Pharmacology, Exam 2: ANS and CV

Botulinum Neurotoxins

Family of proteins called synaptins- proteins that allow the vesicle to fuse with the membrane that allows release Blocks synaptin- ach is then blocked-blocks protein machinery associated with release of NT- synaptins come together, membrane separates, release of NT- botox inhibits the release of Ach Only way to reverse this is synaptic needs to be regenerated by neuron that can take weeks-months- effects last a long time Membrane fusion or release of NT is known as exocytosis, controlled by synaptic

Would the use of an Epi-Pen be an effective therapeutic strategy to treat a hypotensive crisis during anaphylactic shock if the patient is also known to be taking an alpha1 adrenergic receptor antagonist for hypertension?

NO-makes hypotension even worse

Medical breakthrough with LCZ696

Novel drug combination that combines neprilysin inhibitor, sacubitril with an angiotensin II receptor blocker- has been reported to be more effective in preventing cardiac failure than any other drug combination on the market

Tolvaptan

Oral, vasopressin (Adh)receptor antagonist-adh helps you retain water- if you use an antagonist- block water retention, increase UOP, salts are more concentrated as you use water, and reduce fluids with increase in UOP-used for end-stage cardiac failure

Clinical algorithm of hypertension: Textbook

1. Lifestyle changes 2. Drug therapy with single drug with lifestyle changes continuing- dosage should be low then gradually increased 3. Add another drug if first drug was well tolerated or substituted if not well tolerated- before another drug is added consider possible reasons for failure of initial drug-both drugs should have different mechanisms of action- target BP at several sites of action, each drug can be given in lower doses to decrease frequency and intensity of side effects 4. Third of fourth drug may be added 5. Reasons that initial drug not working- poor adherence, excessive salt intake, presence of secondary hypertension Patients without compelling indications: Thiazide diuretic is recommended- reduces morbidity and mortality Next: ACE inhibitor, ARB's, CCB's- equal to diuretics but not as effective in reducing morbidity and mortality Other alternatives have more side effects- central acting sympatholytics, adrenergic neuron blockers, direct acting vasodilators Alpha 1 blockers not recommended Compelling indications: IE heart failure, diabetes post MI, high coronary disease risk, chronic kidney disease, recurrent stroke prevention-table of recommended drugs: HF: diuretic, Beta blocker, ACE, ARB, aldosterone antagonist Post MI: same as HF without diuretic, ARB, CCB Coronary disease: diuretic, BB, Ace inhibitor, CCB Diabetes- all 4 from HF without aldosterone antagonisn Kidney disease: Ace, ARB Stroke: Diuretic, ACE

Lipoprotein biosynthesis

3 major tissues involved in producing lipoproteins- liver- produces VLDL's, LDL's, and HDL's LDL's- lipoproteins have lipid core of cholesterol or triglycerides- LDL's have highest amount of cholesterol-apoprotein that surrounds lipid core- water soluble-an pass and circulate through blood in small droplets 3 building blocks- cholesterol, triglycerides, and apoproteins- cholesterol- LDL's can come from endogenous source-liver can produce own source of cholesterol- rate limiting enzyme- HMG coA reductase-enzyme necessary for production of endogenous cholesterol Can also come from our diet- in the duodenum-fats are broken down by bile salts- droplets- fatty acids and cholesterol- cholesterol transport protein-picks u protein from the diet, stored in chylomicrons- small lipid droplets that are partially metabolized-remnants move cholesterol to liver, cholesterol from diet can also serve as substrate for lipoprotein synthesis Another organ involved- fat cells- specialized for production of triglycerides Triglyceride lipase- enzyme in fat that breaks down triglycerides into fatty acids and glycerol by TG lipase Then enter the blood and are reconverted back to triglycerides-another building block for lipoproteins

Clopidogrel (Plavix)

ADP receptor antagonist on platelets-blocks activation of surrounding receptors by ADP

Cardiac failure drug treatment

ACE inhibitors (captopril) and ARB's (losartan) block the actions of angiotensin II (reduces vasoconstriction and reduces after load pressures) and aldosterone (reduces sodium and fluid retention) Also inhibit the enzyme that metabolizes the inflammatory mediator bradykinin The accumulation of bradykinin along the respiratory airways stimulates an inflammatory-like condition that stimulates mucous secretion that causes a chronic cough in many patients However-bradykinin in the heart stimulates myocardial fibrolysis that reduces the progression of cardiac remodeling (fibrosis and myocardial apoptosis) which then prolongs the life of patients with cardiac failure Diuretics are a first line treatment in patients with fluid overload in combination with ACE inhibitors or ARBS's Aldosterone receptor antagonists (eplerenone) reduce symptoms of edema and block aldosterone's role in promoting cardiac remodeling

Endocrine control of blood pressure by cardiac hormones: ANP

ANP (atrial natriuretic peptide)- begins with an increase in venous return (reacting to fluid overload) causes R atrial stretch- that receives the blood from the periphery, triggers the release of ANP-inhibits the renin/angiotension-aldosterone system- suppresses the release of renin and aldosterone and ADh- begin to lose more sodium and water through the kidneys- decreases blood volume, venous return, right atrial stretch-the need for producing ANP is reverse, compensatory mechanism disappears

Carbonic anhydrase inhibitors

Acetazolamide- used as diuretic and to treat glaucoma Bicarb in nephrons- converted by carbonic anhydrase to hydrogen ions and carbonic acid Acetazolamide inhibits the enzyme carbonic anhydrase- bicarb ions are not reabsorbed, by blocking this series of chemical reactions- increase in solute concentrations created by the bicarbonate ions-increase in solute concentration draws in water, leads to fluid loss- the loss of fluids in the kidney is comparable to fluid loss in the orbits of the eye in patients with glaucoma

Pharmacotoxicology of Cholinolytics

Acts on the entire ANS- side effects include Anticholinergic= only blocks muscarinic receptors SE: Dry mouth (sip fluids, sugar free gum), saliva substitute, alcohol free mouthwash Blurred vision/photophobia, increaded intraocular pressure (Contraindicated in glaucoma patients), urinary retention, constipation, anhidrosis, tachycardia, asthma (thickening and drying of bronchial secretions

Cardiac Failure pathophysiology

Acute response after an MI, or over a period of years associated with cardiac remodeling- fibrosis, myocyte apoptosis CF can lead to decrease in CO, activation of baroreceptors, activates CV control center- increases SNS, increase HR in failing heart- as it increases, puts additional stress on the heart muscle itself- so it also decreases renal blood flow, activates RAAS, more salt and water, edema, peripheral edema or in the lungs- extra blood volume which is additional stress on the failing heart

Adrenergic exception

Adrenergic neurons that innervate sweat glands release Ach rather than NE-produced by post synaptic neuron of SNS going to sweat gland- violation

Endocrine control of BP by endothelial cells that line the inner surface of blood vessels

Adventia- tough connective tissue lining Media- actual layer of tissues that contain smooth muscle cells Intima- endothelial cells that line the inside of blood vesslels-release paracrine regulators of TPR-paracrine is a term that refers to the production of localized hormones that act locally from one cell to another within a given tissue One hormone is endothelian- protein hormone produced by endothelial cells diffuses to smooth muscle cells locally and act on surrounding BV's and the sooth muscle cells that line them- profound vasoconstriction Another regulator of TPR-Nitrous oxide- led to the Nobel prize Endothelial cells produce NO- gas that diffuses to surrounding blood vessels and cause vasodilation, inhibit vasoconstriction

Demographic factors to be considered in the treatment of hypertension: Textbook

African Americans: Develops earlier, has a much higher incidence, likely to be more severe Respond better to some antihypertensive drugs than to others Diuretics are first drug of choice, the CCB's and alpha/beta blockers Monotherapy with ACE inhibitors or beta blockers- less effective in blacks than whites (can be used if strongly indicated for comorbid condition, eg. Type I diabetes with proteinuria) Children and adolescents: same as adults for treatment but smaller doses ACE inhibitors and ARB;s can cause fetal harm-avoid in sexually active/pregnant girls Pregnant Women: Labetalol, methyldopa Breast-feeding women; beta blockers appear safe, as well as diuretics but may suppress lactation Older adults: Target systolic BP is 140 mm Hg for patients 65=79, and 145 mm Hg for patients 80 and older Low dose thiazide, beta blockers, ache inhibitors ARB's, long acting dihydropyridine CCB's- caution for overdiuresis in this population

ACE system inhibitors

Aliskiren-direct inhibitor of renin Captopril- ACE inhibitor Losartan- angiotensin II receptor blocker Similar actions but different safety profiles- more of an ability to tailor to specific needs of the patient Inhibition of ACE reduces the risk of cardiovascular mortality in hypertensive patients Unlike beta-adrenergic receptor antagonists, ACE inhibitors are not contraindicated in patients with asthma- e.g. propranolol- not selective-can block HTN and therapeutic effects in drug used to treat asthma- ACE inhibitors do not interfere with beta 2 receptor mediated bronchiodilation Inhibition of ACE reduces the risk of CV mortality in hypertensive patients Unlike beta adrenergic receptor antagonists, ACE inhibitors are NOT contraindicated in patients with asthma- they do not interfere with. beta 2 receptor mediated bronchodilation

Alpha 2 receptor BP medication

Alpha 2 receptor agonist- clonidine- when clonidine binds to this receptor agonist- increase the activity of the adrenergic receptor which inhibits the release of NE- decreases adrenergic responses and BP

One of the anatomical locations for AChase is the presynaptic membrane of the post synaptic neuron of the PNS

FALSE- there is no ACHase on the presynaptic membrane- POSTsynaptic membrane of the post synaptic neuron

It is reasonable to predict that an alpha 2 receptor antagonist would reduce sympathetic tone (activity) and would be an effective treatment for HTN? T/F

False- alpha 2 receptor blocker- block the feedback control of NE release- more NE release- increase HTN

SNS Neuron Organization

Also a 2 neuron circuit- first neuron originates in the spinal cord, synapses in 2nd neuron that goes to a variety of target tissues Differences: SNS-synapse between the first and second neuron is highly organized and forms a sympathetic chain ganglia=an aggregation of synaptic connections Second neuron of SNS highly branched 1st neuron originates from thoracocolumbar region

Potassium sparing diuretics

Amiloride- inhibits NA+ ATPase that is indirectly linked to K+/H+ exchange in the distal tubule- prevents that development of hypokalemia- often combined with other classes of diuretics-loop and thiazide Direct inhibitor of transport proteins- prevents the exchange of sodium with potassium thats coming from the blood- not aldosterone receptor, but the actual transport proteins- if you inhibit the transport proteins, accumulate salt, diuresis, and water loss

The collecting duct is the segment of the nephron that is the site of action of carbonic anhydrase inhibitors?

False- it is the proximal tubule

Tirofiban

Antagonist to the GPIIb/IIIA platelet receptor which blocks platelet binding to fibrinogen in an area of platelet plug formation-blocks cross bridge formation between platelets These antithrombin drugs as well as tPA are also used to treat ischemia (not hemorrhagic) strokes in emergency situations Preventing the onset or recurrence of ischemic strokes is treated with Aspirin, warfarin, and a newer generation anticoagulant that includes dabigatran (Pradaxa)

An added advantage to treating a patient with epinephrine is the control of the spread on necrosis following an MI.

False-epinephrine will cause the heart to work harder and spread the necrosis Propranolol- reduces the spread of necrosis- beta 1 blocker- blocks fight or flight- heart rate goes down, work of heart goes down- reduces anoxia, reduces spread of necrosis Also can use fibrolytic drugs that dissolve blood clots- clot busters- tissue plasminogen activator (tPA), streptokinase, and urokinase serve as enzymes that catalyze plasmin formation within a clot that leads to fibrolysis

Adrenergic Receptor Subtypes: Beta 2 receptors (textbook)

Arterioles (heart, lung, skeletal muscle)=dilation Bronchi=dilation Uterus=relaxation Liver=glycogenolysis Skeletal muscle=enhanced contraction, glycogenolysis

Antithrombin drugs

Aspirin- reduce platelet aggregation and reduce the risk for reoccurrence of MI's or strokes

Bicarbonate and carbonic acid

Bicarbonate is a physiological buffer- maintains pH homeostasis- filtered into the kidney nephron and in order to maintain pH-most bicarbonate needs to be reabsorbed back into the bloodstream But the bicarb has a negative electrical charge- can't pass across membranes of nephrons to get back into the blood-kidney has a specialized system for returning these bicarbonate ions back into the blood Filtered into the kidney nephron- hydrogen ions are also transported into the kidney nephron Enzyme called carbonic anhydrase- lies on the inner surface of cells that make up the nephron-takes bicarbonate ions and hydrogen--makes carbonic acid (H2CO3) and once thats formed in the kidney nephron, it depolarizes into water and CO2- CO2 is lipid soluble, it can leave the kidney nephron and go into the blood Once in the blood- RBC's can convert CO2 back into the bicarbonate ions- returning bicarb back to the blood through the carbonic anhydrase reaction One of the regulators of the chemical composition of glomerular filtrate as it passes through the kidneys

Myasthenia Gravis

Autoimmune disorder associated with the destruction of nicotinic cholinergic receptors (Nm) at neuromuscular junction of skeletal muscle Progressive loss of skeletal muscle activity- leads to paralysis Produce antibodies against receptors in skeletal muscles- antibodies that destroy nicotinic cholinergic receptors- destroy in skeletal muscle- receptors disappear because you developed antibodies- muscle contraction is compromised- so inhibit achetylcholinesterase- increase Ach-compensates partially for reduced number of receptors by increasing the amount of Ach-what if you destroy all of the receptors- the drug would then not work-only treating the symptoms- once the receptors are destroyed, there is not further therapeutic benefit of the drug

Atropine and treatment of ventricular bradycardia

Autonomic state aka basal heart rate- look at changes in heart rate over time- often times, target tissues have duel innervation- heart innervated by sympathetic and parasympathetic- if parasympathetic is the active one- heart rate goes down- fight or flight, it increases During homeostatic state- increase with SNS, decrease with PNS With atropine- taking for ventricular bradycardia- bringing the heart rate up to homeostatic state- elevating heart rate by inhibiting the cholinergic nervous system, not activating the SNS

Endocrine control of blood pressure by cardiac hormones: BNP

B-type natriuretic peptide- measurements during heart failure is used to assess overall status of cardiac function: high BNP levels coupled with edema reflect a failure to compensate for fluid retention

Where is the acetylcholine coming from?

Biosynthesis of Ach occurs within a cholinergic neuron- synthesized within the axon itself- in axon terminal- stores in little vesicles

Blood clot formation

BV and platelets in the blood- BV in the inner lining coated with endothelial cells Underneath these cells- basement membrane of collagen fibers- blood flow through the blood vessels- 2 platelets in the picture-one of the platelets senses an injury-endothelial cells got damaged, washed away- basement membrane can come in contact with a platelet-that signals that an injury has occured- expose platelets to collagen basement membrane- platelets have receptors for collagen-leads to activation of the COX enzyme- this produces a chemical signal that activates neighboring platelets that are circulating through the blood Thromboxanes- chemical signal thats released from the activated platelet-diffuses through the blood to inactivated platelets- signals that activates neighboring platelets that injury has occured Other injuries that can happen that activates neighboring platelets Another chemical signal that is released is ADP- activates platelet to inactivated platelet in the surrounding area Serotonin can also bind to neighboring inactive platelets-combo of these chemical signals that activate these platelets produces a special receptor known as GPIIB/IIIA receptors-link platelets with fibrinogen- fibrinogen circulating in the blood- molecule can form a bridge between 2 platelets- if GPIIB/IIIA receptor is in active state-bind together when injured- bridge formation is controlled through these chemical signals-platelet aggregation-blood clot formation

Visceral blood vessels- mixed population of receptors-violation of dogma

BV going to gut have a couple of receptors- most fight or flight responses- epi is released, dominant receptor in mesenteric BV is alpha 1 receptor- vasoconstriction that increases TPR- with this epinephrine dose Another experiment was done using increasing doses of epinephrine combined with alpha 1 receptor antagonist-block those receptors- epinephrine reversal- it causes a decrease in blood pressure in the presence of an alpha 1 receptor- beta 2 receptors dominante- evidence that there is mixed population of receptors in blood vessels

Skeletal Muscle relaxants/anti-spastic pharmacology

Baclofen, Pancuronium, succinylcholine, botulinum neurotoxins Baclofen: GABA receptor agonist that suppresses motor neuron activity and nerve conduction

Adrenergic receptor names

Based upon early classification of responses produced by NE on BP that included alpha vasoconstrictive effects and beta, cardiac effects

Peripheral Nervous System:Defined

Begins in the CNS (as a nerve off spinal cord or cranial nerve off brain stem)- nerve track that exits the CNS and innervates some distant target tissue

Heart rate and cardiac output are elevated during fight and flight situations and this response is mediated by:

Beta 1 adrenergic receptors

Adrenergic drugs used in the treatment of HTN

Beta Adrenergic antagonists- propranolol, metoprolol The heart contains beta 1 adrenergic receptors-reduce the sympathetic control over cardiac output- reduce heart rate, force of contraction-reduce CO and BP Alpha 1 adrenergic receptor antagonists- prazosin- block vasoconstriction in renal and mesenteric blood vessels to decrease TPR and blood pressure

Propranolol

Beta adrenergic antagonist- decreases CO, decreases the work of the heart and decreases myocardial anoxia

Metoprolol for heart failure

Beta-adrenergic receptor antagonists reduce sympathetic stress on a failing heart- dose must be carefully monitored to prevent cardiac failure

Pharmacotoxicology of direct-acting cholinomimetics

Bethanechol can induce systemic effects associated with diarrhea, incontinence, bradycardia, hypotension, exacerbation of asthma

Pharmacodyamics: Direct acting cholinomimetics

Bethanechol: attach to receptor on target tissue- cause parasympathetic response- GI motility will increase, urinary bladder paralysis- digestion and vegetation- GI motility, contraction of urinary bladder (mituration) to treat urinary bladder paralysis, and GI motility will increase Pilocarpine: eye drop inserted into a wafer put onto the surface of the eye like a contact lens to treat glaucoma

Losartan

Block vasoconstriction, block release of aldosterone, block sodium and water retnetion- reduce BV and BP

Introduction to diuretics- textbook pages

Blockage of sodium and chloride reabsorption to prevent passive reabsorption of water to promote excretion of solutes and water Drugs that are early in the nephron have the opportunity to block the greatest amount of solute reabsorption Diuretics can cause hypovolemia, acid-base imbalance, and altered electrolyte levels Loop diuretics (High-ceiling diuretics) thiazide diuretics, osmotic, and potassium sparing (which can either be aldosterone antagonists or non-aldosterone antagonists Carbonic anhydrase inhibitors- primarily used to decrease IOP and not increase urine production

Cholinolytic Pharmacology

Blockers of acetylcholine, or antagonists Examples: atropine, scopolamine, and solifenacin Muscarinic cholinergic receptor antagonists No intrinsic activity- bind to receptor but don't cause conformational change- blocks the ST and response that drugs would normally produce- prevents acetylcholine from activating that same receptor Mechanism- post synaptic membrane of post synaptic neuron of PNS-antagonists occupy that receptor and prevent parasympathetic response

TPA, streptokinase, and urokinase

Blood clot formed- certain blood proteins that are trapped in a blood clot- known as plasminogen made by the liver- inactive enzyme that can be slowly activated to active form- plasmin- when its formed, can catalyze the depolymerization of fibrin network within a clot- fibrolysis- breaking down a fibrin network Reinstates blood flow to an area- reduces anoxia and spread of necrosis- rate limiting step in fibrolysis tPA, streptokinase, and urokinase accelerate this conversion of plasminogen -plasmin- reinstate blood flow to an area of the heart that is the source of the spread of necrosis

Anticoagulant sites of action

Blood clotting cascade associated with MI's Coagulation- intrinsic pathway-BV's are damaged, stimulates clotting proteins in the blood clot formation Extrinsic- chemicals produced by damaged cells- clotting cascade Both the intrinsic and extrinsic pathways have a common final pathway- final steps in clot formation Prothrombin-thrombin-active enzyme catalyzes fibrinogen-fibrin- enzyme that forms cross bridges-fibrin molecules that produce blood clot formation Heparin is an antithrombin drug- activates one of the proteins in the blood that is antithrombin-inhibit the enzyme thrombin- block blood clot formation Coumadin- vitamin K antagonist- warfarin inhibits vitamin K dependent enzymes in the liver that produce a number of clotting factors- liver is active in producing clotting factors- being produced in response to vitamin K dependent enzymes Dabigatran- direct inhibitors of thrombin- quick action and onset- blocks clotting cascade

Cardiovascular Pharmacology: Maintenance of BP

Blood pressure is necessary to maintain tissue perfusion- we deliver oxygen and nutrients to cells throughout the body, remove metabolic byproducts that can be toxic the maintenance of blood pressure happens in 3 major organs: Heart=cardiac output, volume of blood (liters) pumped by the heart per minute (4-6 L/minute) BV surrounded by smooth muscle- can either contract or dilate- regulates TPR- when a blood vessel is restricted- more resistance to blood flow, increase TPR, dilated blood vessels=decrease TPE Kidneys is the third organ

Cholinergic Neurons

Both neurons in the PNS are cholinergic and release acetylcholine

Describe a similarity and difference between: Bound versus free states of NE in synaptic vesicle, and presynaptic receptor of NE versus NET, axon-terminal reuptake protein

Bound and free states of NE- both synthesized from tyrosine Both produce fight or flight responses Both become free when enter synapse Difference: Bound state is metabolically stable Free state- always leaking out and will be metabolized by MAO Presynaptic receptor of NE versus NET protein- they both regulate norepinephrine levels in the synapse and the intensity of fight or flight- one is controlling release versus removal Pre-synaptic= telling neuron to not release any more NET= removal

Cholinergic Poisoning- causes and strategies to treat

Cause: Excessive muscarinic stimulation and respiratory depression from CNS depression and depolarizing neuromuscular blockage SLUDGE and killer B's: Salivation, Lacrimation, Urinartion, Diaphoresis/Diarrhea, Gastrointestinal cramping, Emesis, bradycardia, bronchospasm, broncorrhea Treatment: atropine IV, mechanical ventilation, oxygen, suctioning

PNS Neuron organization

Circuit composed of 2 neurons- first neuron originates in the CNS (spinal or cranial nerves) synapses with 2nd neuron-innervates target tissues- digestive and vegetative responses- lots of different drugs that can change the target response Differences: First neuron in the PNS-often times highly branched Second neuron in PNS- simple Originates from the cranio-sacral region- 1st neuron

Major events in neurotransmission: Cholinergic neurons

Cholinergic neuron-what triggers the release of Ach? Nerve impulse- goes into the axon terminal- that excitation triggers the release of Ach Every time a NT is released, its triggered by an electrical event-excitation-secretion coupling- always occurs with any type of neurotransmission Binds to cholinergic neuron/receptor- produces a cholinergic response, acetylcholinesterase then destroys the Ach

Central Nervous System

Composed of the brain and spinal cord-lots of nerve tracks that interconnect different regions of the CNS and spinal cord

Renin-angiotension aldosterone system

Decrease in renal blood flow caused by dehydration, blood loss following injury, disease states such as CHF, atherosclerosis- activates compensatory mechanism that increases renal blood flow- negative feedback control SNS can act to directly control renin through beta 1 receptors Beta 1 receptors in the highest concentration in the heart, but also in the kidneys- regulate renin Protylitic enzyme targets angiotensinogen into angiotensin I--- angiotensin II by ACE Then binds to its own receptors in blood vessels or on adrenal cortex Releases aldosterone which regulates electrolyte balance -increases salt and water retention from kidneys- increase salt into blood which attracts water to increase BV Vasoconstriction and increase BV increase BP

Epinephrine, Dopamine, and Norepinephrine and receptor activation

Epinephrine can activate all alpha and beta receptors, but not dopamine receptors-epi is released from adrenal medulla, not from neurons, and prepares body for fight or flight-only NT that acts on beta 2 receptors Dopamine can activate alpha 1, beta 1, and dopamine receptors Norepi can activate alpha 1, alpha 2, beta 1 receptors but not beta 2 or dopamine receptors

Treatment of cardiac arrest

Epinephrine or isoproterenol- acts on beta 1 adrenergic receptors in cardiac tissue-increases activity of the SA node the induces myocardial systole

Digoxin

Dig and other cardiac glycosides produce a positive inotropic effect on the myocardium-this effect increases CO that helps to maintain tissue perfection

Parasympathetic Nervous System

Digestive and Vegetative Functions, rest and relaxation

Vasodilators

Direct acting on vascular smooth muscle cells Verapamil, hydralazine, nitric oxide, nitroprusside, and minoxidil Verapamil- Calcium channel blocker, hydralazine is a K+ channel and myosin light chain phosphatase (myosin LC Ptase) activator, NO is a guanylyl cyclase myosin LC Ptase activator

Hydralazine

Direct activator of myosin LC phosphatase- associated with lowering calcium-calcium ATPase in active form- leads to vasodilation- its also an activator of the potassium channel

Explain the functional links between urinary output and end diastolic volume

Direct connection between kidney function and BP Kidneys regulate UOP- effects BV, VR, EDV, SV, CO- control of CO will regulate BP

Pharmacodynamics: Donepezil

Donepezil- treat symptoms of Alzheimer's disease associated with loss of cholinergic control of short term memory Sensory inputs- activates certain memory circuits- first stage is acquisition- some neuro circuits use ach as their NT Ach that use din temporary memory short term circuits- activate short term memory Labit- if in accident, traumatized- disrupted cholinergic pathway Activate ST memory- need to convert to long term memory- major mechanisms is repetition- develop new synaptic connection-auction that form between nerve tracts- consolidation-produces permanent changes in the brain that leads to long term memory formation Short term memory loss in Alzheimer's- donepezil- possess BBB-inhibits chase in cholinergic pathways- increased ach levels, receptor activity goes up-increase in cholinergic response- return some short term memory to patients

Cholinergic Pharmacology: Direct acting cholinomimetics

Drugs that mimic Ach Focusing on pharmacodynamics and toxicology for this class Examples: Bethanechol, pilocarpine, nicotine High intrinsic activity in target tissues mimic acetylcholine in nicotinic or muscarinic receptors Bethanechl and pilocarpine- muscarinic cholinergic receptor agonists-post synaptic membrane of post synaptic neuron in PNS Nicotine- nicotinic cholinergic receptor agonist- post-synaptic membrane of presynaptic neuron in PNS From textbook pages- bethanechol- can not use in patient with gastric ulcers- stimulates gastric acid secretion, can cause bleeding and perforation- contraindicated also for use in intestinal obstruction and surgery of the bowel, dysrhythmias in hyperthyroid patients, exacerbation of asthma

End diastolic volume and end systolic volume

EDV=maximum blood volume in the heart after it fills, during relaxation phase ESV=minimum blood volume in the heart after contraction EDV-ESV=stroke volume

Aldosterone receptor antagonist

Eplerenone- aldosterone receptor antagonist that normally functions to regulate the NA+ ATPase enzyme that is linked to K+/H+ exchange in distal tubule Distal tubule is the site for aldosterone receptor- sodium ATPase that is linked to this potassium coupled protein Eplerenone- aldosterone receptor antagonist- blocks the action of aldosterone- so the potassium/sodium/hydrogen exchange doesn't happen- sodium remains in the kidney nephron, draws in water, leads to water loss However- the number of transport proteins controlled by aldosterone is small- mild diuretic

Digoxin and sodium potassium ATPase

Each beat of the heart begins with excitation followed by a contraction-any time the heart beats, it is controlled by the AP that fires off fire- link between excitation contraction coupling AP that occurs over the surface of the heart muscle- AP triggers the release of calcium from internal stores- sarcoplasmic reticulum- series of membranes that store calcium-release Can also come from voltage channels Interacts with actin and myosin- as it slides across, that produces the muscle contraction An AP that occurs in the heart muscle is dependent on the membrane potential-the outside of the heart is positively charged, inside is negative Maintaining a membrane voltage- sodium potasium ATPase- specialized transport protein in excitable tissues Sodium is transferred out of heart cell in exchange for potassium- AGAINST concentration channel- sodium potassium ATP ace Second protein- sodium calcium ATPase- contributes to maintaining a membrane voltage- not as important as sodium potassium ATPase Heart muscle thats treated with digoxin- sodium potassium ATPase inhibitor- inhibits this critical enzyme- sodium is not going out in exchange for potassium-NA accumulates in the heart cell- not being transported out- secondary pump becomes much more active-sodium that can be exchanged for calcium In the presence of dig- extra source of calcium can interact with actin and mysoinand crease a more forceful contraction of the heart- positive inotropic effect Increasing effect- increases the release of ach from parasympathetic neurons- ach release onto the heart muscle- ach slows down the heart rate- negative chronotropic repsonse- heart beats with more efficiency, and not as fast

Neuroanatomy of the PNS neurons

Each neuron forms a synapse- NT begins at one end and ends at opposite end of the synapse Where it beings- where NT Is released is the pre-synaptic- binds to the post synaptic membrane that has a receptor for that NT End of the circuit is the target tissue Have 2nd synapse before we get to the target tissue- where NT begins is the presynaptic membrane- ends at post synaptic membrane Both neurotransmitters are Ach for pre and post synaptic neurons=cholinergic neurons Any neuron that releases ach=cholinergic neurons

Distal tubule and sodium/aldosterone

Elbow-upper region of ascending loop of henle, and first part of distal tubule- sodium ATPase that transports sodium out of the kidney nephron- return sodium into the blood- changing the chemical composition as it passes through the kidney nephron Also site of aldosterone- binds to aldosterone receptors in the distal tubule cells- when its present, activates that receptor which activates genes that produce a transport protein- sodium coupled protein, that protein is coupled with a potassium exchange molecule 3 sodiums that are reabsorbed into the blood, 2 potassium's are exchanged- 2 potassiums also into the kidney nephron Always more sodium returned to blood than is potassium that is lost in the blood-net uptake of salts in the presence of aldosterone

Major events in NT: Adrenergic

Electrical event that stimulates the secretion of NE-excitation-secretion coupling Axon terminal- releases NE_ in the synapse, it can bind to post-synaptic receptors on target tissues to produce F/F There are also presynaptic receptors on the axon terminal- when NE is released, F/F on target tissue, significantly high concentration on synapse- binds to presynaptic receptor- inhibits the excess release of NE-feedback mechanism- F/F response would kill you if you didn't have this mechanism- NE in high concentration in the synapse mechanism for turning it down- binds to presynaptic receptor, keeps F/F in tolerable range- release of NE is inhibited- this reuptake protein is called NE Transporter, or NET All this norepinephrine in the synapse- taken back up into the axon terminal where it is either stored in the vesicle or metabolized Another transport protein- VMAT- known as vesicular monoamine transporter- takes NE into the axon terminal, stores it away in the vesicle- released again during next F/F or broken down into its metabolite Summary: Net proteins are involved in reuptake- control the removal of NE from the synapse The release is controlled by the presynaptic receptor

Neprilisyn

Enzyme that breaks down netriuretic peptides like ANP- inhibition of neprilysin by sacubitril results in the accumulation of ANP's which reduce salt and water retention associated with HF-these therapeutic effects are combined with the additive effects of ARB's Increase in venous return-triggers release of ANP from atria- ANP can be inactivated by the enzyme neprilysin Sacubitril- inhibit the metabolism of ANP- begins to accumulate-reduce the RAAS system- also inhibits ADH release- that combined with the ARB (med) blocks the RAAS system- decrease blood volume, decreases venous return, and reduces the stress on the heart

The combination therapy of erythromycin (antibiotic) with tolterodine (Detrol), a muscarinic antagonist that is used to treat an overactive bladder, can be contraindicated because

Erythromycin inhibits CYP3A4 which can raise levels of tolterodine and intensify beneficial and adverse effects

Endothelians induce vasoconstriction via:

Every hormone has own unique receptor- so its not alpha 1 adrenergic receptors- thats for epi and norepi- none of the above related to the options given in class

Pharmacotoxicology: indirect acting Cholinomimetics

Exaggerated, generalized PNS side effects- AChase inhibition is also the mechanism of action of some toxins- sarin is a nerve gas and parathione is an insecticide- antidote to these poisons is pralidoxime (PAM) which breaks chemical bonds between drugs and ACHase 3 symptoms: diarrhea, bradycardia, pupil constriction, hypotension, uncontrolled salivation, muscle spasms, incontinence

Fibrolytic drugs

Example: tPA- "clot busters" used to dissolve preformed blood clots- these drugs reduce the spread of necrosis that cause tissue damage

Indirect Acting cholinomimetics

Examples: Neostigmine and donepazil Acetylcholinesterase inhibitors- ach accumulates in synapse- produce a cholinergic effect-do not bind to receptors directly

3 types of dysrhythmias

Excess SNS activity- tachycardia- rate disorder Ectopic foci- areas develop d/t myocardial damage following heart attack- electrical activity becomes abnormal Conduction disorder- re-entry dysrhythmias

Adrenergic Receptor Subtypes: Alpha 1 receptors (textbook)

Eye- dilation=mydriasis Arterioles= vasoconstriction (skin, viscera, mucous membranes) Sex organs, male=ejaculation Prostatic capsule=contraction Bladder=contraction of trigone sphincter

SNS target responses

F/F- nerve tract that goes to adrenal gland- release of NE-Epi-adrenaline rush Pupils- mydriasis- radial muscles are attached to the surface of the pupil of the eye- the muscles shorten, pull the pupils of the eye open- dilation of the pupil-want as much visual information as possible Heart- increase CO, increase force of contraction, beating faster Smooth muscles along bronchi- increase need for oxygen to support F/F- bronchodilation- smooth muscle cells will relax to increase air flow Complete redistribution of blood throughout the body- vasoconstriction of blood vessels going to non-vital tissues- shunt blood away from non-vital tissues Up to 25-50% of CO in state of vegetation is through kidneys- but in F/F you don't have time to be forming urine when fighting for your life Increase BF to skeletal muscles-vasodilation- need skeletal muscles to fight Peristalsis decreases as well as other digestive processes Urinary bladder leakage, but not maturation-it actually relaxes Nerve tracts to liver stimulates glycogenolysis- glycogen-glucose to support elevated level of activity RAAS system- SNS regulates salt and water retention by increased renin release- body is preparing for blood loss Kidneys will increase salt and water retention to replace blood loss during fight or flight

Sympathetic Nervous System

Fight or Flight

SNS Neuro anatomy- pre and post synaptic neurons

First neuron releases Ach, second neuron releases NE

Anatomical location and functions of cholinergic receptors in SNS

First neuron-presynaptic neuron-also cholinergic- also contains nicotinic cholinergic receptors post synaptic membrane of presynaptic neuron of SNS

Kidney nephron anatomy

Fluids are filtered from the glomerulus-network of capillaries within the kidney nephron Once filter into the proximal tubule these fluids begin to flow through the loop of hence, descending and ascending loop- into the detail tubule, then collecting duct- released and stored in the urinary bladder Along this entire length from point its filtered into the nephron, to the point where it then leaves the kidney and goes into the urinary bladder- chemical composition of the glomerular filtrate is changing constantly- each segment of the kidney nephron has different function in changing the chemical composition of these fluids

Loop diuretics

Furosemide- blocks Na+ reabsorption that is coupled to CL- ATPases along entire length of ascending loop of Henle- most powerful class of diuretics- increase UOP to over 20 L per day Lasix inhibits the chloride ATPase- blocks reabsorption of chloride and sodium-happens along the entire length of the ascending loop- one of the most active parts of kidney nephron-inhibit those transport proteins- large increase in salt that remains in the glomerular filtrate-draws large volumes of water- then water and solutes are excreted Lasix: textbook:used for pulmonary edema associated with CHF, edema of hepatic, cardiac, or renal origin, hypertension that cannot be controlled with other diuretics SE: Hyponatremia, hypochloremia, dehydration, hypotension, ototoxicity Dysrhythmia risk when digoxin given with oasis

Pilocarpine

Group of muscles in the eye attached to the lens- ciliary muscles- contain muscarinic cholinergic receptors- PNS helps you accommodate images, focus on images- ach acts on muscarinic receptors- causes muscles to contract, pulls on lens of eye, allows you to focus on objects Associated with ciliary muscles, there are canals the are weaving through muscle systems- Schlemm's canal-drain fluids from orbits of eye- when muscarinic cholinergic receptors are activated- contraction of ciliary muscle opens Schlemm's Canals and fluids drain out through canal- reduces ocular pressure used for treatment of glaucoma- pressure causes damage of retina which can lead to blindness

Cardiac output defined

Heart rate times stroke volume Stroke volume is the volume of blood pumped by the heart in a single beat or stroke Heart rate is beats per minute CO=HR x SV Variables that affect stroke volume: EDV,ESV

Adrenergic Receptor Subtypes: Beta 1 receptors (textbook)

Heart- increased rate, force of contraction, and AV conduction velocity Kidney- release of renin

Anticoagulants

Heparin- inhibit the functions of the clotting cascade in the blood which prevents blood clot formation-treats pulmonary embolisms, deep vein thrombosis

Why is sublingual forms of nitroglycerin ineffective when swallowed? What are the routes of administration of this medication?

Highly lipid soluble- and crosses membranes with ease Undergoes rapid inactivation by hepatic enzymes-drug only has a plasma half life of 5-7 minutes When nitroglycerin is given orally, most of each dose is destroyed on its first pass through the liver Comes in sublingual tablets- rapid onset, lasts only 30-60 minutes Translingual spray-same onset and duration Oral capsules- SR- 20-45 minute onset, last for 3-8 hours Transdermal patches- onset 30-60 minutes, last for 24 hours Topical ointment- onset 20-60 minutes, duration of 2-12 hours

Thiazide Diuretics

Hydrochlorothiazide- blocks NA+ ATPase in upper end of ascending loop of Henle and first segment distal tubule Upper region of the loop of henle and distal tubule- thiazide diuretics block sodium ATPase- sodium remains trapped in the kidney nephron- triggers osmosis- water is going to enter the kidney nephron because of the accumulation of salts d/t inhibition of ATPase- increase in salt and water in kidney nephron=diuresis, loss of water Textbook: can not be used in patients who have severe renal impairment- ineffective if GFR is low (less than 15-20ml/mine unlike loop diuretics which are still effective)

Pathophysiology of hyperlipidemias

Hyperlipidemias associated with elevations in LDL's-lead to plaque formation, development of atherosclerosis, and increased risk of spontaneous clot formation

Pharmacotoxicology of diuretics

Hypokalemeia that can cause muscle cramping, cardiac dysrhythmias, CNS confusion, and other disorders Hypersensitivity reactions Photophobia, increase toxicity of lithium and ototoxic effects of NSAiDS and aminoglycoside antibiotics Pregnancy categories B-C

Conduction disorder: re-entry dysrhythmia

Impulse can originate from the SA node---AV node-bundle of his-purkinji fibers-one is healthy, one is damaged by MI- impulse is blocked going down from the damaged branch of purkinje fiber network Systole=myocardial contraction in oral heart Damaged heart- blocked because of the injury Impulses through healthy tissue can wrap around the back heart and reenter damage cardiac tissue the opposite direction and the impulse is not blocked=circus movement- extra systole-multiple contraction from a single impulse-another type of cardiac dysrhythmia

Hydralazine and Nitrates- especially effective in what population of patients?

In AA patients with HTN and heart failure But they are not as responsive to beta blockers

Summary on CV drugs

In summary: Drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) have been foundational to cardiovascular drug therapy for almost three decades. RAAS inhibitors moderate vasoconstriction, myocyte hypertrophy, and myocardial fibrosis, an effect that has translated into clinically meaningful improvements in functional status and survival in patients with heart failure.

Alpha 2 receptor

In the axon terminal of the SNS-releases norepi- when it reaches a high concentration- it can bind to presynaptic receptors on the axon terminal- thats the alpha 2 adrenergic receptor The action is to inhibit excess release of NE-if you release too much, it can be toxic This presynaptic receptor controls the release of excess NE- reduces release of NE in the synapse to decrease adrenergic response

Atropine

Induces mydriasis, reduces secretions preoperatively- don't want to inhale the secretions, get pneumonia, treatment of ventricular bradycardia, treatment of severe diarrhea and urinary bladder incontinence

Ezetimbe

Inhibitor of cholesterol transport protein- blocks absorption of dietary cholesterol and cholesterol that enters the enterohepatic circulation CHolesterol transport protein- duodenum-cholesterol with dietary intake of fats- block the absorption of cholesterol that necessary for productio of chylomicrons- inhibits the use of exogenous cholesterol in the synthesis of lipoproteins- by inhibiting dietary absorption-reduce the cholesterol available thats processed by liver and choletserol available for lipoproteins

Aspirin

Inhibits cyclooxyrgenase which reduces thromboxane production-reduces platelet adhesion

Cholestyramine

Ion exchange resin that binds to bile salts and results in their elimination through the feces- hepatic production of cholesterol is diverted from production of lipoproteins to bile salts Not absorbed from intestine- instead, remains in the intestine, binds to bile salts that are part of enterohepatic circulation-bile salts and the drug is eliminated through the GI tract- never absorbed- by eliminating bile salts, you block the enerohepatic circulation- bile salts normally involved in emulsification of fats are lost-bile salts do not return to the liver- liver begins to divert cholesterol back to bile salts- liver will change its emphasis of cholesterol utilization from lipoproteins to bile salts- reduce the amount of cholesterol available to form lipoproteins

Adrenergic Receptor Subtypes: Dopamine receptors (textbook)

Kidney=dilation of kidney vasculature

Hypokalemia and diuretics

Lasix will block the reabsorption of sodium chloride in the ascending loop of hence Thiazide- inhibits sodium ATPase- remains in the kidney nephron Doesn't inhibit other parts like the distal tubule- all these extra salts move downstream into the distal tubule- once the salts enter- more salts available for this exchange of sodium and potassium- still many more salt molecules than this transport system can handle- but still higher than normal exchange of sodium for potassium-leads to hypokalemia which can be very dangerous

Class I antidysrhythmics

Lidocaine- sodium channel blocker-block the movement of sodium through those sodium channels- in the presence of lidocaine- some of those channels are blocked- phase 0 of the PA begins at the same time point but it will take longer to go through membrane depolarization Rest of the phases of the AP occur normally but by slowing down phase 0 of the AP, the rest of the phases follow-what happens is now it takes longer for the ectopic foci to reach the threshold, because you slowed down phase 0= reduces the automaticity of ectopic foci SA node is not affected by lidocaine because its not inhibited-has different family of sodium channels- hopefully it will recapture the rhythm of the heart If you slow down the AP-you extend the refractory period- block re-entry conduction-if the heart is trying to conduct an impulse through circus movement, won't respond to second stimulus since its still in the refractory period- blocks re-entry

Pathophysiology of hyperlipidemias: Continued

Liver- site of synthesis of lipoproteins-combines cholesterol and triglycerides and apoproteins to make intact proteins LDL's-elevations-endothelial cells have receptors- can be taken into an endothelial cells-can fuse with lysosomes- release of triglycerides (energy) and cholesterol (substrate for synthesis of steroid hormones) If LDL's are too high and exceed the need for normal physiological regulation- cholesterol can then accumulate, LDL's can form plaques- associated with atherosclerosis- as the plaques are calcified- rough surface-can trigger blood clot formation- blood clots and strokes Endogenous cholesteorl- glucose and fatty acids in the liver- cholesterol through HMG CoA reductase Another factor that affects cholesterol formation of LDL's is what comes from the diet- exogenous cholesterols- contain fats, emulsified by bile salts- cholesterol transport protein in duodenum- takes dietary cholesterol and transports into the blood-chylomicrons- lipid droplets that contain dietary fats- digested into remnants- remnants which contain cholesterol are transported to liver- can form lipoproteins- triglycerides-building block for LDL's- stored in the form of fat stores in adipose tissue-converted by triglyceride lipase- fatty acids and glycerol- liver resynthesizes triglycerides-building blocks for LDL's

Locations of M1, M2, and M3 receptors

M3=bladder, GI tract, eye M2=heart M1=salivary glands and CNS

Subtypes of MAO enzymes

MAO-A=metabolize norepinephrine, serotonin, and dopamine MAO-B=only dopamine Application: selegiline in low doses is a selective MAO-B inhibitor- reduces the metabolism of dopamine and is used in the treatment of Parkinsonism (dopamine deficiencies lead to tremors) so the dopamine level in the synapse will be increase

Hypertension- survey of antihypertensive therapies

Mild to severe forms of HTN- non-drug approach first (control diet, salt intake, control ingestion of caffeine, increase exercise) Then move onto different families of drugs, diuretics, etc Beta blockers, alpha 1 blockers, alpha 2 agonists, and methyldopa are all adrenergic drugs

Total Peripheral Resistance

Major influencer: SNS- BS have alpha 1 and beta 2 receptors Adrenergic alpha 1 receptors- vasoconstriction BV Beta 2=dilation Alpha 1 receptors OUTNUMBER beta 2 receptors in the vascular system-so when you increase SNS activity, increase TPR Another factor in TPR is blood volume- increase blood volume by increasing water=increased pressure exerted by the fluids moving through BV's Vascular compliance- physical characteristic of blood vessels and their dispensability in response to pressure changes- when heart beats, large amount of compliance-distend, will respond to that pressure change As we get older dispensability is reduced- elastic fiber decreases, TPR does up and BP does as well

Osmotic diuretics

Mannitol-osmotic diuretic- it is filtered into the kidney nephron-the mannitol itself creates a solute that draws in water- mannitol along with water passes through kidney nephron and causes diuresis Also used for cerebral edema- in that location-it does not pass the BBB- as it passes through capillary systems in the brain- draws water in from surrounding brain tissue to reduce edema- mannitol and water does to kidneys, increases UOP

Metabolism of norepinephrine

Metabolized by MAO (monoamine oxidase) and catachol-o-methyltransferase (COMT) Norepinephrine and epinephrine can both be metabolized by MAO's or COMT's- One those metabolic products are formed, they can be conjugated with gluconic acid and excreted by the kidneys- so if the adrenal gland has a tumor, this can be used as a diagnostic tool to be measured

Methyl-Dopa

Methyl-dopa feeds into the biosynthetic pathway-enters the metabolic pathways that produce epinephrine and norepi- it will ultimately be converted to methyl-nor-epi which is not a naturally produced substance Methyl-dopa enters the biosynthetic pathway- stored with NE and released Methyl-NE is a false NT- its not naturally produced by a neuron- it has high affinity for alpha 2 receptors, binds, low binding affinity for post synaptic receptors (alpha 1 and beta 1 receptors) When a patient is given the methyldopa- activates alpha 2 receptors instead of the adrenergic receptors- inhibit the release of NE-reduces the amount of NE controlled BP and decreases adrenergic responses as well as BP

Organization of the motor nervous system

Motor Neuron-innervates skeletal muscle- motor neuron begins in spinal cord, terminates on skeletal muscle in ONE single neuron system Releases Ach as its neurotransmitter as well to cause skeletal muscle contraction Single motor neuron- terminates for example in neuron on leg-impulse passes down the motor neuron, twitch from a muscle controlled by motor neuron CNS motor control centers that regulate the activity of motor neurons Descending excitatory pathways that go down the spinal cord-form a synapse with motor neuron that go to the tissue, causes a muscle twitch These neurons from excitatory pathways release glutamate which is one of the most abundant excitatory NT in the brain CNS control center-descending pathways that stimulate the neuron to release glutamate- binds to glutamate receptor on motor neuron- activates excitation secretion coupling- ach released from motor neuron-moves across the synapse into the neuromuscular junction Ach binds to nicotinic cholinergic receptor (N subscript M) to cause a muscle twitch- voluntary type of contraction of skeletal muscle involved in locomotion In the NM junction-theres another Achase that will break down ach into choline and acetate, can recircuit and be remade into next release Complex process that involves different parts of the brain- the arm uses one group of muscles that contract which causes arm to flex and opposing group of muscles that are relaxing Biceps- active contraction-opposing groups are inhibited, relaxing so you don have uncontrolled muscle movement-agonist and antagonist muscle movements Another set of nerve tracts- descending inhibitory pathway for opposing muscle groups stimulate the release of GABA-most abundant inhibitory NT in CNS when muscles are moving-opposing muscle groups by GABA- when gaba is released in the spinal cord, binds to gaba receptors in presynaptic membrane of glutamate receptors- when gaba is activated, it inhibits the release of glutamate- skeletal muscle relaxation- when muscles contract one group of muscles is contracting, the other group of opposing muscles is relaxing- different parts of the brain coordinating groups of muscles- different NT and different pathways-complex process

Motor Nervous System

Motor nervous system- different part of PNS- voluntary skeletal muscle contraction-locomotion, breathing- nothing to do with autonomic control (heart, BV, etc)- all autonomic-motor is regulating skeletal muscle contractions-ANS has nothing to do with controlling Controlled by different parts of the brain ANS-homeostasis Motor=locomotion

Baclofen Pharmacodynamics

Motor neuron regulates skeletal muscle contractions-twitches- skeletal muscle contraction CNS_ descending excitatory pathways that regulate motor neuron activity- they release glutamate- binds to glutamate receptor of motor neuron-activates nerve conduction, release of ach, bidning to nicotonic receptor of muscle subtype-binds, muscle contraction, metabolized to choline acetate Descending inhibitory nerve pathways-release gaba-binds to presynpatic receptor-inhibits glutamate release Baclofen-gaba receptor agonist- it binds to presynaptic gaba receptor in spinal cord, inhibits the release of glutamate which blocks activation of glutamate receptor on skeletal muscle- blocks skeletal muscle contractions- turn off the motor neuron by baclofen

Physiology of motor nervous system

Motor neuron-innervates skeletal muscle- it begins in the spinal cord, terminates on skeletal muscle Composed of one single neuron that connects the spinal cord to skeletal muscle Motor neuron does have chemical characteristics of ANS- releases ach, cause skeletal muscle contraction Impulse that passes down the motor neuron-causes a twitch from a muscle controlled by a motor neuron CNS control sites that regulate the activity of motor neurons Descending excitatory pathways that go down spinal cord- form synapse with motor neuron

Baclofen

Movement disorders- muscles that are fully functional-but inhibitory muscles aren't operating properly- exaggerated responses with nothing to counteract Defect in descending inhibitory pathway- using gabs to activate that Spastic disorders- you dont have a normal balance between agonist and antagonist- movement disorders without normal, smooth movement (MS, ALS, cerebral palsy, head injuries)

Cholinergic Receptors

Muscarinic acid and nicotinic responses mediated by Ach response Pharmacologists took known structure of chemical- looked at biological response Muscarinic acid comes from dessert plants- causes hallucinations- studied it, experienced changes in behavior associated with nicotine Looking at BR of peristalsis in GI tract, and skeletal muscle Ach added to intestine- peristalsis, and got muscle contraction- same NT in these target tissues, then the receptors are probably the same as well Took muscarinic acid- put it on the intestine- got peristalsis- but no effect on skeletal muscle-same NT, but not same response-because receptors are different Nicotonic acid- no effect on gut, but mimicked effect of ach on skeletal muscle Ach receptors exist in multiple molecular forms

Cholinergic receptors: Muscarinic and nicotinic

Muscarinic cholinergic receptors- artificially activated by muscarinic acid- 5 different subtypes Nicotinic acid-articificially activated by nicotinic cholinergic receptors Ganglionic nicotinic receptor- located on the postsynaptic membrane of the presynaptic neuron in the PNS and the SNS-drugs that block that receptor- block the PNS and SNS-extremely powerful drug Skeletal muscle nicotinic receptor-part of motor system-N subscript M for muscle- another part of ANS Neuron---skeletal muscle-- has different anatomy- single neuron that connects the spinal cord with skeletal muscle- not a 2 neuron circuit- motor neuron releases Ach and binds to nicotinic receptors on skeletal muscles Neuromuscular junction in between- nicotinic cholinergic receptor-Nsubscript M for muscle- difference drugs will affect one subtype of nicototinic receptor but not another- e.g. a muscle relaxant that targets nicotinic receptors in muscles but not in the ANS See note card with drawing from class

Solifenacin (Vesicare)

Muscarinic receptors have 5 subtypes- muscarinic 3 receptor antagnoist- reduces PNS control over the contractile state of the detrusor muscle- M2 receptors are in the heart, M1 in salivary glands- so this drug targets subtypes and can eliminate other side effects in different target tissues

Alpha 2 receptor

NE too high-binds to presynaptic receptor-inhibits the release of NE-presynaptic receptor is controlling the release of NE-this is the alpha 2 receptor-regulates the release of NE

Subtypes of transporter proteins in a variety of different neurons

NET=Norepi transporter- site of lots of drug effects- cocaine: inhibits the net protein in the SNS-NE accumulates in the synapse- powerful F/F response DAT=dopamine transporter- target for antidepressants- psyche is controlled by catecholamines in the limbic system- depressed catecholamines=psychological depression DAT inhibitor-elevate dopamine, elevate mood SERT= serotonin transporter-inhibit reuptake of serotonin in areas that regulate mood GATS=GABA transporters- certain types of seizures-most abundant inhibitory NT-gaba will go up in the brain, seizure activity is decreased

Phase 0

Na+ channels open and there is NA+ influx that causes rapid depolarization When you reach that threshold- NA channels open, area of high concentration to low concentration into the heart cell- NA +charge-start with -90- but now with more positive that outweighs the negative- heart becomes less and less negatively charged- sodium movement causes positive to be outweighed by negative- depolarization by reversing the electrical charge

Natriuretic peptides

Natriuretic peptides, which include atrial natriuretic peptide, are secreted by the heart, vasculature, kidney, and central nervous system in response to increased cardiac-wall stress and other stimuli. Natriuretic peptides have potent natriuretic and vasodilatory properties, inhibit the RAAS, reduce sympathetic drive, and have antiproliferative and antihypertrophic effects as well. Neprilysin inhibition results in an increased concentration of natriuretic peptides. Thus, the beneficial effects of RAAS inhibition are likely to be augmented by the enhancement of natriuretic peptide activity.

Pharmacodynamics: Neostigmine

Neostigmine used to treat GI and urinary bladder paralysis, glaucoma, myasthenia gravis, treatment of anticholinergic effects produced by drugs like phenothiazines: Side effect of the drugs are anticholinergic effects- so neostigmine treats those symptoms by inhibitor achase- ach goes up, increase ach and outcompete the drug side effects Neostigmine for glaucoma- used as an eye drop- inhibits chase, increases ach and activates muscarinic receptor which causes the ciliary muscle to contract, opens Schlemm's Canal- fluid drainage that causes ocular damage to retina

Novel antihypertensive agents

Nesiritide- analog (agonist) of atrial natriuretic peptide- treatment of decompressed congestive HF agonist for ANP-reduces RAAS system- reduces BV, CO, TPR, and BP Bosentan- endothelin receptor antagonist; treatment of pulmonary hypertension Endothelial cells control TPR- endothelia's produced by endothelial cells- bosentan blocks this profound vasoconstriction and lowers BP

Neuroanatomy

Neuron and target tissue- neuroanatomy of the neurons that make up some circuit Events: nerve impulse goes down an axon that triggers release of neurotransmitter- once its released across synapse, target tissue- produces some response

Warfarin versus Dabigatran

New generation to old generation anticoagulant comparison Warfarin- enzymes in the liver that produce clotting factors- those have to be cleared from the blood-rages days to kick in Pradaxa-short onset, only one protein-thrombin Warfarin effect is compromised by vitamin K rich foods- lots of salads- vitamin K from foot source can antagonize inhibitory effects that warfarin has Blood testing- need constant blood tests to look at clotting times on patients with warfarin-does not need to be performed on new med

Why is cigarette smoking contraindicated in patients with hypertension?

Nicotinic receptors- on the postsynaptic membrane of presynaptic neuron-nicotine binds to that receptor-excitation-release of norepi- binds to receptors in different tissues that control BP-increases hypertension in the patient

Thiazide diuretics produce their therapeutic effect by inhibiting sodium reabsorption in the loop of Henle.

Not doesn't inhibit sodium reabsorption throughout the entire length- it does in the upper regions

Which subtype of muscarinic receptor might an antagonist like vesicle target for the treatment of incontinence/overactive bladder?

OAB-urinary urgency, frequency, noturia, urge incontinence M3 receptor subtype are most prominent in the bladder-also found in GI smooth muscle, the eyes, salivary glands-so can still have some side effects like constipation, blurred vision and photophobia, dry eyes, and some degree of dry mouth-will NOT cause tachycardia, or impairment of CNS function (brain muscarinic receptors mostly M1) Vesicare acts on M3 receptor blockade

Biosynthesis of norepinephrine

Occurs within an adrenergic neuron: Comes from dietary amino acids- part of the proteins we ingest- contains a couple of critical amino acts- phenylonin-tyrosine Enters the biosynthetic pathway, converted to L-dopa-can be used as drug but its a natural product associated with norepinephrine L-dopa is converted to doapmine- come neurons that release dopamine as its neurotransmitters- then it goes to norepinephrine- fight or flight- adrenal medulla can convert norepinephrine-epi-adrenaline rush Ring structure with 2 hydroxyl groups in the same spot- catechol group- attached to this group there is a nitrogen attached- this is called an amine-nitrogen So collective, these neurotransmitters are called catecholamine's- collection of NT

Metabolism of Ach

On the post synaptic membrane of cholinergic membrane-have the enzyme acetylcholinesterase- involved in the metabolism of ach Synthesis of Ach occurs in the axon terminal- it is released, diffused across a synapse- Achase breaks down the ach in the synapse- broken down into choline and acetate- no longer an active neurotransmitter If Ach does leak out of the synapse and gets into the blood- backup enzyme is pseudocholinesterase- will be immediately metabolized by pseudocholinesterase- which is why Ach can not be used as a drug by itself

Verapamil

One of many different calcium channel blockers-if you block calcium channels in smooth muscle cells- block calcium getting into cells, block activation of myosin LC kinase, block vasoconstriction Without calcium actively entering the cell- CA ATPase are in active state- decrease calcium, decrease in calcium activating myosin LC phosphatase- increase vasodilation, decrease TPR and BP

Autonomic Nervous System:Defined

One of the functional divisions of the PNS: composed of the Parasympathetic and sympathetic nervous systems

Minoxidil

Opens potassium channels in smooth muscle cellsthat causes membrane hyperpolarization-prevents excitation-contraction coupling in vascular smooth muscle- absence of contractile activity is associated with smooth muscle relaxation Activates potassium channels- potassium moves out of muscle cells-membrane hyperpolarization- blocks excitation contraction coupling that normally controls opening of calcium channels- blocks activation of calcium channel need for contraction Ca atpase still in active state-calcium moved out, decreased calcium leads to vasodilation

Anatomical location and function of cholinergic receptor subtypes: PNS

PNS- ach binds to nicotinic receptor of the N type-excitation secretion coupling- postsynaptic neuro-receptor Muscarinic cholinergic- located in post synaptic membrane of post synaptic neuron Post synaptic membrane and presynaptic neuron- nicotinic cholinergic Nicotonic cholinergic receptors are located in the synapse between the first and second neurons Muscarinic cholinergic are directly on the target tissues

Overview of normal sinus rhythm

Pace maker is located in the SA node -spreads over the atria, enters the AV node- AV node is slow of electrical transmission-gets through, then enters bundle of His and Purkinji fibers-throughout the ventricular tissues into ventricular muscle- systole Time at which an action potential develops at different parts of the heart- area that depolarizes first in the heart is the SA node- pacemaker- action potentials occur at a time later than in the SA node- pacing the rest of the heart

Therapeutic effects of pancuronium, succinylcholine, and botulinum neurotoxins

Pan. and succ- induce skeletal muscle relaxation and are used during surgery, tracheal intubations, and electroconvulsant shock therapy Botulinum- induces skeletal muscle paralysis at injection sites, use for strabismus, blepharospasm, and cosmetic removal of facial wrinkles

Identify the following neurons and membrane

Presynaptic membrane of the post-synaptic neuron (third circle) Presynaptic membrane of the presynaptic neuron (first circle) Post synaptic membrane of the post synaptic neuron of PNS (last circle) Post synaptic membrane of the pre synaptic neuron=second circle Functional relationships-not strict anatomical locations

Diuretics

Pharmacokinetics: administration- oral route most common, some parenteral administration Half life of 2-36 hours- can pass BBB/placenta/mammary alveoli, some diuretic highly bound Metabolism- phase I and II hepatic metabolism, renal route of elimination common Lasix-98% PPB "Water pills" Increase UOP, decrease BV, VR, EDV, Stroke volume, CO, to decrease BP

Dose response curve of alpha and beta effects and NE

Pharmacologists that were looking at dose response curve- NE on BP- fight or flight response They discovered that when you give doses of norepi- you can cause vasoconstriction- that vasoconstriction is what will control an elevation in BP in fight or flight-these produced at lower doses than what used cardiac affects-ALPHA responses- these occurred first-then named alpha and beta receptors Can increase NE dose further-start to see cardiac effects- increase in CO-beta responses

Adrenergic Receptor Subtypes: Alpha 2 receptors (textbook)

Presynaptic nerve terminals- inhibition of norepinephrine release

Neurochemistry of the SNS: pre and post synaptic neurons

Presynaptic neuron is cholinergic=ach, post synaptic neuron is adrenergic=norepinephrine

Why are antimuscarinic drugs contraindicated in patients with glaucoma?

Prevent contraction of ciliary muscles, block draining of fluids from canal of schlemm's, cause blindness-increase intraocular pressure which can lead to blindness

Gemfibrozil

inhibits hepatic triglyceride synthesis thus suppressing lipoprotein synthesis (VLDL's and sometimes LDL's-increases production of HDL's that activates reverse cholesterol transport from peripheral vascular beds

SNS responses: and adrenergic receptors

Pupils of the eye- dilation=mydriasis- radial muscles shorten to pill the pupils of the eye open- alpha 1 receptors CO during F/F=active beta 1 receptors Bronchioles- dilation to increase gas exchange- passive- beta 2 receptors Blood flow to non-vital tissues- constrict-active- alpha 1 Blood flow to vital tissues like skeletal muscle- dilate- passive, beta 2 GI tract/peristalsis- decreases blood flow, passive- beta 2 Urinary bladder relaxes, passive beta 2 Exception to the heart- RAAS system in the kidneys- enhance salt and water retention in case you lose blood- beta 1 receptors- sub population that exists in the kidneys Glycogenolysis-breaks down glycogen- glucose- whole mixture doesn't fit f/f- alpha 1 and beta 2 receptors Do not apply active and passive to PNS- only to SNS- for PNS you are either supporting digestion or you arent

PNS target responses

Rest and relaxation Pupils: vegging out, pupils will be smaller- miosis- circular muscles that surround the pupils- pupils will become smaller Salivary glands- digesting- salivation will aid in that process- stimulates secretions of large volumes of saliva to aid in the process of digestion Heart rate and CO-decrease- bradycardia Smooth muscle that line bronchi- contract smooth muscle, bronchial contriction- dont need a lot of gas exchange when relaxing- secrete lots of mucous, watery types of saliva while relaxing Gall bladder-contracts-moves bile into the digestive system to aid in digesting fats Perastalsis increases, increases secretion of digestive enzymes Urinary bladder- smooth muscle contracts, nitrogenous enzymes in state of digestion, breaking down metabolic byproducts Contaction of urinary bladder-mituration- void urine from bladder

Myocardial Infarctions: Pathophysiology

Result of interruption in coronary blood flow-cardiac anoxia either from hemorrhaging- BV breaks open, or blood clot that will reduce blood flow to an area to the heart Thrombosis- local blood clot Embolism- traveling blood cot Cardiac anoxia-peotoralis angina- warning signal of impending heart attack Ischemia severe enough-heart cells die, myocardial necrosis- leads to cardiac arrest, spread of necrosis, dysrhythmias, cardiac failure (usually 48 hours after MI)

Ivabradine

SA node has its own unique channels not found in other parts of the heart -this drug targets this unique sodium-potassium channel- if you inhibit that-lowers heart rate and reduces pacemaker activity SA node- AP that fires off-completed during diastole- SA node has spontaneous depolarization-fires off again New drug-ivbradine inhibits the unique sodium potassium channel- AP occurs, spontaneous depolarization occurs more slowly- SA node fires less, allows more time for the blood to flow to the myocadium and slow the heart rate

Role of SNS in maintenance of BP

SNS-fight or flight-number of effects on the major organs that control BP Alpha 1 receptors in vascular beds can cause increase in TPR SNS and epinephrine can increase heart rate and stroke volume/force of contraction Also can stimulate the release of renin

Vytorin

Simvastatin and ezetimbe combination drugr-esults in synergistic cholesterol-lowering effects; 10—80 mg of simvastatin with ezetimibe achieves LDL reductions of approximately > 51% More effective on blood levels of LDL than monotherapy

Pancuronium

Skeletal muscle relaxant- nicotinic receptor antagonist on skeletal muscle- non depolarizing relaxation because it blocks excitation contraction coupling When ACh is released-in NMJ- binds to receptors, causes membrane depolarization- release of calcium-muscle twitch Binds to nicotinic receptor as antagonist- block excitation-non-depolarizing- block contraction-no electrical event

Adrenergic receptors: Active or passive TT responses

Some adrenergic responses produce active and others produce passive adrenergic response Active- tissues have to work hard- remove byproducts, increase the work of target tissue- needs more O2, nutrients etc. Passive- tissue doesn't have to work as hard- doesn't need as much ATP, glucose- relaxing- need both active and passive F/F to survive dangerous situations Release NE- target tissues have alpha 1 receptors- active- worker harder to support F/F Beta 1 receptors- tissue that has the highest concentration of beta 1 receptors is the heart- there are other tissues but the heart is the biggest player- active F/F almost exclusively to heart Beta 2 receptors- passive F/F response

Active fight or flight responses on visceral blood vessels are mediated by alpha-1 adrenergic receptors

Strongly Agree- ask him

Using drugs that prolong one of the phases of an action potential in the heart will reduce the automoticity of ectopic foci.

Strongly agree

Adrenergic receptor subtypes

Subtypes of receptors- alpha receptors, alpha 1 receptors, and alpha 2 receprots Beta 1 and 2 receptors as well Alpha 1 has subtypes of it (A,B,C,D,E) Alpha 2 (A,B,C,D)-etc. But keep at this level Targets for all types of drugs Beta 3-regulate lipolysis, breakdown of fats- controlling obesity

Antiangial Drug

Symptoms are causes by inadequate coronary blood flow (anoxia) generally associated with vasospasm/stress/exercise or atherosclerosis (coronary artery disease) EG. propranolol, nitroglycerin

Ionic basis of cardiac action potential

Target the action potential in the heart- tracing of the changes in the membrane voltage over time Most of the heart-the maximum negative membrane voltage is a RMP of -90mv That negative value is because if you look at the distribution of ions across heart cell- outside is +charged, inside is -charged Critical membrane voltage that occurs known as the threshold potential-critical voltage that triggers an action potential-slowly over time but once you reach that threshold- it occurs very quickly- AP goes through phase 0,1,2,3,4 AP in the heart- ectopic foci in the heart-unstable resting membrane voltage- unlike muscle and nervous system- resting membrane potential is not stable- spontaneous rate of depolarization that occurs- creates condition in the heart known as automaticity-heart can stimulate its own electrical events automaically- can beat independent of other controls- unstable resting membrane voltage can trigger their own contractions Stae 4=threshold potential Unusual characteristic in heart muscle of action potential- prolonged absolute refractory period or relative refractory period In absolute refractory period- heart will not respond to second stimulus at any time Relative- heart might respond to second stimulus, but much larger than normal Plateau phase in AP that you don't see in neural tissue- phase 2 extends the absolute and relative refraction periods in time to prevent tetanization (summation in muscle tissue-short refractory period-muscle twitch- stimulate again-adds on to previous twitch) in the heart you dont want that to happen-if it stays in contacted state it is not pumping blood-want each contraction of heart to be separate from previous retraction- those periods allow the heart to beat completely- independent of previous beat UNLIKE skeletal muscle Heart muscle has automaticity, prolonged refractory period

Exceptions for adrenergic and cholinergic principles

Target tissues for the SNS possess more than one class of adrenergic receptor-NE in some target tissue may bind to more than one different kind of receptor in a target tissue For the most part- affects one, but not the other

Nicotine

Used for treatment of cigarette withdrawal symptoms- varenicline, as a partial agonist, reduces craving for and decreases the pleasure effects of cigarettes- with partial agonist, wont give the patient the full blown sense of pleasure as well as craving

Scopalamine

Used in the treatment of motion sickness- inhibits cholinergic activation of emesis center Movement that occurs- activates areas in inner ear- cholinergic pathways through emesis center- scopalamine-antagonist in the emesis center

Cholinergic and Adrenergic "Dogma"

The descriptions of the structure and functions of the ANS (dogma) as presented are important for understanding the therapeutic actions of most drugs used today but it's also important to know that there are exceptions to this dogma that can help refine your understanding of this topic.

Ionic basis of cardiac action potential-continued

The direction of ion movement across membranes during an action potential is influenced by the concentration gradients of ions and membrane permeability Sodium levels- outside of the heart- 150 mmole, inside is 15 moles Opposite for potassium-outside is 5 moles, inside its 150 mmoles Calcium levels- extracellular calcium is 10-3, 10-7 in the heart- create these changes in membrane voltage

The hypotensive effects of methyl-DOPA therapy could be a compromised if this medication was given with an alpha-2 AR agonist.

The hypotensive effects might be enhanced- both are alpha 2 agonists- have an additive effect with another alpha 2 agonist

Overactive Bladder

Thin layer of smooth muscle that surrounds the urinary bladder- when it contracts, that leads to voiding to voiding of urine- called the detrusor muscle- OAB affects up to 33% of the US population

Lidocaine

Treatment of cardiac dysrhythmias- sodium channel blocker- suppresses the formation of action potentials associated with ectopic foci (areas of spontaneous depolarization that develops independent of SA pacemaker control There are areas of the heart that are damaged by the MI-changes the electrical activity- beats independent compromises CO, blood flow to brain Dysrhythmias typically occur 24-48 hours after an MI

Niacin

Triglyceride lipase inhibitor in adipose tissue that reduces hepatic triglyceride synthesis and lipoprotein synthesis Inhibits the triglyceride lipase in adipose tissue- reduces production of building blocks for lipid proteins- lowers LDL

Both the synthesis and metabolism of NE occurs within the axon terminal of the postsynaptic neuron of the SNS-T or F

True

Adrenergic Neurons: Biosynthesis and metabolism of NE

Tyrosine- synthesized to NE within the axon terminal- stored in the secretory vesicles- packages of NE Little packages of NE_ bound or free- NE binding protein in the synapse- different than PBP in the blood- specialized for NE- some in bound, some in free state Free state NE-more metabolically labile- some of the free can leak out and be stored in the bound state-metabolically stabe If NE is released into the synapse- it all becomes free Once it is released into syapse- vesicle doses with membrane, enters the synapse- how is it now metabolized Very active reuptake protein that removes NE from the synapse very quickly- NE has milliseconds to bind to produce F/F- otherwise, takes NE and transports back to axon terminal-metabolized by MAO into metabolite, some can also return to the vesicle, and some NE that can leak out can also be broken down by Mao

Nitric oxide

Used as a vasodilator after MI- enter smooth muscle cells-activates second messenger cascade- myosin LC phosphatase- calcium transported out, relaxation of actin, myosin- vasodilation

Action of BV contraction

Vascular smooth muscle cell with contractile proteins- thin of actin, thick of myosin- when actin moves across myosin-causes a vasoconstriction Increases in calcium- activates myosin light chain kinase- enzyme phosphorylates myosin Now It can have a cross-bridge formation-in the presence of calcium, and this phosphorylated state, there is movement of actin across myosin-vasoconstriction leads to increased TPR and BP Now within smooth muscle cells- when there is a reduction of calcium, this leads to activation of myosin light chain phosphatase-dephosphorylates (removes phosphate group) from myosin Actin/myosin cros bridges are inhibited- leads to vasodilation-decreased TPR and BP NE causes vasoconstriction on alpha 1 receptors- binds to alpha 1 receptors on blood vessels-activates calcium channels- now allowed to enter smooth muscle cells- increases intracellular calcium, activates myosin LC kinase- phorphylates-actin and myosin slide across and cause vasoconstriction NE disappears after F/F- metabolized- smooth muscles begin to relax-another transport protein in smooth muscle cells-calcium ATPase- exports calcium out of smooth muscle cells- when the alpha 1 receptors are fully active- the calcium channel is open- more calcium entering a cell than being exported When NE disappears- ca channels close, ATPase transports calcium out of muscle cells, reduces calcium, activates myosin LC phosphatase- vasodilation NO-biological gas produced by endothelial cells and other tissues- enter smooth muscle cells- activate guanylyl-increases CGMP which is a second messenger- activates myosin LC phosphatase- dephosphorylates myosin-actin moves away-vasodilation

Venous return definition

Venous return-force of contraction, force in which heart beats Blood volume and hemostasis (blood clotting) impact venous return- blood volume major regulator is urine output which is controlled by the RAAS system in the kidneys

Succinylcholine

Violates our definitions of agonists and antagonists- activates the acetylcholine receptors-causes depolarization, electrical excitation- depolarizing agent- HOWEVER- succinylcholine unlike ach stays bound to the receptor for a prolonged period to time- doesn't;t let go- causes a conformational change in the shape of the receptor which leads to inactivation of the receptor- converted to inactive state that prevents twitch summation- acts as an antagonist by blocking a twitch summation that causes a sustained contraction Initial depolarization- equivalent to excess ACh Sustained desensitization block: equivalent to receptor inactivation

Unlike β-adrenergic receptor antagonists, ACE inhibitors do not interfere with compensatory hyperglycemic responses that can be triggered by insulin-induced hypoglycemia.

When insulin is used and it lowers blood glucose, that will trigger a hyperglycemic resposne- when BG levels go down, that triggers the release of epi- acts on beta receptors in the liver- hyperglycemic response- this compensatory hyperglycemia affect will not occur- insulin can be a lot more dangerous Unlike sympatholytic drugs, ACE inhibitors do not interfere with CV reflex responses such as compensatory adjustments to orthostatic hypotension or exercise

Cardiac failure

can be caused by an MI, chronic hypertension, coronary artery disease, the aging of the myocardium, and is often characterized by a reductio in left ventricular ejection fraction measured by echocardiographs and MRIs CF is coupled to myocardial remodeling Fibrosis- heart muscle is replaced by connective tissue Left ventricle- muscle is thick and strong In a failing heart- chamber is much larger- holds more blood, walls of the heart are not as strong- myocardial apoptosis- heart muscle enlarging, and fibrosis- not contractile in nature- reduces the ability of the heart to maintain normal CO

Lovastatin

hepatic 3-hydroxy-3-methyl-glutarate (HMG) coenzyme A reductase inhibitor which suppresses lipoprotein synthesis HMG coA reductase inhibitor- block endogenous production of cholesterol- block the production of lipoproteins that includes LDL,s

Diphenhydramine, a commonly used antihistamine, is contraindicated in elderly patients with constipation. The non-selective activation of cholinergic receptors in the G-I tract explains the mechanism for this adverse side-effect.

inhibit not activate cholinergic receptors-that would cause constipation Cholinergic receptors-stimulate peristalsis- does that explain constipation-no

Nitroprusside

stimulates NO production and directly activates guanylyl cyclase that induces coronary vasodilation and increases oxygen delivery to the myocardium

Nitroglycerin

stimulates NO production- induces coronary vasodilation and increases oxygen delivery to the myocardium Nitroglycerin- metabolized to nitric oxide-stimulates second messenger by cGMP pathway- myosin LC phosphatase- low concentration of calcium-vasodilation-increased coronary blood flow- therapeutic effect