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FACULTY OF CLINICAL MEDICINE AND SARGERY
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Topic 1.1: Autacoids (Introduction, definition and classification and Amine Autacoids)
An organic substance, such as a hormone, produced in one part of organism and transported by the blood or lymph to another part of the organism where it exerts a physiologic effect on that part.
Types of Autacoids;
- Amines : Histamine,5-Hydroxytryptamine.
- Lipids : Prostaglandins, Leukotriens,
- Platelet activating factor.
- Peptide : Bradykinin , angiotensin.
5-HYDROXYTRYPTAMINE: Serotonin;
SYNTHESIS, STORAGE AND DESTRUCTION
5-HT is β-aminoethyl-5-hydroxyindole. It is synthesized from the amino acid tryptophan and degraded primarily by MAO and to a small extent by a dehydrogenase
The decarboxylase is non-specific, acts on DOPA as well as 5-hydroxytryptophan (5-HTP) to produce DA and 5-HT respectively.
Like NA, 5-HT is actively taken up by an amine pump serotonin transporter (SERT), a Na+ dependent carrier, which operates at the membrane of platelets (therefore, 5-HT does not circulate in free form in plasma) and serotonergic nerve endings.
This pump is inhibited by selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs).
Platelets do not synthesize 5-HT but acquire it by uptake during passage through intestinal blood vessels.
Again like CAs, 5-HT is stored within storage vesicles, and its uptake at the vesicular membrane by vesicular monoamine transporter (VMAT-2) is inhibited by reserpine, which causes depletion of CAs as well as 5-HT. The degrading enzyme
MAO is also common for both. The isoenzyme MAO-A preferentially metabolizes 5-HT
RECEPTORS
Four families of 5-HT receptors
- 5-HT1,
- 5- HT2,
- 5-HT3,
- 5-HT4-7
- Comprising of 14 receptor subtypes have so far been recognized.
All 5-HT receptors (except 5-HT3) are G protein coupled receptors which function through decreasing (5-HT1) or increasing (5-HT4, 5-HT6, 5-HT7) cAMP production or by generating IP3/ DAG (5-HT2) as second messengers.
The 5-HT3 is a ligand gated cation (Na+,K+) channel which on activation elicits fast depolarization.
5-HT1 Receptors
Five subtypes (5-HT1 A, B, D, E, F) have been identified. All subtypes of 5-HT1 receptor couple with Gi/Go protein and inhibit adenylyl cyclase;
5-HT2 Receptors
There are 3 subtypes of 5-HT2 receptor; all are coupled to Gq protein→activate phospholipase C and function through generation of IP3/DAG. 5-HT2A receptor also inhibits K+ channels resulting is slow depolarization of neurones.
α-methyl 5-HT is a selective agonist for all 3 subtypes.
5-HT3 Receptor
This is the neuronal 5-HT receptor which rapidly depolarizes nerve endings by opening the cation channel located within it and corresponds to the original M type receptor. It mediates the indirect and reflex effects of 5-HT
5-HT4–7 Receptors
The 5-HT4 receptor couples to Gs protein, activates adenylyl cyclase and has been demonstrated in the mucosa, plexuses and smooth muscle of the gut → probably involved in augmenting intestinal secretion and peristalsis.
Cisapride and renzapride are selective 5-HT4 agonists.
The recently cloned 5-HT5, 5-HT6 and 5-HT7 receptors are closely related to the 5-HT4 receptor. These are mainly located in specific brain areas, but their functional role is not known.
An interesting finding is that clozapine (atypical antipsychotic) has high affinity for 5-HT6 and 5-HT7 receptors in addition to being a 5-HT2A/2C antagonist.
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Topic 1.2: Autacoids (Introduction, definition and classification and Amine Autacoids)
Actions of Serotonin on different organs.
1. CVS
Arteries are constricted (by direct action on vascular smooth muscle) as well as dilated (through EDRF release) by 5-HT, depending on the vascular bed and the basal tone. Larger arteries and veins are characteristically constricted.
In the microcirculation 5-HT dilates arterioles and constricts venules: capillary pressure rises and fluid escapes. The direct action to increase capillary permeability is feeble.
2. Visceral smooth muscles
5-HT is a potent stimulator of g.i.t., both by direct action as well as through enteric plexuses. Peristalsis is increased and diarrhoea can occur (also due to increased secretion). It constricts bronchi, but is less potent than histamine and leukotrienes.
3. Glands
5-HT inhibits gastric secretion (both acid and pepsin), but increases mucus production. It thus has ulcer protective property.
4. Nerve endings and adrenal medulla
Afferent nerve endings are activated causing tingling and pricking sensation, as well as pain.
Depolarization of visceral afferents elicits respiratory and cardiovascular reflexes, nausea and vomiting.
5. Respiration
A brief stimulation of respiration (mostly reflex from bronchial afferents) and hyperventilation are the usual response, but large doses can cause transient apnoea through coronary chemoreflex.
6. Platelets
By acting on 5-HT2A receptors 5-HT causes changes in shape of platelets, but is a weak aggregator.
7. CNS
Injected i.v., 5-HT does not produce central effects because of poor entry across bloodbrain barrier.
PATHOPHYSIOLOGICAL ROLES OF SEROTONIN
1. Neurotransmitter
5-HT is a confirmed neurotransmitter in the brain; brain 5-HT has a fast turnover rate.
Cells containing 5-HT are present in the raphe nuclei of brainstem, substantia nigra and few other sites—send axons rostrally (to limbic system, cortex and neostriatum) as well as caudally to spinal cord.
5-HT appears to beinvolved in sleep, temperature regulation, thought, cognitive function, behaviour and mood, appetite, vomiting and pain perception.
2. Precursor of melatonin
5-HT is theprecursor of melatonin in pineal gland. It is believed to regulate the biological clock and maintain circadian rhythm.
3. Neuroendocrine function
The hypothalamic neurones that control release of anterior pituitary hormones are probably regulated by serotonergic mechanism.
4. Nausea and vomiting
Especially thatevoked by cytotoxic drugs or radiotherapy ismediated by release of 5-HT and its action on 5-HT3 receptors in the gut, area postrema andnucleus tractus solitarious.
5. Migraine
5-HT is said to initiate the vasoconstrictor phase of migraine and to participate in neurogenic inflammation of the affected blood vessels.
Methysergide (5-HT antagonist) is an effective prophylactic and sumatriptan (5-HT1B/1Dagonist) can control an attack.
Haemostasis
Platelets release 5-HT during aggregation at the site of injury to blood vessel.
Acting in concert with collagen and other mediators, this 5-HT accelerates platelet aggregation and clot formation. Thus, it serves to amplify the response. Its contractile action appears to promote retraction of the injured vessel.
Both the above actions contribute to haemostasis.
6. Raynaud’s phenomenon
Release of 5-HT from platelets may trigger acute vasospastic episodes of larger arteries involved in Raynaud’s phenomena. Ketanserin has prophylactic value.
7. Variant angina
Along with thromboxane-A2, 5-HT released from platelets has been implicated in causing coronary spasm and variant angina.
However, the inefficacy of anti 5-HT drugs inthis condition points to the involvement of other mediators.
8. Hypertension
Increased responsiveness to 5-HT as well as its reduced uptake and clearance by platelets has been demonstrated in hypertensive patients.
Ketanserin has antihypertensive property.
5-HT has been held responsible for pre-eclampticrise in BP.
9. Intestinal motility
Enterochromaffin cells and 5-HT containing neurones may regulate peristalsis and local reflexes in the gut.
This system appears to be activated by intestinal distension and vagal efferent activity.
10. Carcinoid syndrome
The carcinoid tumours produce massive quantities of 5-HT.
Bowel hypermotility and bronchoconstriction incarcinoid is due to 5-HT but flushing and hypotension are probably due to other mediators.
Pellagra may occur due to diversion of tryptophanfor synthesizing 5-HT.
Use
Due to widespread and variable actions,
5-HT has no therapeutic use.
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Topic 1.3: Autacoids (Introduction, definition and classification and Amine Autacoids)
DRUGS AFFECTING 5-HT SYSTEM
1. 5-HT precursor
Tryptophan increases brain 5-HT and produces behavioural effects
2. Synthesis inhibitor
p-Chlorophenylalanine (PCPA) selectively inhibits tryptophan hydroxylase (rate limiting step) and reduces 5-HT level in tissues.
It is not used clinically due to high toxicity.
3. Uptake inhibitor
Tricyclic antidepressants inhibit 5-HT uptake along with that of NA.
The selective serotonin reuptake inhibitors (SSRI) like fluoxetine, sertraline, etc. inhibit only 5-HT reuptake and have anti depressant and antianxiety property.
4. Storage inhibitor
Reserpine blocks 5-HT (as well as NA) uptake into storage vesicles by inhibiting VMAT-2, and causes depletion of all monoamines.
Fenfluramine selectively releases 5-HT by promoting its reverse transport at serotonergic nerve endings in the brain, followed by its prolonged depletion, and has anorectic property.
5. Degradation inhibitor
Nonselective MAO inhibitor (tranylcypromine) and selective MAO-A inhibitor (chlorgyline) increase 5-HT content by preventing its degradation.
6. Neuronal degeneration
5, 6-dihydroxytryptamine selectively destroys 5-HT neurones.
7. 5-HT receptor agonists
A diverse range of compounds producing a variety of actions have been found to activate one or more subtypes of 5-HT receptors.
Notable among these are:
D-Lysergic acid diethyl amide (LSD)
Azapirones (like buspirone, gepirone and ipsapirone) are a novel class of antianxiety drugs which do not produce sedation. They act as partial agonists of 5-HT1A receptors in the brain.
Sumatriptan and other triptans are selective 5-HT1D/1B agonists, constrict cerebral blood vessels and have emerged as the most effective treatment of acute migraine attacks.
Cisapride This prokinetic drug which increases gastrointestinal motility is a selective 5-HT4 agonist. Renzapride is still more selective for 5-HT4 receptors.
8. 5-HT receptor antagonists
A variety of drugs block serotonergic receptors; many are nonselective, but some newer ones are highly subtype selective.
5-HT ANTAGONISTS
1. Cyproheptadine
It primarily blocks 5-HT2A receptors and has additional H1 antihistaminic, anticholinergic and sedative properties.
The anti 5-HT activity of cyproheptadine has been utilized in controlling intestinal manifestations of carcinoid and postgastrectomy dumping syndromes as well as in antagonizing priapism/orgasmic delay caused by 5-HT uptake inhibitors like fluoxetine and trazodone.
Side effects drowsiness, dry mouth, confusion,ataxia, weight gain
2. Methysergide
It is chemically related to ergotalkaloids; antagonizes action of 5-HT on smooth musclesincluding that of blood vessels, without producing other ergotlike effects: does not interact with α adrenergic or dopamine receptors.
Methysergide is a potent 5-HT2A/2C antagonist with some tissue specific agonistic actions as well; but is nonselective—acts on 5-HT1 receptors also.
It has been used for migraine prophylaxis, carcinoid and postgastrectomy dumping syndrome.
Prolonged use has caused abdominal, pulmonaryand endocardial fibrosis
3. Ketanserin
It has selective 5-HT2 receptor blocking property with negligible action on 5-HT1, 5-HT3 and 5-HT4 receptors and no partial agonistic activity.
Among 5-HT2receptors, blockade of 5-HT2A is stronger than 5-HT2Cblockade.
5-HT induced vasoconstriction, platelet aggregationand contraction of airway smooth muscle are antagonized.
4. Ritanserin
5. Clozapine
Atypical antipsychotic is a 5-HT2A/2C blocker.
Clozapine may also exert inverse agonist activity at cerebral5-HT2A/2C receptors which may account for its efficacy in resistant cases of schizophrenia
6. Ondansetron
It is the prototype of the new class of selective 5-HT3 antagonists that have shown remarkable efficacy in controlling nausea and vomiting following administration of highly emetic anticancer drugs and radiotherapy.
Granisetron and Tropisetron are the other selective 5-HT3 antagonists
ERGOT ALKALOIDS
1. Ergotamine
It acts as a partial agonist and antagonist at α adrenergic and all subtypes of 5-HT1 and 5-HT2 receptors, but does not interact with 5-HT3 or dopamine receptors: produces sustained vasoconstriction, visceral smooth muscle contraction, vasomotor centre depression and antagonizes the action of NA and 5-HT on smooth muscles.
It is a potent emetic (through CTZ and vomiting centre) and moderately potent oxytocic.
2. Dihydroergotamine (DHE)
Hydrogenation of ergotamine reduces serotonergic and α-adrenergic agonistic actions, but enhances α-receptor blocking property.
Consequently DHE is a less potent vasoconstrictor; primarily constricts capacitance vessels and causes less intimal damage.
It is a weaker emetic and oxytocic, but has some antidopaminergic action as well.
3. Dihydroergotoxine (Codergocrine)
This hydrogenated mixture of ergotoxine group of alkaloids is a more potent α blocker and a very weak vasoconstrictor.
It has been advocated for treatment of dementia
Bromocriptine
The 2 bromo derivative of ergocryptine is a relatively selective dopamine D2 agonist on pituitary lactotropes (inhibits prolactin release), in striatum (antiparkinsonian) and in CTZ (emetic—but less than ergotamine).
It has very weak anti 5-HT or α blocking actions and is not an oxytocic.
Ergometrine (Ergonovine)
This amine ergot alkaloid has very weak agonistic and practically no antagonistic action on α adrenergic receptors: vasoconstriction is not significant.
Partial agonistic action on 5-HT receptors has been demonstrated in uterus, placental and umbilical blood vessels and in certain brain areas.
It is a moderately potent 5-HT2 antagonist in g.i. smooth muscle and a weak dopaminergic agonist on the pituitary lactotropes as well as CTZ; emetic potential is low.
The most prominent action is contraction of myometrium; used exclusively in obstetrics
Adverse effects of Ergometrin;
Nausea, vomiting, abdominal pain, muscle cramps, weakness, paresthesias, coronary and other vascular spasm, chest pain (due to coronary vasoconstriction) are the frequent side effects. These drugs are contraindicated in presence of sepsis, ischaemic heart disease, peripheral vascular disease, hypertension, pregnancy, liver and kidney disease.
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Topic 1.4: Autacoids (Lipid and peptide Autacoids)
PROSTAGLANDINS AND LEUKOTRIENES (Eicosanoids)
Prostaglandins (PGs) and Leukotrienes (LTs) are biologically active derivatives of 20 carbon atom polyunsaturated essential fatty acids that are released from cell membrane phospholipids.
They are the major lipid derived autacoids.
Also known as Eicosanoids.
CHEMISTRY, BIOSYNTHESIS AND DEGRADATION
PG has a five membered ring and two side chains projecting in opposite directions at right angle to the plane of the ring.
There are many series of PGs and thromboxanes (TXs) designated A, B, C....I, depending on the ring structure and the substituents on it. Each series has members with subscript 1, 2, 3 indicating the number of double bonds in the side chains.
Leukotrienes are so named because they were first obtained from leukocytes (leuko) and have 3 conjugated double bonds (triene). They have also been similarly designated A, B, C.....F and given subscripts 1, 2, 3, 4.
In the body PGs, TXs and LTs are all derived from eicosa (referring to 20 C atoms) tri/tetra/ penta enoic acids. Therefore, they can be collectively called eicosanoids.
In human tissues, the fatty acid released from membrane lipids in largest quantity is 5,8,11,14 eicosa tetraenoic acid (arachidonic acid).
During PG, TX and prostacyclin synthesis, 2 of the 4 double bonds of arachidonic acid get saturated in the process of cyclization, leaving 2 double bonds in the side chain. Thus, subscript 2 PGs are the most important in man, e.g. PGE2, PGF2α, PGI2, TXA2.
During LT synthesis No cyclization or reduction of double bonds occurs—the LTs of biological importance are LTB4, LTC4, LTD4.
Eicosanoids are the most universally distributed autacoids in the body. Practically every cell and tissue is capable of synthesizing one or more types of PGs or LTs.
There are no preformed stores of PGs and LTs.
They are synthesized locally and the rate of synthesis is governed by the rate of release of arachidonic acid from membrane lipids in response to appropriate stimuli. These stimuli activate hydrolases, including phospholipase A, probably through increased intracellular Ca2+.
The cyclooxygenase (COX) pathway generates eicosanoids with a ring structure (PGs, TXs, prostacyclin) while lipoxygenase (LOX) produces open chain compounds (LTs).
All tissues have COX—can form cyclic endoperoxides PGG2 and PGH2 which are unstable compounds.
Lung and spleen can synthesize the whole range of COX products.
Platelets primarily synthesize TXA2 which is—chemically unstable, spontaneously changes
to TXB2.
Endothelium mainly generates prostacyclin (PGI2) which is also chemically unstable and rapidly converts to 6-keto PGF1α.
Cyclooxygenase is known to exist in two isoforms COX-1 and COX-2, both isoforms catalyse the same reactions
COX-1
It is a constitutive enzyme in most cells—it is synthesized and is active in the basal state; the level of COX-1 activity is not much changed once the cell is fully grown.
Eicosanoids produced by COX-1 participate in physiological (house keeping) functions such as secretion of mucus for protection of gastric mucosa, haemostasis and maintenance of renal function
COX-2
Normally present in insignificant amounts, is inducible by cytokines, growth factors and other stimuli during the inflammatory response.
Eicosanoids those produced by COX-2 lead to inflammatory and other pathological changes.
However, certain sites in kidney, brain and the foetus constitutively express COX-2 which may play physiological role.
Lipoxygenase pathway appears to operate mainly in the lung, WBC and platelets.
Its most important products are the LTs, (generated by 5- LOX) particularly LTB4 (potent chemotactic) and LTC4,
LTD4 which together constitute the ‘slow reacting substance of anaphylaxis’ (SRS-A)
A membrane associated transfer protein called FLAP (five lipoxygenase activating protein) carrys arachidonic acid to 5-LOX, and is essential for the synthesis of LTs.
Platelets have only 12-LOX.
HPETEs produced by LOX can also be converted to hepoxilins, trioxilins and lipoxins.
Inhibition of synthesis (Eicosanoids)
- Synthesis of COX products can be inhibited by nonsteroidal antiinflammatory drugs (NSAIDs).
- Aspirin: acetylates COX at a serine residue and causes irreversible inhibition while other NSAIDs are competitive and reversible inhibitors.(BINDS AT ARGININE RESIDUE)
- Most NSAIDs are nonselective COX-1 and COX-2 inhibitors, but some later ones like celecoxib, etoricoxib are selective for COX-2.
- The sensitivity of COX in different tissues to inhibition by these drugs varies; selective inhibition of formation of certain products may be possible at lower doses.
- NSAIDs do not inhibit the production of LTs: this may even be increased since all the arachidonic acid becomes available to the LOX pathway.
- Zileuton: inhibits LOX and decreases the production of LTs.
- Glucocorticosteroids inhibit the release of arachidonic acid from membrane lipids (by stimulating production of proteins called annexins which inhibit phospholipase A2)—indirectly reduce production of all eicosanoids—PGs, TXs and LTs. Moreover, they inhibit the induction of COX-2 by cytokines at the site of inflammation.
Degradation
Biotransformation of arachidonates occurs rapidly in most tissues, but fastest in the lungs.
Most PGs, TXA2 and prostacyclin have plasma t½ of a few seconds to a few minutes.
PGI2 is catabolized mainly in the kidney.
ACTIONS AND PATHOPHYSIOLOGICAL ROLES
(Prostaglandins, thromboxanes and Prostacyclin)
1. CVS
PGE2 and PGF2α cause vasodilatation in most, but not all, vascular beds.
PGF2α cause vasoconstriction jn many larger veins including pulmonary vein and artery.
PGI2 is uniformly vasodilatory and is more potent hypotensive than PGE2.
TXA2 consistently produces vasoconstriction.
PG endoperoxides (G2 and H2) are inherently vasoconstrictor, but often produce vasodilatation or a biphasic response due to rapid conversion to other PGs, especially PGI2 in the blood vessels themselves.
PGE2 and F2α stimulate heart by weak direct but more prominent reflex action due to fall in BP. The cardiac output increases.
Roles of Prostaglandins;
- PGs do not circulate in blood and have no role in regulating systemic vascular resistance. However, PGI2 generated in the vascular endothelium, mainly by COX-2, appears to be involved in the regulation of local vascular tone as a dilator.
- PGE2 is continuously produced locally in the ductus arteriosus by COX-2 during foetal life—keeps it patent; at birth its synthesis stops and closure occurs. Aspirin and indomethacin induce closure when it fails to occur spontaneously. These PGs may also be important in maintaining placental blood flow.
- PGs, generated mainly by COX-2, along with LTs and other autacoids may mediate vasodilatation and exudation at the site of inflammation.
2. Platelets
TXA2, which can be produced locally by platelets, is a potent inducer of aggregation and release reaction.
The endoperoxides PGG2 and PGH2 are also proaggregatory.
PGI2 (generated by vascular endothelium) is a potent inhibitor of platelet aggregation.
PGD2 has antiaggregatory action, but much less potent than PGI2.
PGE2 has dose dependent and inconsistent effects.
Role
TXA2 produced by platelets and PGI2 produced by vascular endothelium probably constitute a mutually antagonistic system: preventing aggregation of platelets while in circulation and inducing aggregation on injury, when plugging and thrombosis are needed.
Aspirin interferes with haemostasis by inhibiting platelet aggregation.
TXA2 produced by platelet COX-1 plays an important role in amplifying aggregation. Before it is deacetylated in liver, aspirin acetylates COX-1 in platelets while they are in portal circulation. Further, platelets are unable to regenerate fresh COX-1 (lack nucleus: do not synthesize protein), while vessel wall is able to do so (fresh enzyme is synthesized within hours). Thus, in low doses, aspirin selectively inhibits TXA2 production and has antithrombotic effect lasting > 3 days.
3. Uterus
PGE2 and PGF2α uniformly contract human uterus, in vivo, both pregnant as well as nonpregnant.
The sensitivity is higher during pregnancy and there is progressive modest increase with the advance of pregnancy. However, even during early stages, uterus is quite sensitive to PGs though not to oxytocin.
PGs increase basal tone as well as amplitude of uterine contractions. At term, PGs soften the cervix at low doses and make it more compliant.
Role
- Foetal tissues produce PGs: At term PGF2α has been detected in maternal blood. It is postulated that PGs mediate initiation and progression of labour. Aspirin has been found to delay the initiation of labour and also prolong its duration.
- Dysmenorrhoea in many women is associated with increased PG synthesis by the endometrium. This apparently induces uncoordinated uterine contractions which compress blood vessels →uterine ischaemia →pain. Aspirin group of drugs are highly effective in relieving dysmenorrhoea in most women.
4. Bronchial muscle
PGF2α, PGD2 and TXA2 are potent bronchoconstrictors (more potent than histamine)
PGE2- powerful bronchodilator. PGI2-mild dilatation. (PGE2 and PGI2 also inhibit histamine release and are effective by aerosol)
Asthmatics are more sensitive to constrictor as well as dilator effects of PGs.
Role
- Asthma may be due to an imbalance between constrictor PGs (F2 , PGD2, TXA2) and LTs on one hand and dilator ones (PGE2, PGI2) on the other.
- In allergic human asthma, LTs play a more important role, and COX inhibitors are without any effect in most patients.
5. GIT
Propulsive activity is enhanced in man, especially by PGE2 →colic and watery diarrhoea are important side effects. PGE2 acts directly on the intestinal mucosa and increases water, electrolyte and mucus secretion.
Role: PGs may be involved in mediating toxin induced increased fluid movement in secretory diarrhoeas. In certain diarrhoeas, aspirin can reduce stool volume, but is not uniformly effective.
PGE2 markedly reduces acid secretion in the stomach. Volume of juice and pepsin content are also decreased. It inhibits fasting as well as stimulated secretion (by feeding, histamine, gastrin). Release of gastrin is suppressed. The gastric pH may rise upto 7.0. PGI2 also inhibits gastric secretion, but is less potent. Secretion of mucus and HCO3¯ by gastric mucosal epithelial cells as well as mucosal blood flow are increased. Thus, PGs are antiulcerogenic.
Role in PUD protection;
- PGs (especially PGI2) appear to be involved in the regulation of gastric mucosal blood flow. They may be functioning as natural ulcer protectives by enhancing gastric mucus and HCO3 ¯ production, as well as by improving mucosal circulation and health. The ulcerogenic action of NSAIDs may be due to loss of this protective influence. Normally, gastric mucosal PGs are produced by COX-1. Selective COX-2 inhibitors are less ulcerogenic.
- However, COX-2 gets induced during ulcer healing, and COX-2 inhibitors have the potential to delay healing.
6. Kidney
- PGE2 and PGI2 increase water, Na+ and K+ excretion and have a diuretic effect. They cause renal vasodilatation and inhibit tubular reabsorption. PGE2 antagonizes ADH action, and this adds to the diuretic effect.
- In contrast, TXA2 causes renal vasoconstriction.
- PGI2, PGE2 and PGD2 evoke release of renin.
Role
- PGE2 and PGI2 produced mainly by COX-2 in the kidney appear to function as intrarenal regulators of blood flow as well as tubular reabsorption in kidney. Accordingly, the NSAIDs, including selective COX-2 inhibitors, tend to retain salt and water.
- Renin release in response to sympathetic stimulation and other influences may be facilitated by PGs.
- Bartter’s syndrome, characterized by decreased sensitivity to angiotensin II is associated with increased PG production; improved by prolonged use of NSAIDs.
7. CNS
Role
PGE2 may mediate pyrogen induced fever and malaise. Aspirin and other inhibitors of PG synthesis are antipyretic. Pyrogens, including cytokines released during bacterial infection, trigger synthesis of PGE2 in the hypothalamus, which resets the thermostat to cause fever. COX-2 is the major isoenzyme involved; selective COX-2 inhibitors are equally efficacious antipyretics. A role of COX-3 has also been proposed.
PGs may be functioning as neuromodulators in the brain by regulating neuronal excitability. A role in pain perception, sleep and some other functions has been suggested.
8. AUTONOMIC NERVOUS SYSTEM
Depending on the PG, species and tissue, both inhibition as well as augmentation of NA release from adrenergic nerve endings has been observed. Role PGs may modulate sympathetic neurotransmission in the periphery.
9. Peripheral nerves
PGs (especially E2 and I2) sensitize afferent nerve endings to pain inducing chemical and mechanical stimuli.
Role
PGs appear to serve as algesic agents during inflammation. They cause tenderness and amplify the action of other algesics. Inhibition of PG synthesis is a major antiinflammatory mechanism.
10. Eye:
PGF2α induces ocular inflammation and lowers i.o.t by enhancing uveoscleral and trabecular outflow.
Role
Locally produced PGs appear to facilitate aqueous humor drainage. The finding that COX-2 expression in the ciliary body is deficient in wide angle glaucoma patients supports this cotention.
11. Endocrine system
PGE2 facilitates the release of anterior pituitary hormones—growth hormone, prolactin, ACTH, FSH and LH as well as that of insulin and adrenal steroids.
12. Metabolism
PGEs are antilipolytic, exert an insulin like effect on carbohydrate metabolism and mobilize Ca2+ from bone. They may mediate hypercalcaemia due to bony metastasis.
LEUKOTRIENS
The straight chain lipoxygenase products of arachidonic acid are produced by a more limited number of tissues but probably they are pathophysiologically as important as PGs.
(LTB4 mainly by neutrophils; LTC4 and LTD4—the cysteinyl LTs—mainly by macrophages),
1. CVS and blood
LTC4 and LTD4 injected i.v. evoke a brief rise in BP followed by a more prolonged fall. The fall in BP is not due to vasodilatation because no relaxant action has been seen on blood vessels.
It is probably a result of coronary constriction induced decrease in cardiac output and reduction in circulating volume due to increased capillary permeability.
These LTs markedly increase capillary permeability and are more potent than histamine in causing local edema formation.
LTB4 is highly chemotactic for neutrophils and monocytes; Migration of neutrophils through capillaries and their clumping at sites of inflammation in tissues is also promoted by LTB4.
The cysteinyl LTs (C4, D4) are chemotactic for eosinophils.
Role
- LTs are important mediators of inflammation. They are produced (along with PGs) locally at the site of injury.
- While LTC4 and D4 cause exudation of plasma, LTB4 attracts the inflammatory cells which reinforce the reaction.
- 5-HPETE and 5-HETE may facilitate local release of histamine from mast cells.
Leukotriens effects on Smooth muscle;
LTC4 and D4 contract most smooth muscles. They are potent bronchoconstrictors and induce spastic contraction of g.i.t. at low concentrations. They also increase mucus secretion in the airways.
Role
The cysteinyl LTs (C4 and D4) are the most important mediators of human allergic asthma.
They are released along with PGs and other autacoids during AG: AB reaction in the lungs.
In comparison to other mediators, they are more potent and are metabolized slowly in the lungs, exert a long lasting action.
LTs may also be responsible for abdominal colics during systemic anaphylaxis.
2. Afferent nerves
Like PGE2 and I2, the LTB4 also sensitizes afferents carrying pain impulses—contributes to pain and tenderness of inflammation.
USES OF PGs
Clinical application of PGs and their analogues is rather restricted because of limited availability, short lasting action, cost and frequent side effects. However, their use in glaucoma and in obstetrics is now common place. Their indications are:
1. Abortion;
- Abortion During the first trimester, termination of pregnancy by transcervical suction is the procedure of choice. Intravaginal PGE2 pessary inserted 3 hours before attempting dilatation can minimise trauma to the cervix by reducing resistance to dilatation.
- Medical termination of pregnancy of upto 7 weeks has been achieved with high success rate by administering mifepristone (antiprogestin) 600 mg orally 2 days before a single oral dose of misoprostol 400 g.
- Ectopic pregnancy should be ruled out beforehand and complete expulsion should be confirmed afterwards. Uterine cramps, vaginal bleeding, nausea, vomiting and diarrhoea are the common side effects.
- Methotrexate administered along with misoprostol is also highly successful for inducing abortion in the first few weeks of pregnancy.
- PGs have a place in midterm abortion, missed abortion and molar gestation, though delayed and erratic action and incomplete abortion are a problem.
- 2. Induction/Augementation of labour;
- Induction/augmentation of labour PGs do not offer any advantage over oxytocin for induction of labour at term. They are less reliable and show wider individual variation in action. PGE2 and PGF2α (rarely) have been used in place of oxytocin in toxaemic and renal failure patients, because PGs do not cause fluid retention that is possible with oxytocin. PGE2 may also be used to augment labour, if it is slow, in primipara. Intravaginal route is preferred now: side effects care milder; extra/intra amniotic route is infrequently used.
3. Cervical ripening
Cervical priming (ripening) Applied intravaginally or in the cervical canal, low doses of PGE2 which do not affect uterine motility make the cervix soft and compliant. This procedure has yielded good results in cases with unfavourable cervix. If needed labour may be induced 12 hours later with oxytocin: chances of failure are reduced.
4. PPH-Post Partum Haemorrhage management;
Postpartum haemorrhage (PPH) Carboprost (15-methyl PGF2 ) injected i.m. is an alternative drug for control of PPH due to uterine atony, especially in patients unresponsive to ergometrine and oxytocin. PGE2 (Dinoprostone) PROSTIN-E2 for induction/augmentation of labour, midterm abortion. Gemeprost for softening of cervix in first trimester—1 mg 3 hr before attempting dilatation; for 2nd trimester abortion/molar gestation— PGF2 (Dinoprost) for midterm abortion/induction of labour (rarely used).
15-methyl PGF2 (Carboprost) PPH, midterm abortion, missed abortion.
5. PUD treatment;
Peptic ulcer Stable analogue of PGE1 (misoprostol) is occasionally used for healing peptic ulcer, especially in patients who need continued NSAID therapy or who continue to smoke
6. Glaucoma/increased intra ocular pressure;
Glaucoma Topical PGF2 analogues like latanoprost, travoprost, bimatoprost that are FP receptor agonists are the first choice drugs in wide angle glaucoma.
7. Management of congenital heart disease
To maintain patency of ductus arteriosus in neonates with congenital heart defects, till surgery is undertaken. PGE1 (Alprostadil) is used; apnoea occurs in few cases.
8. Prophylaxis during haemodialysis;
To avoid platelet damage PGI2 (Epoprostenol) can be used to prevent platelet aggregation and damage during haemodialysis or cardiopulmonary bypass. It also improves harvest of platelets for transfusion. Few cases of primary pulmonary hypertension have been successfully maintained on epoprostenol infusion
SIDE EFFECTS These are: nausea, vomiting, watery diarrhoea, uterine cramps, unduly forceful uterine contractions, vaginal bleeding, flushing, shivering, fever, malaise, fall in BP, tachycardia, chest pain.
PLATELET ACTIVATING FACTOR (PAF)
Like eicosanoids, platelet activating factor (PAF) is a cell membrane derived polar lipid with intense biological activity.
PAF is acetyl-glyceryl ether-phosphoryl choline. The ether-linked alkyl chain in human PAF is mostly 16 or 18 C long.
Synthesis and degradation
PAF is synthesized from precursor phospholipids present in cell membrane by the following reactions:
The second step is rate limiting. Antigen-antibody reaction and a variety of mediators stimulate PAF synthesis in a Ca2+ dependent manner on demand: there are no preformed stores of PAF. In contrast to eicosanoids, the types of cells which synthesize PAF is quite limited—mainly WBC, platelets, vascular endothelium and kidney cells.
PAF is degraded in the following manner:
Actions
PAF has potent actions on many tissues/ organs.
1. Platelets
Aggregation and release reaction; also releases TXA2; i.v. injection of PAF results in intravascular thrombosis.
2. WBC
PAF is a potent chemotactic for neutrophils, eosinophils and monocytes. It stimulates neutrophils to aggregate, to stick to vascular endothelium and migrate across it to the site of infection. It also prompts release of lysosomal enzymes and LTs as well as generation of superoxide radical by the polymorphs. The chemotactic action may be mediated through release of LTB4. It induces degranulation of eosinophils.
3. Blood vessels
Vasodilatation mediated by release of EDRF occurs fall in BP on i.v. injection. Decreased coronary blood flow has been observed on intracoronary injection, probably due to formation of platelet aggregates and release of TXA2. PAF is the most potent agent known to increase vascular permeability. Wheal and flare occur at the site of intradermal injection. Injected into the renal artery PAF reduces renal blood flow and Na+ excretion by direct vasoconstrictor action, but this is partly counteracted by local PG release.
4. Visceral smooth muscle
Contraction occurs by direct action as well as through release of LTC4, TXA2 and PGs.
Aerosolized PAF is a potent bronchoconstrictor.
In addition, it produces mucosal edema, secretion and a delayed and long-lasting bronchial hyper-responsiveness. It also stimulates intestinal and uterine smooth muscle.
5. Stomach
PAF is highly ulcerogenic: erosions and mucosal bleeding occur shortly after i.v. injection of PAF. The gastric smooth muscle contracts.
Mechanism of action
Membrane bound specific PAF receptors have been identified. The PAF receptor is a G-protein coupled receptor which exerts most of the actions by coupling with Gq protein and generating intracellular messengers IP3/DAG Ca2+ release. It can also inhibit adenylyl cyclase by coupling with Gi protein. As mentioned above, many actions of PAF are mediated/ augmented by PGs, TXA2 and LTs which may be considered its extracellular messengers. PAF also acts intracellularly, especially in the endothelial cells; rise in PAF concentration within the endothelial cells is associated with exposure of neutrophil binding sites on their surface. Similarly, its proaggregatory action involves unmasking of fibrinogen binding sites on the surface of platelets.
PAF antagonists
A number of natural and synthetic PAF receptor antagonists have been investigated. Important among these are;
Ginkgolide B (from a Chinese plant), and some structural analogues of PAF. The PAF antagonists have manyfold therapeutic potentials like treatment of stroke, intermittent claudication, sepsis, myocardial infarction, shock, g.i. ulceration, asthma and as contraceptive. Some of them have been tried clinically but none has been found worth marketing.
Alprazolam and triazolam antagonize some actions of PAF.
Pathophysiological roles
PAF has been implicated in many pathological states and some physiological processes by mediating cell-to-cell interaction. These are:
1. Inflammation: Generated by leukocytes at the site of inflammation PAF appears to participate in the causation of vasodilatation, exudation, cellular infiltration and hyperalgesia.
2. Bronchial asthma: Along with LTC4 and LTD4, PAF appears to play a major role by causing bronchoconstriction, mucosal edema, recruiting eosinophils and provoking secretions. It is unique in producing prolonged airway hyperreactivity, so typical of bronchial asthma patient.
3. Anaphylactic (and other) shock conditions: are associated with high circulating PAF levels.
4. Haemostasis and thrombosis: PAF may participate by promoting platelet aggregation.
5. Rupture of mature graafian follicle and implantation: Early embryos which produce PAF have greater chance of implanting. However, PAF is not essential for reproduction.
Ischaemic states of brain, heart and g.i.t., including g.i. ulceration.
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Topic 1: Summary
- An Autacoid is an organic substance, such as a hormone, produced in one part of organism and transported by the blood or lymph to another part of the organism where it exerts a physiologic effect on that part.
- Types of Autacoids include;
- Amines : Histamine,5-Hydroxytryptamine.
- Lipids : Prostaglandins, Leukotriens,
- Platelet activating factor.
- Peptide : Bradykinin , angiotensin.
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Topic 1: Further Reading
Reference Material
- Bennett, P., & Brown, M. (2009). Clinical Pharmacology. London: Churchill Livingstone, ELSEVIER.
- Katzung, B. G., & Trevor, A. J. (2012). Basic & Clinical Pharmacology. London: LANGE.
- Mary, J. (2008). Pharmacology, Lippincott Williams and Wilkins
- Njau, E. (2014). Pharmacology and Therapeutics. Nairobi: Amref.
- Rang, H., Dale, M., Ritter, J., Flower, R., & Henderson, G. (2012). Rang and Dale`s Pharmacology. London: Churchill Livingstone, ELSEVIER.
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Topic 1.1: Management of Peptic Ulcer Disease (PUD), EMETICIS, ANTI EMETICSand ANTIBLOATING (Carminatives)
Gastric acidity
1. Primary secretion
- Also called narrow phase/cephalic/primary phase
- Gastric acid secretion is due to reflex excitation of centers in the medulla oblongata and the efferent pathway in the vagus nerve
- This phase can be stimulated/initiated by either site of food, smell of food or even thought of food.
- Other thoughts that may stimulate it : anger, anxiety, apprehension
- The main transmitter for the phase is acetylcholine
2. Secondary phase
- Mainly involve local reflexes and local hormones in the GIT especially gastrin
- The phase is initiated by the actual presence of food in the stomach which induces mechanical distension of pyloric antrum
- The presence of food stimulate local reflexes by virtue of presence of stimulatory chemical substances in the food like amino acids, peptones, caffeine, ethanol etc
- The local reflexes results in secretion of gastric juice that is rich in HCL
- The chemical transmitter is acetylcholine. Acetylcholine can also cause direct release of gastrin
- Maximum gastric acid secretion requires intact cholinergic nerves and also presence of gastrin
- Involves release of enterogastrin from duodenum
- Also involves release of substances such as cholescystokinin and enteroxyntin
- The mechanisms is not clear
- Serotonin inhibits intestinal phase and its absence induces formation of ulcers
- Substances that cause depletion of serotonin have been known to be ulcerogenic for example reserpine , adrenergic neurone blocker depletes catecholamines and serotonin
Ulcerogenic agents
- Anti-inflammatory drugs e.g. NSAIDs which inhibit prostaglandins that are important for maintenance of integrity of intestinal membrane
- Methylxanthines e.g. xanthines, caffeine, theophiline and theobromide
- Glucocorticoids-cause peptic ulcers after prolonged use
- Prolonged use of vasodilators such as alpha adrenergic blockers e.g. phentolamine, prazosin
- Reserpine-increases gastric acid secretion and vagal activity. Causes depletion of serotonin which is supposed to block or terminate the intestinal phase
- Betahistine-has histamine like effects. Act by inhibiting metabolism of histamine. It’s a vestibular sedative used in management of vertigo and meniers disease.
- Lifestyle-stress
- Excessive alcohol consumption
- Drugs e.g prolonged used of ASA.
- Blood group O+ is at higher risk
- First signs of PUD
- Epigastric pain-pain referred to upper abdomen
- Burning sensation to esophagus
- Blood in stool
- Haematemesis
- Severe generalized abdominal pain in severe cases
Diagnosis of PUD;
- History of epigastric pain
- Endoscopy/gastroscopy
- Barium meal test
- Rapid urease test for H pylori
- Cultures for H pylori detection
Drugs for PUD
- Antacids
- Anti-secrotory agents
- H2-receptor blockers
- Anti-cholinergic agents
- Proton pump inhibitors
- Prostaglandins
1. Antacids
Classification of antacids
- Systemic alkaline antacids
- Non-systemic colloidal antacids
1. Systemic alkaline antacids
Examples of systemic antacids
- NA2HCO3 ( Sodium bicarbonate), used in many effervescent mixtures e.g Eno, Andrews.
2. Non-systemic colloidal antacids
- Ca(OH)2,
- CaCO3,
- Al(OH)3,
- MgCO3 and
- Magnesium trisilicate
- More effective than aluminium hydroxide
- Very good for the treatment of heartburn, reflux esophagitis and flatulence
- Neutralizing activity maintains PH between 3.7-5.8, thus do not deactivate pepsin
- Less expensive and rapid onset of action
- May be absorbed in large doses leading to formation of calcific renal stones
Magnesium salts
- Magnesium trisilicate is commonly used
- Has slow onset of action and longer duration of action
- Its neutralizing capacity may raise PH of GIT to 7
- Can absorb pepsin
- Have a laxative effect and thus are combined with Al(OH)3 or caco3 neutralize this effect
- May cause renal toxicity if used for a long time, CVS impairement, neurological disturbance and death.
Aluminium hydroxide, Al(OH)3
- Most popular antacid
- Have acid neutalizing capacity and buffering capacity, thus potent antacid
- Neutralize gastric acidity to PH 4-6 do not deactivate pepsin
- They coat ulcerated cells and potent against direct contact with acid
- Minimally absorbed from the GIT and cause less systemic effects
2. Anti-secretory agents
1). H2-Receptor blockers
- Are competitive reversible blockers of histamine at H2-receptors
- Decrease gastric acid and pepsin secretion
- May decrease release of intrinsic factor if used for a long time
- Their efficacy can be compared to those of antacids and have lower incidence of relapses
- Metiamide and burimamide were first members to be synthesized but lacked potency and selectivity
- Newer drugs in this group include:
- Cimetidine,
- Ranitidine,
- Famotidine,
- Nizatidine,
- Roxatidine and
- Niperotidine
1. Cimetidine
Adverse effects of Cimetidine
- Acute pancreotitis
- Acute interstitial nephritis
- Induce anti-androgenic effects and decrease libido after long term use
- Endocrine disturbance e.g. can cause plasma increase in prolactins and parathyroid hormone
- May potentiate effects of beta blockers e.g propranolol
- May potentiate the effects of benzodiazepines
- May cause reversible mental confusion especially in very ill and elderly patients
- Can reduce tetracycline absorption by raising gastric PH and interfering with dissolution of tetracycline
- Inhibits liver microsomal enzymes and can potentiate the effects of drugs metabolized by the liver
- Interact with phenytoin,theophiline and chlordiazepoxide and reduce their effects
- By raising gastric PH cimetidine favours the growth of bacteria including the nitrate producing bacteria in the stomach and duodenum and their presence cimetidine is metabolised to nitrosocimetidine which is a potential carcinogenic agent.
- Reduces the rate of hair growth and used in treatment of hirsutism
2. Ranitidine
Uses of H2-receptor blockers
- Management of gastric ulcers
- Management of duodenal ulcers
- Reflux esophagitis
- Zollinger Ellison syndrome
- Tumour of pancrease associated with increased levels of pepsin/HCL.
Typical examples of PPIs
- Omeprazole,
- Lanzoprazole,
- Pentoprazole,
- Rabeprazole and
- Esomeprazole.
- Have similarity in absorption rates, distribution, metabolism and excretion
- All PPIs are extensively metabolised in the liver cytochrome P450 mixed function oxidases especially CYP2C19 and CYP3A4.
- Are well tolerated and excellent safety profile.
Clinical uses of PPIs.
- Management of gastrinomas
- Management of H pylori associated ulcers, typical combination therapies include:
- PPI +Clarithromycin 500 mg + amoxycillin 1g
- PPI + Clarithromycin 500 mg + metronidazole 400 mg
- PPI + Clarithromycin 500 mg + amoxiclav 625 mg
Bismuth salts
- Potentiate the effect of metronidazole and also reduce the rate of development of resistance to metronidazole
- H2 blockers are combined with bismuth e.g. ranitidine + bismuth salts + metronidazole
- Other antibiotics include: tetracyclines, erythromycin and azithromycin
Examples of anticholinergics: Pirenzepine, Benzotropine
Side effects of Anticholinergics;
- •Constipation
- •Acute headaches
Other anti ulcers agents
1. Prostaglandins-PGE2
- Inhibits gastric acid secretion via cAMP system
- Mainly used in management of NSAID induced ulcers
- Also as abortifacient and management of postpartum haemorrhages
2. Carbenoxolone sodium
- Increases rate of mucous secretion
- Prolongs lifespan of mucous cells
- Inhibits action of pepsin
- Can cause Na+ retention and increases K+ excretion and therefore should be used with caution in hypertension
- Promotes ulcer healing by increasing rate of mucous secretion
- Can cause sodium retention due to presence of glycyrrhiza
4. Local anaesthetics
- Useful in PUD
- Used in combination with antacids
- Used in management of pain associated with peptic ulcers
- Examples: Oxythazine and Benzocaine
5. Algnic acid derivatives
- Commonly used in PUD
- Have mucoprotective properties
Antibiotics in PUD;
- Only indicated in duodenal ulcers where H pylori is implicated
Other anti Ulcer agents;
1) Sucralfate
- Contains sulphated polysaccharide plus aluminium complexes
- Have mucoprotective effects and inhibits diffusion of H+ and also potentially inhibits pepsin
- Neutralizes gastric acid locally in the GIT without affecting intra-gastric PH
- Binds bile acids and salts
- Equipotent to H2 antagonists but with minimal side effects
- Form of satchets e.g. 1 g satchets
- Dose: 1 satchet half hour before food tds
2) Garfanate
- Found in white cabbage promotes healing by cytoprotective effects
- In USA used as tabs 100-200 mg bd
3) Sedatives
- Alleviates anxiety and stress associated with increased acid production
- Examples: benzodiazepines such as diazepam, barbiturates
EMETICS
- Centrally acting emetics
- Reflex emetics
1. Centrally acting emetics
- Increased intra occular pressure causes centrally mediated vomiting
- Excessive pain
- Motion sickness
- Feeling of disgust
- Cardiac glycosides and ergot alkaloids
2. Reflex emetics
- Copper sulphate,
- Zinc sulphate,
- Mercuric salts,
- Antimony salts,
- Emetine from ipecacuanha and
- High concentration of sodium chloride, warm.
- Tetracycline
- Colchicine
- Antineoplastic drugs
- NSAIDs
- Chlorohydrate
Chlorpiricin ( vomiting gas )
ANTIEMETICS;
Drugs used to prevent vomiting e.g. in
- Pregnancy
- Motion sickness
- Excessive alcohol
- Chemotherapy
- Anti-migraine drugs
- Radiation therapy
- Disease induced emetics
- Post operative nausea and vomiting
- Phenothiazines
- Antihistamines
- Anticholinergics
- Serotonin antagonists
- Dopamine antagonists
- Steroids
- Vitamin B6
- Benzodiazepines
- Cannabinoids and benzamide derivatives
1. Phenothiazines
- Chlorpromazine,
- Perphenazine,
- Thioperazine,
- Trifluoroperazine ethylperazine and
- Prochlorperazine.
2. Antihistamine
- Dimenhydrinate,
- Cyclizine,
- Ceclizine,
- Diphenhydramine,
- Phenothiazine and
- Hydroxyzine.
3. Anticholinergics
- Hyoscine (Buscopan) and
- scopolamine
- Ondasetron,
- Granisetron,
- Tropisetron,
- Dolasetron and
- Romasetron
- Metochlorpramide ( plasil) block dopamine and 5 HT.
- Dexamethasone,
- Betamethasone and
- Methylprednisolone
6. Vitamin B6 (pyridoxine)
7. Benzodiazepines
- Alprazolam and
- Prolazepam
8. Cannabinoids
- Tetrahydrocannabinoid,
- Dronabidol and
- Nabilone
- Examples:
- Cisapride,
- Clebopride,
- Alizapride
CARMINATIVES
- Ginger,
- Cadamon,
- Fennel,
- Coriander,
- Cloves,
- Cinnamon and
- Nutmeg
BITTERS AND APPETITE BOOSTERS
- Are products taken before meals to improve appetite
- Stimulate taste buds and cause reflex secretion of saliva
- When taken orally increases gastric acid secretion and rate of digestion of food
Examples:
- Tonic mixtures and alcoholic beverages
- Ginseng
- Strychnine pure form/tincture of Nux vomica
- Products with liver extracts
- Preperations with glycerol phosphate
- Cyproheptadine-stimulates appetite
- Chlorpromazine
- Anabolic steroids
- Clonidine
- Amitryptylline
- Gentian root.
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Topic 1.2: ANTIDIARRHOEALS
- Kidney disease
- Liver disease
- Thyroid disease
- Lung disease
- Heart disease
Acute diarrhea
- Characterised by sudden onset or frequent liquid stools
- Patients may also complain of joint pain, weaknesses, fever and vomiting
- It can be due to bacterial infection or often due to bacteria toxins or use of chemicals
- They may lead to inflammation in the GIT mucosa, increased mucous secretion and increased GIT motility
- Bacteria include: clostridium, salmonella
- Chemicals include: lead, mercury, cadmium
- Allergic reactions by food e.g. eggs, milk, wheat
Chronic diarrhea
- Food-food poisoning, change in diet can cause diarrhea
- Emotional disturbance-characterised by psychological disturbance such as anxiety can lead to severe diarrhea
- Infections:
- Parasitic infections especially with Giardia lamblia
- Amoebic dysentery-has two phases, intestinal and hepatic phase
- Bacillary dysentery especially shigella dysentery, Rx amoxicillin and cotrimoxazole
- Typhoid fever caused by Salmonella typhi, Rx ciprofloxacine, amoxiclav and chloramphenical.
- Balantidium dysentery, Rx tetracycline and clioquinol
- Ulcerative colitis
- Neoplasia of colon
- Malabsorption
- Thyrotoxicosis
- Neurotic disorders
- Carcinoid syndrome
- Drugs e.g carthatics, broad spectrum antibiotics
Drugs used in management of diarrhea act in two ways:
- Increasing viscocity of GIT contents by their direct action
- Delaying passage of GIT contents so that there is more time for water to be reabsorbed
Drugs that act by increasing viscocity of GIT contents
- They acts adsorbents and also demulcents i.e. provide a protective coating on GIT mucosa
- Adsorb toxins responsible for diarrhea
- Add solid to the colon improving cosistency of faeces
- Adsorbents are not specicific in function, they can adsorb nutrients and even co administered drugs
Examples of drugs that increase viscosity of GIT Contents:
- Kaolin
- Arrow root
- Chalk
- Attapulgite
- Bismuth subgallate
- Aluminium hydroxide
- Activated charcoal
- Synthetic resins
Drugs delaying passage of GIT contents
- Morphine and derivatives,
- Atropine and its derivative.
Atropine and its derivatives
- Hyoscine,
- Hyoscyamine,
- Propanthine,
- Mebeverine
Morphine and derivatives
- Act by decreasing the propulsive movements of the GIT
- Prolong or increase transit time of GIT content
- They increase water absorption hence leading to better formed stool
- They have risk of dependence and therefore used with care
- Examples of Morphine and its derivatives
- Morphine
- Camphorated tincture of opium
- Diphenoxylate sodium
- Codeine phosphate tabs
- Loperamide
- Fluperamide
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Topic 1.3: CONSTIPATION, HAEMORRHOIDS AND THEIR MANAGEMENT
- Nature of diet
- Relative proportion of indigestible fibres
- Previous straining habits
- Psychological status
- Physical disturbances e.g. trauma
- Drugs used to treat constipation are referred to us carthatics/laxatives/purgatives/evacuants/aperiants.
Causes of constipation
- Drugs e.g.
- Morphine,
- Atropine,
- Sympathomimetics,
- Ganglion blockers,
- General anesthetics,
- Tricyclic antidepressants and
- Sedatives
- Illness
- Reduced food intake
- Psychosomatic disorders
- Atony of colon and or rectum
- Organic causes such as;
- Hyperthyroidism,
- Vasoconstriction,
- Oral lesions and
- Prolonged use of irritant carthatics
1. CARTHATICS
Classification of Carthatics;
- Bulk carthatics-saline and hydrophilic carthatics
- Irritant/stimulant carthatics
- Lubricant carthatics
- Emollients/faecal softeners/surfactants
- Miscelleneous
Mechanism of action
Examples of bulk carthatics
- Saline carthatics-consists of inorganic salts that are insoluble either anion or cation such as;
- Magnesium sulphate,
- Magnesium carbonate,
- Sodium sulphate,
- Sodium-patassium tartarate,
- Tartaric acid and
- Sodium phosphat
- Examples of saline carthatics: rochelle salts, milk of magnesia, glaubers salt, epsom salts .
- 2. Hydrophillic carthatics-consists of natural polysaccharides or cellulose derivatives
- •They absorb water, swell, decrease in bulk and cause reflex stimulation of peristalisis.
- Examples of hydrophillic carthatics:
- Bran,
- Methylcellulose,
- Konsyl,
- Metamucil,
- Plant gums e.g acacia, sodium alginate,lactulose
Examples of Irritant carthatics;
- Emodin type carthatics e.g aloe, senna, cascara, rhubarb and frangular
- Castor oil- obtained from Ricinus communis, very potent and can induce labour
- Croton oil-withdrawn from clinical use due to toxicity, causes GIT perforation in PUD, severe nausea, gastro enteritis, prolapse and protraction
- Resinous irritant carthatics- e.g. jalap, podophyllin, colocynth, ipomoea, cambogia
- Miscelleneous irritant carthatics:
- Glycerin-used in form of supposotories for children and adults
- Mercuric chloride- potent, causes kidney damage
- Bisacodyl- potent, has slow onset of effects between 6-8 hours. Mainly taken at night so that maximum effects is observed in the morning.
- Phenolphthalein-rarely used alone. Its incorporated in some consumer products due to its laxative effects. Found in chewing gums
2) Faecal softeners/emollients/surfactants
Examples of stool softeners;
- Dioctyl sodium sulphosuccinate.
- Polloxakol.
Clinical uses of stool softeners
- Management of spastic constipation since they do not retard absorption of nutrients from intestine
- Management of constipation of hard stool and post surgical paralytic ileus
- Prevent undue straining of stool especially after surgery because it can lead to rapture of operated area
- To relieve constipation
- To prepare patients for anaesthesia and general surgery especially abdominal surgery
- To prepare patients for radiological process e.g. X-rays of the abdomen
- To promote elimination of toxic materials from the GIT
- Promote elimination of intestinal parasites like worms
- To induce labor in full term pregnancy
- Management of hepatic coma; magnesium sulphate is used , the hepatic portal vein is usually congested, magnesium sulphate causes relaxation of hepatic portal vein.
Contraindication of Carthatics
- Advanced pregnancy
- In case of mechanical obstruction and inflammation of the GIT
- Chronic constipation
- Patients with abdominal muscle cramps, colic pain, nausea and vomiting
General side effects of Carthatics;
- Excessive water and electrolytes loss leading to hypokalemia, hyponatremia and hypocalcemia
- Steatorrhea
- Peritonitis in case of perforation of the GIT mucosa
- Blood stool
- Pain
- Inflammation of veins
- Prolapse
Management of Haemorrhoids;
1. Sclerosing agents
Examples of sclerosing agents:
- Sodium tetradecyl sulphate
- Quinine/ urea injections
- Morrhuate injections
- Phenol in almond oil
- Tetracaine,
- Benzocaine,
- Mepivacaine,
- Pramoxine,
- Cyclomethacaine,
- Cinchocaine
- Hydrocortisone,
- Betamethasone,
- Prednisolone and
- Fluticasone
- Neomycin,
- Gramicidin,
- Bacitracin,
- Fusidic acid,
- Antiseptics
- Phenol in almond oil
- Zinc oxide
- Tannic acid
- Aluminium sub acetate
- Bismuth sub gallate
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Topic One: Further Reading
- Bennett, P., & Brown, M. (2009). Clinical Pharmacology. London: Churchill Livingstone, ELSEVIER.
- Katzung, B. G., & Trevor, A. J. (2012). Basic & Clinical Pharmacology. London: LANGE.
- Mary, J. (2008). Pharmacology, Lippincott Williams and Wilkins
- Njau, E. (2014). Pharmacology and Therapeutics. Nairobi: Amref.
- Rang, H., Dale, M., Ritter, J., Flower, R., & Henderson, G. (2012). Rang and Dale`s Pharmacology. London: Churchill Livingstone, ELSEVIER.
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Topic 1.1: OVERVIEW AND CLASSIFICATION OF RESPIRATORY PHARMACOLOGY
- Asthma,
- Chronic obstructive pulmonary disease (COPD), and
- Allergic rhinitis
- Are commonly encountered respiratory diseases.
- Each of these conditions may be associated with a troublesome cough, which may be the patient's only presenting complaint.
- Asthma is a chronic disease characterized by hyperresponsive airways, affecting 10 million patients (four to five percent of the U.S. population), and resulting annually in 2 million emergency room visits, 500,000 hospitalizations, and 5,000 deaths.
- COPD, also called emphysema or
chronic bronchitis, affects approximately 30 million Americans and is currently
the fourth most common cause of preventable deaths in the United States.
Allergic rhinitis, characterized by itchy, watery eyes, runny nose, and a
nonproductive cough, is an extremely common condition that significantly
decreases patient-reported quality of life.
- Allergic rhinitis affects approximately 20 percent of the population. Coughing is an important defensive respiratory response to irritants and has been cited as the number-one reason why patients seek medical care. A troublesome cough may represent several etiologies, such as the common cold, sinusitis, and/or an underlying chronic respiratory disease
- Lifestyle changes/Modification. and
- Medication management.
- Topically to the nasal mucosa,
- Inhaled into the lungs, or
- Given orally or parenterally for systemic absorption.
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Topic 1.2: ASTHMA MANAGEMENT
- Shortness of breath,
- Cough,
- Chest tightness,
- Wheezing, and
- Rapid respiration.
- Nonpharmacologic relaxation exercises,
- Quick relief medications, such as a short-acting -adrenergic agonist
remodeling, resulting in increased severity and incidence of exacerbations
and/or death. - High outpatient costs,
- Numerous hospitalizations, and
- Decreased quality of life
- Reducing impairment:
- Prevent chronic and troublesome symptoms.
-
Require infrequent use (2 days a week) of inhaled short-acting agonist for quick relief of symptoms.
-
Maintain (near) normal pulmonary function.
-
Maintain normal activity levels (including exercise and other physical activity and attendance at work or school).
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Meet patients' and family expectations of and satisfaction with asthma care.
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Reducing risk:
- Prevent recurrent exacerbations of asthma, and minimize the need for emergency department visits or hospitalizations.
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Prevent progressive loss of lung function; for children, prevent reduced lung growth.
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Provide optimal pharmacotherapy with minimal or no adverse effects.
1. ADRENERGIC AGONISTS
- Direct-acting agonists are potent bronchodilators that relax airway smooth muscle.
- Most clinically useful agonists have a rapid onset of action (5-30 minutes) and provide relief for 4 to 6 hours. They are used for symptomatic treatment of bronchospasm, providing quick relief of acute bronchoconstriction. [Epinephrine is the drug of choice for treatment of acute anaphylaxis]
- Agonists have no anti-inflammatory effects, and they should never be used as the sole therapeutic agents for patients with persistent asthma. Monotherapy with short-acting agonists may be appropriate only for patients identified as having mild intermittent asthma, such as exercise-induced asthma.
- The direct-acting -selective agonists, such as
- Pirbuterol [peer-BYOO-ter-ole],
- Terbutaline [ter-BYOO-ta-leen], and
- Albuterol [al-BYOO-teh-rall], offer the advantage of providing maximally attainable bronchodilation with little of the undesired effect of stimulation.
- The agonists are not catecholamines and, thus, are not inactivated by catechol-O-methyltransferase. Adverse effects, such as tachycardia, hyperglycemia, hypokalemia, and hypomagnesemia are minimized with dosing via inhalation versus systemic routes.
- Although tolerance to the effects of agonists on nonairway tissues occurs, it is uncommon with normal dosages. All patients with asthma should be prescribed a quick-relief inhaler and regularly assessed for appropriate inhaler technique.
- Salmeterol [sal-ME-te-rol]
- Xinafoate and
- Formoterol [for-MOH-ter-ol] are long-acting agonists bronchodilators. They are chemical analogs of albuterol but differ by having a lipophilic side chain, increasing the affinity of the drug for the -adrenoceptor.
- Salmeterol and formoterol have a long duration of action, providing bronchodilation for at least 12 hours. Both salmeterol and formoterol have slower onsets of action and should not be used for quick relief of an acute asthma attack. long-acting agonists should be prescribed for routine administration.
- Whereas inhaled corticosteroids remain the long-term control drugs of choice in asthma, long-acting agonists are considered to be useful adjunctive therapy for attaining asthma control. Adverse effects of the long-acting agonists are similar to quick-relief agonists. Appropriate inhaler technique with long-acting agonists is critical to the success of therapy, may differ from the patient's other inhalers (metered-dose inhaler versus dry powder inhaler), and should be reassessed regularly
2. CORTICOSTEROIDS;
- Decreasing the inflammatory cascade (eosinophils, macrophages, and T lymphocytes),
- Reversing mucosal edema,
- Ddecreasing the permeability of capillaries, and
- Inhibiting the release of leukotrienes.
- Inhalation: The development of ICS has markedly reduced the need for systemic corticosteroid treatment to achieve asthma control. Appropriate inhalation technique is critical to the success of therapy.
- Metered-dose inhalers have propellants that eject the active medication from the canister. Patients should be instructed to SLOWLY and DEEPLY inhale upon activation of these inhalers to avoid impaction of the medication onto the laryngeal mucosa rather than the bronchial smooth muscle.
- Improper use of a metered-dose inhaler can result in a large fraction (typically 80-90 percent) of inhaled glucocorticoids to be deposited in the mouth, pharynx, and/or swallowed. The 10 to 20 percent of the metered dose of inhaled glucocorticoids that is not swallowed is deposited in the airway. If ICS are inappropriately inhaled, systemic absorption and adverse effects are much more likely. ICS delivered by dry powder inhalers require a different inhaler technique. Patients should be instructed to inhale QUICKLY and DEEPLY to optimize drug delivery to the lungs. Even properly administered, corticosteroid deposition on the oral and laryngeal mucosa can cause adverse effects such as oropharyngeal candidiasis and hoarseness. Patient counseling incorporating a rinsing of these tissues via the swish and spit method should avoid these adverse events.
- 2. Oral/systemic: Patients with severe exacerbation of asthma (status asthmaticus) may require intravenous administration of methylprednisolone or oral prednisone. Once the patient has improved, the dose of drug is gradually reduced, leading to discontinuance in 1 to 2 weeks. In most cases, suppression of the hypothalamic-pituitary axis will not occur during the short course of oral prednisone typically prescribed for an asthma exacerbation; therefore, dose reduction is not necessary.
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Topic 1.2: ASTHMA MANAGEMENT (Cont')
Spacers;
OTHER ALTERNATIVE DRUGS USED TO TREAT ASTHMA;
- Zileuton [zye-LOO-ton] is a selective and specific inhibitor of 5-lipoxygenase, preventing the formation of both LTB4 and the cysteinyl leukotrienes.
- Zafirlukast [za-FIR-loo-kast] and
- Montelukast [mon-tee-LOO-kast] are selective, reversible inhibitors of the cysteinyl leukotriene-1 receptor, thereby blocking the effects of cysteinyl leukotrienes .
- All three drugs are orally active, although food impairs the absorption of zafirlukast.
- Greater than 90 percent of each drug is bound to plasma protein.
- The drugs are extensively metabolized.
- Zileuton and its metabolites are excreted in the urine, whereas zafirlukast and montelukast and their metabolites undergo biliary excretion.
- Elevations in serum hepatic enzymes have occurred with all three agents, requiring periodic monitoring and discontinuation when enzymes exceed three to five times the upper limit of normal.
- Although rare, eosinophilic vasculitis (Churg-Strauss syndrome) has been reported with all agents, particularly when the dose of concurrent glucocorticoids is reduced. Other effects include headache and dyspepsia.
- Both zafirlukast and zileuton are inhibitors of cytochrome P450. Both drugs can increase serum levels of warfarin.
- Cromolyn [KROE-moe-lin] and
- Nnedocromil [ne-doe-KROE-mil]