Advanced Pharmacology - NSG 531 - Exam

what is the difference between cardiac myocyte action potential and that of the CNS or ANS? nerve cell action potential is very short cardiac action potential is much longer they are longer to have adequate filling time in order to get a good contraction for a reasonable bolus of blood the only way this can happen is if the action potential is longer this will also mean that the refractory period will be longer What are the 5 phases of the non-pacemaker action potential? 0 - depolarization 1 - partial repolarization 2 - plateau 3 - repolarization 4 - resting membrane potential what happens during phase 0 of the non-pacemaker action potential depolarization voltage gated sodium channels are opening up until we get past threshold what happens during phase 1 of the non-pacemaker action potential partial repolarization what happens during phase 2 of the non-pacemaker action potential plateau calcium channels open (L-type because they are long) potassium is still open potassium out and calcium in - they are opposing each other in voltage giving the plateau this is when the ventricles are filling what happens during phase 3 of the non-pacemaker action potential repolarization calcium channels are closed potassium channels are the only thing open taking their positive charge with them making the interior more negative what happens during phase 4 of the non-pacemaker action potential resting membrane potential where we are in between action potentials there is no net change in ovltage inside the cell When does contraction take place? begins towards the end of repolarization and ends at some point during repolarization refractory period during phase 0, 1, 2, and part of phase 3 the cell is refractory to the initiation of new action potentials many antiarrhythmic drugs increase the Refractory period which reduces myocyte excitability what are the benefits of the refractory period limits frequency of cardiac contractions allows for adequate filling time prevents sustained contractions how are pacemaker cells different from non-pacemaker cell no resting membrane potential - no point where it is flat there are very few sodium channels in pacemaker - sodium channels are not driving depolarization - calcium is only 3 phases comprised of cells within the SA node generate regular, spontaneous action potentials what are the phases of pacemaker action potential 0 - rapid depolarization 3 - repolarization 4 - slow depolarization what happens during phase 0 of the pacemaker action potential Rapid depolarization something is coming to open voltage gated calcium channels (L-type) calcium comes rushing in what happens during phase 3 of the pacemaker action potential repolarization potassium channels now open up, potassium rushes out, repolarizes what happens during phase 4 of the pacemaker action potential slow depolarization with potassium rushing out we are all the way down at -60 funny sodium channels open up until voltage reaches -50 T-type (transient) calcium channels open up until voltage reaches -40 L-type calcium channels then open back up Describe how non-pacemaker APs can mimic pacemkaer APs Hypoxia and ischemia when the resting membrane potential is not getting enough oxygen it is going to become more positive because you need oxygen to produce ATP. If we are deficient in ATP then the NA K ATPase pump wont be functioning if someone is hypoxic in a focal area - say they have a resting membrane potential at -45 - the fast sodium channels won't open - they start using calcium to open - so they would convert into action potentials that use calcium (hence how they mimic pacemaker APs) excitation-contraction coupling sequence of events from motor neuron signaling to a skeletal muscle fiber to contraction of the fiber's sarcomeres conversion of depolarizing currents into contractile force L-type calcium channels open up in phase 2 in nonpacemaker - calcium comes flooding into myocytes, so we now have calcium in the cell and a sarcoplasmic recticulum (a resovior for calcium) receptors called RYR (ligand gated calcium channels) calcium then comes out - coming int the cell from the calcium channels and the sarcoplasmic recticulum describe how calcium binds to cause contraction when there is an influx of calcium in the cell there is a myosin head separated by troponin. little binding sites for the myosin exist on the aktin but it can't get to it because of the troponin. calcium therefore binds to the tropinin causing a confirmational change in troponin so it will move and take the tropomyosin with it. the myosin can then bind to the aktin molecules when it binds it activates ATP the ATP will be used to generate the sliding of the aktin and the myosin filaments against each other shortening the muscle cell causing contraction Describe how adrenergic stimulation increases the force of contraction through inotropic effects NE and epi bind to adenylyl cyclase coupled g proteins (beta 1) leads to phosphorylation of Ca channels and opens them increases inward movement of Ca there is also increased release of Ca from the SR increases actin/myosin interaction increases force of contraction Describe how adrenergic stimulation increases the force of contraction through chronotropic effects NE and epi bind to adenylyl cyclase coupled g proteins (beta 1) results in phosphorylation of Ca2 channels and opens them increases inward movement of Ca2 shortens phase 0 by increasing the opening of L-type calcium in pacemaker heightened sympathetic state shortens effective refractory period increases rate of contraction how do catecholamines effect the NaK ATPase Pump epi to beta 1 - g coupled protein receptor increase in cAMP activate protein kinase phosphorylate and increase in ATPase proteins available on the cell surface this is why we give epi during hypoxia - cardiac arrest - so that we can initiate more action potentials how does cholinergic stimulation work to decrease heart rate effects on m2 receptors acetylcholine binds to g coupled, alpha subunit comes off can bind to t-type calcium channel - opens after funny sodium and before L-type - if it binds it will inhibit it which will decrease the heart rate it can also bind to potassium channels increasing intracellular potassium causes repolarization and actually hyperpolarization both will have negative chronotropic effects and decrease the heart rate reduces opening of Ca2 channels on the surface of the nodal cells - Ach opens K+ channels and hyperpolarizes nodal cells moving them further away from threshold heart block one of the main phenomena causing pathological disturbances in rhythms arises from fibrosis or ischemia damage in the conducting system - usually in the AV node ectopic pacemaker one of the main phenomena causing pathological disturbances in rhythms pacemaker activity can arise from other tissue when there is ischemia or increased catecholamines they increase intracellular Ca2 concentration raise resting membrane potential and can close Na channels after depolarizations one of the main phenomena causing pathological disturbances in rhythms -spontaneous depolarizations of nonpacemaker cells during either phase 3 (repolarization) or phase 4 (RMP); occur after ERP what causes after depolarizations most often caused by elevated intracelluar calcium that triggers abnormal action potentials associated with hypercalcemia and excessive catecholamines treated with calcium channel blockers and beta blockers what are the main phenomena causing pathological disturbances in rhythms after-depolarizations heart block ectopic pacemaker re-entry Re-entry one of the main phenomena causing pathological disturbances in rhythms a signle impulse re-enters an area of the heart and repeatedly excites it the impulse circles around and is not extinguished typically impulses run into each other and die out if they have a unidirectional block there is no second impulse coming around to block the other one that will then circle conditions leading to re-entry physiologic ring unidirectional block conduction timeERP what are the two main symptoms we see with re-entry tachycardia and atrial flutter Wolf-Parkinson-White Syndrome ventricular preexcitation syndrome accessory conduction pathway from atria to ventricle (bundle of Kent), bypassing AV node ventricles begin to partially depolarize earlier -- delta wave on EKG can result in reentry current leading to supraventricular tachycardia tx: (type Ia) quinidine, disopyramide, procainamide slows AP conduction in myocardium, helps suppress bundle of Kent also do ablation of kent bundle DO NOT USE types II (beta block), IV (Ca block)...these incr AV node refractoriness and would worsen condition what are the different anti-arrhythmic drug classes class I - sodium channel blockers class II - beta adrenergic blockers class III - potassium channel blockers - drugs that prolong cardiac action potential increase in the refractory period Class IV - calcium channel blockers Class I anti-arrhythmic agents act on myocytes not pacemaker cells (driven by sodium) effect on the action potential is to prolong depolarization (phase 0) are use dependent because they work better at faster heart rates (bind preferentially to open or inactivated channels) what are the three states that the sodium channels exist in threshold depolarizing spike refractory Class IA antiarrhythmics -slow depolarization (phase 0) -bind to open Na channels -dissociate from Na channels with intermediate kinetics -also prolong repolarization and refractory period by blocking potassium channels examples - disopyramide, quinidine, procainamide competitive reversible antagonists - prolonging repolarization afib atrial flutter v tach Class Ib anti-arrhythmic dissociate from the Na channels with rapid kinetics (come off fast - they gon on and stay on long enough to block ectopic impulse but allow a normal impulse to occur) preferentially bind to inactivated channels which results in preferential effects in ischemic tissue ischemic tissues characterized by depolarization they take longer to repolarize (phase 3) thus Na channels are in inactivated state longer than in normal tissue don't bind to K channels (no effect on ERP) more selective - look for areas of hyperexcitability - ischemic areas - keep in inactive state longer Class Ic anti-arrhythmic dissociate from Na channel with slow kinetics - stay on longer bind to open Na channels cause general reduction in excitability because they stay on longer don't bind to K channels could end up blocking a normal impulse because they stay on so long what are the main differences in action with Class Ia Ib and Ic antiarrhythmic durgs 1a - inbetween in terms of fast on off. they like open channels. slow rate of depolarization prolong repolarization 1b - doesn't effect the action potential it didn't have an effect on k+ channels - don't effect depolarization they should stop an abhorrent impulse but come off quick enough the normal impulse can act 1c - slows phase 0 the most because it stays on the longest no effect on k+ channels so we are not effecting the refractory period what does blocking Na channels do prolong depolarization what does blocking open and inactivated channels correlate with use-dependence what does blocking inactivated channels correlate with selective suppression in ischemic tissue Class II drugs beta blockers reduce cAMP production resulting in decreased calcium currents beta 1 to norepi or epi - gcoupled activated adenylyl cyclase leads to decrease in heart rate increase in contractility decreasing cAMP decreasing second effects of calcium tapping down response of catecholamines decrease HR (negative chronotropic effects) decrease force of contraction (negative inotropic effects) Class III drugs blocking of K channels prolong action potentials by increasing time of repolarization increase the refractory period of the membrane action potential without altering the phase of depolarization or the resting membrane potential block K channel you are going to extend the length of the action potential increasing time of repolarization class III drug effect on non-pacemaker action potential substantially prolongs phase 3 class IV drugs block L-type calcium channels slow conduction through SA and AV node and increase the duration of phase 0 depolarization (negative chronotropic effects) cause negative inotropic effects cause dilation of blood vessels we don't want to block the t-type which bridge the gap from funny to L decrease HR and BP Cardiac Glycosides (digoxin) stimulate the vagus (negative chronotropic effect) inhibit NaKATPase pump (positive inotropic effect) (decreased HR due to stimulation of the vagus) (increase force of contraction due to action on the pump) increased intracellular Na slows the extrustion of Ca via the NaCa pump increased intracellular Ca increases actin/myosin interaction and force of contraction digoxin inhibits the Na Ca exchange pump intracellular sodium is going to effect the calcium out if sodium is higher because of the inactivation of the pump we have more calcium hanging around so force of contraction goes up. inflammation response to injury or infection involves redness, swelling, heat, loss of function histamine release released by basophils (circulating in the plasma) and mast cells (extravasate from the plasma and get in tissue) in response to direct trauma or exposure to allergen both WBCs contain histamine waiting to be released in response to direct trauma or allergen what produces IgE b lymphocytes in response to exposure to allergen each antibody has a part of the antibody that is specific and will only bind to its allergen another part has the FC that binds to the FC receptor on the surface of cells such as mast or basophils mast cell degranulation 1. capillary vasodilation 2. increased capillary permeability 3. exudation of plasma and cells into tissues mast cell has FC receptors if we get subsequent exposure to the allergen there is a cascade of signals that eventually releases calcium from the ER which mediates the release of the histamine effect of histamine on the lungs bronchoconstriction - astma like symptoms effects of histamine on vascular smooth muscle postcapillary venule dilation terminal arteriole dilation venoconstriction erythema effects of histamine on vascular endothelium contraction and separation of endothelial cells edema effects of histamine on peripheral nerves sensitization of afferent nerve terminals itch, pain effects of histamine on the heart minor increase in contractility and HR effects of histamine on the stomach increased gastric acid secrtion peptic ulcer disease, heart burn effects of histamine on the CNS neurotransmitter circadian rhythms, wakefulness what does activation of the histamine 1 receptor increase intracellular Ca histamine binds to the histaminne 1 receptor histamine binds to g coupled activating g alpha cub unit phospholipase c beta IP3 binds to ER release of calcium what is the difference between H1 and H2 histamine receptors H1 - smooth muscle, contraction of the cells in the vascular endothelium, weightfulness in the brain all things we would expect of calcium H2 - g couple dlinked to adenylyl cyclase increases cAMP instead how does H1 increase smooth muscle contraction? by increasing Ca increases when Ca enters the cell and is released from the sarcoplasmic reticulum simultaneously How does H2 receptor activation induce HCL release H2 largely found in the stomach ATP to cAMP which is a second messenger takes hydrogen potassium ATPase and moves it from the cytoplasm to the cell membrane every time the pump cycles it pumps out 1 hydrogen ion and pumps in one potassium ion hydrogen out into the stomach binds with chloride and forms HCl How does histamine act in the CNS H3 receptors H3 on the presynaptic neuron binding of histamine to H3 receptors inhibits the further release of histamine from that neuron there are H3 receptors expressed on other neurons other than those that release histamine so histamine can regulate the release of other neurons histamine effects on immune cells H4 receptors on the dendritic and T-cells activates dendritic cells which release cytokine that can activate t helper cells histamine can therefore up-regulate an immune response What is an inverse agonist? Agonist that binds to the same site as an agonist however produces an opposite response binds and tells the cell to do the opposite what are the three pharmacological strategies of modulating histamine response administer an inverse agonist of the histamine receptor - bind to the cell and tell it to do the opposite prevent mast cell degranulation - basically works as a calcium channel blocker administer physiologic antagonist to counter the pathological effects of histamine - for example giving epi in anaphylaxis Mast Cell Stabilizers MOA prevent mast cell degranulation by blocking ca2+ channels reduce bronchial hyperresponsiveness block IgE regulated calcium channels essential for mast cell degranulation what are the main differences between first and second generation antihistamines benadryl (1st) crosses BBB - antimuscarinic effects claritin (2nd) does not cross the BBB due to water solubility and does not have antimuscarinic effects - selective Eicosanoids lipids derived from arachidonic acid prostaglandins, thromboxanes, and leukotrienes similar to hormones where is arachidonic acid located? fatty acid tails of the cell membrane what does phospholipase a2 do? cleaves arachidonic acid off the phospholipid -does this in response to a stimulus activated by cytokines, pH, O2, temperature, etc. when is the rate of release of arachidonic acid increased? in an inflammatory state what are the three different pathways that arachidonic can act within after being cleaved from the phospholipid COX LOX CYP What does the COX pathway produce? prostaglandins prostacyclins thromboxanes what are prostaglandins involved in inflammation and pain in the stomach increase mucous secretion which provides protection against the low pH environment maintain blood flow in kidneys maintain vascular homeostasis what are prostacyclins involved in proliferation what are thromboxanes involved in platelet aggregation Cox 1 enzyme that is expressed in virtually all tissues when arachidonic acid is cleaved off and acted on by cox 1 we get prostaglandins cox-1 are also in platelets so that they can produce thromboxane when their arachidonic acid is acted on Cox 2 not present already - it is induced in response to a stimulus an inflammatory signal like cytokines is what causes certain cells to synthesize cox-2 - (WBC in response to cytokines) induces cox-2 and produces prostaglandins increase blood flow at the site of inflammation becuase they are in WBC at the site of injury cox2 is localized to immune cells and because immune cells are localized to site of injury or infection what types of cells are stimulated to produce cox-2 WBC in response to inflammatory cytokines what is the main difference between cox1 and cox2 cox 1 is constitutively expressed in most cell types and involved in producing prostaglandins for homeostatic functions inflammatory cytokines induce cox-2 in macrophages and endothelial cells so effects are at sites of tissue inflammation what are the functions of prostaglandins bronchoconstriction vasodilation inflammatory cell activation fever cytoprotective: modulates gastric acid secretion, mucus, and blood flow prostacyclin (PGI2) functions primary prostaglandin of vascular endothelium vasodilation inhibition of platelet aggregation thromboxane functions primary eicosanoid of platelets vasoconstriction induces platelet aggregation which is weaker TXA2 or TXA3? TXA3 is weaker than TXA2 TXA3 has weaker vasoconstriction and platelet aggregation than TXA2 describe the balance between prostacyclin and thromboxane the local balance between prostacyclin and thromboxane is critical in regulating systemic BP and thrombogenesis opposing effects between these two both produce these responses after cox acts on arachidonic acid prostacyclin - vasodilates, inhibits platelet aggregation thromboxane - vasoconstricts, promotes platelet aggregation you don't want one to over power - just the right amount of all to keep you functioning throughout the day Why should we eat fish? we will then have a greater concentration in omega 3 fatty acid tails than omega 6 with omega 6 you produce TXA2 (weaker) and PGI2 (more inflammatory) decreased vasodilation and increased platelet aggregation and increased inflammation with omega 3 you produce TXA3 (stronger) and PGI3 (less inflammatory) increased vasodilation, decreased platelet aggregation, decreased inflammation True or False TXA3 has weaker vasoconstrictive and platelet aggregation effects than TXA2 and flips prostacyclin/TXA balance in favor of prostacyclin true what does the LOX pathway do converts arachidonic acid into leukotrienes LOX are in myeloid cells which are non lymphocyte WBC (monocytes, macrophages, basohils, mast cells, neutrophils) not T and B cells Leukotriene functions binds to GPCRs expressed on surface of WBCs, spleen, thymus, and induce pro-inflammatory effects chemotaxis and aggregation of neutrophils increased phagocytosis increased cytokine production and NK activity vasoconstriction, bronchoconstriction, increased vascular permeability leukotrienes circulate, there are a lot of receptors on WBC, but also on other tissues like the lungs and vascular tissues effects can be seen outside of the immune system anti-inflammatory drugs - phospholipase inhibitors favorably modulate the COX and LOX one thing we give is cortisol - anti-inflammatory binds to intracellular receptors then DNA transcribe to mRNA and get proteins one thing cortisol can create is lipocortin which binds to phospholipase A2 and inactivates it inhibits COX and LOX pathways by inhibiting the cleavage of arachidonic acid non-selective cox inhibitors aspirin, ibuprofen, naproxen binds to 1 and 2 inhibits the release of prostaglandins, prostacyclines, and thromboxane anti inflammatory, antiplatelelt not specific for cox-1 so we will also tamp down an immune response if you inhibit cox-1 one thing it does is produce prostaglandins that help with the mucous for the stomach lining to protect so aspirin can cause gastric erosion. that's why we came up with selective cox-2 inhibitors - we don't want to inhibit our normal homeostatic functions thrombogenesis and selective cox-2 inhibitors cox-1 found in platelets makes TXA2 which causes vasoconstriction and platelet aggregation cox-2 found in endothelial cells - makes prostacyclin which causes vasodilation and inhibits platelet aggregation people that were taking cox-2 were having thrombotic effects and having heart attacks cox 1 platelets cox2 immune cells cox 1 acts on arachidonic acid and it makes TXA2 which is stronger cox-2 inhibitrs platelelt aggregation if you selectively inhibit cox-2 you are tipping the balance in favor of TXA 2 vasoconstriction and platelelt aggregation cytokine inhibitors humira, remicaid antigen presenting cell presents the antigen to the T cell, activates macrophages, releases inflammatory cytokines such as tumor necrosis factor alpha those durgs are TNF alpha monochromal antibodies - bind to the TNF alpha released by the antibodies and prevent it from producing inflammatory effects anakirna blocks action of IL1 antagonist receptor for cytokines the problem with this is that you could inhibit your immune system by blocking those binding sites leukotriene inhibitors drugs that bind to the receptor for leukotriene and lock those sites up - or we can give a drug that blocks the LOX enzyme itself flag inhibitors - inhibits the formation of leukotriene statins as anti-inflammatory drugs inhibit the cholesterol synthesis pathway HMG CoA is inhibited by the statins blocking the pathwya by blocking that early in the pathway you also inhibit isoprenoids which are inflammatory byproducts pediatric issues of GI absorption gastric pH at birth is 6-8 gradually declines until adult values reached by 2-3 years of age evidence that active and passive transport do not fully develop until four months not known when efflux pumps or intestinal P450 enzymes develop slowed gastric emptying evidence that switch from breast milk to formula induces hepatic P450 enzymes what does a high gastric pH at birth effect? base drugs will be better absorbed and acidic drugs will not - kids are the opposite of adults describe issues of GI transport in pediatrics because of the transporter proteins not being developed in infants a drug will struggle if it is dependent on transportation across the gut into the circulation via transporter proteins describe issues of efflux pumps in GI for pediatrics pumps develop at different ages - depending on whether that drug is able to bind to the efflux pump and back into the intestine will effect whether or not it will end up in circulation pediatric issues of intramuscular absorption decreased skeletal muscle blood flow and inefficient movement may decrease absorption may be offset by increased capillary density skeletal muscle mass is still relatively low and they can't make the same efficient movements as adults - this decreases absorption See 34 more Add or remove terms You can also click the terms or definitions to blur or reveal them