Autacoids (trans 10) Flashcards
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
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)
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
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
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.
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
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
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.
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
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.
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
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
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.
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
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
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
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
- 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
- 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
- Vacuum erection device
- Penile implants
- Urethral suppository – alprostadil
- Intracavernosal injection – alprostadil, phenotolamine
- 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
- Contraindicated: concomitant use with nitric oxide donors
- Use with caution
Antihypertensives
Alpha-adrenergic blockers – for BPH
CYP3A4 inhibitors – will increase blood levels of PDE-5 inhibitors
