Autacoids (trans 10) Flashcards by Vin James Penalosa

Autacoids
 Diverse group of biologically active substances that are common in the ability act on smooth muscles
 Sometimes called local hormones

A. Histamine
B. Serotonin
C. Ergot alkaloids
D. Prostaglandins
E. Nitric Oxide

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HISTAMINE

 Biogenic amine derived from amino acid histidine

Storage sites:
o Mast cells in tissues, basophils in blood
o CNS (neurotransmitter), ECL cells of stomach fundus (activates acid-producing cells in gastric mucosa)

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Release of histamine:
1. Immunologic – binding of antigen to IgE attached on cell receptors attached on sensitized mass cells and basophils; requires energy and Ca2+; mediator of Type I/ Immediate Hypersensitivity Reactions

Displacement – doesn’t require energy; degranulation doesn’t take place; e.g. morphine
Mechanical/Physical Cell Injury – mass cell damage leading to degranulation

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Actions of histamine

– via 4 types of GPCR (constitutive activity):

(constitutive activity):

H1 – Gq; related to muscarinic or cholinergic receptors
H2 – Gs; related to 5-HT1 receptors
H3 – Gi
H4 – Gi

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Effects of histamine:
o On smooth muscle:
 Vascular smooth muscle – dilatation of terminal arterioles and post-capillary venules (H1)
 Sense of warmth, flushing, erythema; headache due to increase in blood and engorgement of vessels
 Bronchial smooth muscle – marked constriction in sensitive airways (H1) (normal airways do not)
 GIT smooth muscle – contraction, diarrhea (in large doses)
 Pregnant, with anaphylaxis – abortion due to uterine contractions

o On sensory nerve endings: depolarization of afferent nerve terminals (H1)
 Insect bites: itch and pain
o Direct cardiac effects:
 Increase force of contraction/inotropic effect (H2)  increase amount of Ca2+ that enters the myocytes
 Increase rate of depolarization in SA node
 increase pacemaker rate (H2)
 Decrease arterial muscle contractility (H1)
 Overall: Decrease BP (due to pronounced vasodilatation) with reflex tachycardia
o On secretory tissue: increase gastric acid secretion by gastric parietal cells (H2)
o On CNS: maintenance of sleep-wake cycles, appetite suppression, memory, etc.

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Counteracting histamine effects:

Physiologic antagonism – epinephrine binds to non-histamine receptors, reversing bronchoconstriction => bronchodilation
Prevention of mast cell degranulation – mechanism in acute asthmatic attacks; e.g. cromolyn, nedocromil – mast cell stabilizers
Use of anti-histamines via H-receptors – H1 anti-histamines; H2 antihistamines

H1 anti-histamines:
- 1st Generation H1 antihistamines
1. Ethanolamines – e.g. diphenhydramine, dimenhydrinate, doxylamine
2. Alkylamines – e.g. chlorphenamine, brompheniramine
3. Phenothiazines – e.g. promethazine
4. Piperazines – e.g. hydroxyzine, meclizine
- 2nd Generation H1 antihistamines
1. Piperazines:
Cetirizine: metabolite of hydroxyzine (1st gen)
Levocetirizine: active enantiomer of cetirizine
2. Piperidines:
Loratidine
Desloratidine: active enantiomer of loratidine
Fexofenadine: metabolite of terfenadine (early 2nd gen drug no longer available; cardiotoxicity)
3. Phthalazinones – e.g. Azelastine

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HISTAMINE - Pharmacokinetics of H1 antihistamines
Pharmacokinetics of H1 antihistamines
1. Absorption: good (both 1st and 2nd gen H1 antihistamines are rapidly absorbed)
2. Peak plasma concentration levels: 1-2 hours
3. Duration of effect
 2nd gen effects lasts longer than 1st
 1st generation: 4-6 hours (for most); 12-24 hours (for meclizine)
 2nd generation: 12-24 hours
4. Distribution
 1st generation: can penetrate the blood-brain barrier into CNS due to lipid solubility
 2nd generation: minimal/no entry into CNS
- less lipid soluble (reduced penetration in membranes)
- has P-glycoprotein substrates (efflux pump that expels foreign molecules)
5. Metabolism: mostly via CYP450

Pharmacodynamics of H1 antihistamines

 MOA: reversible competitive binding to H1 receptors => reduce or block histamine effects

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Clinical uses (and non-uses) of antihistamines
(Generally: to combat allergic symptoms) - Urticaria (hives)

 Well-circumscribed wheels with erythematous borders, accompanied by itching
 control of itching, redness/erythema and edema
 For most cases, both 1st and 2nd gen are efficacious orally. But 2nd gen preferred due to better ADR profile.
 For localized wheels, topical antihistamine (e.g. Caladryl, containing diphenhydramine) may be used
 For intense wheels and severe itching, antihistamine may be introduced parenterally.

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Clinical uses (and non-uses) of antihistamines
(Generally: to combat allergic symptoms) - Allergic rhinitis

 Sneezing, itching of nose/throat, rhinorrhea (runny nose), nasal congestion
 1st and 2nd gen drugs equally efficacious in terms of reliving nasal itching and sneezing
 Rhinorrhea (runny nose) and nasal congestion only to a certain extent, hence antihistamines are usually given with decongestants
 Again, 2nd generation drugs are preferred.
 Intranasal AH also relieves sneezing and itching, while relieving runny nose and nasal congestion better than oral antihistamines

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Clinical uses (and non-uses) of antihistamines
(Generally: to combat allergic symptoms) - Allergic conjunctivitis

 Edema and congestion of eyelids and conjunctivae
 Relieve ocular itching, watering, redness
 Ophthalmic preparations used due to more rapid effect. However, they must be administered several times a day.

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Clinical uses (and non-uses) of antihistamines
(Generally: to combat allergic symptoms) - Asthma

 NOT treated by antihistamines due to the involvement of other inflammatory mediators
 Asthma requires bronchodilators for acute attack, and inhaled glucocorticoid for prevention of future attacks
 Antihistamines are NOT bronchodilators

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Clinical uses (and non-uses) of antihistamines
(Generally: to combat allergic symptoms) - Laryngeal angioedema and anaphylaxis

 Breathing obstruction in angioedema, anaphylaxis involves a systemic response to the presence of histamine, resulting in urticaria and hypotension.
 Life-threatening, treated with epinephrine via ampule or auto-injector (epi-pen)
 Antihistamines are only SECOND-LINE drugs as they are NOT vasoconstrictors

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Clinical uses (and non-uses) of antihistamines
(Generally: to combat allergic symptoms) - Atopic dermatitis, wheels, itching, local reactions (as in insect bites)

AH may be used for relief.

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Clinical uses (and non-uses) of antihistamines
(Generally: to combat allergic symptoms) - Motion sickness

 Caused by conflict signals from the eyes and vestibular apparatus, presents with nausea/vomiting
 1st generation antihistamines are used to prevent/treat motion sickness
 1st gen antihistamines can enter CNS, block the histamine and muscarinic receptors in vestibular nuclei and vomiting center
 Take at least 1 hour before travel or any activity involving motion sickness
Ex. diphenhydramine, dimenhydrinate, meclizine, promethazine
 12-24 hours efficacy
 Another effective drug: Scopolamine (anti-cholinergic drug, effective due to blockage of cholinergic impulses to the vestibular nuclei and vomiting center), available as patch on prescription, it is applied behind the ear 6-8 hours before travel, effective for 72 hours

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Clinical uses (and non-uses) of antihistamines
(Generally: to combat allergic symptoms) - Vomiting due to radiation or chemotherapy (anti-emesis)

 Promethazine – though it is not used as much anymore because it causes orthostatic hypotension

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Clinical uses (and non-uses) of antihistamines
(Generally: to combat allergic symptoms) - Anti-Parkinsonism

 Antihistamines counteract rigidity, tremors, abnormal movements secondary to anti-psychotic drugs
 Diphenhydramine injection

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Clinical uses (and non-uses) of antihistamines
(Generally: to combat allergic symptoms) - Insomnia

 Sleep aids, with hypnotic effect

 Doxylamine, diphenhydramine

Adverse drug reactions of antihistamines

SEDATION (very pronounced)
BLOCKAGE OF CHOLINERGIC/MUSCARINIC RECEPTORS
BLOCKING OF ALPHA-ADRENORECEPTORS
GIT EFFECTS

Adverse drug reactions of antihistamines - SEDATION (very pronounced)

common in 1st gen (varying among subgroups), less/absent in 2nd gen
a) sleepiness, low alertness, slow rxn time
 interferes with daily activities
 impairs motor activities
b) agitation and restless in children
 less common
 no explanation for this

Adverse drug reactions of antihistamines - BLOCKAGE OF CHOLINERGIC/MUSCARINIC RECEPTORS

Common in 1st gen, absent in 2nd gen
a) Dry mouth and respiratory passages
 Lead to cough
b) Constipation
 Due to decrease in intestinal motility
c) Urinary retention
 Due to decreased bladder smooth muscle contraction
 May precipitate symptoms in men with enlarged prostates
d) Blurred vision
 Due to mydriasis (dilatation of the pupils) and cyclopegia (paralysis of accommodation)

Adverse drug reactions of antihistamines - BLOCKING OF ALPHA-ADRENORECEPTORS

common in the phenothiazine subgroup

a) orthostatic hypotension
b) syncope in susceptible individuals

Adverse drug reactions of antihistamines - BLOCKING OF ALPHA-ADRENORECEPTORS

common in the phenothiazine subgroup

a) orthostatic hypotension
b) syncope in susceptible individuals

Adverse drug reactions of antihistamines - GIT EFFECTS

a) nausea, vomiting
b) loss of appetite
c) epigastric distress

SEROTONIN (5-HYDROXYTRIPTAMINE)
 synthesized from tryptophan
 storage: enterochromaffin cells, platelets, CNS
 stored in vesicles rapidly inactivated
 pineal gland serves as precursor to melatonin
 functions: mood, sleep, appetite, temp and BP reg, vomiting
 actions mediated by serotonin receptors
 sumatriptans and its analogs activates serotonin receptors
 no clinical use of serotonin
o its receptors are of clinical value

Clinical Application: Migraine
o unilateral throbbing headache, hours or few days
o vascular theory: dilation of cranial arteries innervated by CN V; extravasation of plasma and protein => edema

5-HT receptor agonist: Sumatriptan and analogs o use: to abort acute migraine attacks o only used for migraine relief not for prophylaxis

Mode of Action: activate 5-HT receptors on: o Nerve terminals => inhibit release of vasodilators o Cranial arteries => constrict the dilated blood vessels  Adverse effects: coronary spasms, chest discomfort or pain, muscle weakness, tingling

``` Triptans Contraindications o Coronary artery disease o Angina pectoris o Peripheral vascular disease o Hypertension o 5-HT receptors ANTAGONIST: Ondansetron & analogs ```

MOA: binds to HT3 receptors o In vomiting center (central) o On intestinal vagus nerve terminals (peripheral) Use: to prevent nausea and emesis associated with o Cancer chemotherapy o Radiation therapy o Surgery o Alternative to Promethazine (doesn’t produce orthostatic hypotension) Adverse effects: headache, dizziness, constipation, QT prolongation

ERGOT ALKALOID  Products of fungus (Claviceps purpurea)  Causes : ”ergotism” (poisoning from consuming cereals) - gangrene, dementia, convulsion  MOA: act on the ff. receptors o 5-HT o α- adrenergic o dopamine

1. Ergonovine / Methylergonovine | 2. Ergotamine / Dihydroergotamine

ERGOT ALKALOID - Ergonovine / Methylergonovine

 Use: to prevent or control postpartum hemorrhage  MOA: stimulate uterine smooth muscle contraction  (5-HT and α- adrenoceptor agonist)  Given AFTER delivery of baby and placenta

ERGOT ALKALOID - Ergotamine / Dihydroergotamine

```  Use: to abort acute migraine attacks  MOA: partial agonist actions on 5- HT and α- adrenergic receptors => vasoconstriction  Caution: not more than 6 mg orally per attack o Not more than 10 mg per week  Adverse effects o Nausea, vomiting, diarrhea o Gangrene, bowel infarction o Chest pain or discomfort o Contraindications o Peripheral vascular disease o Coronary artery disease o Hypertension o Pregnancy ```

``` PROSTAGLANDINS  Prostanoids derived from arachidonic acid  Bind to G-protein coupled receptors  Drug groups with clinical usefulness o PG analogs o Enzyme inhibitors – NSAIDS ```

``` Prostaglandin analogs A. Misoprostol-PGE1 analog (ex Cytotec) B. Dinoprostone C. Carboprost D. Latanoprost and analogs E. Alprostadil ```

PROSTAGLANDINS - Misoprostol-PGE1 analog (ex Cytotec)

 MOA: Inhibits secretion of gastric acid and stimulates uterine contractions  Use: to prevent NSAID-induced gastric ulcers (FDA – approved)

Prostaglandin analogs - Dinoprostone

```  MOA: stimulate uterine contractions Uses: o To terminate pregnancy in 2nd trimester o To induce labor  ADR: emesis, diarrhea ```

Prostaglandin analogs - Carboprost

```  MOA: stimulate uterine contractions Uses: o To terminate pregnancy in 2nd trimester o To treat postpartum bleeding  ADR: emesis, diarrhea ```

Prostaglandin analogs - Latanoprost and analogs

 MOA: increase outflow of aqueous humor from anterior chamber => Decrease intra-ocular pressure (IOP)  Use: to treat high IOP in px with open-angle glaucoma (ocular hypertension)  Other effects: o Brown pigmentation of iris (irreversible) o Eyelash lengthening, thickening (reversible) *Bimatoprost (Lumigan) – used to bring down IOP *Bimatoprost (Latisse) – application on the upper lid  Use: to treat hypotrichosis of eyelashes (thinning of the eyelashes); for longer, fuller, darker eyelashes  Once a day for 16 weeks; reversible: when you stop the usage, the effect will be gone

Prostaglandin analogs - Alprostadil 1. MOA: vasodilation Use: to maintain patency of ductus arteriosus after birth o ductus arteriosus normally closes shortly after birth because of decreased prostaglandin levels  Short half-life: 5-10 mins therefore is given as IV infusion  For babies who have congenital cardiac anomalies, keeping the ductus arteriosus open is life-saving  Conditions that may require an open ductus arteriosus (congenital cardiac anomalies): o Transposition of the great vessels - aorta and artery are not the in the normal position o Pulmonary artery stenosis – there is constriction o Pulmonary valve atresia – pulmonary valve is either closed or absent

2. MOA: relaxes the smooth muscles of the penile corpora cavernosa Use: to treat penile dysfunction **Medicated Urethral Suppository for Erection (MUSE)  Dosage form: Urethral Suppository (semi-solid pellet)– ready to use prefilled plastic applicator  Maximum dose: 2x in 24 hrs only because it may cause prolonged erection or priapism **Alprostadil  Dosage form: solution for intracavernosal injection (painful)  Maximum dose: 3x/week at 24 hr intervals  High discontinuous rate because it is invasive, painful and have a high risk of priapism (penile erection lasting more than 4 hours)

NITRIC OXIDE  Gaseous highly reactive signaling molecule  Regulates a wide range of physiologic and pathologic processes  Endogenous activator of soluble guanylate cyclase --. cGMP formation  Vasodilator effect is mediated by cGMP  Pharmacologic manipulation of nitric oxide

Nitric oxide gas inhalation  Can be stored as a compressed gas mixture with nitrogen  Inhaled NO: decrease pulmonary artery pressure; improves perfusion of ventilated areas in the lungs  For px who have pulmonary hypertension and those suffering from acute hypoxemia

NITRIC OXIDE Nitric oxide donors  Drugs that release NO – for smooth muscle relaxation o Organic nitrates and nitrites: anti-angina o Treat angina pectoris (chest pain) from myocardial ischemia o Sodium nitroprusside – used in hypertensive emergencies and heart failure => blood pressure must be lowered

 Nitroglycerin  Isosorbide dinitrate and mononitrate  Amyl nitrite

NITRIC OXIDE Prevents cGMP degradation **cGMP effects and degradation. Since it is cGMP that mediates the vasodilation action of the NO, cGMP must be maintained. Normally, the physiologic degradation of cGMPs is carried out by phosphodiesterase enzyme

**cGMP effects and PDE-5 inhibitors. Erection requires the presence of cGMP, which is produced from the release of NO. NO requires parasympathetic discharge from an intact motor innervation activated by libido or sexual arousal. Therefore, the phosphodiester 5 inhibitors will not be affected in men who suffer from spinal cord injury or damaged innervation or those who don’t have libido

Treatment options for erectile dysfunction 1. Vacuum erection device 2. Penile implants 3. Urethral suppository – alprostadil 4. Intracavernosal injection – alprostadil, phenotolamine 5. Oral medication – sildenafil and analogs

Adverse Effects of PDE-5 inhibitors 1. Headache, nasal congestion, dizziness 2. Vision abnormalities  Blurring/loss of vision: called non-arterititc ischemic optic neuropathy (NAION)  Impaired color discrimination (blue/green) o PDE-6 inhibition in retina

NITRIC OXIDE | Drug Interactions

1. Contraindicated: concomitant use with nitric oxide donors 2. Use with caution  Antihypertensives  Alpha-adrenergic blockers – for BPH  CYP3A4 inhibitors – will increase blood levels of PDE-5 inhibitors