Core Concepts in Pharmacology Second Edition

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Drugs for Seizures
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Epilepsy - Recurrence of Seizures

• Symptoms depend on type of seizure
• Include blackout, fainting spells, sensory
  disturbances, jerking body movements, temporary
  loss of memory

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Seizures - Disturbances of Electrical Activity in
the Brain

• May affect consciousness, motor activity,
  sensation
• Caused by abnormal or uncontrollable neuronal
  discharges in the brain
• Electroencephalogram (EEG) measures this activity
• All seizures are not convulsions

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Convulsions - Involuntary, Violent Spasms of
Large Skeletal Muscles

• Face, neck, arms, and legs
• All convulsions are seizures

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Causes of Seizure Activity

• Acute Infectious Diseases
• Trauma
• Metabolic Disorders
• Vascular Disorders
• Respiratory hypoxia, in oxygenation
• Hypotension
• Pediatric Disorders - Rapid Increase in Body
  TemperatureNeoplastic Disease - Rapidly Growing
  Brain Tumors

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Continued

• Medications
• Eclampsia During Pregnancy
• Low Tolerance to Environmental Triggers
• Sleep deprivation
• Exposure to strobe or flickering lights
• Small fluid and electrolyte imbalances
• Idiopathic - No Known Cause

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Atonic Seizures

• Last for seconds
• Patient stumbles or falls for no reason

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Tonic-Clonic Seizures - Most Common Type in All
Age Groups

• Last 1 to 2 minutes
• Preceded by an aura - a warning
• Described as a spiritual feeling
• A flash of light
• Special noise
• Tonic phase - intense muscle contractions
• Hoarse cry - air forced from lungs
• Temporary loss of bladder and bowel control
• Breathing shallow or stops momentarily

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Drugs that Reduce Seizure Activity by
Intensifying GABA Action

• Examples
• Barbiturates - phenobarbital (Luminal),
  amobarbital (Amytal)
• Benzodiazepines - clonazepam (Klonopin),
  clorazepate (Tranxene), diazepam (Valium)
• Miscellaneous drugs - gabapentin (Neurontin),
  tiagabine (Gabitril)

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Succinimides Delay the Influx of Calcium into the
Neuron

• Examples - ethosuximide (Zarontin)
• Mechanism of action - block calcium channels in
  neuron membrane which increases the electrical
  threshold of neurons which decreases abnormal
  firing of neurons
• Primary uses - absence seizures, myoclonic
  seizures, akinetic epilepsy
• Adverse effects - hiccups, epigastric pain,
  drowsiness, increased bleeding time

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Drugs for Coagulation Disorders
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Coagulation-Modifier Drugs

• Anticoagulants
• Thrombolytics
• Hemostatics

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Anticoagulants - Prevent the Formation of Clots

• Inhibiting specific clotting factors in the
  coagulation cascade
• Diminishing the clotting action of platelets
• Both ways increase the time to form clots

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Thrombolytics

• Dissolve life-threatening clots

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Hemostatics

• Promote formation of clots
• Inhibit removal of fibrin

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Anticoagulants Prevent the Formation and
Enlargement of Clots

• Examples - heparin (Heplock), warfarin (Coumadin)
• Mechanism of action - inhibit specific clotting
  factors which interfere with coagulation cascade
  in order to prevent formation or enlargement of
  clot
• Primary use - thromboembolic disease prevent
  formation of clots in veins
• Adverse effects - abnormal bleeding

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Antiplatelet Agents Prolong Bleeding Time by
Interfering with Platelet Aggregation

• Example - ticlopidine (Ticlid)
• Mechanism of actions
• Aspirin inhibits thromboxane2, which prevents
  aggregation of platelets
• ADP receptor blockers interfere with platelet
  plasma membrane, which prevents platelet
  aggregation
• Glycoprotein IIb/IIIa inhibitors glycoprotein
  IIb/IIIa enzyme inhibited which prevents platelet
  aggregation

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Thrombolytics Are Used to Dissolve Existing Clots

• Example - alteplase (Activase)
• Mechanism of action - convert plasminogen to
  plasmin which causes fibrin to degrade, then
  preexisting clot dissolves
• Primary uses - acute MI, pulmonary embolism,
  acute ischemic CVA, DVT, arterial thrombosis,
  coronary thrombosis, clear thrombi in
  arteriovenous cannulas and blocked IV catheters
• Adverse effects - abnormal bleeding
  contraindicated in patients with active bleeding
  or recent trauma

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Hemostatics Are Used to Promote the Formation of
Clot

• Example - aminocaproic (Amicar)
• Mechanism of action - prevent fibrin from
  dissolving, which enhances stability of the clot
• Primary use - prevent and treat excessive
  bleeding from surgical sites
• Adverse effects - none listed

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Disorders Associated with Heart Failure

• Mitral stenosis
• Myocardial infarction
• Chronic hypertension
• Coronary artery disease
• Diabetes

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First-Choice Drugs - ACE Inhibitors and Diuretics

• Given first
• Reduce most symptoms of mild to moderate heart
  failure
• Fewer side effects

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Second-Choice Drugs - Phosphodiesterase
inhibitors, vasodilators, and beta-adrenergic
blockers

• Used in severe heart failure
• First-choice drugs not effective

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Nonpharmacological Methods for Controlling Heart
Failure

• Stop using tobacco
• Limit salt (sodium) intake and eat foods rich in
  potassium and magnesium
• Limit alcohol consumption
• Implement a medically supervised exercise plan
• Learn and use effective ways to deal with stress
• Reduce weight to an optimum level
• Limit caffeine consumption

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Cardiac Glycosides Increase the Force of
Myocardial Contraction

• Example - digoxin (Lanoxin)
• Mechanism of action - 1) positive inotropic
  effect more blood ejected per beat leads to
  increased cardiac output in order to meet, the
  metabolic demands of tissues 2) slow electrical
  conduction through the heart, which creates fewer
  beats per minute and decreases heart rate

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ACE Inhibitors Have Become First-Line Drugs for
Heart Failure

• Example - lisinopril (Prinivil)
• Mechanism of action - blocks ACE enzyme, which
  lowers blood pressure, increases cardiac output,
  decreases preload and reduces peripheral edema
  increased excretion of sodium and water leads to
  decreased blood volume
• primary use - heart failure and hypertension
• Important adverse effects - elevated potassium
  levels, cough, taste disturbances, hypotension

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Diuretics Relieve Symptoms of Heart Failure by
Reducing Blood Volume

• Example - furosemide (Lasix)
• Mechanism of action - prevents reabsorption of
  sodium by the nephron of the kidney, which
  increases excretion of sodium and water
  decreases blood volume, edema, and congestion
  lowers blood pressure, and reduces workload on
  heart. Cardiac output then increases
• Primary use - acute heart failure
• Important adverse effects - electrolyte imbalances

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Phosphodiesterase Inhibitors Are Used for
Short-Term Therapy of Advanced Heart Failure

• Example - milrinone (Primacor)
• Mechanism of action - blocks phosphodiesterase
  enzyme, which increases the amount of calcium
  available for myocardial contraction, which then
  increases force of contraction and vasodilation
• Primary use - short-term support of advanced
  heart failure
• Important adverse effects - ventricular
  dysrhythmia

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Vasodilators Reduce Symptoms of Heart Failure by
Decreasing Cardiac Oxygen Demands

• Example - Isosorbide (Isordil)
• Mechanism of action - relaxes vascular smooth
  muscle, which leads to vasodilation, which
  decreases cardiac workload and increases cardiac
  output
• Primary use - cannot tolerate ACE inhibitors,
  angina pectoris, hypertension
• Important adverse effects - headache,
  hypotension, reflex tachycardia

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Beta-Adrenergic Blockers Are Used in Combination
with Other Drugs to Slow the Progression of Heart
Failure and to Prolong Patient Survival

• Example - carvedilol (Coreg)
• Mechanism of action - blocks beta1, beta2, and
  alpha1 receptors, which decreases heart rate and
  blood pressure, decreases afterload, and reduces
  the workload on the heart

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Beta-Adrenergic Blockers Are Used in Combination
with Other Drugs to Slow the Progression of Heart
Failure and to Prolong Patient Survival (contd)

• Primary use - slow progression of heart failure
  and increased exercise tolerance when combined
  with other heart failure drugs
• Important adverse effects - worsen heart failure

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Hyperlipidemia - Excess Amounts of Lipids in the
Blood

• Major risk factor for cardiovascular disease
• Hypercholesterolemia
• Saturated fats

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Three Basic Classes of Lipids

• Triglycerides
• Steroids
• Phospholipids

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Three Most Common Lipoproteins, Based on Weight
or Density

• Low-density lipoproteins (LDL)
• High-density lipoproteins (HDL)
• Very low-density lipoproteins (VLDL)

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Low-density Lipoproteins (LDL)

• Highest amount of cholesterol
• Created in liver
• Build plasma membranes and produce steroids
• Stored in tissues
• Contribute to plaque deposits and CHD
• Aka bad cholesterol

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High-Density Lipoproteins (HDL)

• Picks up cholesterol
• Returns it to the liver
• Becomes part of bile and excreted in feces
• Aka good cholesterol

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Very Low-Density Lipoproteins (VLDL)

• Triglyceride carrier
• Converted to LDL in blood
• High levels are associated with pancreatitis

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HMG CoA Reductase Inhibitors (Statins)

• Drugs of first choice in reducing blood lipid
  levels
• Reduce LDL, triglyceride, and VLDL levels
• Raise HDL levels (good cholesterol)

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Drug Profile - HMG-CoA Reductase Inhibitor
(Statin)

• Atorvastatin (Lipitor)
• Actions
• Adverse effects and interactions

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Newer Approaches to Treating Hyperlipidemia

• Ezetimibe (Zetia)
• Fixed-dose combination therapy

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Ezetimibe

• Blocks absorption of dietary cholesterol
• LDL and triglycerides are reduced
• Slight increase in HDL
• Well tolerated by patients

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Two Categories of Drugs Used to Treat

• Preventers - used prophylactically
• Antihistamines
• Glucocorticoids
• Mast cell stabilizers
• Relievers - used to provide immediate, temporary
  relief of symptoms
• Nasal decongestants - oral and intranasal
  sympathomimetics

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Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

• Primary treatment for mild to moderate
  inflammation
• Includes aspirin, ibuprofen, and COX-2 inhibitors

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Aspirin Treats Inflammation by Inhibiting
Cyclooxygenase

• Aspirin
• Ibuprofen is an Alternative to Aspirin
• Additional Cyclooxygenase Inhibitors
• Celecoxib, refecoxib, and valdecoxib
• Newest and most controversial class of NSAID

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Drug Profile - Nonsteroidal Anti-Inflammatory Drug

• Naproxen (Naprosyn) and naprox sodium (Aleve,
  Anaprox)
• Actions and uses
• Adverse effects and interactions
• Mechanism in action

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Systemic Glucocorticoids

• Effective in treating severe inflammation
• Naturally released by adrenal cortex
• Suppress histamine and prostaglandins
• Can inhibit immune system to reduce inflammation

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Serious Adverse Effects

• Can suppress adrenal gland function
• Can mask infections
• Creates potential for existing infections to grow
  rapidly and undetected
• Contraindicated with active infections

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H1 Receptor Blockers (Antihistamines)

• Block action of histamine at H1 receptor
• Used in OTC preparations for relief of
• Allergy symptoms
• Motion sickness
• Insomnia
• Can cause sedation

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Drug Profile - Nonsedating Antihistamine

• Fexofenadine (Allegra) - 2nd generation H1
  receptor antagonist nonsedating
• Actions and uses
• Adverse effects and interactions

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Immunosuppressants

• Used to inhibit immune response
• Primarily used to avoid tissue rejection
  following organ transplant

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Transplanted Organs Have Antigens that Trigger
the Immune Response

• Transplant rejection
• Humoral response - acute response
• Antibodies destroy transplanted tissue
• Acute response occurs in days
• Cell-mediated response slower
• Starts about 2 weeks following surgery
• Chronic rejection can occur months or years after
  surgery

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Immunosuppressants

• Dampen immune response following organ
  transplants
• May be used for severe cases of inflammatory
  diseases
• Very toxic to bone marrow
• Risk of infections
• Lymphomas

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Drug Profile - Immunosuppressant

• Cyclosporine (Neoral, Sandimmune)
• Actions and uses
• Adverse effects and interactions
• Mechanism in action