What is the rate limiting step in the renin/angiotensin system?
What are the effects of the renin/angiotensin system at AT1 and AT2 recepors?
- Renal Effects:
- Constrict efferent arterioles
- Increase sodium reabsorption in proximal tubule
- Increase Aldosterone
- Increase ADH
- Other Effects:
- Increase syNS
- Vascular/cardiac remodeling
- Hypertrophy and hyperplasia
Describe: Aliskiren (Tektura)
- Renin Inhibitor
- Function: Prevent the formation of Angiotensin I
Describe: Captopril, lisinopril, enalapril, benazepril
- ACE Inhibitors
- Function: Increase bradykinin levels + reduce ANG II levels
Describe: Losartan, candesartan, irbesartan, eprosartan
- ANG II Receptor Antagonists
- Competitive antagonist at AT-1 Receptor
What are the effects of bradykinins at B1 and B2 receptors?
- Increased vascular permeability
- Pain mediation
- Competitive antagonist to B2 receptors for Bradykinin
- Function: lower pain, lower hyperplasia, lower inflammation and bronchoconstriction
- Inhibits synthesis of Bradykinins
- Can be used in conjunction with NSAIDs
What are the effects of endothelium at the ETa and ETb receptors (GPCR receptors)?
- Nonvascular smM contraction
- SmM proliferation
- Positive inotrophy
- Cardiovascular regulation
Describe: Bosentan, Ambrisentan, Sitaxsentan
- Antagonists of endothelin receptors
- Function: Treat pulmonary hypertension
Define the signaling cascade of ETa receptors?
ETa - PLC - IP3 + DAG - Increase Calicum release from SR
Defien the signaling cascade of ETb receptors?
ETb - PGI2 + NO - Decrease Calcium realease - vasodilation + actions as a mitogen to stimulate cell proliferation
Describe: Nesiritide, ularitide
- Treatment of refractory heart failure
- Ularitide: Phase III for decompensated heart failure
Describe: Omapatrilat, sampatrilat, fasidotrilat
- Neutral Endopeptidase Inhibitors
- Function: Decrease peripheral resistance and BP; may be useful to treat CHF - not approved due to angioedema
What are the 2 improtant subclasses of Tachykinins?
- Substance P: Pain perception/response through dorsal horn
- Neurokinin A and B: Contraction of smooth muscle
- Neurokinin-1R antagonist
- Function: Chemotherapy induced emesis
Describe the function fo the 3 major vasopressin subclasses?
- V1A: Vasocontriction
- V1B: Increase release of ACTH in Pituitary
- V2: Water reabsorption in kidney (ADH like)
Describe the location and function of the Calcitonin Gene Related Peptides (CGRP)?
- Location: CNS and PNS
- Function: Migranes (release from CN V), peripheral cardiovascular regulation, potent vasodilator
Describe the location and function of Neurotensin?
- Location: CNS, GI tract, circulation
- Effects: Neurotransmitter/neuromodulator in CNS (may play role in Schizophrenia, PD, drug abuse) and important in the GI to regulate acid/pepsin secretion and Gi motility
Describe function of Adrenomedullin?
Physiological antagonist against endogenous vasoconstrictors
Describe the function of Urotensin?
- May be invovled in HTN, heart and/or renal failure, DM
What is the rate limiting step in the synthesis of 5-HT?
What is the major catabolism enzyme of 5-HT? Final product?
MAO to 5-hydroxyindeleacetic acid (5-HIAA)
What is the function of L-Trypthophan? How is it used as a natural supplement? Associated S/E?
- Function: Used to make melatonin in pineal gland
- Natural Supplement: Sleep aid and antidepressent
- S/E: Blood dyscrasias and muscle wasting
Describe physiological effects of 5-HT in neurons, GI smM, platelets and vasculature?
- Neurons: Regulate sleep, appetite, mood, temperature, pain
- GI smM: Gi motility (5-HT-2R)
- Platelets: Increase platelet aggregation (5-HT-2R)
- Vasculature: Vasoconstriction (5-HT-2R) and vasodilation (endothelial cell mediated)
Describe carcinoid syndrome and its effect on 5-HT production?
- It's a tumor of the enterochrommafin cells in the GI tract
- Produces large amounts of 5-HT
Briefly describe the 5 5-HT receptors that we know of?
- 5-HT-1A: Gi coupled, lowers cAMP
- 5-HT-1D/B: Gi coupled, lowers cAMP
- 5-HT-2A: Gq coupled, increases IP3/DAG
- 5-HT-3: Works via Na/K channels
- 5-HT-4: Gs coupled, increases cAMP
- Agonist at 5-HT-1A
- Function: Anxiety
- Agonist at 5-HT-1D/B
- Function: Migranes
- Agonist at 5-HT-2A
- Function: Happiness
Agonsit at 5-HT-4
Describe: Clozapine, methylsergide, cyproheptadine
- Antagonists at 5-HT-2
- Oppose LSD Action
Antagonist of 5-HT-3
What are the 4 major pharmacological drug actions pertaining to 5-HT?
- Receptor antagonism
- Synthesis inhibition
- Reuptake blocking
- MAO inhibitors
What is seen in Ergotism?
Dementia, hallucinations, vasospasms (pain, gangrene), and uterine stimulation
What are the effects of ergots in CNS, vascular tissue and uterine smM?
- CNS: Hallucination, dopamine receptors to slow prolactin release
- Vascular: Prolonged vasoconstriction - partial agonists at both alpha and 5-HT receptors. Can produce epinephrine reversal
- Uterine smM: Large contraction, especially in pregnant uterus
Describe: Ergotamine, dihydroergotamine, metylsergide
Used for migranes
Describe: Bromocriptine, cabergoline
Used for hyperprolactinemia
- Cautious use for postpartum hemorrhage
- NEVER use before delivery