•acetylcholine •ionotropic (ion channel) •location: -parasympathetic and sympathetic ganglia -chromaffin cells of adrenal medulla -neuromuscular junction of somatic nerves and skeletal muscle •direct agonists: -nicotine "depolarization shock" loss of activity of the post ganglionic neuron, increased parasympathetic and sympathetic •antagonists: -ganglionic blockers -neuromuscular blocking agents
•acetylcholine •metabotopic: Gq -M1 - neurons -M3 - sweat, salivary, lacrimal, GI, eye, bronchial, smooth muscle -M5 Gi -M2 - heart and smooth muscle -M4 location: -parasympathetic -sympathetic - sweat glands ***decrease heart rate - chronotropic ***decrease heart force of contractility •••artery and vein dilation via EDRF (NO) absence of cholinergic innervation •direct agonists "SLUDGE" -acetylcholine -bethanecol -methacholine -pilocarpine •anragonists -atropine -scopolamine -ipratropium
agonists for both nicotinic and muscarinic receptors - reversible
•physostigmine •neostigmine •pyridostigmine •edrophonium •donezepil •tacrine
agonists for both nicotinic and muscarinic receptors - irreversible
•malthion •sarin and other nerve gases
•norepinephrine •epinephrine •metabotropic Gq location: -sympathetic ***artery vasoconstriction + ***vein vasoconstriction •direct agonist -norepinephrine -epinephrine -phenylephrine -dopamine - high doses •antagonist -phentolamine -phenoxybenzamine -prazosin -terazoin -doxazosin
•norepinephrine •epinephrine •metabotropic Gs location: -sympathetic •••increase rate of contractility chronotropic ***increase force of contractility ionotropic renin release lipolysis •direct agonist -norepinephrine -epinephrine -dobutamine -isoproteronol -dopamine - moderate dose •indirect agonist -pseudoephedrine -meth and aphetamine -cocaine *antagonist -propranolol -tmolol -metoprolol
*epinephrine •metabotropic - Gs location: -sympathetic ***skeletal muscle vasodilation •direct agonist -epinephrine -metaproterenol -isoproterenol •antagonist -propanolol -timolol
rapid reflex control of high BP
•decrease in sympathetic and increase in parasympathetic •dilation of vessels --> decrease CO -arteries - decrease in total peripheral arterial resistance -veins- decrease in venous return --> decrease in preload,blood pools in veins •decrease in HR and contractility --> decrease CO •contractility is still increased (parasympathetic does not affect contractility) so the mean pulse pressure goes up mean pulse pressure = SBP (nothing is affecting this) - DBP (goes up a little, not much)
rapid reflex control of low BP
•increase in sympathetic and decrease in parasympathetic •constriction of vessels --> increase CO -arteries - increase in total peripheral arterial resistance -veins- increase in venous return --> increase in preload,blood does not pool in veins •increase in HR and contractility --> increase CO
pathway of baroreceptor nerves
•nerves --> medulla oblongata (NST) ---> cardiovascular centers (pons + medulla oblongata) 1. vasomotor control center -diameter of blood vessels -sympathetic 2. cardiac control center -cardiac accelerator (HR) - sympathetic -cardiac decelerator (HR) - parasympathetic -cardiac contractility - sympathetic ONLY
•baroreceptors and chemoreceptors •vagus nerve - CN X
•baroreceptors and chemoreceptors •glossopharyngeal nerve - CN IX
rapid reflex control of blood volume increase
•increased HR --> increased CO --> increased blood to kidneys --> water and sodium excretion which decreases blood volume •stimulate secretion of atrial natriuretic peptide from atrial muscle cells --> renal artery dilation --> increased blood filtering and decreased reabsorption of sodium and water •vagus --> hypothalamus too! -decrease in vasopressin (ADH) --> decrease in water reabsorption
rapid reflex control of blood volume decrease
•decreased HR --> decreased CO --> decreased blood to kidneys --> restricts water and sodium excretion which increases blood volume •no stimulation of secretion of atrial natriuretic peptide •vagus --> hypothalamus too! -increase in vasopressin (ADH) --> increase in water reabsorption
•aortic and carotid sinuses •monitor the pO2, pCO2, pH •glossopharyngeal and vagus nerves --> respiratory centers in medulla oblongata and pons ---> cardiovascular centers •hypoxemia, hypercapnia, acidemia all: * increase sympathetic on vessels --> vasoconstriction --> increased TPR -blood flow limited to periphery (saved for the brain and heart) -decreases metabolic rate and Co2 production -increased venous constriction --> no blood pooling and an increased preload and CO *decreased sympathetic on heart --> decreased HR and decreased contractility *increased parasympathetic on heart --> decreased HR
•increases cAMP, PKA •indirectly alter ion channel function •change gene transcription
•decrease cAMP, PKA •indirectly alter ion channel •change gene transcription
•phospholipase C --> PIP2 --> IP3 --> Ca++ •phospholipase CC --> PIP2 ---> DAG --> protein kinase C
•PLA2 --> arachidonic acid --> 12 lipoxygense --> 12 HPETE • PLA2 --> arachidonic acid --> cyclooxygenase (COX 1 constitutive, COX 2 inducible) --> prostaglandins, thromboxane •PLA2 --> arachidonic acid --> 5 lipoxygenase --> leukotrienes
•adrenergic agonist •produces marked pressor effects that can be used to raise blood pressure and increase contractility of the heart in cases of severe hypotensive shock. •This pressor property is problematic, however, because it causes profound constriction of renal blood vessels and can reduce renal blood flow to a dangerous level. •As norepinephrine is a catecholamine, it is not effective when given orally because of extensive metabolism in the stomach, small bowel and liver. Thus, it has to be given intravenously. • However, if the drug solution extravasates into tissues around the vein and arterioles, potentially harmful intense vasoconstriction can occur. •Local administration of an alpha-l receptor antagonist can reverse the vasoconstrictor effect. •Norepinephrine does not cross the blood-brain barrier (BBB).
•adrenergic agonist •(Adrenalin) is used as a cardiac stimulant in emergencies and as a bronchial dilator. Its bronchial dilator effect occurs via beta-2 receptors but is complicated by cardiac stimulation (beta-l) and elevations in blood pressure (alpha-l). •Epinephrine can be life-saving in the emergency management of anaphylactic shock, which is characterized by severe bronchial constriction and cardiovascular collapse. •Epinephrine and other beta-l agonists can produce cardiac arrhythmias when used in high doses. •Epinephrine can also be included as a vasoconstrictor agent in some local anesthetic preparations (1:100,000 dilution) to limit diffusion of the local anesthetic away from the injection site thereby prolonging its duration of action. •It does not cross the BBB. •At relatively high concentrations epinephrine acts on vascular alpha-l receptors to induce contraction. •At higher doses the beta-2 agonist action is overwhelmed by the alpha-1 effect. •Local anesthetic preparations containing epinephrine must be used with care in areas with terminal end arteries, such as fingers, to avoid gangrene caused by intense vasoconstriction. •Epinephrine is a catecholamine and is essentially inactive when administered orally. It is generally given intravenously for systemic action, and by inhalation for bronchial dilation.
increase in vasoconstriction ...
...increases diastolic BP because it measures peripheral circulation
increase in contractility...
...increases systolic BP because the pressure on the heart increases
•cholinergic nicotinic receptor agonists •is a natural plant alkaloid obtained from tobacco leaves. Nicotine’s therapeutic use is that of an aid to smoking cessation. Its greater relevance to medicine results from tobacco use. Nicotine has both central and peripheral effects. It is a mild CNS stimulant which can stimulate respiration and induce vomiting. Tolerance to the respiratory stimulant and emetic effects occur readily with continued use. In the periphery, low doses of nicotine, associated with use of tobacco, stimulate ganglionic nicotinic cholinergic receptors in both sympathetic and parasympathetic divisions.
•cholinergic nicotinic receptor agonists •)[Chantix] is a partial agonist at the alpha4-beta2 subunit of the nicotinic cholinergic receptor in the CNS and is used to treat nicotine addiction. It occupies nicotinic cholinergic receptors on dopamine neurons thereby preventing nicotine from stimulating those receptors. Partial agonist.
•nicotinic receptor antagonist
neuromuscular blocking agents
•nicotinic receptor antagonist
•cholinergic muscarinic agonist •has a structure conferring negligible metabolism by cholinesterase and thus a long duration of action and selectivity for muscarinic cholinergic receptors. When given orally or subcutaneously in therapeutic doses, it exerts only mild cardiovascular effects (some hypotension, slowing of heart rate) while acting mainly in the gastrointestinal tract and urinary bladder. Its principal use is to increase tone and contractions of the intestine and bladder in patients with postpartum or postsurgical ileus and urinary retention. However, in high doses it can precipitate a cholinergic crisis. •Certain adverse responses to muscarinic cholinergic agonists can be life threatening: cardiac slowing or arrest, severe hypotension, and bronchial constriction are special hazards. These adverse effects can be blocked or reversed by a muscarinic receptor antagonist. Therefore atropine should always be readily available whenever muscarinic agonists are administered parenterally.
•cholinergic muscarinic agonist •is a natural plant alkaloid that exhibits primarily muscarinic receptor agonist actions. It does not have an ester linkage and therefore it is not degraded by cholinesterases. Pilocarpine can be used topically in the eye for management of glaucoma or to treat patients with dry mouth (xerostomia). •Certain adverse responses to muscarinic cholinergic agonists can be life threatening: cardiac slowing or arrest, severe hypotension, and bronchial constriction are special hazards. These adverse effects can be blocked or reversed by a muscarinic receptor antagonist. Therefore atropine should always be readily available whenever muscarinic agonists are administered parenterally.
•indirect acting cholinesterase inhibitor - reversible •Inhibition of acetylcholinesterase leads to an increase in synaptic levels of acetylcholine. These agents are not selective since they enhance the levels of acetylcholine which can activate both nicotinic and muscarinic receptors. •Physostime can be used as an antidote to atropine poisoning, but is only occasionally used for this purpose