene, Amiloride
2. Angiotensin-converting Enzyme (ACE) inhibitors:
Captopril, Lisinopril., Enalapril, Ramipril, Fosinopril
3. Angiotensin(AT1 receptor) blockers:
Losartan, Candesartan, Valsartan, Telmisartan
4. Direct renininhibitor
 Aliskiren

8. Classification of Antihypertensive Drugs
5. Calcium Channel Blockers (CCB):
Verapamil, Diltiazem, Nifedipine, Amlodipine,
6. ß-adrenergic blockers:
Non selective:Propranolol
Cardioselective: Metoprolol, atenolol
7. ß and α–adrenergic blockers:
Labetolol, carvedilol
8. α–adrenergic blockers:
Prazosin, terazosin, doxazosin,
phenoxybenzamine, phentolamine
9. Centrally acting:
Clonidine, methyldopa

9. Classification of Antihypertensive Drugs
10. Vasodilators:
Arteriolar : Hydralazine, Minoxidil, Diazoxide
Arteriolar + venous: Sodium Nitroprusside
Pnemonic: ABCD
A (ACEI, ARBs, alpha blockers) B(beta blockers)C (CCB,
centrally acting) D (Diuretics, direct renininhibitors,
dilators)

10. Each group of drugs will be discussed
under the following headings
Examples of drugs under each group
Mechanism of antihypertensive action
Desirable properties as antihypertensives
Drawbacks as antihypertensives
Current status in treatment of hypertension

11. Diuretics
Examples :
Thiazides: Hydrochlorothiazide,
Chlorthalidone, Indapamide
High ceiling: Furosemide
K+ sparing: Spironolactone, Triamterene,
Amiloride

12. Diuretics
Mechanism of antihypertensive action: (Thiazides)
Act on Kidneys to increase excretion of Na and H2O 
decrease in blood volume decrease in COP & hence
decrease in BP.
After 4 -6 weeks, compensatory mechanisms operate to regain
Na+ balance, plasma volume and Cardiac output but BP
remains low. Why?
Answer: Even after the compensatory mechanisms, there
exists a small deficit of Na+ in the vessel wall. This Na deficit
reduces stiffness of vessel wall leading to vasodilation. This
leads to decrease in TPR and fall in BP.
So, the initial fall in BP due to thiazidesis due to fall in COP
but fall in BP is sustained due to fall in TPR.

13. Diuretics
Mechanism of antihypertensive action (high ceiling
diuretics)
Fall in BP is dependent only on reduction in plasma volume
& Cardiac output (similar to the initial fall in BP due to
thiazides) but unlike thiazidesthe Na deficit is not persistent
due to short action of high ceiling diuretics . Hence no fall in
t.p.rand no sustenance of BP fall.

14. Diuretics
Desirable properties of Diuretics as antihypertensives
-Once a day dosing
-No fluid retention
-No tolerance development to antihypertensive action
-Low incidence of postural hypotension
-Effective in isolated systemic hypertension
-Less risk of fractures in elderly (hypocalciuricaction of
thiazides)
-Low cost

15. Diuretics
Drawbacks of Diuretics as antihypertensives
Hypokalaemia–muscle pain and fatigue
Hyperglycemia
Hyperlipidemia
Hyperuricaemia
Sudden cardiac death –tosadesde pointes due to
hypokalemia
All the above adverse effects occurrat higher doses of
thiazides(50 –100 mg per day). These adverse effects
are minimal with low doses (12.5 to 25 mg). So, low
doses of Thiazidesare used as antihypertensivesnow.

16. Diuretics
Current status
Thiazidesare mild antihypertensives, cause fall of
abt10mm Hg in BP. Alone they are used only in
mild HTN (stage 1 HTN). Low dose of thiazide
therapy is used preferably with a potassium sparing
diuretic as first choice in elderly.
They prevent tolerance to other antihypertensives.
Can be used as combinationin any grade of HTN.
Indapamide: modified thiazidewith minimal side effects
It has very mild diuretic action and is used mainly as
antihypertensive and not as diuretic.

17. Diuretics
Loop diuretics
Cause more fluid & electrolyte imbalance. They are
indicated in HTN only if it is complicated by:-
-Chronic renal failure
-Refractory CHF
-Resistance to thiazides
-Marked fluid retention.
K+ sparing diuretics
Used only in conjunction with Thiazidesto prevent K+
loss & to supplement their antihypertensive action.

18. AngiotensinConverting Enzyme (ACE)
Inhibitors
Examples :-
Captopril, Lisinopril., Enalapril, Ramipril, Fosinopril
Mechanism of antihypertensive action
Inhibit the ReninAngiotensinAldosteronesystem (RAAS).
WHAT IS RAAS???
Next slide

19. RAAS
Reninis produced by JG cells of kidney in response to
Fall in BP or blood volume
Decrease Na+ in macula densa
Reninacts on a plasma protein Angiotensinogento convert it
to Angiotensin-I
Angiotensin-Iis rapidly converted to Angiotensin-IIby ACE
(present in luminal surface of vascular endothelium)
Angiotensin-IIis degraded by peptidases to produce
Angiotensin-III
AngiotensinII causes vasoconstriction (increased TPR) leading
to rise in diastolic BP.
Both Angiotensin-IIand Angiotensin-IIIstimulates Aldosterone
secretion from Adrenal Cortex . Aldosteronepromotes Na+ &
water reabsorptionby the kidneys leading to increased blood
volume & increased COP & systolic BP.

20. RAAS -Diagram
Vasoconstriction
Na+ & water
retention
(Adrenal cortex)
Kidney
Increased
Blood Vol.
Rise in BP

21. ACE inhibitors
MOA : Inhibit synthesis of AngiotensinII by
inhibiting ACE –> decrease in (tpr) and blood
volumefallin diastolic and systolic BP.

22. ACE inhibitors
Desirable properties of ACEI as antihypertensives
No postural hypotension
Not much electrolyte imbalance
Renal perfusion well maintained
Reverses the ventricular hypertrophy
No hyperuricemia
No deleterious effect on plasma lipid profile
No rebound hypertension
Only minimal worsening of quality of life like general
wellbeing, sleep and work performance.

23. ACE inhibitors
Drawbacks/ adverse effects
Cough –persistent brassy cough due to inhibition of bradykinin
breakdown in lungs
Hyperkalemia(in renal failure patients, those with K+ sparing
diuretics, NSAID and beta blockers (routine check of K+ level))
First dose Hypotension –sharp fall may occur
Angioedema: swelling of lips, mouth, nose etc.
Rashes, urticaria
Dysgeusia: loss or alteration of taste
Foetopathic: hypoplasiaof organs, growth retardation etc
Neutropenia
Proteinuria
Acute renal failure ( occurs in patients with bilateral renal artery
stenosis)

24. ACE inhibitors
Current status
1
st
line antihypertensive Drug
Used in relatively young patients
Most appropriate antihypertensivesin patients with:-
Diabetes,
Chronic kidney disease,
CHF
Left ventricular hypertrophy,
Angina, post MI, stroke
Dyslipidemia,
Gout
Avoid in :Pregnancy, bilateral renal artery stenosis,
hypersensitivity , hyperkalaemia, Preexisting dry
cough

25. ACE inhibitors (2 important ones)
Captopril
Sulfhydrylcontaining dipeptide.
Not a prodrug. Has drawbacks mentioned earlier
Half life: 2 Hrs, multiple doses
Enalapril
Prodrug–converted to enalaprilate
Advantages over captopril:
More potent
Longer duration of action-once daily dose
Absorption not affected by food
Rash and loss of taste are less frequent
Slower onset of action, hence first dose hypotension
less marked.

26. ACE inhibitors –other uses
(to be discussed under ACE inhibitors chapter)
Congestive Heart Failure
Myocardial Infarction
Prophylaxis of high CVS risk subjects
Diabetic Nephropathy
Schlerodermacrisis

27. AngiotensinReceptor Blockers (ARBs)
Examples
Losartan, Candesartan, Valsartan,Telmisartan
Mechanism of antihypertensive action
AngiotensinReceptors (AT1 & AT2) are present on
target cells. Most of the physiological actions of
angiotensinare mediated via AT1 receptor.
ARBs are competitive antagonists and inverse
agonist of AT1 receptor. Blocks all the actions of A-II
mediated by AT1 like vasoconstriction, aldosterone
release and renal actions of salt & water
reabsorption.

28. ARBs
Current status of ARBs
Similar to ACEI BUT theoretical superiority over ACEIs is
claimed due to following reasons:
Cough is rare –no interference with bradykinin
degradation.
Complete inhibition of AT1 & action of angiotensinII is
fully blocked–(In case of ACEI, AngiotensinII formed
by other mechanisms not involving ACE can act on
AT1 reeptor& produce the effects)
AT1 blockade results in indirect activation of AT2 –
vasodilatation (additional benefit)
Rare 1
st
dose hypotension
Low dysgeusia& angioedema
Fetopathiclike ACEI & hence should not be used in
pregnancy.

29. Direct renininhibitor-Aliskiren
Inhibits production of AngiotensinI & II.
Equally effective as ACEI & ARBs.
Since experience with it is limited, so it is used only
as a second line antihypertensive when more
established ACEI & ARBs cannot be used.

30. Beta blockers
Examples
-Non selective:Propranolol
-Cardioselective: Metoprolol,Atenolol
Mechanism of antihypertensive action
-Decreases heart rate, contractility, conduction velocity,
cardiac output (inverse agonist on β1 ). Total peripheral
resistance increases initially.
-Initial phase : COP decreases (systolic BP decreases), t.p.r
increases (diastolic BP increases) overall little BP
change.
-With prolonged use resistance vessels adapt to decreased
COP so that t.p.rdecreasesboth systolic & diastolic BP
decrease

31. Beta blockers
Desirable properties as antihypertensives
No postural hypotension
No salt and water retention
Low incidence of side effects
Low cost
Once a day regime
Drawbacks of non selective beta blockers:-
Fatigue, lethargy (low CO?)–decreased work capacity
Bradycardia
Loss of libido –impotence
Cognitive defects –forgetfulness
Worsening of carbohydrate tolerance, lipid profile, PVD,
asthma.
Sudden withdrawal—chance of rebound HTN,
precipitation of MI or angina

32. Beta blockers
Advantages of cardio-selective beta blockers over non-
selective beta blockers:
Safer in asthmatics (no bronchoconstriction)
Safer in diabetes (no interference with hypoglycemia
induced glycogenolysis)
Less worsening of PVD
Lipid profile-less deterioration

33. Beta blockers
Current status:
As first line drugs cardioselectivebeta blockers alone
in mild/moderate HTN
-Action maintained over 24hrs
Preferred in:-
-Young non-obese hypertensivesthose with coexisting
anxiety, migraine, tachycardia & those with IHD
-For preventing sudden cardiac death in Post MI
patients
-In stable heart failure along with ACEI
Not preferred in old

34. Αlphablockers
Examples
Non selective alpha blockers (Phenoxybenzamine,
Phentolamine) not used in chronic essential
hypertension but used in Pheochromocytoma.
Specific alpha-1 blockers like prazosin, terazosinand
doxazosineare used in HTN treatment
Mechanism of antihypertensive action
Blockade of vasoconstrictor αreceptors
-pooling of blood in capacitance vesselsdecreased
venous return & decreased COPfall in BP

35. Αlphablockers
Adverse effects:
postural hypotension
salt and water retention
Nasal stuffiness
Miosis
failure of ejaculation in males
Current status:
But not used as first line agent,
May be added to diuretics + beta blockers if target
bpis not achieved with their use alone.

36. Alpha + beta blockers
Labetalolused IV for rapid BP reduction. Orally used
for severe HTN.
Carvedilolused as antihypertensive as well as in
CHF.

37. Calcium Channel Blockers -
Classification

38. Calcium Channel Blockers
Mechanism of antihypertensive action
Three types of Ca+ channels in smooth muscles –Voltage
sensitive, receptor operated and leak channel
Voltage sensitive are again 3 types –L-Type, T-Type and N-
Type
Normally, L-Type of channels admit Ca+ and causes
depolarization –excitation-contraction coupling through
phosphorylationof myosin light chain –contraction of vascular
smooth muscle –vasoconstriction--elevation of BP
CCBs block L-Type channel resulting in :-
-Smooth Muscle relaxation
-Negative chronotropic, ionotropiceffects on heart.
DHPshave highest smooth muscle relaxation and vasodilator
action followed by verapamiland diltiazem. Hence DHPs are the
CCBs used in HTN.

39. Calcium Channel Blockers
Desirable properties
Do not compromise haemodynamics–no
impairment of work capacity
No deleterious effect on lipid profile, uric acid or
electrolyte balance.
Can be given to asthma, angina and PVD patients
No renal and male sexual function impairment
No adverse fetal effects and can be given in
pregnancy
Minimal effect on quality of life

40. Calcium Channel Blockers
Drawbacks
-Worsen GERD
-Negative chronotropiceffect can worsen Conduction
defects
-Worsen BHP & bladder voiding difficulty in males

41. Calcium Channel Blockers
Current status
Used as 1
st
line by many because of excellent
tolerability and high efficacy.
Preferred in elderly/asthma/COPD/PVD/
stroke/DM/pregnant/isolated systolic HTN
To be avoided in:-
Myocardial inadequacy, CHF
Conduction defects
Receiving beta blockers
IHD, post MI cases.
Enlarged prostate
GERD

42. Assignment
Contrast Nifedipineand Amlodipine

43. Vasodilators
Hydralazine
Directly acting vasodilator
MOA: hydralazinecauses NO release –relaxation of
vascular smooth muscle –fall in BP.
Uses: 1) Moderate hypertension when 1
st
line fails
2) Hypertension in Pregnancy
Minoxidil
Relaxes smooth muscle & relaxes arterioles.
Used only in life threatening HTN & topically in alopecia

44. Sodium Nitroprusside
Rapidly acting vasodilator (both arteriolar & venous)
MOA:RBCs convert nitroprussideto NO (enzymatically)
& non enzymaticallyby glutathione to NO & CN-–..>NO
causes vasodilationof both resistance (arterioles) and
capacitance vessels (veins) and reduces t.p.rand CO
(decrease in venous return)
Uses: Hypertensive Emergencies
Adverse effects: Palpitation, pain abdomen,
disorientation, psychosis, weakness and lactic acidosis.
Psychosis is due to CN-formation

45. Centrally acting Drugs
Alpha-Methyl dopa: (Alpha methyl analogue of DOPA) -a
prodrug
MOA:Getsconverted to alpha methyl Noradrenaline.
which acts on alpha-2 receptors in brain and causes
inhibition of adrenergic discharge –fall in BP
Only used therapeutically now in Hypertension
during pregnancy.
Clonidine:Agonist of central alpha-2 receptor
Not frequently used now because of tolerance and
withdrawal hypertension

46. Some important points
Antihypertensivespreferred in a patient with coexisting DM:-
-ACEI, ARBs, CCBs, Diuretics(less prefererredas
compared to other 3 due to hyperglycemia)
Antihypertensivespreferred in a patient with coexisting
asthma/copd–CCBs, ARBs
Antihypertensivespreferred in a patient with coexisting
CAD:-Diuretics, ACEI, ARBs, cardioselectivebeta
blockers
Antihypertensivespreferred in a patient with coexisting
stroke –diuretics, ACEI, ARBs, CCBs

47. Drugs for Hypertension in pregnancy
Drugs found safe for treating HTN in pregnancy
-Alpha methyl Dopa
-CCBs like Nifedipine(BUT they should be stopped before
labouras they weaken uterine contractions)
-Cardioselectivebeta blockers & those with ISA (atenolol,
Metoprolol) used only if no other choice available
-Prazosin, Clonidine
-Hydralazine

48. Drugs for Hypertension in pregnancy
Drugs to be avoided
-ACEI: fetopathic
-Diuretics: reduce uteroplacentalcirculation
increased risk of fetal death
-Non selective beta blockers : causes low birth
weight, neonatal bradycardiaand hypoglycemia.
-Sodium nitroprusside

49. Drugs for Hypertensive Emergencies
Hypertensive emergencies : Systolic BP > 220 or diastolic
BP > 120 mm Hg with evidence of active end organ damage.
Hypertensive urgency : Systolic BP > 220 or diastolic BP >
120 mm Hg without overt signs of endorgandamage.
Controlled reduction of BP is required to prevent :-
1. Cerebrovascularaccident (haemorrhage)
2. Hypertensive encephalopathy
3. Hypertensive acute LVF and pulmonary edema.
4. Unstable angina or MI with raised BP.
5. Dissecting aortic aneurysm.
6. Acute renal failure with raised BP.
7. Eclampsia

50. Drugs for Hypertensive Emergencies
Oral therapy (not recommended due to problems)
-Nifedipine(causes abrupt fall in BP and precipitates
MI or stroke, or may be fatal).
-Captopril(response is variable and it carries risk of
excessive hypotension).
-Clonidine(produces sedation and rebound rise in BP
on stopping the drug).

51. Drugs for Hypertensive Emergencies
Parenteraltherapy
-Sodium nitroprusside: DOC for emergencies due to its
instantaneous, balanced arteriovenousvasodilatory
action & lack of development of tolerance.
-GTN: Acts in 2–5 min and has brief titratableaction, but is
a less potent hypotensive. Its predominant venodilator
action makes it particularly suitable for lowering BP in
acute LVF, MI, unstable angina.
-Hydralazine: is less predictable, and not a first line drug.
Used in eclampsia.
-Esmolol: Useful when cardiac contractility and work is to
be reduced, such as in aortic dissection.

52. Drugs for Hypertensive Emergencies
-Phentolamine: Drug of choice for hyperadrenergic
states, e.g. hypertensive episodes in
pheochromocytoma, cheese reaction or clonidine
withdrawal.
-Labetalol: Can be an alternative in pheochromocytoma,
etc. Also used to lower BP in MI, unstable angina,
eclampsia.
-Furosemide: as an adjunct with any of the above drugs
if there is volume overload (acute LVF, pulmonary
edema, CHF)

53. Principles of HTN treatment
NON PHARMACOLOGICAL MEASURES
Diet
Salt restriction in diet
Aerobic activity or exercise
Weight reduction
Reduce alcohol intake
Mental relaxation

54. Principles of HTN treatment
 Stage I HTN treatment
-Start with a single appropriate drug. A B C D rule (A—ACE
inhibitor/ARB; B—β blocker; C—CCB, D—diuretic). A & B
are preferred in younger patients (<55 years), C & D are
preferred in the older (> 55 years) for step 1 treatment.
-Initiate therapy at low dose; if needed increase dose
moderately.
-If only partial response is obtained, add a drug from another
complimentary class.(step 2).

55. Principles of HTN treatment
Stage II HTN treatment
Started on a 2 drug combination; one of which usually is a
thiazidediuretic.(directly step 2)
Rationale for combination therapy : Since BP is regulated
by several interrelated factors, an attempt to block one of
them tends to increase compensatory activity of the others.
Hence drugs with different mechanisms of action are
combined.
Eg: Drugs which increase plasma reninactivity—diuretics,
vasodilators, CCBs, ACE inhibitors may be combined with
drugs which lower plasma reninactivity—β blockers,
clonidine, methyldopa.

56. Steps of therapy
In step 2 when two drugs are to be used, combine
one out of A or B with one out of C or D.
When 2 drugs are inadequate in achieving target BP
lowering, 3 drug regimen is prescribed. Both C and D
are combined with A or B
Patients who fail to reach the goal BP with 3 drugs
are labelledas ‘resistant hypertension’. In them even
4 drug therapy (step 4 )may have to be given to
achieve the target BP.

57. THANK YOU