SCO Pharmacology II

  1. What is Heart Failure?
    • Progressive disease
    • heart is unable to pump enough blood to meet body's needs
  2. What are the symptoms of heart failure?
    • Dyspnea (shortness of breath)
    • Fatigue
    • Fluid retention
  3. Pharmacokinetics
    • What happens to a drug as it passes through the body
    • cause of variability seen between patinets
    • can be affected by disease states
  4. Four entitied of Pharmacokinetics
    • Absorption
    • Distribution
    • Metabolism
    • Excretion
  5. Pharmacokinetics: Excretion
    • —Describes
    • how drug enters the body

    • —Mouth,
    • IM injection, subdermal
    • injection, inhalation, sublingual, etc.

    • —Route
    • of administration affects bioavailability

    • —IV
    • drugs have 100% bioavailability

    • —First-pass
    • effect

    • —Drugs
    • absorbed via GI tract are often significantly changed by the liver before
    • reaching circulation
  6. Pharmacokinetics: Distribution
    • —Transfer
    • of drug from one body compartment to another

    • —Volume
    • of distribution (Vd)

    • —Vd =
    • amount of drug in the body/concentration in plasma

    • —Lower
    • Vd =
    • safer medication (more in plasma)

    • —Vd can
    • be increased with liver and kidney disease and decreased by dehydration
  7. Pharmacokinetics: Metabolism
    • —Chemical
    • modification of drugs in the body

    • —Can
    • either make drug more active or easier to eliminate

    • —Phase
    • I

    • —Involves
    • the liver’s cytochrome
    • P-450 system

    • —Many
    • P-450 enzymes

    • —One
    • drug may compete with another

    • —Phase
    • II

    • —Aids
    • in elimination
  8. Pharmacokinetics: Exretion
    • —Physical
    • removal of drug from body

    • —Primarily
    • through kidney

    • —Most
    • eliminated by first-order kinetics

    • —Constant
    • fraction eliminated per unit of time

    • —Half-life:
    • the amount of time it takes for half of the drug to be eliminated from the body

    • —Usually
    • takes 4-5 half-lives to totally eliminate a drug

    • —Zero-order
    • kinetics

    • —Constant
    • amount eliminated per unit of time

    • —If
    • concentration doubles, amount of time to eliminate doubles

    • —Ex.
    • Alcohol
  9. Pharmacodynamics
    The effect of the drug on the body
  10. Effective dose
    amount of drug needed to produce a therapeutic effect
  11. Toxic dose
    amount of drug required to produce adverse symptoms
  12. Therapeutic Index (TI)
    • compares toxicity between drugs
    • higher TI = safer medication
  13. Potency
    the amount of drug required to produce an effect
  14. Efficacy
    the strength of the effect of a drug
  15. Affinity
    a drug that binds to a receptor and stimulates cellular activity
  16. Antagonist
    a drug that binds to a receptor and blocks their activation
  17. Receptor
    • Any macromolecule in the body to which a drug must bind to achieve its effects
    • - can be molecules, cell membrane proteins, intracellular proteins, or nucleic acids
    • "lock and key"
  18. Autonomic Nervous System Pharmacology
    • Involves automatic, unconscious, and involuntary bodily activities
    • - digestion
    • - cardiac output
    • - blood flow
    • - glandular secretions
  19. Parasympathetic phase of ANS pharmacology
    • exhalation
    • bronchi constrict
    • carbon dioxide transfers out of bloodstream
    • hearbeat rate decreases
    • arterial pressure decreases
    • arterial blood flow decreases
    • arterial relaxation/elastic contraction
    • peripheral arterial pressure decreases
    • venous blood flow decelerates
    • venous reservoirs empty
  20. Sympathetic Phase of ANS Pharmacology
    • inhalation
    • bronchi dilate
    • oxygen transfers into bloodstream
    • heartbeat rate increases
    • arterial pressur increases
    • arterial blood flow increases
    • arterial constriction/elastic distention
    • peripheral arterial pressure increases
    • venous blood fow accelerates
    • venous reservoirs fill
  21. ANS Neurotransmitters
    • Preganglionic neurons transmit acetocholine
    • adrenal medulla accepts acetocholine and transmits epinephrine into blood to adrenergic receptors
    • postganglionic neurons accept acetocholine and transmit either norepinephrine or acetocholine to adrenergic receptor organs or muscarinic receptor organs respectively
  22. Cholinergic Agonists
    • stimulate parasympathetic system
    • - direct acting (bind directly to receptors)
    • -- acetylcholine, pilocarpine, bethanechol, carbachol
    • -indirect acting (inhibit acetylcholine re-uptake or breakdown
    • -- demecarium, echothiophate, physostigmine, pyridostigmine, isoflurophate, neostigmine
    • -- Endrophonium used in diagnosis of myasthenia gravis
  23. Cholinergic Antagonists
    • Counter effects of parasympathetic system
    • -scopolamine (used to treat motion sickness)
    • -tropicamide
    • -atropine
    • -homatropine
    • -cyclopentalate
    • can be either nicotinic antagonists or muscarinc antagonists
  24. Adrenergic Agonists
    • Stimulate sympathetic system
    • -Alpha 1 and Alpha 2 receptors
    • -Beta 1 and Beta 2 receptors
    • Drugs can be specific or non-specific
  25. Metaproterenol
    (Adrenergic Agonists)
    • Beta 2 agonist
    • bronchodilator - used for asthma treatment
  26. Clonidine (Adronergic Agonist)
    • Alpha 2 agonist
    • decreases vascualr resistance and heart rate
    • common treatment for hypertension
  27. Albuterol
    (Adrenergic Agonists)
    • B2>B1
    • used in treatment of asthma and COPD
  28. Phenylephrine (Adrenergic Agonist)
    • A1>A2
    • used topically for pupil dilation
    • -stimulates dilator muscle
  29. Epinephrine
    (Adrenergic Agonists)
    non-selective Alpha and Beta
  30. Alpha Blockers
    (Adrenergic Antagonists)
    • prazosin, doxazosin, terazosin, alfuzosin, tamsulosin
    • -used to treat hypertension and BPH
    • -use caution with cataract surgery
  31. Beta Blockers
    (Adrenergic Antagonists)
    • labetolol, propranolol, atenolol, metoprolol
    • -used mainly to treat hypertension
    • -many side effects -- depression, decrease HR, bronchospasm, nausea, impotence
  32. Neurotransmitters
    • signals in the brain are carried from neuron to neuron by neurotransmitters
    • -CNS diseases are caused by either too much or too little neurotransmission
    • Major Neurotransmitters:
    • norepinephrine
    • dopamine
    • serotonin
    • acetylcholine
    • GABA
    • glutamate
    • opioids (endorphins, enkephalins, dynorphins)
  33. Depression
    thought to be caused by scarcity of NE, dopamine, or serotonin transmission
  34. Mania
    thought to be caused by excessive transmission of NE, dopamine, or serotonin
  35. Bipolar Disorder
    dramatic changes from depression to mania
  36. Tryclic Antidepressants
    • block reuptake of NE, dopamine, and serotonin
    • Ex: amitriptyline, imipramine
  37. Monoamine Oxidase Inhibitors (MAOIs)
    • blocks metabolims of NE, dopamine, and serotonin
    • Ex: phenelzine
  38. Serotonin Uptake Inhibitors
    • selective for seotonin
    • Ex: fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil)
  39. Antipsychotics
    • the exact cause of psychosis is unknown but it is believed to be related to excessive dopamine neurotransmission
    • -successful treatment aimed at blocking dopamine receptors
    • because dopamine is an inhibitory neurotransmitter, side effects of treatment include:
    • -spasms (dystonia), parkinsonism, rigidity, restlessness
    • Ex: chlorpromazine (Thorazine), thioridazine
  40. Anti-Parkinson Drugs
    • Caused by decreased dopamine transmission/ degredation of neurons
    • treatment aimed at increasing dopamine transmission
    • Ex: levodopa, bromocriptine, selegeline, amantadine
  41. Anxiolytics and Sedatives
    • enhance actions of GABA
    • barbiturates
    • -cause retention of GABA at receptor
    • -Ex: phenobarbital
    • Benzodiazepines
    • -enhance action of GABA
    • -Ex: diazepam (Valium), alprazolam (Xanax)
    • Zolpidem (Ambien)
    • -mimics bensodiazepines
  42. Anticonvulsants
    • siezures caused by hyperactivity of neurons in the brain
    • Ex: phenytoin (Dilantin)
    • -reduces sodium, calcium, and potassium currents
    • can also treat w/ barbituates and/or benzodiazepines
  43. Analgesics
    • used for pain relief
    • Opioids
    • -mimic actions of endorphins, enkephalins, and dynorphins
    • -do NOT block pain signal
    • -Ex: morphine, codeine, oxycodone, tramadol
    • Non-opioids
    • -Acetaminophen (Tylenol)
    • --MOA not understood
    • --NOT an anti-inflammatory drug
  44. General Anesthetics
    • Used for sedation, muscle relaxation, and analgesia
    • inhalation only - MOA unknown
    • Ex: thiopental, propofol
  45. Local Anesthetics
    • block pain conduction by decreasing Na permeability
    • -action potential cannot be generated
    • topical or injection
    • Ex: lidocaine, bupivacaine, procaine, tetracaine
    • often combined with epinephrine
    • -causes vasoconstriction
  46. Arrhythmia
    • •The
    • heart contains specialized cells that intrinsically generate action potentials

    • –Absence
    • of external stimuli

    • •Spontaneous
    • depolarization is caused by inward positive current carried by sodium and
    • calcium ion flow

    • •Dysfunction
    • of impulse generation OR conduction can cause abnormality in cardiac rhythm
  47. Arrhythmia Disorders
    • Bradycardia - heart beats too slowly
    • Tachycardia - heart beats too rapidly
    • "sinus" - regular beat
    • fibrillation - irregular beat
    • often named after cavity it originates in
    • -Ex: "atrial fibrillation"
  48. Causes of Arrythmia
    –Abnormal Automaticity

    •SA node = “pacemaker”

    •If sites other than SA node show enhanced automaticity, they may generate competing stimuli

    •If myocardial cells are damaged, they may remain partially depolarized

    –Reach firing threshold earlier


    –Drugs block either Na or Ca channels to reduce the ratio to K

    –Decreases the frequency of discharge

    –Abnormal impulse conduction

    •Block of nerve impulse can cause “short-circuit”

    –Reentry defect

    –Premature contraction


    –Prevent reentry by slowing conduction and/or increasing the refractory period

    »Converts a unidirectional block into a bidirectional block
  49. Arrhythmia Treatment
    –Aim of drug therapy is to modify impulse generation and conduction

    –Only certain drugs are useful in certain types of arrhythmias

    •Some can actually cause arrhythmia in certain situations

    •Implantable defibrillators are becoming more widely used
  50. Antiarrhythmic Drug Classification
    •Classified according to predominant effects on the action potential

    • •Class I (A, B, and C)
    • –Na channel blockers

    • •Class II
    • –Beta blockers

    • •Class III
    • –K channel blockers

    • •Class IV
    • –Ca channel blockers
  51. Antiarrhythmic Class IA Drugs
    • Na+ channel blocker
    • Slows Phase 0 depolarization in ventricular muscle fibers
    • slows conduction
    • prolongs action potential
    • increases refractory period
  52. Antiarrhythmic Class IB Drugs
    • Na+ channel blocker
    • Shortens Phase 3 depolarization in ventricular muscle fibers
    • shortens repolarization
    • -decreases duration of action potential
    • --less risk of inducing arrhythmia
    • -rapidly associat and dissociate from Na+ channels
    • --useful for emergency treatment
  53. Antiarrhythmic Class IC Drugs
    • Na+ channel blocker
    • Markedly slows Phase 0 depolarization in ventricular muscle fibers
    • -little effect on duration of action potential or refractory period
    • slowly dissociate from resting Na+ channels
    • --show prominent effects even at normal heart rates
  54. Antiarrhythmic Class II Drugs
    • Beta-Adrenoreceptor blocker
    • Inhibits Phase 4 depolarization in SA and AV nodes
    • -depresses automaticity
    • -decrease heart rate and contractility
    • useful in treating arrhythmias caused by increased sympathetic activity
  55. Antiarrhythmic Class III Drugs
    • K+ channel blocker
    • Prolongs Phase 3 repolarization in ventricular muscle fibers
    • -do not alter phase 0 or resting membrane potential
    • -prolong effective refractory period
    • all have potential to induce arrhythmias
  56. Antiarrhythmic Class IV Drugs
    • Ca2+ channel blocker
    • Inhibits action potential in SA and AV nodes
    • -results in decreased rate of phase 4 spontaneous depolarization
    • -bind only to open, depolarized channels
    • --prevent repolarization
    • --block most effectively when heart is beating rapidly
    • --slow conduction and prolong the effective refractory period
  57. quinidine
    (Class IA antiarrythmic drug)
    • rapidly and completely absorbed after oral administration
    • extensive metabolism by CP450 enzymes
    • -forms active metabolites
    • adverse effects
    • -development of arrhythmia
    • -GI disturbances
    • -blurred vision
    • also shows alpha blocking activity
    • increases steady-state concentration of digoxin
    • -displaces from tissue-binding sites
    • -decreases renal clearance
  58. procainamide
    (Class IA antiarrythmic drug)
    • Derivative of procaine
    • short half-life
    • metabolites show class III activity
    • -can cause arrhythmia
    • lupus-like syndrome develops in 20-30% of patients
    • fewer GI effects than quinidine
    • CNS side effects
  59. disopyramide
    (Class IA antiarrythmic drug)
    • similar actions to quinidine
    • half is excreted unchanged by kidneys
    • metabolite is less active
    • similar side effects to anticholinergic:
    • dry mouth
    • urinary retention
    • blurred vision
    • constipation
  60. lidocaine
    (Class IB antiarrythmic drug)
    • also local anesthetic
    • little effect on atrial or AV junction arrhythmias
    • -does not slow conduction
    • given IV due to extensive first-pass transformation
    • large therapeutic index
    • mild CNS side-effects
  61. mexiletine
    (Class IB antiarrhythmic Drugs)
    • similar to lidocaine
    • can be given orally
    • mexiletine often used after MI
    • tocainide has pulmonary toxicity
  62. flecainide
    (Class IC antiarrhythmic Drug)
    • absorbed orally
    • minimal biotransformation
    • laong half-life
    • adverse effects:
    • -dizziness
    • -blurred vision
    • -headache
    • -nausea
    • -can induce arrhythmia
  63. propafenone
    (Class IC antiarrhythmic Drug)
    • slows conduction in ALL cardiac tissues
    • -considered "broad spectrum" antiarrhythmic
    • similar to flecainide
  64. propranolol
    (Class II antiarrhythmic Drug)
    • reduces incidence of sudden arrhythmic death after MI
    • significantly reduces mortality rate in first year after heart attack
  65. metoprolol
    (Class II antiarrhythmic drug)
    • most widely used beta-blocker to treat cardiac arrhythmias
    • reduces the risk of bronchospasm
  66. esmolol
    (Class II antiarrhythmic drug)
    • short acting
    • used IV to treat arrhythmias that occur during surgery or in emergency situations
  67. amiodarone
    (Class III antiarrhythmic drug)
    • complex drug (shows class I, II, III, and IV actions
    • has some antianginal activity
    • therapy of choice for atrial fibrillation
    • most commonly prescribed antiarrhythmic!!!
    • Pharmacokinetics:
    • -incompletely absorbed
    • -half-life of several weeks
    • --full clinical effects may not be achieved until 6 weeks after starting treatment
    • Adverse effects
    • -often causes discontinuation of treatment
    • -interstitial pulmonary fibrosis
    • -GI intolerance
    • -Tremor, ataxia, dizziness
    • -blue skin discoloration
    • -NAION and whorl keratopathy
  68. dronedarone
    (Class III antiarrhythmic drug)
    • amiodarone derivative
    • shorter half-life
    • fewer side effects
    • -mainly GI
  69. sotalol
    (Class III antiarrhythmic drug)
    • also has potent beta blocker activity
    • lowest rate of acute or long-term adverse effects
  70. dofetilide
    (Class III antiarrhythmic drug)
    • high risk of pro-arrhythmia
    • can only be prescribed after specific manufacturer's training session
    • 10 hr half life
    • 80% of drug is eliminated unchanged
  71. verapamil
    (Class IV antiarrhythmic drug)
    • also used to treat hypertension and angina
    • Pharmacokinetics:
    • -absorbed well after oral administration
    • -verapamil is extensively metabolized by the liver
    • --caution in hepatic dysfunction
    • Adverse effects:
    • -have negative inotropic properties
    • contraindicated in patients w/ depressed cardiac function
  72. digoxin
    (other antiarrhythmic drug)
    • shortens refractory period in atrial and ventricular myocardia cells while prolonging the effective refractory period
    • -diminishes conduction velocity in the AV node
    • used to control the ventricular response rate in atrial fibrillation
    • can cause ventricular tachycardia and fibrillation at high concentrations
  73. adenosine
    (other antiarrhythmic drug)
    • naturally occuring nucleoside
    • decreases conduction velocity, prolongs refractory period, and decreases AV automaticity at high doses
    • short duration of action
    • -used to treat acute supraventricular tachycardia
  74. Cuases of Heart Failure
    • –Arteriosclerotic heart disease
    • –Myocardial infarction
    • –Hypertension
    • –Valvular heart disease
    • –Dilated cardiomyopathy
    • –Congenital heart disease
    • --Left systolic dysfunction secondary to coronary artery disease is most common cause (70% of all cases)
    • more people survive heart attacks, so more people diagnosed with heart failure...
  75. Heart Failure Overview
    • •HF is due to an impaired ability of the heart to adequately fill with and/or eject
    • blood
    • –Often accompanied by abnormal increases in blood volume and interstitial fluid
    • •Often referred to as “Congestive Heart Failure”
    • –Pulmonary congestion in left HF
    • –Peripheral edema in right HF
  76. Pathophysiology of Heart Failure
    • angiotensinogen is converted to angiotensin by the enzyme renin
    • -renin secretion is increased through beta stimulation and decreased through alpha stimulation
    • angiotensin causes the release of aldosterone
    • -aldosterone causes Na+ retention
    • --increased blood volume and increased BP
    • chronic activation of sympathetic nervous system and release of aldosterone is associated w/ remodeling of cardiac tissue
    • -loss of myocytes
    • -hypertrophy
    • -fibrosis
    • the heart becomes more spherical
    • -less efficient pump
    • -prompts additional sympathetic activation
  77. Goals of pharmacological intervention in Heart failure
    • alleviate symptoms
    • slow progression
    • improve survival
  78. Effective drug classes for heart failure
    • inhibitors of renin-angiotensin system
    • beta blockers
    • diuretics
    • vasodilators
    • intropic agents
    • aldosterone antagonists
    • One or more drug classes may be used in treatment
  79. Benefits of treatment in Heart Failure
    • reduced load on heart
    • decreased extracellular fluid volume
    • improved cardiac contractility
    • slower rate of cardiac remodeling
  80. Physiology of Muscle contraction
    • •Myocardium responds to stimulation by depolarization of the membrane
    • –Leads to shortening of the contractile proteins and then relaxation
    • –Respond to stimuli as a unit
    • •Cardiac muscle cells are interconnected in groups
  81. Action Potential (muscle contraction)
    • cardiac muscle cells are electrically excitable
    • show spontaneous, intrinsic rhythm
    • -generated by "pacemaker" cells
    • --located in sinoatrial (SA) and atrioventricular (AV) nodes
    • have long action potential
    • -five phases
  82. Phase 0 of Cardiac contraction action potential
    • Na+ channels open resulting in a fast, inward current
    • upstroke ends as Na+ channels are rapidly inactivated
    • Na+ current is blocked by antiarrhythmic agents, such as quinidine
  83. 18
Card Set
SCO Pharmacology II
Test 1, Heart and blood stuff