10b – Autacoids (histamine, angiotensin, bradykinin, prostaglandins, factors affecting autacoids biosynthesis and therapeutic implications)

  • Autacoids

- This word is derived from the Greek words autos (self) and akos (medicinal agent or remedy)—hence self agent.

- Autacoids are heterogeneous substances that have different structures and pharmacological activities.

- They all have the common features of being formed by the tissues on which they act. Thus, they function as local hormones.

- They are produced by many tissues.

 Histamine

- Histamine is derived from the decarboxylation of amino acid histidine by histidine decarboxylase.

- It is found in most tissues – high conc. in the lung, skin, and GIT.

- Stored: circulating basophils and tissue mast cells.

- Release: - It is released from mast cells by exocytosis during inflammatory or allergic reactions.

- The secretory process triggered by binding of specific antigen to IgE surface – ‘degranulation’.

- Functions:

i) It plays an important pathophysiologic role in seasonal rhinitis (hay fever), urticaria, and angioneurotic edema.

ii) Physiologic role in the control of acid secretion in the stomach.

iii) It acts as a neurotransmitter.

- Mechanism of action

- It exerts its effects by binding to one or more of four types of histamine receptors.

- H1 and H2 receptors are widely expressed and are the targets of clinically useful drugs.

- H3 and H4 receptors are expressed in only a few cell types, and their roles in drug action are unclear.

- Receptors and effects

1) H1 – Vasodilatation- Bronchoconstriction

- Increased vascular permeability- Pain and itching

2) H2 – Cardiac stimulation

- Stimulation of gastric secretion

3) H3 – at presynaptic sites inhibit the release of a variety of neurotransmitters

- Therapeutic uses: Histamine has no therapeutic uses but drugs that block histamine’s effects on H1 and H2 are used clinically.

H1 Receptor antagonists (antihistamine)

- There are 2 generations

1) 1st generation – Diphenhydramine (highly sedating, with significant autonomic receptors blocking effects)

- Promethazine

- Chlorpheniramine & Cyclizine (less sedating, with less autonomic receptors blocking effects)

2) 2nd generation – Fexofenadine- Cetirizine

- Loratadine- Acrivastine

They are less lipid soluble

They have reduced sedating and autonomic effects

- Pharmacokinetics – Well absorbed from GIT (oral)

- Metabolized extensively in the liver

- Half life t1/2 = 4-12h for 1st generation

- Half life t1/2 = 12-24h for 2nd generation

- Excretion – kidneys

- Mechanism of action – competitive pharmacological antagonists at H1 receptor

- Clinical uses: 1) for allergic reactions-type 1 – rhinitis (hay fever), urticaria, insect bites, drug hypersensitivity

2) as antiemetics – for the prevention of motion sickness, nausea and vertigo

3) for sedation

- Side effects

i) Sedation – common with 1st generation

ii) Anti-muscarinic effects – dry mouth, blurred vision (with some 1st generation in some patients)

iii) α blocking action – orthostatic hypotension (e.g. promethazine)

H2 Blocker

- Cimetidine, ranitidine, famotidine, nizatidine

- These drugs do not resemble H1 blockers structurally.

- They are orally active.

- They block H2 receptor and have no significant blocking actions at H1 or autonomic receptors.

- Therapeutic uses: peptic ulcer – inhibits gastric acid secretion

- Side effects

i) Cimetidine – potent inhibitor of hepatic drug metabolizing enzyme

- antiandrogenic effects in patients receiving high dose

ii) Ranitidine – weaker effect on hepatic drug metabolizing enzyme and has no antiandrogenic effect

 Angiotensin

- It is derived from the precursor molecule angiotensinogen, a serum globulin produced in the liver.

- It plays an important role in the renin-angiotensin system.

The system can be activated when there is a loss of blood volume or a drop in blood pressure (such as in hemorrhage) perfusion of the juxtaglomerular apparatus in the kidney’s macula densa  the juxtaglomerular cells release renin angiotensin II  vasoconstriction, increased blood pressure, release of aldosterone from adrenal cortex.

Angiotensin antagonists

1) Angiotensin II-Receptor Blockers

Mechanism of action / - block type 1 angiotensin II (AT1) receptors
 lower blood pressure
Therapeutic uses / - hypertension
- heart failure
Drugs / - Candesartan - Losartan
- Eprosartan - Olmesartan
- Irbesartan - Telmisartan
Side effects / Similar to ACE inhibitors except the risk of dry cough and angioedema are decreased(not increase bradykinin levels)
Contraindication / Pregnancy (fetotoxic)

2) Angiotensin Converting Enzyme (ACE) inhibitors

Mechanism of action / - block the ACE  inhibit formation of angiotensin II
- block the breakdown of bradykinin  increase bradykinin levels
Effects / - vasodilation (arterial & venous)  reduce arterial & venous pressure
 reduce ventricular afterload & preload
- decreased blood volume - natriuretic
- diuretic
- depress sympathetic activity
Therapeutic uses / - Hypertension
- Heart failure
- Post-myocardial infarction
Drugs / - Benazepril - Captopril - Enalapril
- Fosinopril - Lisinopril - Moexipril
- Quinapril - Ramipril
Side effects / - rash - dry cough (increased levels of bradykinin)
- fever - hypotension
- hyperkalemia

 Bradykinin

- It is an endogenous vasodilator peptide, released from plasma globulins called kininogens.

- Synthesis: The kinin-kallikrein system makes bradykinin by proteolytic cleavage of its kininogen precursor, high-molecular-weight kininogen (HMWK ), by the enzyme kallikrein.

- Metabolism: Bradykinin is broken down by kininases (angiotensin-converting enzyme (ACE), aminopeptidase P, carboxypeptidase N)

- Mechanism of action: Stimulation of B1 and B2 receptors

i) B1 – induced by trauma and pathologic conditions

ii) B2 – mediates the majority of the effects

- Pharmacologic effects

i) Vasodilation

ii) Increase in capillary permeability

iii) Cardiac stimulation

iv) Stimulation of the pain nerve endings

v) Contraction of smooth muscle

vi) Stimulate release of antidiuretic hormone and has a natriuretic action.

- Overactivation/increase levels of bradykinin  angioedema, dry cough

- Bradykinin inhibitors/antagonists – Icatibant

- Therapeutic implications – Effect of bradykinin on vasodilation and the consequent fall in blood pressure leads to development of ACE inhibitors which are anti-hypertensive drugs that increase bradykinin by inhibiting its degradation.

 Prostaglandins

- Prostaglandins are produced by all nucleated cells except lymphocytes.

- They are autocrine and paracrine lipid mediators that act upon platelets, endothelium, uterine and mast cells.

- They are rapidly metabolized to inactive products at the site of action. (short half-life)

- Synthesis

- primary precursor – Arachidonic acid

- They are synthesized via the cyclooxygenase pathway.

i) COX-1 - physiologic production

ii) COX-2 –produces prostaglandins through stimulation

- Inflammation- oxidative stress

- injury- ischemia

- seizures- neurodegenerative diseases

- The actions of prostaglandins are mediated by their binding to variety of cell membrane receptors. Therefore they have variety of effects depending on the tissues. For examples:

i) Constriction or dilation in vascular smooth muscle cells

ii) Aggregation of platelets

iii) Sensitize spinal neurons to pain

iv) Decrease intraocular pressure

v) Regulate inflammatory mediation

vi) Stimulate contractility of uterine and other smooth muscle

vii) Regulate acid secretion of stomach

- Therapeutic uses:

1) Abortion – e.g. misoprostol (synthetic prostaglandins E1 analog)

- It is administered vaginally

- Common complications – infection, hemorrhage, retained tissue

2) Peptic ulcers – e.g. misoprostol

- It inhibits secretion of HCl and pepsin, and enhances mucosal resistance.

- Useful in patients with gastric ulcer who chronically take aspirin.

3) Treatment of glaucoma

4) In pulmonary hypertension

5) As a vasodilator in severe Raynaud’s phenomenon or ischemia of a limb

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