Professor Dr. Imad A-J Thanoon Autacoids Presented by : Professor Dr. Imad A-J Thanoon

Angiotensin 1. Angiotensinogen Circulating protein formed mostly in liver Its production is increased by: corticosteroids (mainly glucocorticoids), estrogens, thyroid and angiotensin II. 2. Renin Protease enzyme formed mainly in the juxta-glomerular apparatus in kidney.

Renin secretion is controlled by Renin level by 1. Decreased renal perfusion 2. Decreased Na in macula densa (part of distal tubules) 3. Sympathetic stimulation (mostly β1 receptor) + Renin level by Angiotensin II. Vasopressin Hyperkalemia

Angiotensin 3. Angiotensin converting enzyme ACE = Kininase II = Dipeptidyl carboxy-peptidase. Present in capillary endothelium especially in the lung Metabolizes other autacoids e.g. bradykinin & substance-P

Angiotensin Actions: 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. +

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. 5. Positive inotropic effect on heart and has mitogenic effect on vascular and cardiac muscle cells which may contribute to cardiovascular hypertrophy.

Angiotensin Therapeutic uses 6. Spasmogenic effect on smooth muscles. 7. Stimulates drinking (dispogenic effect), increases vasopressin and ACTH. Therapeutic uses In treatment of hypotension especially due to overdose of α - blockers. It is given by injection

Angiotensin II ANGIOTENSIN II - SUPPORT OF THE BLOOD PRESSURE Cardiac & Vascular Hypertrophy Vasoconstriction Direct Renal Sodium Retention ↑ Cardiac Contractility Aldosterone Secretion Angiotensin II Sympathetic Facilitation: Central Nerve terminal (ganglionic ?) ↑ Thirst ADH Release All known physiologic effects are mediated by the angiotensin II type 1 receptor

Drugs affecting renin / angiotensin system 1. Drugs inhibiting renin secretion: - β-blockers. - α 2 agonists (clonidine; guanaracine, guanabenz & methyldopa). 2. Angiotensin converting enzyme inhibitors (ACE inhibitors): captopril, enalapril .........

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

Adverse Effects Hypotension 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). Kinin-related

Losartan, candesartan, telmisartan, irbesartan and valsartan Angiotensin 3. Angiotensin receptor blockers: Losartan, candesartan, telmisartan, irbesartan and valsartan Compete with angiotensin II for AT1 receptors They are pure antagonists. They are effective orally Therapeutic uses: similar to ACE.I used in hypertension. Side effects Similar to ACE.I. but not dry irritant cough

Hageman factor, trypsin and plasma kallikrein. Kinins Hageman factor, trypsin and plasma kallikrein. Bradykinin Kallidin  Plasma Prekallirein plasma kallikrein  HMW kininogen inactive Aminopeptidase Kininase I & II LMW kininogen inactive  Tissue kallikrein.

They act on (B1&B2) receptors Actions of Kinins Kallidin Bradykinin 10 aminoacid 9 amino-acid They act on (B1&B2) receptors 1-Vasodilatation of vascular bed (10 times more potent than histamine). The vasodilatation may result from a-Direct inhibitory effect of kinin on arteriolar smooth muscle b-mediated through release of NO or vasodilator PGs as PGE2

They relax arterioles but veins are contracted Actions of Kinins They relax arterioles but veins are contracted They decrease B.P. and increase H.R. and COP (reflex and direct action).

2. Increase capillary permeability. 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 Drugs affecting kinin system: Trasylol (aprotinin) is a kallikrein inhibitor used to minimize bleeding in patients undergoing coronary bypass. ACE inhibitors as captopril is a kinase 11 inhibitor so enhance the action of kinins. PG synthesis inhibitors as aspirin is a kinins inhibitor

Substance-P It is a polypeptide It is present in: 1. C.N.S. (acts as a chemical transmitter) 2. Gut (acts a local hormone). It has a vasodilator effect on the arterioles but spasmogenic on veins, intestinal and bronchial muscles. It causes salivation and diuresis. Opioid (e.g. morphin) and endorphins & enkephalins →↑ Opiate receptors →↓ release of substance-P → analgesia.

Endothelin Other active peptides 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.

Vasoactive intestinal polypeptide (V1P) OTher active peptides Vasoactive intestinal polypeptide (V1P) Relaxes smooth muscles, Increase glycogenolysis, growth hormone, renin and prolactin. Potent V.D.→ coronary V.D and postive ino and chronotropic effect Atrial natriuretic peptide (ANP) Released from atrium and increase the glomerular filtration rate →↑Na excretion in urine Inhibit renin and aldosterone secretion. +