Review of Hemodynamics (Chapter 42)



Review of Hemodynamics (Chapter 42)

Arterial Pressure Regulation

Overview of control system:

• Arterial pressure = peripheral resistance × cardiac output

• Arterial pressure is regulated by

– Autonomic nervous system (ANS)

• Seconds to minutes

– Renin-angiotensin-aldosterone system

• Hours to days

• Renin- raises BP

• Angiotensin- raises BP

• Aldosterone- raises BP

– Kidneys

• Weeks

– Family of natriuretic peptides

• Where sodium goes water follows, lowers BP

ANS & Regulation of AP

• Steady-state control via ANS

– Tone

– Adjusts cardiac output (CO) and peripheral resistance (SVR)

• Rapid control by ANS: baroreceptor reflex

– HR -(Constricts nearly all arterioles, veins and Sympathetic branch of ANS

– Resets to “new” norm if sustained for 1-2 days

RAAS Regulation of AP

• Renin-angiotensin-aldosterone

• Constriction of arterioles and veins (angiotensin II - vasoconstrictor)

– hours

• Retention of water by the kidney (aldosterone)

– days

Kidneys & Regulation of AP

• Retention of water

– Process: (BP((GFR((H20 retention

• Postural hypotension

– Aka orthostatic hypotension

• Natriuretic peptides

– Relieve preload fr. hypervolemia

– Protect CV system fr. volume overload

• Atrial natriuretic peptide (ANP)

• B- or brain natriuretic peptide (BNP)

• C-natriuretic peptide (CNP)

Drugs Acting on the Renin-Angiotensin-Aldosterone System (Ch. 43)

• Physiology of the renin-angiotensin-aldosterone system (RAAS)

• Angiotensin-converting enzyme inhibitors

• Angiotensin II receptor blockers

• Aldosterone antagonists

Physiology of the Renin-Angiotensin-Aldosterone System

• Angiotensins I, II, & III

• Actions of angiotensin II

– Vasoconstriction

– Release aldosterone

– Alter structure of heart and vessels

• Actions of aldosterone

– Sodium and water

– Fibrosis of vessels

Formation of Angiotensin II

• Renin

– Released in response to BP, Na+, volume, and renal perfusion

– Converts angiotensinogen to angiotensin I

• Angiotensin-converting enzyme (ACE)

– Catalyzes conversion of angiotensin I (inactive) into angiotensin II (highly active)

Regulation of BP by RAAS

• Effect modest in normal hemodynamics & Na+

• Effect MAJOR in hemorrhage, dehydration, or sodium depletion

• Acts in two ways

– Constricts renal blood vessels

– Stimulates release of aldosterone fr. Adrenals thereby ….

• Tissue (local) angiotensin II production

Angiotensin-Converting Enzyme (ACE) Inhibitors = the “Prils”

|Prototypes: captopril (Capoten), ramipril (Altace) |

|MOA / TE |Reduces angiotensin II & increases bradykinin to dilate vessels, excrete Na+ & H20, conserve K+ &|

| |help prevent vessel and heart tissue changes |

|Uses |HTN |

| |heart failure |

| |diabetic nephropathy |

| |prevention of MI |

| |stroke and death |

|Special benefits of ACE |Do NOT interfere with heart reflexes – ok with exercise |

|Inhibitors |Safe in asthma |

| |Do NOT cause hypokalemia, hyperuricemia, or hyperglycemia |

| |Do NOT induce lethargy, weakness or sexual dysfunction |

| |DO reduce risk of cardiovascular mortality fr. HTN, MI, & stroke (22%) |

| |Reduce mortality following MI |

| |Reduce chance of developing heart failure |

| |Slow progression of renal disease |

|ADME |Nearly all are PO |

| |Captopril and moexipril NOT with food |

| |Renal excretion (monitor who?) |

|Adverse effects |1st Dose hypotension |

| |Cough |

| |Hyperkalemia |

| |RF in renal artery stenosis |

| |Angioedema |

| |Neutropenia (rare) |

| |Dysgeusia and rash |

| |People with Lupus |

|Drug ( Drug |Diuretics – withdraw 1 wk prior |

| |Antihypertensive agents |

| |Drugs that raise potassium levels |

| |Lithium - raised |

| |Nonsteroidal anti-inflammatory drugs |

Angiotensin II Receptor Blockers (ARBs) – the “Sartans”

|Prototypes: iosartan (Cozaar), valsartan (Diovan) |

|MOA / TE |Blocks action of angiotensin II |

| |Protects fr. cardiovascular structural changes |

| |Reduces excretion of K+ and ( aldosterone |

| |Increases renal excretion of Na++ & H2O |

| |Useful in migraine |

| |Does not inhibit kinase II or increase bradykinin |

| |MAIN difference between ACEs & ARBs – no cough or hyperkalemia with ARBs |

|ADME |All PO |

| |All ok with or without food |

|Adverse effects |Same as ACEs |

| |1st Dose hypotension |

| |Cough |

| |Hyperkalemia |

| |RF in renal artery stenosis |

| |Angioedema |

| |Neutropenia (rare) |

| |Dysgeusia and rash |

| |People with Lupus |

|Drug(Drug |Antihypertensives |

Aldosterone Antagonists

|Prototype: eplerenone [Inspra] |

|MOA / TE |Selective blockade of aldosterone receptors for tx of HTN and heart failure |

| |Requires 4 weeks |

| |Benefit in preventing mortality unknown |

|ADME |Absorption is not affected by food |

|Adverse effects |hyperkalemia |

|Drug(Drug |Inhibitors of CYP3A4 |

| |Can significantly raise levels of eplerenone |

| |Drugs that raise potassium levels |

| |Caution when combined with lithium |

|Prototype: Spironolactone [Aldactone] – older drug |

|MOA |Blocks aldosterone receptors |

| |Binds with receptors for other steroid hormones |

|Therapeutic uses |Hypertension and heart failure |

|Adverse Effects |Hyperkalemia |

| |Gynecomastia |

| |Menstrual irregularities |

| |Impotence |

| |Hirsutism |

| |Deepening of the voice |

Calcium Channel Blockers (CCBs)

• Normal physiology:

– Calcium in = (contraction / (force

• Effects of Blocking

– Dilation of Vascular Smooth Muscles (VSM) = dilated peripheral arterioles / arteries & arteries of heart

• Heart Ca++ Blocking Effects

– ( Inotropic effect

– Slows conduction thru SA & AV nodes

– Same effect as Beta1 blockers

|Prototypes: Verapamil [Calan, Isoptin, Verelan] |

|Diltiazem [Cardizem, Diltia XT] |

|Amlodipine (Norvazac) |

|MOA / TE |Peripheral arterial dilation, ( arterial pressure, ( coronary perfusion, blockade at SA & AV |

| |nodes ( HR, ( force of contraction aiding in the relief of: |

| |Angina pectoris |

| |Essential hypertension –1st line for chronic |

| |Cardiac dysrhythmias – A-flutter / fib / SVT |

| |Migraine |

|Adverse Effects of verapamil / |Constipation – can be severe in elderly |

|diltiazem |Diltiazem not as constipating |

| |Dizziness, Facial flushing |

| |Headache |

| |Edema of ankles and feet |

| |Gingival hyperplasia |

| |Bradycardia |

| |Heart block & ( stroke volume |

| |Contraindications? |

|Drug(Drug |Digoxin & Beta-adrenergic blocking agents – use caution! (Can slow HR too much!) |

| |Separate doses of Beta blockers and CCBs |

|Toxicity |Severe hypotension |

| |Bradycardia and AV block |

| |Ventricular tachydysrhythmias |

| |Treat w Calcium Gluconate, nor-epi, atropine, pacer, cathartics, cardioversion |

|Prototype: Nifedipine [Adalat,Procardia] |

|MOA / TE |dilates arterioles ( lowers BP |

| |no cardiac effect |

| |can increase HR via baroreceptor effect |

| |no decreasing contraction force or affect on automaticity of conduction - used in: |

| |Angina pectoris |

| |Hypertension |

| |Investigational basis to relieve migraine headache and to suppress preterm labor |

|Adverse Effects of nifedipine |Flushing - Dizziness |

| |Headache |

| |Peripheral edema |

| |Gingival hyperplasia |

| |Reflex tachycardia |

|Drug(Drug |Beta-adrenergic blockers |

| |Used intentionally to prevent reflex tachycardia |

Vasodilators (Ch. 45)

• MOA / TE

– Selectively dilate arteries, veins, or both

• Principal indications

– Essential hypertension & Hypertensive crisis

– Angina pectoris & Myocardial infarction

– Heart failure

– Pheochromocytoma

– Peripheral vascular disease

– Pulmonary arterial hypertension

– Production of controlled hypotension during surgery- to decrease bleeding

|Hydralazine [Apresoline] |

|MOA / TE |Selectively dilates VSM of arterioles lowering BP and reducing afterload for treatment of |

| |Essential hypertension |

| |Hypertensive crisis (IV form) |

| |Heart failure |

|ADME |Inactivated by acetylation (genetic trait) |

| |Rapid vs slow acetylators |

|Adverse effects |Reflex tachycardia (baroreceptors) |

| |Increased blood volume |

| |SLE-like syndrome (drug induced Lupus) |

| |6 mo to reverse |

| |Pain, nephritis, fever, joint pain, ANA+ |

|Drug(Drug |Other antihypertensive agents |

| |Combine with Beta blocker to prevent ? |

| |To prevent reflux tachycardia |

|Minoxidil [Loniten] |

|MOA / TE |Selective dilation of arterioles and decreases afterload for the treatment of severe |

| |hypertension. |

| |Used for hair growth |

|Adverse effects |Reflex tachycardia |

| |Increased cardiac oxygen demand |

| |Sodium and water retention |

| |Hypertrichosis - hair |

| |Pericardial effusion |

Other Vasodilators

• ACEs, ARBs, CCBs

• Organic nitrates (NTG)

• Sodium Nitroprusside (Nipride)

– Both venous and arterial

• Sympatholytics

• Nesiritide (Natrecor)

Drugs for Hypertension (Ch. 46)

Types of Hypertension

• Primary (essential) hypertension

• Secondary hypertension

• Review JNC (Joint National Committee on Prevention, Detection and Treatment of Hypertension)

• nhlbi.guidelines/hypertension/express.pdf

Consequences of Hypertension

• Heart disease

– Myocardial infarction (MI)

– Heart failure

– Angina pectoris

• Kidney disease

• Stroke

Pharmacological Treatment/ Therapy

• Meds targeted to affect

• Heart rate

• Myocardial contractility

• Blood volume

• Venous return / resistance

• Individualizing therapy

• Initial Tx: Thiazides (cheap, reduces morbidity, well tolerated)

• Beta Blocker, ACE (renal protective- good for use with ESRD), ARB

• Patients with comorbid conditions

• Renal disease

• Diabetes

• Minimizing adverse effects

• Promoting adherence

• Why difficult to achieve?

• Ways to promote adherence

• Educate patient

• Teach self-monitoring

• Minimize side effects – given med for HTN can cause hypoTN so they need to be careful going from laying down to sitting and sitting to standing

• Establish collaborative relationship

• Simplify regimen

• Other measures

Special populations

• African Americans

– Diuretics / CCBs

– Children and adolescents

– avoid ACEs & ARBs in teenage girls

• The elderly

– Helps prevent stroke / MI

– Beta blockers and diuretics reduce mortality

Drugs for Hypertensive Emergencies

• Sodium nitroprusside (Nipride)

• Fenoldopam

• Labetalol

• Diazoxide

Alpha & Beta Adrenergic Antagonists (Ch. 18)

Therapeutic Effect of Alpha (() Blockade

• Essential hypertension

– Vasodilation

• Reverses toxicity fr (1 agonists (EPI)

– Systemically & extravasation

• Benign prostatic hyperplasia

– ( smooth muscle contraction in bladder neck

• Pheochromocytoma

– Catecholamine secreting tumor

• Severe!!

• Raynaud’s disease

– Vasodilation

|Selective (1 Blocker |

|Prototype: Prazosin (Minipress) |

|MOA / TE |dilates arterioles & veins |

| |relaxes smooth muscle in bladder neck and prostate capsule (off label for BPH) |

|Adverse effects |Orthostatic hypotension (1 % - consciousness – 1st dose – start low – warnings – 1st dose at |

| |night) |

| |Reflex tachycardia - baroreceptor |

| |Inhibition of ejaculation - reversible |

| |Nasal congestion - vasodilation |

|Non-selective (1 & (2 Blockade |

|Prototype: phentolamine (Regitine) |

|MOA / TE |dilates arterioles & veins |

| |relaxes smooth muscle in bladder neck and prostate capsule (off label for BPH) |

| |used for tx of pheochromocytoma and prevent tissue necrosis in extravasation of norepinephrine |

|Adverse effects |Same – has more reflex tachy effect |

Therapeutic Effects of Beta Blockade - the “olols and lols”

• Major effects:

– ( heart rate & (force of contraction

– ( velocity of impulses through AV node

• Therapeutic management of

– *Angina pectoris & Myocardial infarction

– *Hypertension

– *cardiac dysrhythmias

– Heart failure

– Hyperthyroidism, migraine, stage fright

– Pheochromocytoma

– Glaucoma

|Non-Selective |

|Beta (() Blockers |

|Prototype: propranolol (Inderal) |

|MOA / TE |Major effects: |

| |( heart rate & (force of contraction |

| |( velocity of impulses through AV node |

| |Therapeutic management of |

| |*Angina pectoris & Myocardial infarction |

| |*Hypertension |

| |*cardiac dysrhythmias |

| |Heart failure |

| |Hyperthyroidism, migraine, stage fright |

| |Pheochromocytoma |

| |Glaucoma |

|Adverse effects |Bradycardia |

| |AV heart block |

| |*Precipitation of heart failure |

| |Reduced cardiac output |

| |Rebound cardiac excitation w abrupt cessation (ST and VT) |

| |Bronchoconstriction (Beta2) |

| |Blockade of glycogenolysis (Beta2) |

|Precautions / contraindications |Severe allergic conditions |

| |If occurs beta blockade interferes w EPI |

|Diabetes |Compensatory glycogenolyis is impaired |

| |Can mask sxms of hypoglycemia (ST) |

| |Heart failure |

| |AV block |

| |Bradycardia |

| |Asthma |

| |Bronchospasm and depression (crosses easily into CNS) |

|Drug interactions |Calcium channel blockers – esp. verapamil |

| |Insulin – sxms of hypoglycemia |

|Nsg Implications |Taper off gradually |

| |Masking of hypoglycemia reactions |

| |Heart rates: Brady or Rebound tachy |

|Cardioselective Beta1 Blockers |

|Prototype: metoprolol (Lopressor, Toprol) |

|MOA / TE |Beta1 AT THERAPEUTIC DOSES |

| |Global at higher doses |

| |Don’t cause bronchoconstriction – otherwise same as propranolol |

|Adverse effects |same EXCEPT bronchoconstriction and glycgogenolysis |

| |safer in asthmatics and diabetics |

Indirect-Acting Antiadrenergic Agents (Ch. 19)

|Centrally Acting Alpha2 Agonists |

|Prototype: clonidine (Catapres) |

|MOA / TE |decreases release of norEpi, limiting vasoconstriction, therefore lowering blood pressure and |

| |heart rate. Also used in severe pain of cancer |

|ADME |Effects start in 30’ and can last for 24 hrs |

|Adverse Effects |Rebound HTN fr. sudden withdrawal |

| |Drowsiness |

| |Xerostomia (DRY MOUTH) |

| |Embryotoxic |

| |Constipation |

| |Impotence |

| |gynecomastia |

|Administration |PO and patches |

Anticoagulant, Antiplatelet, and Thrombolytic Drugs (Ch. 51)

Review: Physiology & Pathophysiology of Coagulation

• Hemostasis

– Stage 1 - Platelet plug via aggregation

– Stage 2 - Intrinsic & Extrinsic pathways

– Keeping hemostasis under control

– Physiologic removal of clots

• Thrombosis

– Arterial thrombosis

– Venous thrombosis

Parenteral Anticoagulants I: Heparin and Related Drugs

|Prototype: Heparin (unfractionated) |

|MOA / TE / Uses |rapid-acting anticoagulant interfering w Thrombin & Factor to treat; |

| |Pulmonary embolism (PE) |

| |Evolving stroke |

| |Massive deep venous thrombosis (DVT) |

| |Is DANGEROUS |

|ADME |IV only – no po |

|Adverse effects |Hemorrhage |

| |Heparin-induced thrombocytopenia (HIT) – immune response |

| |Hypersensitivity reactions |

| |Long term – osteoporosis |

|Warnings |Hemophilia |

| |PUD |

| |Aneurysm |

| |HTN |

| |Threatened AB |

|Contraindications |Bleeding |

| |Thrombocytopenia |

| |Surgeries of eye, brain, or spine |

|Given in units- 2 nurses must |Intermittent via INT |

|check! |Continuous – loading dose common |

| |Deep subcut – well away from umbilicus |

| |Low-dose pre-op prophylactically |

|Protamine Sulfate |For OD |

|Monitoring |Activated partial thromboplastin time (aPTT) – |

| |Increase from norm (40 sec) 1.5 to 2 times |

| |Above 80 seconds too long |

Low-Molecular-Weight Heparins

|Prototype: enoxaparin (Lovenox) |

|MOA / TE / Uses |Heparin preparations w shorter molecules than unfractionated that selectively inactivates Factor |

| |Xa & used in |

| |Prevention of DVT following surgeries |

| |Treatment of established DVT |

| |Prevention of ischemic complications |

|Benefits of Lovenox over Heparin |Can be fixed dose, can be used at home, less thrombocytopenia |

|Adverse effects and interactions |Bleeding |

| |Immune-mediated thrombocytopenia |

| |Cost |

|Nursing considerations |Hypersensitivity to pork |

Oral Anticoagulants

|Prototype: warfarin (Coumadin) |

|MOA / TE / Uses |Antagonist of vitamin K, blocks biosynthesis of factors VII, IX, X, and prothrombin used in |

| |Long-term prophylaxis of thrombosis |

| |Prevention of VTE and associated PE |

| |Prevention of thromboembolism (in patients with prosthetic heart valves) |

| |Prevention of thrombosis during AF |

|ADME |Longer onset sec. to circulating clotting factors – may be days on & off |

| |Implications for surgery, ok for DDS |

|Adverse effects |Hemorrhage |

| |Teratogenesis (Cat X) |

| |Red-orange urine (not blood) |

| |Alopecia |

|D(D & D(F (Table 51-4) |Drugs that (or( anticoagulant effects |

| |Drugs that promote bleeding: NSAIDs – including acetominphen, Heparin |

| |Foods: broccoli, spinach, dark greens |

|Nursing considerations |Monitoring INR, PT (Table 51-3) |

| |Vit K for OD (po, diluted IV - NO subcut) |

Anti-platelet Drugs

Class is used to prevent arterial thrombosis

|Protoype: acetylsalicylic acid (Aspirin) ASA – she said to review notes on this!! |

|MOA / TE / Uses |Non-selective COX Inh (inhibits cox 1 & 2) |

| |Analgesic, antipyretic, anti-inflammatory |

| |Suppression of platelet aggregation |

| |Irreversible for 8 d – life of platelet |

| |Treat / prevent Ischemic stroke (lack of oxygen), TIA, MIs (acute & old), anginas, adjunct to |

| |angioplasty & revascularization |

| |Helps blood to flow smoothly through vessels (manages angina) |

| |Dysmenorrhea - cramps |

| |Cancer prevention |

| |Prevention of Alzheimer’s disease – but not treatment |

| |An initial DOC for RA and juvenile arthritis |

| |Dose related to use! |

|ADME |Rapidly absorbed orally, slower rectally |

| |Half-life (2 h to 20 h) |

| |Distributes to all body tissues – pregnant? – don’t use if pregnant - contraindicated |

| |Excretion pH dependent (increase pH increase excretion 4x) |

|Side effects |Gastric distress, heartburn, nausea |

|Adverse effects (hidden) |Gastrointestinal – (occult- occult blood in stool) and overt) |

| |Bleeding |

| |Renal impairment – Signs? |

| |acute/reversible – Na+/H2O |

| |Pre-existing condition dependent |

| |Salicylism – acid/base – tinnitis (ringing of the ears –sometimes irreversible) |

| |Reye’s syndrome – liver failure or impact on the liver in children (don’t give aspirin to |

| |children) |

| |Hypersensitivity – asthma – rhinorrhea to shock |

|Contraindications |PUD & Bleeding disorders |

| |Hypersensitivity |

| |Extreme caution in pregnancy |

|D(D |Anticoagulants & other NSAIDs |

| |Glucocorticoids (gastric ulcertion) |

| |Ibuprofen – impairs cardio protective properties |

|Acute Poisoning |LD adult = 20-25 g - LD children = 4 g |

| |Sxms |

| |Resp excitation ( depression ( hyperventilation |

| |Hyperthermia, stupor, coma, death |

| |Treatment |

| |Supportive, charcoal, alkalinization of urine (give them a base) |

| |Dialysis |

| |Hyperthermia – ice packs to arm pits, groin |

|Ticlopidine [Ticlid] & Clopidogrel [Plavix] |

| |Irreversible blockade of ADP-mediated aggregation |

|Adverse effects |Neutropenia / agranulocytosis / thrombotic thrombocytopenic purpura |

Thrombolytic Drugs

|Prototype: Streptokinase [Streptase] |

|MOA / TE |Binds plasminogen to make plasmin to break up clot & is used in |

| |Acute coronary thrombosis (acute MI) |

| |Deep venous thrombosis (DVT) |

| |Massive pulmonary emboli |

|Adverse effects |Bleeding, hypotension |

| |Antibody production, fever |

Drugs for Deficiency Anemias (Ch. 54)

• Anemia—decrease in erythrocytes (RBC)

– Number, Size, Color

– Look in patho unit 4 lectures

• Causes

– Blood loss

– Hemolysis

– Bone marrow dysfunction

– Deficiencies

Iron Deficiency: Oral Treatment

|Prototype: Ferrous sulfate (Feosol) |

|MOA / TE |DOC -restores iron for production of hemoglobin to prevent or relieve symptoms of microcytic |

| |hypochromic anemia |

|ADME |Absorbed fr Fe rich foods, uptake in GI tract, stored by liver |

| |Lose 1 g / d - requirements r/t rate of RBC production - ( pregnancy / menses |

|Adverse effects |GI: N, heartburn, bloating, constipation, & diarrhea |

| |Aggravation of: PUD, regional enteritis, ulcerative & colitis – shouldn’t take p.o. |

| |Dark green / black stools |

| |Liquid form – stains teeth – drink thru straw and avoid teeth all together |

|Toxicity |Leading cause of poison death in kids |

| |Tx: Lavage if tabs in gut / deferoxamine |

|D(D |Antacids – reduce (2 hrs before, 4 hrs after) |

| |Tetracycline - reduce |

| |Ascorbic acid – increases & potentiates adverse effects |

|D(F |Absorbs best w/o food |

| |Foods protect against bad effects |

| |Milk, cereals, dietary fiber, tea, coffee, and eggs, may decrease absorption |

Iron Deficiency: Parenteral Tx

|Prototype: Iron dextran (INFeD) |

|MOA / Use |Indicated when orals don’t work – can’t be absorbed – blood loss is excessive – and GI problems |

|Adverse effects |Anaphylaxis fr. Dextran |

| |Hypotension |

| |Pain / tumors at IM sites – intervention? |

| |[pic] |

|Nursing Implications |Monitor serum Fe for rise of 2 g /dL – goal is 15 g / dL |

| |If unresponsive – monitor for adherence |

| |Therapy possibly for months |

|IV |test dose |

| |25 mg |

| |Monitor 15 min |

|Avoid IM site if possible |Tumors |

| |Greatest risk of anaphylaxis |

| |Prolonged pain / discoloration at site |

Vitamin B12 Deficiency Treatment

|Prototype: Vitamin B12 (Cyanocobalamin) |

|MOA / Uses |provide B12 for synthesis of DNA to alleviate macrocytic anemia, neuro damage, and GI |

| |disturbances from deficiency |

|ADME |A: requires intrinsic factor (IF) |

| |E: very slow – stored ______________ |

| |Routes: PO, IM, deep SubQ, Intranasal |

| |No IV |

|Adverse effects |Secondary hypokalemia |

|Dietary sources |Microorganisms |

| |Animal products (liver, dairy products) |

| |Fortified foods |

|Treatment regimen |Lifelong if Ø IF |

Folic Acid Anemia: Treatment

|Prototype: Folic acid aka folate |

|MOA / Uses |replace vitamin essential for DNA synthesis, replication, cell division to prevent neural tube |

| |defects, colorectal cancers, and treat megaloblastic anemia |

|ADME |A: early segment small intestine |

| |E: Significant amounts daily |

| |Daily requirements |

| |Dietary sources—all foods |

|Treatment |Oral supplementation |

|Monitor Labs | |

Basic Principles of Neuropharmacology (Ch. 12)

Basic Mechanisms of NeuroPharm Actions

• Synapse

– Predominant

• Axonal

– Local anesthetics

– non-selective

• Receptors

– All effects from drugs - direct / indirect (except anesthetics)

Physiology of the Peripheral Nervous System (Ch. 13)

Primary Parasympathetic NS Functions r/t Drugs

1. Slows heart rate

2. Increases gastric secretion

3. Empties the bladder

4. Empties the bowel

5. Focuses eye for near vision

6. Constricts the pupil

7. Contracts bronchial smooth muscle

Primary Sympathetic NS Functions r/t to Drugs

1. Regulates cardiovascular system

– Blood flow to brain, body during exercise & compensation in blood loss

2. Regulates body temperature

– Temp via blood flow to skin, secretion of sweat, “goose pimples” aka piloerection

3. Implements “fight” / “flight”

– (HR, shunts blood to muscles, dilates bronchi & pupils, mobilizes energy stores

ParaSympathetic & Sympathetic Relationship

• Innervation by both in opposition

• Innervation by both in compliment

• Innervation by only one

• Major mechanisms

– Feedback systems

– Baroreceptor reflex – most important

– Autonomic tone – ParaS for most organs

• Exception - vasculature

Neurotransmitters of the Peripheral Nervous System

• Acetylcholine (Ach)

– Employed at most junctions of the peripheral nervous system

• Norepinephrine (NE)

– From postganglionic neurons to sympathetic

• Epinephrine (EPI)

– From the adrenal medulla

– Increased HR and increased pressure

Receptors of the Peripheral Nervous System

• Cholinergic receptors – regulated by Ach

– NicotinicN & release of epi at adrenals

– NicotinicM

– Muscarinic (glandular)

• Adrenergic receptors – regulated by Epi / Norepi

– Alpha1 and alpha2, beta1 and beta2

– Dopamine

– Comes from adrenelin

Receptor Subtypes

• Alpha1 (eyes, vessels, male sex organ, prostatic capsule & bladder)

– Vasoconstriction

– Ejaculation

– Contraction of bladder neck and prostate

• Alpha2 (nerve terminals) – not clinically sign.

– Located in presynaptic junction

– Minimal clinical significance

• Beta1-Adrenergic Receptor Subtypes

– Kidney

• Renin release

– Heart

• Increase rate

• Increase force of contraction

• Increase velocity of conduction of AV nodes

• Beta2-Adrenergic

– Various effects

• Bronchial dilation

• Relaxation of uterine muscle

• Vasodilation

• Glycogenolysis

– Dopamine

• Dilates renal blood vessels

• Receptor Subtypes

Specificity of Adrenergic Neurotransmitters

• Epinephrine

– Activates all alpha & beta receptors

– Does NOT activate dopamine receptors

• Norepinephrine

– Activates alpha1 & 2 and beta1

– Does NOT activate beta2 or dopamine receptors

• Dopamine

– Only transmitter that can activate dopamine receptors

– Activates alpha1, beta1, and dopamine receptors.

Muscarinic Agonists and Antagonists (Ch. 14)

Muscarinic Agonists

|Prototype: Bethanechol (Urecholine) |

|MOA / Uses |binds reversibly to muscarinic cholinergic receptors to activate and selectively produce effects |

| |on the |

| |Heart ((HR) |

| |Exocrine glands ((sweating, salivation, bronchial secretions, gastric acid) |

| |Smooth muscles (constriction of bronchi & ( tone & motility of GI tract) |

| |Contraction of detrusor – relaxation of trigone/sphincter |

| |Eye (miosis and accommodation) |

|Principle indication |Urinary retention |

|Adverse effects |Hypotension and bradycardia |

| |Bloating, cramps, hypersecretions of acid, involuntary defecation |

| |Bladder rupture in persons with urinary tract obstruction or weak bladder wall |

| |Bronchoconstriction |

| |Dysrhythmias in hyperthyroid |

Muscarinic Antagonist: Atropine

|Prototype: atropine (Sal-Tropine) |

|MOA / TE |Competitive blocking of Ach at muscarinic receptors to treat the following: |

| |Pre-anesthetic medication |

| |Disorders of the eye (surgery) |

| |Bradycardia |

| |Intestinal hypertonicity and hypermotility |

| |Muscarinic agonist poisoning (WMDs) |

| |Peptic ulcer disease (Not DOC) |

| |Asthmas (Not DOC) |

| |Biliary colic |

| |Increase HR |

| |Decrease secretions from glands |

| |Relaxation of bronchi, decrease bladder tone, decrease GI motility |

| |Dilation of pupil and focus for far vision |

| |High doses can cause CNS excitation and ultimately death |

|Adverse Effects |Xerostomia (dry mouth) |

| |Blurred vision, photophobia |

| |( intraocular pressure (glaucoma) |

| |Urinary retention |

| |Constipation |

| |Anhidrosis (no sweating) |

| |Tachycardia |

| |Thick bronchial secretions |

|D(D |Antihistamines |

| |Phenothiazine antipsychotics |

| |Tricyclic antidepressants |

[pic]

Too high = Death

Anticholinergics for OAB

|Prototype: oxybutynin (Ditropan) |

|MOA / TE |Partially selective for M3 receptor blocking to target bladder detrusor and alleviate sxms |

| |associated with urge incontinence & urinary frequency |

|Adverse effects |like those of Atropine |

| |DRY mouth, constipation, impaired vision |

|Antidote |Physostigmine – Charcoal |

Other Anticholinergics

|Scopalamine |Like atropine – except: sedative, antiemetic |

|Ipratropium Bromide (Atrovent) |Inhaled – so fewer SE (dryness, etc) |

Drugs for Epilepsy (Ch. 24)

Antiepileptic Drugs

• Effects

– Suppress discharge of neurons at focus

– Suppress propagation of seizure activity from focus to other areas of brain

• Mechanisms of action

– Suppress sodium influx – reversible binding

– Suppress calcium influx

– Antagonize glutamate – excitatory transmitter

– Potentiate GABA – an inhibitory transmitter

Epilepsy: Therapeutic Considerations

• Diagnosis and drug selection

• Drug evaluation – seizure freq. chart

• Non-drug therapy

– Neurosurgery (best success rate)

– Vagal nerve stimulation

– Ketogenic diet

• Monitoring plasma drug levels

– Traditional AEDs

• Promoting patient adherence

• Withdrawing antiepileptic drugs

Classification of Antiepileptic Drugs

• Traditional antiepileptic drugs (AEDs)

– Phenytoin (Dilantin)

– Carbamazepine (Tegretol)

– Valproic acid (Depakote)

– Phenobarbital

• Newer AEDs

– Oxcarbazepine, gabapentin, zonisamide, and others

|AED: Phenytoin [Dilantin] |

|MOA / Uses |Selective inhibition of sodium channels to suppress cerebral irritability to treat partial and |

| |tonic-clonic seizures & selected cardiac dysrhythmias |

|ADME |Varied oral absorption |

| |Half-life 8 to 60 hours |

| |Metabolism variance |

| |Blood levels (10 mcg/mL) |

|Adverse effects |Nystagmus, diplopia |

| |Sedation |

| |Ataxia - gait |

| |Cognitive impairment |

| |Gingival hyperplasia – floss / gum massage |

| |Skin rash – stop therapy (Stevens-Johnson) |

| |Effects in pregnancy - teratogen |

| |Cardiovascular effects – IV use in SE, heart blocks |

|D(D |Phenytoin decreases effects of |

| |oral contraceptives, warfarin (Coumadin), and glucocorticoids |

| |Drugs that increases phenytoin levels:\ |

| |diazepam (Valium), isoniazid, cimetidine (Tagamet), alcohol (acute), valproic acid (Depakote) |

| |Drugs that decrease phenytoin levels |

| |Carbamazepine, phenobarbital, chronic ETOH |

|ADME |Administration: po with food |

| |IV – slowly! – compatibility issues |

|Additional Nsg considerations |Driving |

| |Hazardous work |

|AED: Carbamazepine [Tegretol] |

|MOA / Uses |Much like phenytoin & used to treat epilepsy (not absence), Bipolar disorder, trigeminal and |

| |glossopharyngeal neuralgias – minimal effects on cognitive function |

|Adverse effects |Nystagmus, ataxia, HA, blurred vision, vertigo |

| |Leukopenia, anemia, thrombocytopenia |

| |Hypo-osmolarity – water excretion |

| |Rash, photosensitivity reactions & teratogenic |

|D(D |Decreases effect of warfarin and contraceptives |

| |Is decreased by phenobarbital |

| |Is increased by grapefruit |

|Nsg Considerations |Minimal cognitive impairment effects |

| |Tolerance to other SE develops |

|AED: Valproic Acid [Depakote] |

|MOA / Uses |Seizure disorders (all) – including absence seizures, Bipolar disorder, & migraine |

|Adverse effects |GI effects |

| |Hepatotoxicity: liver failure |

| |Pancreatitis |

| |Teratogenic effects |

|AED: Phenobarbital |

|MOA / Uses |known since 1912 – potentiates GABA |

| |Epilepsy (partial and generalized tonic-clonic seizures) |

|Adverse effects |Promotes sleep and sedation |

| |Physical dependence |

| |Rickets, osteomalacia |

Newer Antiepileptic Drugs

|Prototype: oxcarbazepine (Trileptal) |

|MOA / Uses |Blocks sodium channels and is indicated for monotherapy & adjunctive therapy of partial seizures |

| |in children & adults |

|Adverse effects |better tolerated than Tegretol |

| |Dizziness, drowsiness, nystagmus, HA |

| |Hyponatremia |

| |Skin reactions – Stevens-Johnson |

|Gabapentin (Neurontin) |

|MOA / Uses |May increase production of GABA. Approved for partial seizures & post-herpetic neuralgia. |

| |80% of use is off-label (Neuropathic pain & Migraine prophylaxis). Well tolerated. |

|Adverse effects |Somnolence, dizziness, ataxia, fatigue, nystagmus & peripheral edema |

Management of SE

• Medical emergency

– ETOH story

• IV meds

– Benzodiazepine (Ativan or Valium)

• Oral management once controlled

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