Respiratory module (2nd stage)

Lec. 1: Autacoids
Dr. Estabraq Mahmood
MBChB MSc PhD (Neuropharmacology)
Assistant professor of molecular neuropharmacology
 Learning objectives
❖To classify autacoids.

❖To illustrate the detailed mechanism of action and pharmacologic

effects of selected autacoids.

❖To outline the main drugs that interfere with the synthesis and actions
of autacoids.

❖To outline the receptors involved.

Classification
1- Lipid-derived autacoids e.g. prostaglandins and leukotrienes.
2- Peptide-derived autacoids e.g. bradykinin and angiotensin.
3- Amine-derived autacoids e.g. histamine and serotonin (will be explained separately in lectures 2 and 3).

Lipid-derived autacoids
Prostaglandins (PGs)
❖ They are released from cell membrane phospholipids.
❖ There are no preformed stores for prostaglandins.
❖ Prostaglandins are synthesized locally.
❖ Their synthesis is controlled by the release of arachidonic acid from membrane phospholipids. This action is done by
the enzyme phospholipase A2 in response to a stimulus. These stimuli are sometimes elicited through hormones such
as epinephrine and bradykinin.
❖ Arachidonic acid is converted to PGG2 by cyclooxygenase, which is then converted to PGH2 by peroxidase.
❖ Their synthesis occurs in the endoplasmic reticulum.
❖ PGH2 serves as a precursor for different types of prostaglandins and thromboxanes. This is known as the cyclic
pathway of arachidonic acid.
❖ The enzyme cyclooxygenase (a suicide enzyme) can partly control the prostaglandin synthesis by its suicidal activity.
❖ This enzyme is capable of undergoing self-catalysed destruction to switch off PGs synthesis.
5-HPETE

Figure 1: Synthesis of prostaglandins & leukotrienes.

Prostanoid receptors
❖ DP:
1- Activated by PGD2 (Greatest affinity) & PGE2.
2- Activation results in inhibition of platelet aggregation.
❖ EP:
1- Subtypes include EP1→ Smooth muscle contraction & EP2 → Smooth muscle relaxation.
2- Activated by PGE2 (Greatest affinity). EP1 are also activated by PGF2α.
3- Enprostil is a selective agonist.
❖ FP:
1- Activated by PGF2α (Greatest affinity).
2- Fluprostenol is a selective agonist.
3- Activation results in smooth muscle contraction.
❖ IP:
1- Activated by PGI2 (Greatest affinity) & PGE.
2- Cicaprost is a selective agonist.
3- Activation results in inhibition of platelet aggregation & smooth muscle relaxation.
❖ TP:
1- Activated by TXA2 (Greatest affinity) & PGH2.
2- Activation results in smooth muscle contraction.
Inhibition of prostaglandins
❖ Corticosteroids (e.g. cortisol) can prevent the formation of arachidonic acid by inhibiting the enzyme
phospholipase A2.
❖ Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit the synthesis of prostaglandins, prostacyclin
and thromboxanes by blocking the action of the enzyme cyclooxygenase.
❖ Aspirin irreversibly inhibits cyclooxygenase.

Prostaglandins mechanism of action

Cardiovascular system
❖ PGE2 and PGF2α cause vasodilatation in most vascular beds.
❖ PGF2α constricts many larger veins including pulmonary vein and artery.
❖ PGI2 is a more potent hypotensive than PGE2.
Uterus
❖ PGE2 and PGF2α uniformly contract human uterus.
❖ Prostaglandins increase tone as well as amplitude of uterine contractions.
Bronchial muscle
❖ PGF2α, PGD2 and TXA2 are potent bronchoconstrictors while PGE2 is a powerful bronchodilator.
❖ PGI2 produces mild dilatation.
❖ Asthma may be due to an imbalance between constrictor prostaglandins and dilator ones.
GIT
❖ PGE2 acts directly on the intestinal mucosa and increases water, electrolyte and mucus secretion.
Kidney
❖ PGE2 and PGI2 increase water, Na+ and K+ excretion and have a diuretic effect.
Eye
❖ PGF2α induces ocular inflammation and lowers intraocular tension by enhancing uveoscleral outflow.
Table 1: Preparations & uses of prostaglandins.
Don’t memorise the information in this table.

Clinical uses of prostaglandins

❖ Abortion.
❖ Cervical priming.
❖ Induction and augmentation of labour.
❖ Peptic ulcer.
❖ To maintain patency of ductus arteriosus.
❖ To avoid platelet damage.
 Non-steroidal anti-inflammatory drugs (NSAIDs)

Figure 2: Inhibition of prostaglandins synthesis by NSAIDs.

COX: Cyclooxygenase
Leukotrienes
❖ Leukotrienes (A4, B4, C4, D4 and E4) are synthesized by leukocytes, mast cells, lung, heart,
spleen, etc. through the lipoxygenase pathway of arachidonic acid by action of the enzyme 5-
lipoxygenase.
❖ This enzyme catalyses arachidonic acid to form 5-hydroperoxyeicosatetraenoic acid (5-
HPETE), the precursor of leukotrienes.

Figure 3: Synthesis of leukotrienes.

Leukotriene receptors
Leukotriene receptors are G-protein coupled receptors which include:
❖ Leukotriene B4 receptors (BLT receptors) which have been subdivided into BLT1 and BLT2.
❖ Cysteinyl leukotriene receptors (CysLT receptors) which have been subdivided into CysLT1
and CysLT2.

Leukotrienes mechanism of action

Cardiovascular system and the blood
❖ LTC4 and LTD4 injected intravenously evoke a brief rise in BP followed by a more
prolonged fall.
Smooth muscle
❖ LTC4 and D4 contract most smooth muscles.
❖ Leukotrienes may also be responsible for abdominal colics during systemic anaphylaxis.
❖ The cysteinyl leukotrienes are the most important mediators of human allergic asthma.

Watch this video about leukotrienes production, mechanism of action and inhibitor drugs (copy
and paste the link into your search browser): https://youtu.be/H7JJEF1hrUg
Table 2: The expression of leukotriene receptors.
Figure 4: Leukotriene pathway
inhibitors.
Peptide-derived autacoids
Bradykinin
❖ Plasma kinins are polypeptides split off from a plasma globulin (Kininogen) by the action of
specific enzymes (Kallikreins).
❖ The two important plasma kinins include Kallidin and Bradykinin.
❖ Kininogens are the precursors of kinins.
❖ Two kininogens are present in plasma: a low-molecular-weight form (LMW kininogen) and a
high-molecular-weight form (HMW kininogen).

Kinin receptors
❖ There are two types of kinin receptors, termed B1 and B2; both are G protein-coupled
receptors.
❖ Bradykinin displays the highest affinity in most B2 receptor systems.
❖ Inflammation induces synthesis of B1 receptors, so that they might play a major role at
inflamed sites.
Figure 5: The kallikrein-kinin system.
Bradykinin’s mechanism of action
Cardiovascular system
❖ Kinins are more potent vasodilators than ACh and histamine.
❖ Injected i.v. kinins cause flushing, throbbing headache and fall in BP.
❖ Kinins markedly increase capillary permeability.
❖ Kinins have no direct action on the heart.

Smooth muscle
❖ Kinin induced contraction of the intestine is slow.
❖ They cause bronchoconstriction in asthmatic patients.

Kidney
❖ Increase renal blood flow.
❖ Facilitate salt and water excretion.

Neurons
❖ Kinins release catecholamines from the adrenal medulla.
❖ Increase permeability of the blood brain barrier.
❖ Kinins strongly stimulate nerve endings that transmit pain and produce a burning sensation.
Ecallantide:
❖ It is a recombinant inhibitor of human plasma kallikrein. It reduces
the conversion of high molecular weight kininogen to bradykinin and
is used in the treatment of acute attacks of hereditary angioedema (an
inherited disease characterized by recurrent attacks of severe swelling
of the skin and mucous membranes). Three subcutaneous doses of
l0mg are given as a single treatment; the 3 injection sites may be in the
same or different anatomical areas (abdomen, thigh, or upper arm),
but should be separated by at least 5cm and away from the site of the
attack. If the attack persists, a second dose of three 10mg injections
may be given within 24 hours.

❖ Hypersensitivity reactions, including pruritus, rash, and urticaria,

have occurred in patients given ecallantide. Anaphylaxis has also been
reported, usually within 1 hour of dosing, and must be distinguished
from hereditary angioedema, which has similar symptoms.

❖ Other adverse effects include headache, nausea, diarrhoea, and

pyrexia.
Icatibant:
❖ Icatibant acetate is a selective bradykinin B2 antagonist used in the symptomatic treatment of acute
attacks of hereditary angioedema in adults. Icatibant acetate is given by subcutaneous injection,
preferably into the abdomen, in a dose equivalent to 30mg of Icatibant. Due to the large injection
volume of 3 mL, it should be given slowly.
❖ A single dose is usually enough to treat an acute attack but a second dose may be given after 6 hours if
required. Not more than 3 doses should be given in a 24-hour period, each given at 6-hourly intervals.
❖ Mild and transient injection site reactions, including erythema, swelling, warm sensation, burning,
itching, and skin pain are common.
❖ Nausea, vomiting, headache, dizziness, asthenia (sudden loss of strength), nasal congestion, and rashes
have also been reported.
❖ Icatibant should be given with caution to patients with acute ischaemic heart disease or unstable
angina pectoris, and to patients who have recently had a stroke.
Angiotensin
❖ Angiotensin-I (A-I) is hydrolytically released from angiotensinogen (Catalysed by renin). A-I is
converted to A-II by a converting enzyme. This is then converted to inactive fragments by
angiotensinases.
Angiotensin receptors:
❖ Two subtypes (AT1 and AT2) have been identified. Both subtypes are G-protein coupled receptors. A-
II binds equally to both subtypes
❖ The functional role of AT2 receptor is not clearly defined, but is generally opposite to that of AT1
receptors.
❖ Activation of AT2 receptors promotes apoptosis, myocardial fibrosis and inhibits cell proliferation.
Angiotensin’s mechanism of action:
Cardiovascular system:
❖ Enhances the release of adrenaline (Adr) / noradrenaline (NA) from adrenergic nerve endings.
❖ A-II is a more potent antihypotensive agent than NA.
❖ A-II increases the force of myocardial contraction.
Peripheral sympathetic structures
❖ A-II releases Adr from the adrenal medulla.
Adrenal cortex
❖ A-II enhances the synthesis and release of aldosterone.
 Table 3: ACE inhibitors.
Memorise the information mentioned about captopril, ramipril and enalapril only.
 Table 4: Angiotensin-II receptor
antagonists.

HTN: Hypertension
HF: Heart failure

Memorise the information mentioned about

candesartan and eprosartan.
Thank you