Presented by : Professor Dr. Imad A-J Thanoon
AngiotensinogenAngiotensin I (10 amino acid)
Angiotensin II (8 amino acid) -- constrict arterioles and veins
Angiotensin III (7 amino acid) Aldosterone - mineralocorticoid-- v/c arterioles/veins(retain Na+ / blood volume) Inactive products
Renin
Renal arterial pressure (via intrarenal baroreceptors)NaCl flux in macula densa cells (in thick ascending limb)Renal sympathetic nerve (1) Angiotensin converting enzyme ( ACE or kininase II) in vascular endothelium and blood
Circulating protein formed mostly in liver
Angiotensin1. Angiotensinogen
Protease enzyme formed mainly in the juxta-glomerular apparatus in kidney.
2. Renin
Its production is increased by: corticosteroids (mainly glucocorticoids), estrogens, thyroid and angiotensin II.
1. Decreased renal perfusion2. Decreased Na in macula densa (part of distal tubules)3. Sympathetic stimulation (mostly β1 receptor) Renin secretion is controlled by
Renin
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Angiotensin II. Vasopressin Hyperkalemia
Renin level by
Renin level by
Angiotensin
3. Angiotensin converting enzymeACE = Kininase II = Dipeptidyl carboxy-peptidase.Present in capillary endothelium especially in the lungMetabolizes other autacoids e.g. bradykinin & substance-P
Act on specific receptors (angiotensin receptors AT1 and AT2) 1. Pressor effect on blood vessels especially arterioles of renal, skin and mesenteric vessels which is 40 times more than noradrenaline. 2. Increases proximal Na tubular reabsorption, inhibits renin release and increases angiotensinogen production.
Actions:
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Angiotensin
3. Increases biosynthesis and release of aldosterone from adrenal cortex. 4. Stimulates catecholamine release from adrenal medulla, stimulates autonomic ganglia and facilitates sympathetic transmission.
Angiotensin
5. Positive inotropic effect on heart and has mitogenic effect on vascular and cardiac muscle cells which may contribute to cardiovascular hypertrophy.
6. Spasmogenic effect on smooth muscles. 7. Stimulates drinking (dispogenic effect), increases vasopressin and ACTH.
Angiotensin
In treatment of hypotension especially due to overdose of α - blockers. It is given by injection Therapeutic uses
Angiotensin II
VasoconstrictionAldosterone Secretion
Direct Renal Sodium Retention
↑ Thirst ADH Release
↑ Cardiac Contractility Sympathetic Facilitation: Central Nerve terminal (ganglionic ?)
Cardiac & Vascular Hypertrophy
All known physiologic effects are mediated by the angiotensin II type 1 receptor
ANGIOTENSIN II - SUPPORT OF THE BLOOD PRESSURE
1. Drugs inhibiting renin secretion:- β-blockers.- α 2 agonists (clonidine; guanaracine, guanabenz & methyldopa).2. Angiotensin converting enzyme inhibitors (ACE inhibitors): captopril, enalapril ......... Drugs affecting renin / angiotensin system
Angiotensin
Angiotensin Converting Enzyme Inhibitors
Large number of drugs available differ mainly in the following: Potency Route of elimination Duration of action Being prodrugs or active drugs Similar therapeutic indications, adverse effects and contraindications
BLOCKERS OF THE RENIN-ANGIOTENSIN SYSTEM Angiotensin converting enzyme (ACE) inhibitor: captopril (2 amino acid), enalapril (3 amino acid)
Vasodilatation and decrease in blood pressure via: ANG II ( concentrations of renin and ANG I) Bradykinin (vasodilator) Activity of sympathetic nervous system Blood volume ( Na+ reabsorption at renal tubules)Dilate arterioles: renal blood flow -- glomerular filtration rate (GFR) blood volume Dilate capacitance vessels (venodilation, venous return and cardiac work)Patients with high plasma renin activity are particularly sensitive to ACE inhibitors
Kinin-related
Adverse EffectsHypotension Renal Insufficiency (if bilateral renal artery stenosis) Hyperkalemia why(?) Cough (20 %) Angioedema With captopril especially: neutropenia, nephrotic syndrome, skin rash, taste disturbances (SH group- related).
Compete with angiotensin II for AT1 receptorsThey are pure antagonists.They are effective orally Angiotensin
3. Angiotensin receptor blockers:
Losartan, candesartan, telmisartan, irbesartan and valsartan
Therapeutic uses: similar to ACE.I used in hypertension. Side effects Similar to ACE.I. but not dry irritant cough
Bradykinin
Kallidin
Kinins Aminopeptidase
inactive
Kininase I & II
Hageman factor, trypsin and plasma kallikrein.
plasma kallikrein
Tissue kallikrein.
Plasma Prekallirein
HMW kininogen
LMW kininogen
inactive
Actions of Kinins
KallidinBradykinin
10 aminoacid
9 amino-acid
They act on (B1&B2) receptors
1-Vasodilatation of vascular bed (10 times more potent than histamine).
a-Direct inhibitory effect of kinin on arteriolar smooth muscle
b-mediated through release of NO or vasodilator PGs as PGE2
The vasodilatation may result from
They relax arterioles but veins are contracted They decrease B.P. and increase H.R. and COP (reflex and direct action). Actions of Kinins
Actions of Kinins
2. Increase capillary permeability.3-Spasmogenic action on GIT and bronchi.
4-Potent algesic on nerve endings.
They may have role in inflammation, anaphylaxis, shock, acute pancreatitis and inactivation of various prohormones as prorenin and proinsulin.
PG synthesis inhibitors as aspirin is a kinins inhibitor Kinins
Drugs affecting kinin system:ACE inhibitors as captopril is a kinase 11 inhibitor so enhance the action of kinins. Trasylol (aprotinin) isa kallikrein inhibitor used to minimize bleeding in patients undergoing coronary bypass.
It is a polypeptide
It is present in:1. C.N.S. (acts as a chemical transmitter) 2. Gut (acts a local hormone).
Opioid (e.g. morphin) and endorphins & enkephalins →↑ Opiate receptors →↓ release of substance-P → analgesia. It has a vasodilator effect on the arterioles but spasmogenic on veins, intestinal and bronchial muscles. It causes salivation and diuresis.
Is a potent Vaso.Const. isolated from endothelium of various tissues and may have role in cardiovascular diseases.N.B.: Bosentan is orally active competitive inhibitor of endothelin approved for use in pulmonary hypertension. It is hepatotoxic and teratogenic. Endothelin
Relaxes smooth muscles, Increase glycogenolysis, growth hormone, renin and prolactin.Potent V.D.→ coronary V.D and postive ino and chronotropic effect Vasoactive intestinal polypeptide (V1P)
Released from atrium and increase the glomerular filtration rate →↑Na excretion in urine Inhibit renin and aldosterone secretion. Atrial natriuretic peptide (ANP)
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