Why is blood pressure important?

-> In order to move the blood in different parts of the body

The sources that generate pressure in our body

1. Heart
2. Blood vessels – Arteries and Veins

Arteries Veins
Carries oxygen rich blood Carries deoxygenated blood
Arteries have higher pressure than veins Least pressure
Aka resistance vessels Aka capacitance vessels

Why is the blood pressure higher than arteries?

- Because the blood from arteries directly came from the contraction of the heart, also the tunic media of arteries
are also much thicker than veins which results in faster delivery of nutrient rich-blood in different sites of the
body.

Hydraulic equation of blood pressure

Blood pressure = Cardiac Output x Systemic Vascular Resistance

Cardiac Output and Systemic vascular resistance are both directly proportional to blood pressure

1. Cardiac Output- The “volume” of the blood pump out by the heart every minute
Cardiac output = Heart Rate (HR) x Stroke Volume (SV)
A. Heart Rate (Chronotropy)– The number of heart beats per minute
B. Stroke Volume – The “volume” of blood pump out every contraction of the heart

2 major Factors that are affecting the stroke volume

1. Strength of the contraction (inotropy)

2. Cardiac Preload/ Venous return/End Diastolic ventricular volume
Defined as the volume of the blood in the heart at the end of the relaxation (Diastole). If there is a relaxation
the heart will be filled with blood; if the heart contracts it will eject all the blood generated by diastole.

2 Factors that affects the cardiac pre-load

1. Tone of the “veins” or the pressure generated by the veins – if there is a higher pressure in vein
(vasoconstriction) the blood will return more quickly and there will be more blood during heart relaxation or
sometimes it might overflow.
2. Fluid content of the blood = refers to the level of Sodium ions and water molecules in the blood.

2. Systemic Vascular Resistance – The resistance needed to be overcome by the blood to eject its blood content
through ventricular contraction

Aka: Cardiac Afterload, Peripheral Vascular Resistance

SVR – is determined by the tone/constriction of arterioles

Cardiac preload vs afterload

Preload Afterload
The volume of the blood brought by veins into the heart This is the arteriolar resistance needed to overcome by
Results in: the left ventricle in order to pump the blood into the
-hypervolemia systemic circulation.
-Regurgitation of cardiac valves
- Heart Failure Vasoconstriction of the arteries will lead into
This 3 happens because the heart cannot accommodate hypertension
the large amount of blood brought by the veins FD

Mechanism of blood pressure control (Compensatory mechanism)

2 major compensatory mechanism

1. Baroreceptor complex – Responsible for the regulation for short term activities for example, jumping, crawling,
squatting (postural changes)
Components of baroreceptor complex
A. Baroreceptors component – are found in the aortic arch of the heart and carotid sinus.
B. Afferent pathways (cranial nerves)
- Cranial nerves 9 or glossopharyngeal it carries the impulse generated (low pressure) by
baroreceptor in the carotid sinus into the brain.
- Cranial nerves 10 or vagus nerve it carries the impulse generated (high pressure) by
baroreceptor in aortic arch
C. Vasomotor center of the brain
- Receives the impulses generated by cranial nerves 9 and 10
D. Efferent pathway
- Vagus nerves send parasympathetic reflex to heart (bradycardia)
- Glossopharyngeal nerves sends sympathetic reflex to heart (tachycardia)
E. Heart
2. Renin-Angiotensin-Aldosterone-System (RAAS) – Responsible for maintaining blood pressure for the long term
 Blood pressure categories
American Heart Association (2017)

Etiology of hypertension

PRIMARY – 90-95% of the patient; hypertension with no identifiable cause

Influenceable factors

1. Lifestyle such as diet, smoking, obesity, Increase salt intake, Lack of Calcium, Magnesium, Potassium intake

Non-influenceable

1. Family History
2. Insulin Resistance
3. Age and Sex
4. Defect of local vasomotor regulation

SECONDARY – 5% of the causes of hypertension; identifiable cause of hypertension.

1. Artery stenosis – Narrowing of the large arteries which results in the increase cardiac afterload
2. Pheochromocytoma – tumor in adrenal medulla
3. Coarctation of aorta – a birth defect in which the aorta is much narrower compared to average
4. Hypertension due to pregnancy
5. Drug induced hypertension
6. Neurologic disease
Complications of hypertension

1. Cardiac Heart Failure – The heart is pumping inefficiently which results in low oxygen distribution in the body
2. Coronary Artery Disease – blockage in the artery
3. Renal Disease -
4. Ischemic stroke
5. Retinal Disease
6. Aneurysm
7. Cardiomyopathy

Summary of increased cardiac output and SVR effects

4 Classification of ANTI-HYPERTENSIVE AGENTS

1. DIURETICS – Decreases the blood volume

2. SYMPHATOPLEGICS – Decreases SVR and CO
3. DIRECT VASODILATORS – decreases SVR
4. ANGIOTENSIN ANTAGONISTS – Decreases blood volume
DIURETIC AGENTS – Decreases the amount of sodium ions and water molecules to decrease the blood contents.

Natriuresis – Urinary excretion

Aquaresis – Water excretion

Diuretic – combination of natriuresis and aquaresis

Regions of Kidney

1. PCT – Proximal Convoluted tubules

- The main site of Bicarbonate reabsorption
- Sodium Reabsorption
- Water permeable
2. Loop of Henle
A. Thin Descending Limb
- Water permeable
B. Thick Descending Limb
- Reabsorption of Na, K, Cl
- Secondary reabsorption of Ca and Mg
- Water impermeable
3. Distal Convoluted tubule
-Sodium and Chloride reabsorption
-presence of parathyroid hormone which
regulates the reabsorption of calcium in the
kidney
- Water impermeable
4. Collecting Duct
- Sodium ion reabsorption
- Potassium ion excretion to the urine
CLASSIFICATION OF DIURETIC AGENTS

Diuretics that affect the excretion of salt Diuretics that affect the excretion of water
Carbon Anhydrase Inhibitors -> PCT ADH antagonists
Loop Diuretics -> Loop of Henle Osmotic Diuretics
Thiazides -> Distal Convoluted Tubule
Potassium sparing – Collecting Duct

Carbon Anhydrase Inhibitors (CAIs)

These are drugs that have sulfonamide-like structure

EXAMPLE:
Acetazolamide
Dorzolamide
Brinzolamide
Dichlorphenamide

MOA of CAIs in Proximal Convoluted Tubule

PCT – Facilitates the Sodium Ion reabsorption and Bicarbonates reabsorption

Physiology of PCT

1. Sodium-Proton exchanger – Re-

absorb sodium from urine in
exchange of hydrogen ions.
2. The protons in urine will react
with bicarbonate anions (HCO3-)
And for carbonic acid (H2CO3)
3. The Carbonic acid will be
dehydrated by Carbonic
anhydrase which will split into
two molecules: Water and CO2
4. The water and CO2 will diffuse
inside the PCT

5. Carbonic anhydrase will rehydrate the CO2 and H2O back into carbonic acid (H2CO3)

6. The carbonic acid will undergo ionization the positive charge Hydrogen will be separated from the negative
charge bicarbonate

7. Bicarbonate and Sodium will finally be reabsorbed into the blood through the Sodium-Bicarbonate co-
transporter.

MOA of CAIS: Prevents the synthesis of Carbonic Anhydrase – Thus decreasing the
amount of Sodium and bicarbonate ions in the blood
Pharmacological effects of CAIs

1.Provides Short Action of Natriuretic effect

-> The natriuretic effect only last for not more than 3 days. The problem with this is” Diuretics are usually used
as Maintenance drug for anti-hypertension.
->However; the continuously inhibits the reabsorption of bicarbonate ions which will results in metabolic
acidosis.
2. Inhibits Carbonic anhydrase in ciliary bodies
-> The ciliary bodies are the site for aqueous humor production in the eyes. One of the enzymes needed to
produce aqueous humor is the carbonic anhydrase enzymes. Which may lower the inflow Humors
3. Inhibits the production of CSF in choroid plexus

Clinical Indications of CAIs

1. Treatment of glaucoma
2. Urinary alkalinization – used in treatment of drugs that causes acidic urine e.g.
3. Treatment of metabolic alkalosis
4. Treatment of Acute Mountain Sickness
Acute mountain sickness – The overproduction of CSF when climbing high-altitude area which results in
swelling of the head
5. Treatment of Catamenial seizure – Epilepsy during menstruation (Acetazolamide)

Toxicity of CAIs

1. Hyperchloremic metabolic acidosis – Increase acidity of the blood due to lack of bicarbonate
2. Formation of renal stones
3. Renal Potassium Wasting
4. Drowsiness
5. Sulfonamide associated toxicities – SJS 10, Urticaria, Aplastic anemia. Hemolytic anemia, Neutropenia
Crystalluria

Contraindication of CAIs

1. Chronic Obstructive Pulmonary Diseases – Patient with COPD already have an acidic body; CAIs will further
aggravate the acidity of the blood.
2. Chronic Liver Disease –
Patient with Liver disease cannot convert ammonia into urea; thus it will use compensatory mechanism of the
body to excrete the toxic compound. Thus, the ammonium is directly excreted in the urine
-The use of CAIs will result in the enhance level of Bicarbonates. Remember that ammonium and Bicarbonates
are both basic, so they cannot be excreted all at the same time.
-The compounds that is being continuously place in the urine is the one that will be excreted; and the other
compound will be reabsorbed. In this case, Bicarbonate will be excreted and Ammonia will be reabsorbed.
-Accumulation ammonia will result into encephalopathy
LOOP DIURETICS aka high ceiling diuretics

->Highest efficacy in mobilizing Na ions and chloride ions from the body.
->They are called high ceiling diuretics because their effects increase when increasing their doses unlike other
diuretics that have a maximal effect.
->Considered as the most efficacious commercially available diuretic agents

Common Drug Examples:

Furosemide

Ethacrynic acid

Bumetanide

Torsemide

Physiology of Thick Ascending Limb

1. Sodium (+1), Potassium (+1) and two

chloride (-2) ions will enter the Thick
ascending limb through the Sodium-
Potassium-Chloride cotransporter.
2. Once they enter the TAL. They will be
reabsorbed into the blood through the
potassium/Chloride transporter.
Sodium ion will be reabsorbed
through the Na/K ATPase
3. The potassium ion that has been
released through the ATPase will be
excreted to the urine
4. The potassium ion will alter the charge
of the urine making it more positive

5. A positively charge urine will push Divalent cations into the blood through the paracellular
transport in order to lessen the positive charge of the urine.
Paracellular transport is the small gap between the cells of Thick ascending Limb where Divalent
cations can pass through.

MOA of Loop Diuretics: Inhibits the NKKC2 (Sodium-Potassium-2Chloride

Cotransporter)
Pharmacological effects of Loop Diuretics

1. Lowers Sodium and Chloride ion level in the blood as well as the divalent ions
2. Theoretically, they can cause hypocalcemia. However, the body have a compensatory mechanism
for lowering of calcium. The body will enhance the effect of Parathyroid Hormone and absorption
of Vitamin D to enable more calcium absorption.
3. Induces formation of COX-2 - PGE2. PGE2 further enhances the Diuretic effect in the kidney.
However, they will interact with NSAIDs
NSAID can block COX-2, thus it will lower the product of PGE2 effects on the kidney

Clinical Indications of Loop Diuretics

2 major clinical uses of Loop diuretics:

A. Edematous cases such as heart failure and pulmonary edema

Heart failure – there is an accumulation of blood (cardiac preload) because the heart has a lower contractility
capability
Pulmonary Edema – Furosemide is most specifically used. Because it is the only loop diuretics with venodilating
effects
B. Non-edematous cases
->Treatment of HyperKalemia
->Treatment of Acute Renal Failure
->Treatment Anion overdose = most specifically the halogens

Toxicity of Loop Diuretics

1. Hypokalemic metabolic acidosis

2. Ototoxicity – All loop diuretics have ototoxic effect, but ethacrynic acid have the greatest risk.
They target CN8 – Vestibulocochlear nerve which is responsible for hearing
Drug interaction: Additive ototoxic effect with aminoglycosides (antibiotic) and cisplatin (anti-cancer)
3. Causes Hyperuricemia
Contraindicated to people with gout
4. Allergic Reactions – Sulfonamide like reactions
Example: Furosemide and Bumetanide
5. Hypomagnesemia
THIAZIDES DIURETICS

These drugs also have sulfonamide like structures

Benzothiadiazides Thiazide-like compounds

Not structurally thiazide but have the
same effects with thiazides
-Chlorothiazide -Indapamide
-Hydrochlorothiazide (HCTZ) -Metolazone
-Chlorthalidone

Physiology of Distal Convoluted Tubule

1. Sodium ion and Chloride ion enters through

the Distal Convoluted Tubule via NCC
(Sodium-Chloride Co-transporter)
2. Sodium are re-absorbed into the blood
through Sodium-ATPase
3. Thiazides diuretics do not blocks the
Parathyroid hormones and its calcium
absorption. But enhances the action of PTH

MOA of thiazides: Inhibits the

function of Sodium-Chloride co-
transporter

Pharmacological effects of Thiazide Diuretics

1. Inhibition of sodium chloride absorption

2. Also causes Potassium and Magnesium wasting although they are not elaborated in the MOA
3. Enhances the action of PTH, which may cause hypercalcemia
4. Affects prostaglandin production – Increases PGE2 synthesis which increases the Diuretic effects
5. Reduces peripheral vascular resistance

Timeline of Thiazide pharmacological effects

In the first 2 weeks of Thiazides administration: Blockage of Sodium-Chloride Co-transporter

After those 2 weeks: Thiazides will begin to cause vasodilation in the peripheries
Clinical Uses of Thiazide Diuretics

1. First line agent for hypertension along with ACE, ARBs and CCBs
2. Treatment of Heart failure
 Sometimes loop diuretics and Thiazide diuretics are being combine to treat heart failure however the
potassium level must be strictly monitored.
3. Nephrolithiasis due to idiopathic hypercalciuria
 Formation of renal stones due to increase production of Calcium by PTH. Excess calcium ions in the kidneys
will further attract the calcium ions from the blood, which will cause hypercalcemia in the kidney and
hypocalcemia in the blood.
Accumulation of calcium ions will in the kidney will form calcium oxalate (kidney stones).
4. Nephrogenic Diabetes insipidus
 Increases vasopressin (ADH). Vasopressin are responsible for increasing water reabsorption needed by
people with insipidus

Toxicity of Thiazide Diuretics

1. Hyponatremia and hypochloremia

2. Hyper GLU (Glycemia, Lipidemia, Uricemia)
People with gout should be monitored
3. Sulfonamides like reactions – SJS10, Urticaria, Crystalluria, Aplastic anemia, Hemolytic anemia, neutropenia
POTASSIUM SPARING DIURETICS

 Prevention of K ion secretion in the collecting tubules by blocking the action of aldosterone.

Classification of Potassium sparing diuretics based on their mechanism of actions

1. Direct action mineralocorticoid Receptor antagonism

Example: Spironolactone, Eplerenone
2. Inhibition of Na ion influx in the luminal membrane aka (ENaC inhibitors epithelial sodium channel
inhibitor
Example: Amiloride, Triamterene

Physiology of Collecting duct

1. Sodium ions will enter the collecting duct

through ENaC. However, ENaC must be
activated by aldosterone first to open .
2. Once the Sodium ion entered the collecting
duct, it will be reabsorbed in the blood
through Sodium-potassium ATP-pump
3. The potassium ion will be secreted into the
urine

MOA

ENaC inhibitors – inhibits aldosterone from binding

to ENaC receptors

Direction Action mineral corticoid antagonist –

inhibits the aldosterone itself
Pharmacological effects of Potassium sparing Diuretics

1. Reduction of sodium ion reabsorption in the blood

2. Inhibits the secretion of potassium
3. Also increases the synthesis of PGE2

Clinical Uses of Potassium sparing Diuretics

1. Use in the treatment of diuretic-induced hypokalemia (especially furosemide)

2. Treatment of secondary hypertension due to hyperaldosteronism
3. Treatment of Heart Failure
4. Spironolactone is being used to treat resistant hypertension
5. Spironolactone is being used to treat ascites
6. Polycystic Ovarian Syndrome – development of hirsutism and prone to acne
Spironolactone have anti-androgenic effect by PCOS
Toxic Effects Potassium sparing Diuretics

1. Hyperkalemia
2. Hyperchloremic metabolic acidosis
3. Gynecomastia – tenderness of the breast due to anti-androgenic effect of spironolactone
4. Acute Renal Failure – observe in Triamterene
5. Kidney stones – observed in Triamterene
SUMMARY OF DIURETICS AND ITS ACTION ON ELECTROLYTES

Carbon Anhydrase Inhibitors Lowers bicarbonate ion in the blood

(Hypobicarbonaturia)
Lowers sodium ions in the blood
(Hyponatremia
Increase chloride ions in the blood
(Hypochloremia)
Increases bicarbonate ions in the urine
Increases sodium ion in urine
Hyperchloremia metabolic acidosis

Loop Diuretics Lowers Sodium Ions in the blood

(Hyponatremia)
Lowers Chloride ions in the blood
(Hypochloremia)
Lowers Potassium ions in the blood
(Hypokalemia)
Lowers Calcium ions in the blood
(Hypocalcemia)
Lowers Magnesium ions in the blood
(hypomagnesemia)

Hypokalemic metabolic alkalosis

Thiazides Lowers Sodium ion level in the blood
(hyponatremia)
Lowers Chloride ion level in the blood
(hypochloremia)
Lowers magnesium ion level in the blood
(hypomagnesemia)
Lowers Potassium ion in the blood
(hypokalemia)
Increases calcium ion levels in the kidney
(hypercalcemia)

Potassium Sparing Lowers Sodium level in the blood

(Hyponatremia)
Lowers bicarbonate level in the blood
Increases the Potassium level in the blood
(hypernatremia)
(hypobicarbonaturia)
Increases chloride ions in the blood
(hyperchloremia)
AQUARETIC AGENTS

Two major types of aquaretic agents

Osmotic Diuretics (Mannitol) Vasopressin receptor antagonists

Mannitol effects based on mode of administration

Per Oral – Osmotic cathartic effect

Intravenous – Osmotic Diuretic

What is osmosis?

1. The water molecule from high concentration will diffuse into the lower concentration of water
2. The water molecules will be attracted in gradient with higher solute concentration, especially to ions such as
Na+ because water can easily form bond with.

Mechanism of Action of Mannitol

 When Mannitol is administered via I.V. it will be rapidly diffused in the kidney due to its high glomerular
filtration rate. Mannitol being a large and impermeable solute, it will create an osmotic gradient between
the PCT, TAL and collecting duct and lumine urine.

 Mannitol in the lumen urine will attract water molecules from the kidney and blood into the urine.

Clinical uses of Mannitol

 Can be used to decrease intracranial pressure in patients with cerebral edema

Adverse effects of Mannitol

 Dehydration
 Hypernatremia – Due to water and sodium ratio imbalance in the blood
 Hypovolemia – due to loss of water molecules
ANTI-DIURETIC HORMONES (vasopressin)

Vasopressin-1 : Constricts blood vessels

Leading to enhance SVR

Vasopressin-2: Increase water reabsorption in

Kidney (collecting duct) leading to enhance blood tone

Physiology of vasopressin-2

1. ADH Binds to vasopressin-2 receptors in

collecting duct.
2. This will binding will translocate aquaporins
into the membrane of the collecting ducts
3. Water molecule from urine can enter the
collecting duct through the aquaporins

Classification of ADH Antagonists

1. Non-selective drugs
a. Lithium
b. Demeclocycline
c. Conivaptan
2. V2-selective drugs
a. Tolvaptan
b. Lixivaptan
c. Satavaptan
Clinical uses of ADH-antagonist

1. Treatment of SIADH (Syndrome of inappropriate antidiuretic hormone secretion)

2. Other conditions with elevated ADH disease

Adverse effects of ADH-antagonist

1. Induce nephrogenic Diabetes insipidus

2. Renal Failure

Anti-hypertensive Diuretic drug combinations

1. Treatment of Edematous case such as heart failure Desmopressin
 Furosemide and Thiazides
 Monitor Potassium level when using
Sympathoplegics

Drugs that paralyze sympathetic effects such as tachycardia and vasoconstriction.

Therapeutic goals of symphatoplegics

 Lowers peripheral vascular resistance

 Inhibits cardiac function
 decrease cardiac preload by increasing venous pooling in capacitance vessels -> Dilates vein so it can
accommodate more blood

TWO CLASSIFICATIONS OF SYMPHATOPLEGICS

Centrally Acting Symphatoplegics Peripherally acting symphatoplegics

Affects the vasomotor center of the brain A. ganglionic blockers
B. Adrenergic Neuronal blockers
Are technically alpha-2 agonists C. alpha blockers
D. Beta blockers

CENTRALLY ACTING SYMPHATOPLEGICS

1.Methydopa – these are prodrugs that are converted into alpha-methyl norepinephrine, in which they
reduces renal vascular resistance.
Advantage: FDA approved anti-hypertensive for pregnant women
Other approved anti-hypertensive for pregnant: Labetalol, Hydralazine , Nifedipine
Adverse effect: Sedation and depression of the brain due to alpha-2 activation
False positive in Coomb’s test
2.Clonidine – are rapid acting anti-hypertensive and use in hypertensive emergencies
Initial effect: spike in hypertension
Prolonged effect – Hypotension
3.Guanabenz -
4.Guanfacine
PERIPHERALLY ACTING SYMPHATOPLEGICS

1, Ganglionic blockers (Nn blockers)

Example: Mecamylamine, Trimethaphan, Hexamethonium

 Are no longer used today due to anti-cholinergic effect

2.Adrenergic Neuronal Blockers –

Example: Guanethidine, guanadrel, reserpine

Reserpine – inhibits the storage (vesicles) of adrenergic neurotransmitters

Guanadrel, Guanethidine, Bretylium – Blocks the docking protein of Vesicles.

Guanethedine – rarely used because of its pharmacologic sympathectomy – marked postural hypotension, impaired
ejaculation (retrograde ejaculation) and diarrhea
VASODILATORS

Mainly dilates resistance vessels through relaxation of vascular smooth muscles

May also dilate capacitance vessels in some instances

PHYSIOLOGY OF NITRIC OXIDE – NO enhances the production of cGMP to produce a relaxation effect

MOA of nitrovasodilators

1. Nitrates are converted NO synthase into

Nitric Oxide (CO)

2. NO stimulates Guanidyl cyclase from

In converting GTP into cGMP
3. cGMP inhibits phosphorylation of MLC
resulting to vasodilation
 cGMP
c-GMP dephosphorylates
myosin light chain kinase
which will inhibit the
contraction of MLC, causing
vascular relaxation

Physiology of vascular muscle hyperpolarization 1. A ligand binds to the receptor of

potassium channel; allowing the
exit of potassium ions to the
extracellular fluid
2. The potassium inside the vascular
smooth muscle will be depleted,
and thus the positive charge ions
decrease
3. The anions will dominate in the
intracellularly making the vascular
smooth muscle hyperpolarized
4. Hyperpolarization will cause the
vascular smooth muscle to relax
and thus the blood vessel will also
be able to relax.
3 Major classifications of Vasodilators

Arteriolar (direct) vasodilators Arterial and venous vasodilators CCBs

(non-selective)
1. Hydralazine 1. Sodium Nitroprusside 1. Non-Dihydropyridine
2. Minoxidil 2. Alpha-adrenoreceptor 2. Dihydropyridines
3. Diazoxide blockers
4. Fenoldopam

FENOLDOPAM = a D1-receptor
agonist which may cause
diuresis (Renal vasodilation)
Common Compensatory Response when vasodilators are used as monotherapy

1. Reflex tachycardia – increases cardiac demand for oxygen

 Remedy: Combined with Beta-blockers to counteract reflex tachycardia
2. Peripheral edema – increases blood tone
 Remedy: Combined with diuretics to decrease blood volume

DIRECT VASODILATORS – arteries only

1. Minoxidil
MOA: Hyperpolarization of smooth muscle
 Orally active vasodilators
 Only dilates arterioles
 Promotes hirsutism / hypertrichosis
 Are also being used as topical for hair-growth (Rogaine)
2. Hydralazine
MOA: Release of Nitric Oxide
 FDA-approved for management of hypertension in pregnant women
 Are combines with Isosorbide Dinitrate to manage heart failure

Adverse effect of Hydralazine

 Distinct ADR for hydralazine: Systemic Lupus Erythematosus

 Hypotension
 Reflex tachyardia
 Palpitation
 Angina
 Headache
 Anorexia
 Nausea
3. Diazoxide
MOA: Hyperpolarization of smooth muscles
 Long-acting arteriolar dilator
 Used in treatment of hypertensive emergencies
 Also used in treatment of secondary hypoglycemia due to insulinoma by inhibiting the insulin release from
the pancreas

Adverse effects of Diazoxide

 Hypotension
 Hyperglycemia
 Reflex tachycardia
4. Fenoldopam
MOA: D-1 agonists which dilates peripheral arteries and promotes GFR which results to natriuresis
 Used as alternative agent for hypertensive emergencies and post-operative hypertension

Adverse effects of Fenoldopam

 Headache
 Flushing
 Increases IOP
NON-SELECTIVE VASODILATORS – Targets both arteries and veins

1. Sodium Nitroprusside
MOA: Stimulates the release of NO which causes the reduces peripheral vascular resistance (SVR) and venous
return (CO)
 First line agent for hypertensive emergencies worldwide

Are only use for emergency and not long-term

administration due to possible risk of cyanide
accumulation

Adverse effects of Sodium nitroprusside

 Hypotension
 Metabolic acidosis
 Arrhythmias
 Methemoglobinemia
 Cyanide poisoning – most serious toxicity of sodium nitroprusside (Canines inhibits the function of CYP450)

Remedy for Cyanide poisoning

 Cyanide antidote kit = Amyl Nitrite, Sodium Nitrite, Sodium thiosulfate

 Hydroxocobalamin
 High Dose Methylene Blue
Vasodilators Calcium Channel Blockers

Mechanism of vascular smooth muscle contraction

 1. The sarcoplasmic reticulum – an specialized ER that sequesters/stores large amount of calcium
2. For the sarcoplasmic reticulum to release calcium = A trigger calcium from extracellular cell will
come inside the cells and binds to Ryr (Ryanodine receptors)
3. The binding of trigger calcium and Ryanodine receptors will cause the Reticulum to release large
amount of calcium ions in the intracellular cell
4. The calcium ions will complex with calmodulin and activate Myosin Light Chain Kinase (MLCK)
5. The activation of MLCK enzyme will phosphorylates the myosin light chain in order to caused
contraction of blood vessels

MOA of calcium channel blockers

- Blocks the L-type channel in order to inhibit the trigger calcium from stimulating ryanodine receptor and
ultimately there will be no calcium release which are needed for MLC contraction of vascular smooth muscles

Classes of CCB’s based on SOA

1. Non-Dihydropyridine = contains phenylalkylamines (verapamil) and benzothiazepines (diltiazem)

 Targets the heart itself
 Verapamil – most cardio selective CCBs
 Benzothiazepine – targets both heart and arteries
2. Dihydropyridines – targets the arteries only (Suffix of their drugs is (“dipine”) e.g. amlodipine

Classes of CCB’s based on Duration of action

Intrinsically Short-acting

 All non-dihydropyridines
 All DHP except Lercanidipine, Amlodipine, Lacidipine

ADR: Reflex tachycardia and Edema

Long Acting CCB’s = Lower reflex tachycardia and edema compared to intrinsically short acting

 Lercanidipine, Amlodipine, Lacidipine

Modified Long-Acting = These are intrinsically short acting CCBs but are design to become a modified release.

Example: Verapamil SR

Clinical uses of CCBs

- First line agent against hypertension along with ARBs, & ACE inhibitors, Diuretics specifically Thiazides
- Treatment of Angina
- Treatment of Supraventricular tachycardia – Verapamil is the one used because it is the most cardio
selective
- Treatment of Raynaud’s Syndrome – vasospasm of the digits due to vasoconstriction of the peripheral
arteries/veins because of hypothermia
- Migraine
- Preterm labor
- Stroke
- Hemorrhagic stroke – nimodipine
Adverse effects of CCBs
- Constipation – Most extracardiac effect of verapamil
- Pretibial edema
- Dizziness N&V
Angiotensin Antagonist -Inhibition of synthesis and action of ACE

Classification of angiotensin antagonists

1. ACE inhibitors – Inhibits the synthesis of angiotensin

2. ARBs – inhibits the action of angiotensin
3. Renin inhibitor – Aliskerin

MOA of Aliskerin

MOA of ACE inhibitors – reversible antagonists of ACE II thus inhibiting the formation of angiotensin II

MOA of ARBs – Reversible antagonists of angiotensin II receptors

Other Effects of ACE inhibitors

 Facilitate the increase

level of bradykinin level
In the body because it
stops the ACE from
destroying Bradykinin

Bradyinin – caused a
vasodilation effect on
the whole body.

Example of ACE inihbitors – ends in “pril”

Majority of the ACE inhibitors are prodrugs except

Captopril, Lisinopril and enalaprilat.

Acute ACE inhibitors – Captopril, Lisinopril and Enalaprilat

because they not need to be metabolized to take effect
Adverse effects of angiotensin antagonist

ACE inhibitors only side effect – Angioedema and Cough

Once ACE inhibitors exhibits the effect of angioedema, immediately stop and use ARBs instead

Cough is due to accumulation bradykinins in the lungs. Decrease the dosing of ACE inhibitors to stop coughing or stop
the use of ACE inhbitors temporarily.

IF coughing is still present even after doing the remedies, stop and use ARBs instead

ADR of both ACEi and ARBs

1. Renal damage

Hyperkalemia = C/I with K sparing diuretics

Hypotension

Contraindications of all angiotensin antagonists

Less than 100mmHg

Pre-existing in hyperkalemia

Pregnancy due to its teratogenic effect most especially during the 2 nd and 3rd trimester - Fetal hypotension, Anuria, Renal
dysgenesis of fetus
Antihypertensive Combinations – the combination of drug is used to battle the compensatory mechanism of the body.

Choice of anti-
hypertensive based on
patient’s diseases

The only B-blockers for

CHF

1. Bisoprolol
2. Carvedilol
3. Nebivolol
4. Metoprolol
succinate
Choice of anti-hypertensive
based on patient’s diseases

ACE Inhibitors and

Furosemide