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1. HDS Cardiology > Pharmacology > Flashcards

Pharmacology Flashcards

1
Q

Antiplatelet Agents

A
  • ⊗ COX-1
    • Aspirin
  • ⊗ P2Y12 receptor
    • Clopidogrel
    • Ticlopidine
    • Prasugrel
  • ⊗ IIb/IIIa receptor
    • Abciximab
    • Eptifibatide
    • Tirofiban
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2
Q

Aspirin

Mechanism

A

Antiplatelet Agent

  • Irreversible inhibitor of COX-1
    • ⊗ thromboxane A2 synthesis
      • ⊗ platelet aggregation via this pathway
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3
Q

Aspirin

Indications

A

5-20% of population may be resistant to ASA

  • Low dose (81 mg/day)
    • Prophylactic against first and subsequent MI
      • Pt w/ prior hx of CAD
      • Risk factors: age, smoker, HLD, HTN
    • Taken for > 5 yrs ⇒ ↓ mortality w/ colorectal cancer
  • High dose (320 mg/day)
    • Taken @ first sign of MI ⇒ ↓ mortality
    • Stable and unstable angina ⇒ ↓ MI
    • S/P CABG ⇒ ↓ thrombotic graft closure and long-term graft arteriosclerosis
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4
Q

Aspirin

Contraindications/Side Effects

A

GI irritation d/t inhibition of PGE2 synthesis

PGE2 stimulates mucous secretion

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5
Q

P2Y12 Receptor Inhibitors

Meds and Mechanism

A

clopidogrel (Plavix), ticlopidine, prasugrel (Effient)

Antiplatelet agent

Prevents ADP-mediated platelet aggregation

Useful for pt who cannot tolerate ASA

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6
Q

clopidogrel (Plavix)

A
  • P2Y12 receptor inhibitor
  • Prodrug activated by CYP2C19
    • Reduced activity ⇒ low response to normal dose
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7
Q

prasugrel (Effient)

A
  • 3rd gen drug
  • More potent than clopidogrel
  • Higher risk of bleeding
  • Prodrug
    • Not dependent on CYP2C19
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8
Q

P2Y12 Receptor Inhibitors

Indications

A
  • Not superior to ASA alone
  • ASA + clopidogrel
    • ↓ risk of re-occlusion s/p MI
      • Compared to either drug alone
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9
Q

Glycoprotein IIb/IIIa Inhibitors

A

Antiplatelet agents

Target platelet receptors for integrin & other aggregating substances

Abciximab, Eptifibatide, Tirofiban

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10
Q

Glycoprotein IIb/IIIa Inhibitors

Delivery and Indications

A

All given IV and combined with ASA and anticoagulant therapy.

Main use in high-risk ACS and s/p PCI.

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11
Q

Abciximab

A
  • Chimeric Ab against IIb/IIIa receptors
  • Used w/ ASA or heparin in angioplasty
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12
Q

Anticoagulants

A
  • Heparin
  • LMW Heparin
    • Enoxaparin
    • Dalteparin
  • VKOR inhibitors
    • Warfarin/Coumadin
    • Dicumarol
  • Selective Factor Xa Inhibitors
    • Fondaparinux
    • Apixaban (Eliquis)
    • Rivaroxaban (Xarelto)
  • Direct Thrombin Inhibitors
    • Desirudin
    • Bivalirudin
    • Argatroban
    • Dabigatran (Pradaxa)
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13
Q

Heparin

Mechanism

A

Heterogeneous mix of sulfated mucopolysaccharides

  1. Binds antithrombin III (ATIII) ⇒ major effect
    • ↑ inhibition of clotting factors by ATIII
  2. Direct ⊗ of Factor Xa ⇒ minor effect
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14
Q

Heparin

Administration

A
  • IV or SC
  • Monitor efficacy ⇒ aPTT
  • Reversal ⇒ stop med + protamine sulfate
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15
Q

Heparin

Indications

A
  • Prevent or treat DVT
  • Acute MI ⇒ heparin + thrombolysis or PCI
  • Anticoagulation in pregnant women
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16
Q

Heparin

Toxicity

A
  • Bleeding ⇒ major effect
    • More common in elderly females and pts w/ impaired renal function
  • Thrombocytopenia ⇒ 3-5% of pts
  • Osteoporosis and spontaneous fractures ⇒ long-term therapy
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17
Q

LMW Heparin

Mechanism

A

Enoxaparin, Delteparin ⇒ all end in “parin”

Fragments of standard heparin

  1. ⊗ Factor Xa activity ⇒ major effect
  2. Binds ATIII to ↑ ⊗ of clotting factors ⇒ minor effect
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18
Q

LMW Heparin

Administration

A
  • Given SC qD
  • Preferred over heparin
    • More convenient
    • Doesn’t need aPTT monitoring
    • ↓ risk of infection
  • More expensive
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19
Q

LMW Heparin

Indications

A

Prevent DVT s/p surgery

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20
Q

LMW Heparin

Toxicity

A
  • Fewer bleeding side effects than standard heparin
  • Lower risk of infection
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21
Q

warfarin (Coumadin)

Mechanism

A

Analog of Vit K

  • ⊗ VKOR ⇒ ⊗ 𝛾-carboxylation of glutamate residues on gla-proteins
    • Factors II, VII, IX, X
  • Results in non-functional clotting factors
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22
Q

warfarin (Coumadin)

Administration

A
  • Given PO
    • Start w/ small daily dose
    • Varied efficacy d/t VKOR polymorphisms
  • Slow onset
    • 8-12 hr delay in onset of effects
    • 1-3 day delay in peak effects
  • Monitor w/ PT, expressed as INR
  • Slow reversal
    • Stop med & give Vit K and/or Factor IX concentrates
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23
Q

warfarin (Coumadin)

Indications

A
  • A. Fib
  • Prosthetic heart valves
  • TERATOGENIC ⇒ cannot give to pregnant women or those contemplating pregnancy
    • Use LMW Heparin
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24
Q

warfarin (Coumadin)

Drug Interactions

A
  • > 80 drug interactions
  • Especially agents that inc. anticoagulant effects
    • Pharmacokinetic & pharmacodynamic mechs
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25
Q

Selective

Factor Xa Inhibitors

A
  • Fondaparinux
  • Apixaban (Eliquis)
  • Rivaroxaban (Xarelto)
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26
Q

Fondaparinux

A
  • Synthetic pentasaccharide
  • Indirect Factor Xa inhibitor
    • Binds ATIII to inactivate Xa
  • Given SC
  • Indications
    • DVT
    • Acute PE
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27
Q

Apixaban (Eliquis)

A
  • Direct inhibitor of Factor Xa
  • Given PO
  • Approved for non-valvular A. fib
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28
Q

Rivaroxaban (Xarelto)

A
  • Direct inhibitor of Factor Xa
  • Given PO
  • Indications
    • Prophylaxis for venous thromboembolism s/p knee and hip replacements
    • Prophylaxis for stroke in pts w/ nonvalvular A. Fib
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29
Q

Direct Thrombin Inhibitors

A
  • Desirudin
  • Bivalirudin
  • Argatroban
  • Dabigatran etexiliate (Pradaxa)
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30
Q

Desirudin

A
  • Derivative of hirudin
  • Direct thrombin inhibitor
  • Indications
    • Prevent post-op venous thromboembolism
  • Given SC
  • Demonstrated superiority to LMW heparin
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31
Q

Bivalirudin

A
  • Synthetic peptide analog of hirudin
  • Direct thrombin inhibitor
  • Given IV
  • Used during PCI
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32
Q

Argatroban

A
  • Direct thrombin inhibitor
  • Given IV
  • Indications
    • Thrombosis in pts w/ HIT (heparin-induced thrombocytopenia)
    • During PCI in pts w/ HIT
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33
Q

dabigatran etexiliate (Pradaxa)

Mechanism & Admin

A
  • Direct thrombin inhibitor
  • Given PO
  • Prodrug ⇒ activated by a CYP450
  • Does not require monitoring
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34
Q

dabigatran (Pradaxa)

Indications & Side Effects

A
  • Approved for stroke prevention in A. Fib
  • Efficacy equal to warfarin
  • May haved reduced risk of bleeding vs warfarin
  • Pregnancy category C drug
    • Weigh risks vs benefits
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35
Q

Fibrinolytic Agents

A

↑ plasmin activation ⇒ fibrin degradation ⇒ thrombolysis

  • Streptokinase
  • Anistreplase
  • tPA
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36
Q

Streptokinase

A
  • Protein from Strep
  • Activates plasminogen ⇒ plasmin
  • Given IV over 30-60 mins
  • Less effective than tPA for CVA
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37
Q

Anistreplase

A
  • Plasminogen + streptokinase
    • Protein acetylated to protect active site
  • Given IV over 30-60 mins
    • Protecting group comes off in plasma
  • Less effective than tPA for CVA
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38
Q

Tissue Plasminogen Activator (tPA)

Mechanism and Admin

A
  • Protease that preferentially activates plasminogen bound to fibrin
  • Given IV bolus ⇒ immediate action
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39
Q

tPA

Indications

A
  • Ischemic strokes
  • Multiple PEs
  • Central DVTs
  • Acute MI
    • Given within 1st hour ⇒ ↓ mortality
    • Given within 6 hours ⇒ ↓ mortality vs streptokinase
  • NOT used for unstable angina or NSTEMI
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40
Q

Blood Schizontocides

A
  • Attack plasmodium in erythrocyte stage
    • Provides cure for plasmodium w/o exoerythrocytic stage
    • P. vivax and P. ovale ⇒ only suppresses attack but relapses can occur
  • Includes:
    1. Chloroquine/hydroxychloroquine
    2. Quinine
    3. Mefloquine
    4. Pyrimethamine + sulfadoxine
    5. Aretemether+lumefantrine
    6. Atovaquone+proguanil (Malarone)
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41
Q

Chloroquine/Hydroxychloroquine

Mechanism

A

Exact mechanism unknown

  • Weak base ⇒ accumulates in lysosomes of parasites
  • May prevent metabolism of Hb by inhibiting heme polymerase
    • Heme accumulates causing oxidative stress
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42
Q

Chloroquine/Hydroxychloroquine

Administration

A
  • Usually given PO
    • Rapidly and completely absorbed in GI tract
    • Antacids interfere w/ absorption
  • Can be given IM or IV but PO safer
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43
Q

Chloroquine/Hydroxychloroquine

Indications

A
  • Used in an acute attack or for prevention
    • P. falciparum resistant in many areas
    • Use where plasmodium sensitive to tx
  • Drug of choice for pregnant women w/ uncomplicated cases of chloroquine-sensitive malaria
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44
Q

Chloroquine/Hydroxychloroquine

Adverse Effects

A
  • Low dose PO ⇒ prophylaxis
    • Few side effects
  • High dose PO ⇒ treatment for attacks
    • Retinopathies
      • Taken up by tissue w/ high [melanin]
    • Corneal opacity
    • Porphyrias
    • Headache and confusion
    • Extraocular muscle palsies
    • Pruritus and skin eruptions
    • Depigmentation of hair
    • Partial alopecia
    • Exacerbation of psoriasis
  • High dose IV
    • Affects Na+ channels ⇒ hypotension or arrhythmias
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45
Q

Quinine (Quinidine)

Mechanism

A

Mechanism unclear.

May act similar to hydroxychloroquine ⇒ affects heme metabolism.

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46
Q

Quinine

Administration

A
  • PO
    • T1/2 is 10 hours, longer w/ severe cases of malaria
    • Antacids inhibit absorption
  • IV
    • Used for severe cases of malaria
    • Requires cardiac monitoring
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47
Q

Quinine

Indications

A

Effective against all erythrocyte forms of malaria.

No effect on exoerythrocytic forms.

  • PO
    • Treat chloroqine-resistant falciparum and vivax
      • Not as effective as chloroquine
      • Uusally use in combo w/ other drugs like Doxycycline
    • Quinine + clindamycin for chloroquine-resistant P. falciparum in pregnant patients
  • IV
    • Severe cases of falciparum whether resistent to chloroquine or not
  • Not used for prophylaxis
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48
Q

Quinine

Adverse Effects

A
  • Cardiac muscle sensitivity
    • Arrhythmias
    • Hypotension
  • CNS disturbances
  • Causes release of insulin ⇒ hypoglycemia
  • Gastric irritant ⇒ nausea/vomiting
  • High doses needed for falciparum ⇒ cinchonism
    • Nausea, dizziness, tinnitus, HA, blurred vision
  • Prolonged use ⇒ Blackwater fever
    • Acute hemolytic anemia associated with renal failure
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49
Q

Mefloquine

Mechanism

A

Exact mechanism unknown.

Drug intercalates into DNA.

May disrupt polymerization of hemozoin.

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50
Q

Mefloquine

Administration

A
  • Only given PO
  • T1/2 of 13-33 days ⇒ given once a week
  • Should not be combined with other drugs that effect cardiac conduction
    • Ex. Quinidine or β-blockers
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51
Q

Mefloquine

Indications

A
  • 1° for prophylaxis for chloroquine-resistant P. falciparum
    • Pregnancy category B ⇒ may be used during pregnancy for prophylaxis
  • Can be used to treat acute cases of resistant P. falciparum
    • Not as quick as quinine
    • Does not replace quinine for severe cases
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52
Q

Mefloquine

Adverse Effects

A
  • Low dose ⇒ prophylactic
    • Vivid dreams
  • High dose ⇒ treatment
    • Neuropsychiatric sx
    • Vertigo and lightheadedness
    • Visual disturbances
    • GI disturbances
    • Nausea
    • HA
    • Insomnia
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53
Q

Mefloquine

Contraindications

A

Pts with hx of epilepsy or psychiatric disorders.

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54
Q

Pyrimethamine + Sulfadoxine

Coverage and Mechanism

A
  • Coverage
    • Primarily active against erythrocytic forms
    • Some activity against primary plasmodium infection in the liver
  • Mechanism
    • Pyrimethamine ⇒ ⊗ dihydrofolate reductase
      • More specific for enzyme in protozoa
    • Sulfadoxine ⇒ ⊗ dihydropteroate synthase
    • Together ⊗ sequential steps of folic acid pathway
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55
Q

Pyrimethamine + Sulfadoxine

Administration

A
  • Only given PO
  • Generally used in combo w/ quinine
  • Use w/ caution in pregnancy
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56
Q

Pyrimethamine + Sulfadoxine

Indications

A

Usually used in combo with quinine for acute cases

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57
Q

Pyrimethamine + Sulfadoxine

Adverse Effects

A
  • Blood dyscrasias
    • Granuloytopenia
    • Thrombocytopenia
    • Neutropenia
    • Aplastic anemia
  • Folic acid deficiency
    • Supplement if during pregnancy
  • Steven Johnson syndrome
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58
Q

Aretemether + Lumefantrine

Mechanism

A

Combo more effective than monotherapy.

  • Aretemether ⇒ free radical mechanism
  • Lumefantrine ⇒ may work similar to chloroquine
    • Maybe affects heme metabolism
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59
Q

Aretemether + Lumefantrine

Administration

A

Given oral only

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60
Q

Aretemether + Lumefantrine

Indications

A
  • For chloroquine-resistant P. falciparum
  • Not effective for prophylaxis
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61
Q

Aretemether + Lumefantrine

Adverse Effects

A
  • Well-tolerated
  • May cause
    • GI symptoms
    • Palpitations
    • MSK sx
    • Neurological sx
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62
Q

Atovaquone/Proguanil (Malarone)

Mechanism

A
  • Atovaquone ⇒ ⊗ cytochrome bc1 complex (III) of ETC in plasmodia
  • Proguanil ⇒ lowers effective concentration at which atovaquone collapses the mitochondrial membrane potential
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63
Q

Atovaquone/Proguanil (Malarone)

Indications

A
  • Recommended for prophylaxis
    • Does not have neuro side effects of mefloquine
  • Treatment of uncomplicated chloroquine-resistant or multidrug-resistant malaria
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64
Q

Atovaquone/Proguanil (Malarone)

Adverse Effects

A
  • Abd pain
  • Nausea
  • Diarrhea
  • Headache
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65
Q

Atovaquone/Proguanil (Malarone)

Contraindications

A
  • Use with caution in severe renal impairment
  • Contraindicated in pregnancy
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66
Q

Primaquine

Coverage & Indications

A

Only drug effective against exoerythrocytic stage.

  • Primaquine + drug for erythrocytic stage
    • Radical cure of plasmodium vivax and ovale
  • Can be used in terminal prophylaxis for known exposure to P. vivax and P. ovale
  • Somewhat effective against the primary form
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67
Q

Primaquine

Administration

A

Only given PO.

T1/2 of 3-6 days ⇒ requires daily dosing

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68
Q

Primaquine

Adverse Effects & Contraindications

A

Generally well-tolerated.

Contraindicated in G6PD deficiency and pregnancy.

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69
Q

Malaria Treatment

Summary

A
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70
Q

Malaria Prophylaxis

Summary

A
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71
Q

PNS

Overview

A
  • Long pregnanglionic neurons ⇒ ACh ⇒ neuronal type nicotinic receptors
  • Short postganglionic neurons ⇒ ACh ⇒ muscarinic receptors
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72
Q

Nicotinic Receptors

A
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73
Q

Muscarinic Receptors

A
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74
Q

SNS

Overview

A
  • Short preganglionic neurons ⇒ ACh ⇒ neuronal-type nicotinic receptors
  • Long postganglionic neurons ⇒ NE ⇒ alpha or beta adrenergic receptors
    • Except sweat glands ⇒ use M3 receptors
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75
Q

Adrenergic Receptors

A
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76
Q

Muscle-type nicotinic receptors selectively blocked by…

A

curare

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77
Q

Ganglionic nicotinic receptors selectively blocked by…

A

hexamethonium

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78
Q

All muscarinic receptors selectively blocked by…

A

atropine

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79
Q

Acetylcholine

Metabolism

A
  • Synthesis
    • Choline + acetate CoA by choline acetyltransferase
  • Stored in vesicles
  • Degraded by acetylcholinesterase
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80
Q

Norepinephrine

Metabolism

A
  • Synthesis
    • Tyrosine → DOPA by tyrosine hydroxylase
      • Rate-limiting
    • L-DOPA → dopamine by decarboxylase
    • Within vesicles
      • Dopamine → NE by dopamine β-hydroxylase
    • In the adrenal medulla
      • NE → Epi by PNMT
  • Termination of action
    • Reuptake
    • Degradation by MAO and COMT
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81
Q

Lung

Autonomics

A

SNS ⇒ β2 ⇒ bronchodilation

PNS ⇒ M3 ⇒ bronchoconstriction

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82
Q

Heart

Autonomics

A
  • SNS ⇒ β1
    • SA node ⇒ inc. HR (+ chronotropic)
    • AV node ⇒ inc. conductance (+ dromotropic)
    • Myocytes ⇒ inc. FOC (+ ionotropic)
  • PNS ⇒ M2
    • SA node ⇒ dec. HR (- chronotropic)
    • AV node ⇒ dec. conductance (- dromotropic)
    • No innervation of ventricles
      • Exogenous ACh ⇒ dec. FOC (- ionotropic)
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83
Q

Vasculature

Autonomics

A
  • SNS
    • Skin and viscera ⇒ α1 by Epi/NE ⇒ vasoconstriction
    • Skeletal muscle ⇒ β2 by Epi ⇒ vasodilation
  • PNS
    • No innervation
    • Exogenous muscarinic agonists ⇒ NO ⇒ vasodilation
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84
Q

Pupil

Autonomics

A
  • SNS ⇒ α1 ⇒ dilator radial muscle contraction ⇒ pupil size inc.
  • PNS ⇒ M3 ⇒ constrictor circular muscle contraction ⇒ pupil size dec.
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85
Q

Ciliary Muscle

Autonomics

A
  • SNS ⇒ β2 ⇒ relax ciliary muscle ⇒ tension on suspensory ligaments ⇒ flat lens ⇒ far vision
  • PNS ⇒ M3 ⇒ contract ciliary muscle ⇒ relax suspensory ligaments ⇒ convex lens ⇒ near vision
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86
Q

Liver

Autonomics

A

SNS ⇒ β2 ⇒ glycogenolysis ⇒ inc. BGL

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87
Q

Autonomic Reflex Loop

A
  • Activated by sensory afferents
  • Can occur along multiple levels
    • Ganglion or spinal cord
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88
Q

ANS

Central Regulation

A

Controlled by hypothalamic and brain stem centers.

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89
Q

SNS

Innervation Summary

A
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90
Q

PNS

Innervation Summary

A
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91
Q

Organ Autonomics

Summary

A
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92
Q

Cholinomimetics

A

Direct ⇒ receptor agonists

Indirect ⇒ acetylcholinesterase inhibitors

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93
Q

Effects of ACh

Overview

A
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94
Q

Vasculature

ACh Response

A

ACh ⇒ M3 receptors ⇒ NO by endothelial cells ⇒ vasodilation

  • Low dose ACh IV ⇒ ↓ BP ⇒ reflex ↑ HR
  • High dose ACh IV ⇒ profound bradycardia
    • Due to direct effect on the heart
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95
Q

Skeletal Muscle

ACh Response

A
  • ACh
    • First excite nicotinic receptors
    • Continued stimulation ⇒ desensitization
      • Normally prevented by action of AChE
  • In the presence of AChE inhibitors
    • Endogenous ACh causes fasciculations then paralysis
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96
Q

Effects of ACh and Cholinomimetics

A

Due to muscarinic > nicotinic stimulation.

DUMBELS

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97
Q

Acetylcholine

Clinical Uses

A

Rapidly hydrolyzed ⇒ limited applications

  1. Intraocularly ⇒ produce miosis s/p lens extraction
  2. Intracoronary
    • Cause vasodilation during dx coronary angiography
    • Dx vasospastic angina via direct effect on smooth muscle causing contraction
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98
Q

Methacholine

A
  • Action:
    • Agonist @ mAChRs
  • Indications:
    • Test for bronchial hyperreactivity & asthmatic conditions
      • Carefully ⇒ dangerous drug
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99
Q

Carbachol

A
  • Action:
    • Agonist at all AChRs
  • Indication:
    • Wide-angle glaucoma
      • Not the preferred agent
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100
Q

Bethanechol

A
  • Action:
    • Agonist at GI mAChRs
  • Indications:
    1. Post-op for abdominal surgery
    2. Post-partum to reduce bladder distention
    3. Promote salivation
      • Alternative to Pilocarpine
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101
Q

Choline Esters

Adverse Effects

A

Methacholine and Betanechol ⇒ mAChR activities

Carbachol ⇒ mixed AChR activities

  • Decreased night vision
  • Difficulty focusing on distant objects
  • DUMBELS
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102
Q

Choline Esters

Contraindications

A
  1. Asthma
    • May precipitate an asthma attack d/t M3 mediated bronchoconstriction
  2. Urinary obstruction
  3. Acid-peptic disease
    • May induce gastric acid secretion
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103
Q

Choline Esters

CNS Effects

A
  • ACh and related esters charged quaternary amines
  • Do not enter CNS
  • Most muscarinic agonists may cause arousal response @ high doses
  • At “normal” therapeutic doses ⇒ actions confined to peripheral tissues
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104
Q

Pilocarpine

Action and Indications

A
  • Action:
    • Agonist @ mAChRs
    • 3° amine ⇒ enters CNS
      • May cause hallucinations and convulsions
  • Indications:
    • Eye drops ⇒ miotic agent (lasts about 1 day)
      • Wide-angle glaucoma
        • Not the preferred agent
      • Acute closed-angle glaucoma
        • If pressure too high
    • PO
      • Xerostomia ⇒ stimulation salivation
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105
Q

Pilocarpine

Side Effects

A
  • Chronic use
    • Decreased night vision
    • Difficulty focusing on distant objects
  • DUMBELS without muscle effects
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106
Q

Muscarine

A
  • Found in some species of mushrooms
  • Ingestion ⇒ muscarine poisoning
    • DUMBELS
  • Reversed with atropine
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107
Q

Nicotine

A
  • Action:
    • Activates ganglionic nACh receptors
    • Receptor blockade w/ persistent stimulation
  • Nicotine patches for smoking cessation
  • Potential for ganglionic blockade @ high doses ⇒ Nicotine poisoning
    • May be used as a pesticide
    • Complex effects
      • Depends on dose and timing
      • Tachy or brady
      • HTN or hypotension
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108
Q

Acetylcholinesterase

A
  • Mechanism
    1. ACh binds ⇒ choline released
    2. Hydrolysis of acyl intermediate
  • Blood has ‘true’ AChE inside RBCs
  • Plasma has butyrylcholinesterase
    • Hydrolyzes butyrylcholine faster than ACh
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109
Q

Cholinesterase Inhibitors

“Anticholinesterases”

A

Block AChE ⇒ ↑ [ACh]

  • Found in agricultural pesticides
  • Some used as chemical warfare agents
  • 3° vs 4° amines
  • Reversible
    • Edrophonium
    • Carbamates
      • Physotigmine
      • Neostigmine
      • Pyridostigmine
  • Irreversible
    • Organophosphates
      • Echotiophate
      • Malathion
      • Parathion
      • Sarin/Soman
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110
Q

Edrophonium

A
  • Reversible competitive cholinesterase inhibitor
    • Blocks ACh access to active site
  • 4° amine
    • Does not enter CNS
    • Short duration of action ⇒ 1-5 mins
  • Used to test for myastenia gravis
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111
Q

Carbamates

A
  • Reversible AChE inhibitor
    • Block active site while undergoing slow hydrolysis
  • Includes:
    • Physotigmine
    • Neostigmine
    • Pyridostigmine
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112
Q

Physostigmine

A
  • Reversible competitive substrate for AChE
  • Indications:
    • Wide-angle glucoma ⇒ faciliate efflux of aqueous humor
      • Not the preferred agent
  • 3° amine ⇒ enters CNS
    • Reverses effect of atropine & other antimuscarinic drugs
  • Adverse effects ⇒ cataracts
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113
Q

Neostigmine

A
  • Reversible competitive substrate of AChE
  • Indications:
    • Paralytic bladder or GI tract
    • Myastenia gravis
  • 4° amine ⇒ does not enter CNS
  • Short duration of action ⇒ 2-4 hours
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114
Q

Pyridostigmine

A
  • Reversible competitive substrate of AChE
  • Indications:
    • Choice for myastenia gravis
      • Longer acting ⇒ 3-6 hrs
    • Nerve gas prophylactic
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115
Q

Myasthenia Drugs

Adverse Effects

A
  • Some muscarinic side effects
    • Tolerance usually develops w/ extended use
  • May exacerbate
    • COPD
    • Asthma
    • Gastric ulcer
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116
Q

Irreversible Cholinesterase Inhibitors

Mechanism

A

Inactivate AChE by covalent attachment

  • Organophosphate hydrolyzed by AChE
  • Acyl intermediate replaced by phosphoryl group
    • Cleaved extremely slowly
  • Bond can be strengthened over time ⇒ aging
  • AChE can be reactivated w/ strong nucleophile during early stages of inhibition before aging
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117
Q

Echothiophate

A
  • Only clinically useful organophosphate
  • Used in glaucoma
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118
Q

Malathion

A
  • Pro-drug insecticide organophosphate
  • Once activated undergoes detoxification in mammals via plasma esterases
  • Involved in farm poisonings
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119
Q

Parathion

A
  • Potent insecticide ‘pro-drug’ organophosphate
  • Metabolized by mixed-function oxygenases
  • Responsible for most cases of poisoning and death
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120
Q

Sarin/Soman

A
  • “Nerve gas”
  • Extremely toxic organophosphate
  • Used in chemical warfare
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121
Q

Organophosphate

Toxicity

A

Acute intoxication ⇒ mix of muscarinic, nicotinic, and CNS effects

SLUDGE-BAM

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122
Q

Organophosphate vs Carbamate

Toxicity

A
  • Organophosphate ⇒ much longer lasting AChE inhibition
    • See signs of nicotinic excess
  • Carbamates
    • Mostly muscarinic parasympathetic symptoms
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123
Q

Death from cholinesterase inhibitor poisoning is usually due to…

A

Respiratory failure

  • Bronchoconstriction
  • Bronchorrhea
  • Central respiratory depression
  • Weakness/paralysis of respiratory muscles
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124
Q

Organophosphate Poisoning

Treatment

A
  1. Atropine
    • Reverse muscarinic effects
  2. Pralidoxime (PAM)
    • Reactivate phosphoryl enzyme
      • Only effective early before “aging”
  3. Diazepam
    • Prevent/alleviate convulsions
  4. Supportive measures for respiratory distress
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125
Q

Anti-Muscarinics

Overview

A
  • Actions d/t ⊗ of PNS influence in tissues
  • Predominantly PNS tone in most tissues except vasculature and sweat glands
  • mAChR blockade lets SNS influence predominant
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126
Q

Atropine

Effects

A

Non-specific muscarinic antagonist.

3° amine ⇒ enters CNS

  • Ocular
    • Mydriasis
    • Blocks accommodation
    • Inhibits lacrimation
  • Cardiac
    • Standard doses ⇒ blocks vagal input
      • ↑ HR and AV conduction
    • Very low doses ⇒ block presynaptic receptors
      • May initially ↓ HR
  • Respiratory
    • Bronchodilation
    • Inhibit secretion
  • GI
    • ↓ lower esophageal tone
    • ↓ GI tone ⇒ ↑ transit time
    • ↓ gastric acid secretion
  • GU
    • Relaxes detrusor ⇒ urinary retention
  • CNS
    • Stimulation then sedation
    • Dizziness and imbalance
    • High doses ⇒ confusion and/or hallucinations
  • Others
    • Inhibits sweating ⇒ hyperthermia ⇒ cutaneous vasodilation
    • Dry mouth
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127
Q

Atropine

Indications

A
  1. Reverse muscarinic or AChE inhibitor poisoning
  2. Long-lasting pupil dilation for eye exams
    • Not preferred
  3. Combo w/ diphenoxylate (Lomotil) ⇒ anti-diarrheal
  4. “Pharmacological patch” for amblyopia
  5. Sinus bradycardia and AV block
  6. Prevent muscarinic side effects in AChE inhibitor treatment in Myastenia gravis
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128
Q

Scopolamine

A
  • Muscarinic antagonist
  • Used for motion sickness
  • Administered as a patch
  • Side effects ⇒ drowsiness
    • 3° amine ⇒ enters CNS
    • More sedating than Atropine
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129
Q

Tropicamide or Homatropine

A

Muscarinic antagonist.

Fast but short acting mydriatic agents.

May be used in combo w/ alpha-adrenergic agonist.

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130
Q

Iprotropium

A
  • Muscarinic antagonist
  • 4° amine given by inhalation
  • Bronchodilator for asthma and COPD
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131
Q

Tiotropium

A
  • Similar to ipratropium
    • Inhaled muscarinic antagonist
  • Longer acting
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132
Q

Tolterodine, oxybutynin, and solifenacin

A
  • Antagonist at bladder mAChRs
  • Management of overactive bladder
  • Fewer adverse effects like dry mouth and blurred vision
  • Contraindicated in pts w/ narrow-angle glaucoma
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133
Q

Dicyclomine and Hyoscyamine

A
  • Muscarinic antagonist @ GI mAChRs
  • Relaxes intestinal smooth muscle
  • Used for irritable bowel symptoms
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134
Q

Glycopyrrolate

A
  • Muscarinic antagonist
  • Low doses preferentially inhibit secretion
    • Used pre-op to inhibit secretions
    • Prevent excessive sweating
  • Prevent muscarinic side effects of Neostigmine to reverse NMJ block
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135
Q

Benztropine

A
  • Lipid soluble mAChR antagonist
  • Used to relieve extrapyramidal sx
    • Parkinson’s
    • Pts taking antipsychotics
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136
Q

Anti-muscarinics

Adverse Effects

A
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137
Q

Partial Antimuscarinic Activity

Drug Classes

A
  • Antihistamines
    • Diphenhydramine
  • Antidepressants
    • Tricyclics (e.g. amitriptyline)
  • Phenothiazine antipsychotics
    • Chlorpromazine
138
Q

Ganglionic Blockers

Overview

A
  • Act by ⊗ neuronal nAChR of all autonomic ganglia
  • Apparent effects still mostly sympathetic-like
    • Blocks all autonomic influence
    • Removes the predominant PNS tone of most tissues
    • Apparent opposing effect
139
Q

Hexamethonium (C6)

A
  • Ganglionic blocker
  • Prevents baroceptor reflex
  • First effective anti-hypertensive
    • No longer used
  • Poorly absorbed
  • Autonomic side effects
140
Q

Mecamylamine

A
  • Ganglionic blocker
  • Uses:
    • Improve GI absorption
    • Tourette’s syndrome
141
Q

α1 Receptor

Effects

A

Acts via Gq.

142
Q

α2 Receptor

Effects

A

Acts via Gi.

143
Q

β1 Receptor

Effects

A

Acts via Gs.

144
Q

β2 Receptor

Effects

A

Acts via Gs.

145
Q

β3 Receptor

Effects

A

Acts via Gs.

146
Q

Receptor Desensitization

A
  • Long-term ⇒ via transcription or translation changes
  • Short-term ⇒ via phosphorylation
  • Homologous ⇒ receptor unresponsive to its own agonist
  • Heterologous ⇒ activation of one receptor leads to desensitization of another receptor
147
Q

α1 Agonist

Cardio Effects

A
  • Mechanism
    • α1 ⇒ Gq ⇒ ↑ Ca2+ ⇒ ⊕ MLCK ⇒ myosin-℗ ⇒
      • Contraction of arterial resistance vessels
      • ↓ venous capacitance
  • Predominate in skin and splanchnic vessels
  • Pure α1 agonist
    • ↑ BP ⇒ reflex bradycardia
      • Blocked by ganglionic blockers or anti-muscarinics
  • Useful in hypotension
  • Overstimulation ⇒ hemorrhage d/t ↑ BP
148
Q

α2 Agonist

Cardio Effects

A
  • Stimulated when NE released into synapse
  • Results in dec. NE release
  • α2 agonist PO ⇒ ⊕ α2 receptors in CNS ⇒ ↓ SNS output ⇒ ↓ BP
149
Q

β1 Agonist

Cardio Effects

A
  • Mechanism
    • β1 ⇒ Gs ⇒ cAMP ⇒ ℗ of Ca2+ channels ⇒ Ca2+ influx
      • + chronotropic, inotropic, and dromotropic
    • May also ⇒ ℗ of troponin C ⇒ inc. sensitivity of contractile apparatus
  • Useful in cardiogenic shock
  • Overstimulation ⇒ arrhythmias
150
Q

β2 Agonist

Cardio Effects

A
  • Mechanism
    • β2 ⇒ Gs ⇒ cAMP ⇒ PKA ⇒ phosphorylation and inhibition of MLCK ⇒ vasculature relaxation and vasodilation
151
Q

Pulse Pressure

A

PP = SBP - DBP

  • Some agents ↑ PP
    • ↑ SBP
    • No effect or ↓ DBP
152
Q

Total Peripheral Resistance

A

(Mean arterial pressure - Mean venous pressure) / CO

153
Q

Adrenergic Agonists

Receptor Affinities

154
Q

Phenylephrine

Cardiac Effects

A

Pure α agonist

⊕ α1 ⇒ vasoconstriction ⇒ ↑ BP ⇒ reflex bradycardia

No effect on β1 ⇒ no effect on PP

155
Q

Norepinephrine

Cardiac Effects

A
  • No effect on β2 ⇒ acts like α-agonist w/ β1 activity
  • Injected NE ⇒ ↑ BP and ↑ PP
  • Reflex bradycardia masks the direct stimulatory effects of β1 activation on the heart
156
Q

Low Dose Epi

Cardiac Effects

A

Activates β receptors.

↑ HR and ↑ PP

↓ BP

157
Q

Moderate Dose Epi

Cardiac Effects

A

β activation > α activation

Combined effect of β2 > α1 ⇒ modest ↑ BP

158
Q

High Dose Epi

Cardiac Effects

A

α1 predominates

Significant ↑ BP ⇒ reflex bradycardia

Looks more like a response to NE

159
Q

Isoproterenol

Cardiac Effects

A

Non-selective β activation

  • β1 ⇒ heart ⇒ ↑ SBP, ↑ HR
  • β2 ⇒ vasodilation of vascular beds ⇒ ↓ DBP
  • Results in ↑ PP
160
Q

Dopamine

Cardiac Effects

A

High doses ⇒ ⊕ dopamine, ⊕ beta, and ⊕ alpha receptors

  • β1 ⇒ ↑ HR , ↑ SV
  • β2 ⇒ vasodilation ⇒ ↓ TPR ⇒ ↓ BP
  • α1 ⇒ ↑ SBP
  • D1 ⇒ ↓ DBP
    • Via renal, skin, and splanchnic vasodilation
  • D2 ⇒ ⊗ NE release
161
Q

Lung

Sympathomimetics

A

Stimulate beta-2 receptors ⇒ bronchodilation & relax SM in other areas

Used for asthma or to prolong labor.

162
Q

Eye

Sympathomimetic Effects

A
  • Alpha-1 agonists
    • Contract dilator muscles ⇒ mydriasis
    • Used w/ muscarinic antagonists for eye exams
  • Alpha-2 agonists
    • Work on ciliary body ⇒ ↓ aqueous humor secretion
    • Used to treat glaucoma
  • Beta-2 agonists
    • Relax ciliary muscle ⇒ allows aqueous humor to escape via uveoscleral pathway
    • Treat glaucoma (not preferred)
163
Q

GU

Sympathomimetic Effects

A
  • Alpha-1 agonists
    • Contraction of urethral sphincters
  • Beta-2 and beta-3 agonists
    • Relaxation of detrusor muscle
  • Net effect of sympathetic stimulation ⇒ urinary retention
164
Q

Salivary Glands

Sympathomimetic Effects

A
  • PNS > SNS in causing salivation
    • PNS ⇒ watery secretion w/ K+ and amylase
  • Alpha-1 agonists
    • Small and transient inc. in watery secretion w/ K+
  • Beta-1 agonists
    • Enhances effect of PNS on amylase secretion
  • Net effect of sympathetic stimulation ⇒ small amount of thick saliva
165
Q

Metabolic Effects

Sympathomimetics

A

Epi has complex effects on BGL

  • Liver ⇒ α1 and β2 ⇒ inc. glycogenolysis and gluconeogenesis ⇒ hyperglycemia
  • Pancreas
    • First activates alpha-2 ⇒ dec. insulin secretion ⇒ large inc. in BGL
    • Then activates beta-2 receptors ⇒ modest inc. in insulin ⇒ allows muscle to use glucose
166
Q

CNS

Sympathomimetic Effects

A

CNS has alpha, beta, and dopamine receptors.

  • Epi cannot enter CNS except @ high doses
    • Adrenaline rush or feeling of disaster
  • Some agents can enter CNS
    • Arousal, euphoria, anorexia, etc
167
Q

Direct Acting Adrenergic Agonists

A

NE, Epi, and Dopamine

168
Q

Norepi

Indications

A

Direct Acting Adrenergic Agonist

  • Potent vasoconstrictor
  • Used for hypotension
169
Q

Epi

Indications

A

Direct Acting Adrenergic Agonist

  • Drug of choice for anaphylactic shock
  • Cardiac arrest
  • Reduction of bleeding during surgery
  • Prolonging action of some local anesthetics
170
Q

Dopamine

Indications

A

Direct Acting Adrenergic Agonist

  • Cardiogenic shock
  • Septic shock
  • Adjunct in hypovolemic shock
171
Q

Phenylephrine

A

Direct pure alpha-1 agonist

  • Mydriasis w/o cycloplegia (dilate)
  • Nasal decongestant
  • Terminate paroxysmal atrial tachycardia (reflex effect)
  • Hypotension
172
Q

Clonidine

A

Direct pure alpha-2 agonist

Vascular and CNS

  • HTN esp. in renal disease
    • Central action ⇒ dec. SNS outflow ⇒ dec. BP
  • Analogues used in glaucoma
  • Benzo and opiate withdrawal
173
Q

Methyldopa

A

Converted to methyl-NE centrally

Direct alpha-2 agonist in CNS

Dec. SNS outflow ⇒ dec. BP

174
Q

Dobutamine

A

Direct β1 > β2 agonist

  • Inotropic vasodilator
  • Uses:
    • Cardiogenic shock
    • Acute heart failure
    • Cardiac stimulation
175
Q

Isoproterenol

A

Non-specific β-agonist

  • Not the drug of choice for anything
  • Uses
    • Bronchospasm and asthma
      • Not DOC
    • Refractory heart block
    • Refractory bradycardia
176
Q

Albuterol

Metaproterenol

Terbutaline

Salmeterol

A

Direct β2 Agonists

Used for asthma, COPD, and bronchitis.

Salmeterol is long-lasting.

177
Q

Mirabegron

A

Beta-3 agonist

Overactive bladder

178
Q

Ephedrine

Pseudoephedrine

A

Causes release of NE.

Weak adrenergic activity.

Significant CNS stimulation

  • Uses
    • Decongestant (main use)
    • Bronchospasm
    • Hypotension
179
Q

Indirect Acting Sympathomimetics

A

Cocaine

Amphetamine

Tyramine

180
Q

Cocaine

A
  • Peripharal
    • Blocks NE reuptake ⇒ inc. NE ⇒ inc. sympathetic responses
  • CNS
    • Blocks dopamine reuptake ⇒ profound stimulatory effect
181
Q

Amphetamine

A
  • Substrate for NE transporter
    • Enters vesicles ⇒ displaces NE ⇒ NE exits presynaptic terminal
  • Stimulant used in ADHD
182
Q

Tyramine

A
  • Found in some food
  • Normally metabolized by MOA in liver and GI tract
  • Drugs that block MAO allows tyramine into circulation
  • Actions similar to amphetamine
    • Releases large amount of NE
  • Can cause a hypertensive crisis
183
Q

Acute Hypotension

Treatment

A
  • Place in recumbent position & fluid resusitate
  • Vasoconstrictive agents only in an emergency to preserve profusion to critical organs
    • Can also cause dec. flow
184
Q

Shock

Treatment

A

Cardiogenic vs septic vs hypovolemic

Goal to maintain tissue perfusion.

  • Usual treatment
    • Volume replacement
    • Treat underlying problem
  • Vasoconstriction ⇒ shock
    • Use alpha-blockers
  • Vasodilation ⇒ shock
    • Use vasoconstrictor (alpha-1 agonist)
  • Cardiogenic shock
    • Dopamine or dobutamine
      • Dopamine
        • beta-1 ⇒ stimulates heart
        • D1 ⇒ maintain kidney profusion
185
Q

Heart Block and Cardiac Arrest

Treatment

A
  • Epi short term
    • Help redistribute blood flow to the heart during resuscitation
  • Pacemaker should be placed ASAP
  • NO Isoproterenol ⇒ more likely to inc. cardiac work
186
Q

Local Vasoconstriction

A
  • Epinephrine
    • Control bleeding during surgery on external areas
    • Prolong action of local anesthetics by restricting blood flow
  • Cocaine
    • Used for nasopharyngeal surgery
      • Vasoconstriction
      • Anesthetic
  • Agents w/ alpha-1 agonist activity
    • Nasal decongestants
      • Dec. volume of nasal mucosa
      • Cause rebound hyperemia when stopped
    • Local application w/ nasal sprays can cause ischemic changes in mucosa
187
Q

Pulmonary

Sympathomimetic Treatments

A

Beta-2 selective drugs preferred.

Albuterol, metaproterenol, terbutaline, salmeterol

Mainly for asthma.

188
Q

Anaphylaxis Treatment

A

Epinephrine drug of choice

  • beta-2 ⇒ bronchodilation
  • beta-1 ⇒ stimulates heart
  • alpha-1 ⇒ maintains perfusion
189
Q

Eye

Sympathomimetic Treatments

A
  • Phenylephrine
    • Dilate eyes
    • Allergic hyperemia
  • Apraclonidine
    • Alpha-2 agonist for glaucoma
  • Epinephrine
    • Acting as beta-2 agonist ⇒ rarely used
    • Beta-blockers first line agents
190
Q

Alpha-adrenergic Antagonists

Physiological Effects

A
  • Cardiovascular
    • Orthostatic hypotension
      • ⊗ alpha-1 ⇒ dec. peripheral vascular resistance ⇒ dec. BP
    • ± Reflex tachy
      • More likely w/ nonspecific alpha blockers
        • ⊗ presynaptic alpha-2 ⇒ inc. NE @ heart
    • Abrupt withdrawal after long-term treatment can cause rebound HTN
  • GU
    • Alpha-1 activation ⇒ contraction of urethral sphincters and prostate
    • Blockade can facilitate flow
191
Q

Epinephrine Reversal

A
  • High dose Epi ⇒ alpha > beta effect
    • ↑ BP
  • If alpha-antagonist given before Epi
    • Only see beta effects
    • β2 ⇒ ↓ BP
    • β1 and reflex tachy ⇒ ↑ HR
192
Q

Alpha-Blockers

Adverse Effects

A
  • Miosis
  • Nasal stuffiness
  • GI hypermotility
  • Sexual dysfunction (centrally mediated)
  • Dry mouth
  • Dizziness
  • Somnolence
  • Headache
193
Q

Phenoxybenzamine

A

Irreversible non-selective alpha blocker

  • Indications
    • HTN due to Pheochromocytoma
      • Dec. BP when SNS tone high
    • Raynaud’s
  • Adverse effects
    • Tachycardia
      • Due to block of presynaptic alpha-2 and reflex mechanisms
194
Q

Phentolamine

A

Competitive non-selective alpha blocker

  • Indications
    • Hypertensive emergencies
  • Short half-life
  • Adverse effects
    • Tachycardia d/t α2 block
195
Q

Prazosin

A

Competitive α1 blocker

  • Indications
    • Mild HTN
  • Adverse effects
    • Less likely to cause tachycardia
196
Q

Terazosin / Doxazosin

A

Selective alpha-1 blocker

Longer half-life than Prazosin

  • Indications
    • Mild HTN
    • BPH
  • Adverse effects
    • Less likely to cause tachycardia
197
Q

Tamsulosin

A

Selective alpha 1A and 1D blocker.

Predominant in prostate.

Used in BPH.

198
Q

Pheochromocytoma

Treatment

A
  • Tumor of adrenal medulla releasing NE and Epi
    • HTN, HA, tachycardia, sweating
  • Alpha-1 blockers used pre-operatively
    • Phenoxybenzamine most often
      • Also used for inoperable tumors
  • Beta-blockers may be given
    • Only after alpha-1 blocker to avoid unopposed alpha-1 vasoconstriction
199
Q

Chronic HTN

Treatment

A
  • Beta-blockers
  • Alpha-1 blockers
200
Q

Peripheral Vascular Disease

Treatment

A
  • Prazosin or phenoxybenzamine ⇒ alpha blockers
    • Treat vasospasm in peripheral circulation (Raynaud’s phenomenon)
  • Calcium channel blockers preferred
  • Behavioral modifications first
201
Q

BPH

Treatment

A

Use alpha-1 blocker

  • Prazosin or doxazosin
  • Tamsulosin more selective for prostate
    • Less effect on BP
    • Can use for pt w/ prior orthostatic hypotension
202
Q

Phentolamine part of mix injected for….

A

erectile dysfunction

203
Q

Beta-blocker

Dynamics

A

Low bioavailability d/t significant 1st pass metabolism

Several drugs metabolized by CYP450 enzymes

204
Q

Beta-blocker

Cardiac Effects

A
  • Bradycardia
    • Treat w/ glucagon
    • Rebound HTN w/ abrupt withdrawal
  • Dec. contractility
  • Dec. excitability
  • Inc. BP then dec. BP
    • Early rise due to unopposed alpha-1
    • Late fall due to
      • Dec. renin
      • CNS effects
      • Inhibit NE effects @ heart
  • Can precipiate heart failure in patients with abnormal cardiac function
205
Q

Beta-blocker

Pulmonary Effect

A
  • Block β-2 ⇒ bronchoconstriction
    • Worse w/ asthmatics
      • Avoid non-specific beta blockers
206
Q

β-blocker

Eye Effects

A

Dec. production of aqueous humor.

Most widely used drug for glaucoma.

207
Q

β-blocker

Metabolic Effects

A
  • β2 blockade
    • Inhibit epi mediated stimulation of glycogenolysis
    • Can mask sx of hypoglycemia by blocking tachycardia and tremors
208
Q

β-blocker

Lipid Effects

A
  • Non-specific beta blockers inhibit hormone sensitive lipase
    • Inc. VLDL and triglycerides
    • Dec. HDL
    • No change to LDL
    • Inc. LDL/HDL ratio due to HDL decrease
  • Less likely to occur when beta-blocker has intrinsic sympathomimetic activity
209
Q

β-blocker

Membrane Stabilizing Action

A

Propranolol, pindolol, and metoprolol

  • Via blockade of sodium channels
    • Has local anesthetic action
  • Can affect myocyte sodium channels
    • Only a problem at high doses
      • Prolong QRS duration
      • Impair cardiac function
  • Contraindicated in patients with glaucoma
210
Q

β-blocker

Intrinsic Sympathomimetic Activity

A

Pindolol and Acebutolol have beta-agonist properties.

Considered partial agonists.

  • Capable of β stimulation, especially when catecholamines low
    • Less bradycardia
    • Slight vasodilation
    • Minimal change in lipids
211
Q

β-blocker

CNS Effects

A

If they can enter the CNS:

  • Dizziness
  • Fatigue
  • Depression
  • Sexual dysfunction
212
Q

Propanolol

A

Non-specific β-blocker

  1. Many indications
    • HTN
    • Angina
    • Arrhythmias
    • Migraine
    • Thyroid toxicosis
    • Essential tremor
  2. Readily enters CNS
    • Can cause excessive somnolence and impaired cognition
  3. Membrane-stabilizing activity (highest)
    • High doses ⇒ prolong QRS and impair cardiac conduction
    • Contraindicated in glaucoma
213
Q

Timolol

A

Non-specific β-blocker

  • Indications:
    • Widely used for glaucoma
    • HTN
    • MI
  • No membrane stabilizing activity
214
Q

Nadolol

A

Non-specific β-blocker

  • Same indications as propanolol
    • HTN
    • Angina
    • Arrhythmias
    • Migraine
    • Tyroid toxicosis
    • Essential tremor
  • Very long half-life
215
Q

Pindolol

A

Non-selective β-blocker with intrinsic sympathomimetic activity.

Used for HTN in pts w/ bradycardia or PVD.

Less likely to cause bradycardia and lipid changes.

216
Q

Atenolol & Metoprolol

A

β1-selective

  • Preferred in pts who had bronchoconstriction after propanolol
  • Used in pts w/ COPD, DM, PVD with caution
  • Atenolol
    • Very low lipid solubility ⇒ does not enter CNS
    • Widely used for HTN
  • Metoprolol
    • High lipid solubility ⇒ enters CNS
    • MSA
    • Still widely used for HTN, MI, angina
217
Q

Esmolol

A

β1-selective

  • Very short acting w/ T1/2 10 mins
  • Good for critically ill pts
  • Indications:
    • Intraop and postop HTN
    • Arrhythmias
218
Q

Betaxolol

A

β1-selective

  • Less likely to cause bronchoconstriction
  • Used for glaucoma
219
Q

Acebutolol

A

β1-selective blocker with intrinsic sympathomimetic activity.

Used for HTN in patients w/ bradycardia.

Less likely to cause bradycardia and lipid changes.

220
Q

Labetalol

A

Nonspecific β blocker, less than propranolol.

Some ISA at β2.

α1 blocker, less than phentolamine

Used for HTN and severe HTN.

221
Q

Carvedilol

A

Non-specific β-blocker > α1 blocker.

Used to treat CHF and HTN.

Contraindicated in severe heart failure.

Effectiveness in CHF partially due to:

  • Attenuation of oxygen free radical action
  • Inhibition of vascular smooth muscle mitogenesis
222
Q

Reserpine

A

Indirect acting adrenergic antagonist

  • Blocks vesicular transport system both peripherally and centrally
    • NE not take up into vesicles
    • Also effects dopamine and serotonin
  • Depletion of amines in CNS
    • Severe adverse effects
      • Depression
223
Q

β-blockers

Clinical Uses

A
  1. HTN
    • Usually in combo w/ diuretics or ACEi
  2. Ischemic heart disease
    • Timolol, propranolol, and metoprolol
    • Reduces freq. of angina & improves exercise tolerance
    • Contraindicated in bradycardia or hypotension
  3. Arrhythmias
    • Slow AV nodal conduction
      • Used for A. Fib and A. Flutter
    • Treat ventricular arrhythmia w/ ectopic beats d/t excess E/NE
  4. Heart failure
    • Carvedilol in moderate heart failure
    • Not used in acute heart failure
  5. Glaucoma
    • Most widely used along w/ prostaglandin analogues
    • Applied directly to eye but has some systemic absorption
      • Can effect heart or cause bronchoconstriction
      • May combine w/ Ca2+ channel blockers to slow AV nodal conduction
  6. Hyperthyroidism
    • Ideal for condition
    • Blocks beta-activation by ANS
    • Blocks conversion of thyroxine to triiodothyronine
  7. Migraines
    • Prophylaxis of headaches
  8. Tremors, performance anxiety
    • Low doses used to reduce tremors
224
Q

Statins

Mechanism

A

⊗ HMG-CoA reductase

  • Rate-limiting step in cholesterol biosynthesis
    • Moderate transient ↓ [cellular cholesterol]
      • Activation of SREBP2 signal cascade
  • SREBP2 transcription factor
    • ↑ LDL receptor expression
      • ↑ uptake of LDL
        • ↓ plasma LDL
225
Q

Statins

Efficacy

A
  • Primary prevention ⇒ ↓ mortality from CVD in people without CVD
  • Secondary prevention ⇒ ↓ mortality from CVD after MI
    • Reduction greater in secondary
  • Max 60% ↓ in LDL
    • Depends on dose and med used
  • Max 10% ↑ in HDL
226
Q

Statins

Adverse Effects & Contraindications

A
  • Generally well-tolerated
  • Adverse effects
    • Myopathy and/or rhabdomyolysis
      • <0.1% of pts on high dose of potent statin
    • ↑ liver enzymes
      • Need q6-month LFTs
  • Contraindications
    • Liver disease
    • Pregnancy
      • Cholesterol needed for fetal growth
227
Q

Bile Acid Sequestrants

Names

A

Cholestyramine

Colesevelam

Colestipol

228
Q

Bile Acid Sequestrants

Mechanism

A

Bind bile acids and promote excretion.

  1. ↑ excretion shunts more cholesterol into bile acid synthetic pathway
  2. ↓ hepatic cholesterol
  3. ↑ LDL receptor expression
  4. ↓ plasma LDL
229
Q

Bile Acid Sequestrants

Efficacy

A

All 3 sequestrants produce similar effects.

  • Max 25% ↓ in LDL
  • Should be present in small intestine following a meal for max effect
  • Usually taken with food
230
Q

Bile Acid Sequestrants

Adverse Effects & Interactions

A
  • Adverse effects
    • Bloating
    • Dyspepsia
    • May lead to ↑ serum triglycerides
      • Caution in pts with hypertriglyceridermia
      • Or use in combo with agent that ↓ TAG
  • Contraindications:
    • Dysbetalipoproteinemia
    • TAG > 400 mg/dL
  • Interactions
    • Binds other lipid soluble compounds
      • Can bind other drugs and cause excretion
        • Statins
        • Thiazides
        • Warfarin
        • Thyroxine
        • Digoxin
      • Should not take these meds 1 hour before - 4 hours after taking sequestrant
    • Interferes with Vit K
      • ↑ risk of excessive bleeding on warfarin
231
Q

Cholesterol Absorption Inhibitors

Names

A

Ezetimibe

Plant sterols

232
Q

Cholesterol Absorption Inhibitors

Mechanism

A

Prevent absorption of cholesterol by small intestine.

Dec. delivery of cholesterol to liver leads to dec. plasma LDL.

233
Q

Cholesterol Absorption Inhibitors

Admin, Efficacy, and Adverse Effects

A
  • As a monotherapy ⇒ max 15-20% ↓ in LDL
  • Can be used in combo w/ statin
    • Effects are additive
  • Minimal adverse effects
234
Q

Fibrates

Names

A

Gemfibrozil

Fenofibrate

235
Q

Fibrates

Mechanism

A

Activate peroxisome proliferator-activated receptor α (PPARα).

  • PPARα is a nuclear receptor
    • Dimerizes w/ retinoid X receptor (RXR)
  • Activates genes associated w/ FA metabolism including
    • Lipoprotein lipase
    • Apo AI
  • Net effect
    • ↓ TGL levels
    • ↑ HLD levels
236
Q

Fibrates

Indications

A
  • 1° for hypertriglyceridemia and/or to raise HDL levels
    • Max 50% dec. TGL
    • Max 20% inc. HDL
  • As monotherapy, moderate effect in LDL levels
  • Can be used w/ statins
237
Q

Fibrates

Adverse Effects, Contraindications, and Interactions

A
  • Adverse effects
    • GI discomfort
    • Gallstones
    • Hepatotoxicity
  • Contraindications
    • Severe renal disease
    • Severe hepatic disease
  • Can inc. free warfarin levels
    • Inc. risk of bleeding
238
Q

Niacin

Mechanism

A

“Nicotinic acid or Vit B3”

  • At low physiological levels (10-20 mg/day)
    • Need for synthesid of NAD and NADP
  • At high doses (1500-3000 mg/day)
    • Acts via GPCR to dec. adipocyte hormone sensitive lipase activity
      • Less substrate for hepatic lipoprotein synthesis
      • Dec. plasma TGL and LDL
    • Inc. plasma Apo AI levels
      • Inc. HDL
239
Q

Niacin

Efficacy

A
  • Most effective agent to inc. HDL
    • Max 35%
  • Dec. TGL max 50%
  • Dec. LDL max 25%
240
Q

Niacin

Admin

A

Used as monotherapy for moderately high LDL with low HDL.

Used as an adjunct to statin therapy.

241
Q

Niacin

Adverse Effects

A
  • Common
    • Flushing
    • Itching
  • Can be reduced by taking ASA or other NSAIDs
  • Time-release formulas (Niaspan) can reduce incidence
  • Less common / more severe
    • Hepatoxocitity
    • Hyperuricemia
    • Impaired insulin sensitivity
    • Potentiation of statin-induced myopathy
  • Contraindications:
    • Chronic liver disease
    • Severe gout
242
Q

Omega-3 Fatty Acids

A

“Fish oils, EPA, DHA”

  • Mech. appears to involve regulation of transcription factors PPARα, PPAR𝛾, SREBP-1c
    • Dec. TGL synthesis and inc. FA oxidation
  • Can dec. TGL max 50% in hypertriglyceridemia
    • Used when plasma TGL > 500 mg/dL
  • Lovaza ⇒ prescription strength
243
Q

PCSK9 Antibodies

A

alirocumab (Praluent)

evolocumab (Repatha)

  • PCSK9 affects LDL-R recycling
    • ↑ PCSK9 activity ⇒ ↓ LDL-R
  • Monotherapy ⇒ max 40-50% dec. in LDL
  • Combo w/ statins ⇒ max 70% dec. in LDL
  • Use approved for pts who cannot achieve LDL goals with other treatments
244
Q

Bempedoic Acid

(Nexletol)

A
  • Mechanism
    • Substrate for VLC acyl-CoA synthetase-1 (ACSVL1)
    • CoA derivative of drug inhibits ATP citrate lyase (ACL)
    • Inhibition of ACL reduces choleserol synthesis
    • Skeletal muscle does not have ACSVL1 ⇒ med is liver-specific
  • Shown in trials to reduce LDL w/o muscle side effects of statins
245
Q

Lipid Lowering Agents

Summary

246
Q

HLD

Treatment Guidelines

A

Released in 2019

  • Focuses primarily on statin use
  • Requires LDL testing 3 months after starting or changing dose
    • Every 6-12 months afterwards
  • For patients nonresponsive to statins, recommend adding ezetimibe and/or PSCK9 inhibitors
    • No others currently recommended
247
Q

Anginal Therapy

Goals

A

↑ O2 delivery to cardiac tissue by ↑ coronary blood flow

and/or

↓ O2 demand by ↓ cardiac work

  • Stable angina ⇒ dec. cardiac work through systemic vasodilation
  • Unstable angina ⇒ dec. cardiac work & thrombogenesis
  • Variant angina ⇒ reverse coronary spasm
248
Q

Myocardial Oxygen Demand

Determinants

A
  • HR
  • Contractility (inotropic state)
  • Arterial pressure (afterload)
  • Ventricular volume (wall stress, preload)
249
Q

Coronary Blood Flow

Determinants

A
  • Aortic diastolic pressure
  • Duration of diastole
  • Coronary vascular resistance
250
Q

Vascular Tone

Determinants

A

Arteriolar and venous tone ⇒ ∆ peripheral vascular resistance ⇒ ∆ arterial blood pressure

251
Q

Smooth Muscle Relaxation

Mechanisms

A

SM uses MLCK to trigger crossbridge formation.

  1. ↑ cGMP
    • cGMP facilitates de-Phos of MLCK
    • Prevents myosin interaction w/ actin
    • Ex. organic nitrates
  2. ↓ [Ca2+] by preventing entry
    • ↓ activity of MLCK
    • Ex. Ca2+ channel blockers (verapamil, diltiazem, dihydropyridines)
  3. Stabilize/prevent membrane depolarization by ↑ K+ permeability
    • Prevents activation of voltage-gated Ca2+ channels
    • Ex. K+ channel openers (minoxidil, hydralazine)
  4. ↑ cAMP
    • cAMP ↑ rate of inactivation of MLCK
    • Not used in treatment of angina d/t effects on HR and contractility
252
Q

Nitrates

Mechanism

A
  • Release NO @ target tissues
  • NO activates guanylyl cyclase ⇒ cGMP ⇒ de-℗ of MLCK ⇒ vasodilation
  • At therapeutic doses ⇒ actions mostly confined to smooth muscles
    • Venodilation ⇒ ↓ preload and ventricular filling ⇒ ↓ myocardial O2 demand
      • Main effect
    • Dilation of large coronary arteries and arterioles ⇒ redistribution of blood flow from epicardial to endocardial regions ⇒ some relief from ischemia
253
Q

Nitrate

Admin

A
  • Isosorbide 5-mononitrate can be given PO
    • Avoids extensive 1st pass metabolism seen w/ nitroglycerin and isosorbide dinitrate
    • Longer duration of action
  • Nitroglycerin & isosorbide dinitrate given sublingual and slow-release buccal
    • Bypass liver and 1st pass
    • Reach terapeutic levels rapidly
  • Amyl nitrite given by inhalation
    • Also bypass hepatic system
  • IV preparations available
  • Rapid metabolism ⇒ only used for acute treatment
  • Long-lasting slow release preps available but usefulness limited by tolerance
254
Q

Nitrates

Tolerance

A
  • Repeated admins ⇒ loss of effectiveness
    • Tolerance seen after use of long-acting or IV for severals hours
  • Large degree of cross-tolerance between nitrates
  • Maybe due to dec. release of NO but mech. unknown
  • Systemic compensation w/ salt and water retention can also be involved
255
Q

Calcium Channel Blockers

Mechanism & Classes

A

↓ Ca2+ influx ⇒ ↓ intracellular Ca2+ ⇒ relaxation

  • Main target is L-type Ca2+ channels
  • Two classes ⇒ bind to different sites
    • Dihydropyridines (DHPs)
      • nifedipine, amlodipine, felodipine
      • Major effect as vasodilators only
        • ↓ arterial tone and systemic vascular resistance
        • Arterial dilation (major)
        • Venodilation
        • ↑ coronary blood flow
    • Non-DHPs
      • verapamil and diltiazem
      • Vasodilators and negative inotropes and chronotropes
        • ↓ myocardial contractile force
256
Q

Calcium Channel Blockers

Indications

A
  • All CCBs
    • Stable angina
    • HTN
  • Verapamil and diltiazem only
    • Unstable angina
    • SVT
257
Q

Calcium Channel Blockers

Side Effects

A
  • All CCBs
    • Hypotension
      • Reflex tachycardia (DHP only)
  • Verapamil and diltiazem only
    • Bradycardia
    • Reduced cardiac contractility
258
Q

Calcium Channel Blockers

Contraindications

A
  • All CCBs
    • Hypotension
  • Verapamil and Diltiazem only
    • Sick sinus syndrome
    • AV nodal disease
    • Heart failure
    • Use with care with β-blockers
259
Q

β-blocker

Anginal Treatment

A
  • All β-blocker equally effective
    • ↓ HR and ↓ contractility ⇒ ↓ myocardial O2 demand
  • Often used w/ DHP CCBs
    • Do not use w/ verapamil or diltiazem
      • These already have their own neg. inotropic/chronotropic effects
260
Q

Ranolazine

A
  • Thought to inhibit late Na+ current
    • ↓ Na+ entry ⇒ ↑ Ca2+ transport by Na+/Ca2+ exchanger ⇒ ↓ ischemia-induced Ca2+ overload
      • Improved diastolic function
      • Dec. O2 demand
  • For stable angina in pts who do not respond to other treatments
  • Contraindicated in pts w/ QT prolongation
    • Due to actions on cardiac channels
    • May cause arrhythmias
261
Q

Unstable Angina

Treatment

A

Primary goal to reduce myocardial oxygen consumption.

  • Hospitalize/bed rest
  • β-blockers
  • Antiplatelet (ASA, clopidogrel) & anticoagulant (heparin, LMWH)
  • Long term: use lipid lower drugs like statins
    • Reduce further plaque formation
  • Catherizations
  • Not used:
    • CCBs ⇒ do not prevent progression to MI or reduce mortality
    • Fibrinolytic agents ⇒ ineffective
262
Q

Prinzmetal’s Angina

Treatment

A
  • Caused by reversible coronary vasospasm
  • Usually responsive to nitrates and all CCBs
  • Do not use β-blockers ⇒ may exacerbate
263
Q

Ischemic Heart Disease

Treatment Summary

264
Q

Arrhythmia

Pathogenesis

A

All arrhythmias result from:

  1. Disturbances in impulse formation ⇒ ectopic pacemakes
  2. Disturbances in impulse conduction ⇒ nodal block or re-entry circuits
  3. Both

Many underlying causing including ischemia, hypoxia, autonomic influences.

265
Q

Re-Entry Arrhythmia

Pathogenesis

A
  • Normal conduction
    • Impulse travels down α and β paths at the same speed
    • Refractory period prevents impulse from travel back up
    • AP travels in the right direction
  • Abnormal conduction
    • Unidirectional block prevents/slows travel down β path
    • Impulse from α path can go in both directions @ junction
    • Impulse can travel up β path back to atrial tissue
  • Unidirectional block due to paths α and β having different refractory periods ⇒ “temporal block”
266
Q

Antiarrhythmic

Mechanisms

A
  1. Sodium channel blockade
    • Affects phase 0 of atrial/ventricular muscle and His/Purkinje system
    • Raises threshold and reduces conduction velocity
  2. Block SNS effects / Inc. PNS
    • Affects SA pacing and AV conduction
  3. Prolong effective refractory period (ERP) via K+ channel blockade
    • Blocks re-entry
    • Rephases heart
  4. Calcium channel blockade
    • Affects SA pacing and AV conduction
267
Q

Ectopic Pacemakers

Treatment Approachs

A
  1. Selectively inhibit Na+ or Ca2+ channels of depolarized cells
    • Drugs with high affinity for activatable channels (Phase 0) or inactivated channels (Phase 2) but low affinity for resting channels
    • Use or state dependent blockade
  2. Block electrical activity where there is a fast tachycardia
    • Many activations and inactivations per unit time
  3. Block electrical activity where there is significant depolarization of the resting potential
    • Many inactivated channels during rest
268
Q

Abnormal Automaticity

Treatment Approaches

A
  1. Reduce Phase 4 slope by blocking Ca2+ or Na+ channels
    • Dec. rate of phase 4 depolarization
  2. Block sympathetic effects directly
    • Inc. threshold for firing
269
Q

Re-entry Arrhythmias

Treatment Approaches

A
  1. Prolong ERP in delayed β path to stop re-entry
    • Keep things in phase
  2. Impair propogation in β path to prevent retrograde travel
    • Make block bi-directional
  3. Steady-state reduction in the number of available channels
270
Q

Classes of Antiarrhythmics

A

Vaughn Williams Classification

  • Class I ⇒ Na+ channel blockers
    • “Membrane stabilizing agents”
    • Further subdivided into IA, IB, IC
  • Class II ⇒ β-blocking agents
  • Class III ⇒ K+ channel blockers
    • Prolong AP by inhibiting repolarization
    • Increases ERP
  • Class IV ⇒ Ca2+ channel blockers
  • Others:
    • Digoxin
    • Adenosine
    • Mg2+
    • Ivabradine
271
Q

Class I

Antiarrhythmics

A
  • All Na+ channel blockers
  • Bind to the open and/or inactivated states
    • Traps channel in non-functional state
    • Drug must dissociate before channel can reopen
  • All show use or frequency dependent block
    • Inc. frequency of AP firing leads to inc. block
  • Useful in treating tachycardias
272
Q

Class IA

Names and Actions

A

Quinidine, procainamide, disopyramide

  • Strongly blocks activated Na+ channels ⇒ inhibits fast Na+ current (Strong Class I effect)
    • Slows phase 4 in Purkinje and ventricular muscle
    • Slows phase 0
    • ↑ threshold for AP
  • Weakly blocks K+ channels (Mild Class III effect)
    • ↑ AP duration
    • ↑ ERP
  • Antimuscarinic (vagolytic) activity
    • ↑ SA rate
    • ↑ AV conduction
    • Pro-arrhythmic
  • Effects on EKG
    • ↑AP duration
    • ↑ QRS
    • ↑ QT
273
Q

Class 1A

Complications & Clinical Use

A
  • Depressed conduction & lengthened repolarization ⇒ refractory heterogeneity
    • Torsade de pointes
    • Quinidine syncope
      • Recurrent episodes of lightheadedness
    • Proarrhythmic
  • Not shown to reduce mortality
  • Never first-line agents
274
Q

Quinidine

A

Class IA

  • Actions:
    • Strong Na+ and moderate K+ block
    • Anti-muscarinic activity
    • Weak α blocker activity
  • Indications:
    • All forms of arrhythmias
    • Esp. A. Fib and A. Flutter
  • Lots of drug interactions
    • Quinidine-digoxin
    • ↑ digoxin levels ⇒ digitalis toxicity
  • Pro-arrhythmic
275
Q

Procainamide

A

Class IA

  • Actions:
    • Strong Na+ and moderate K+ block
    • Less antimuscarinic effects
  • Indications:
    • Similar to quinidine
    • Sustained ventricular arrhythmias asociated with acute MI
  • IV-only
    • No long term use
  • Lupus-like condition in ⅓ of pts after 6 months of use
    • Rash, inflammation
    • Disappear after withdrawal
276
Q

Disopyramide

A

Class IA

  • Actions:
    • Strong Na+ and moderate K+ block
    • Strong antimuscarinic effects
    • ⊖ inotrope
      • Unknown mech
  • Indications:
    • Ventricular arrhythmias
277
Q

Class IB

Names and Actions

A

Lidocaine, mexiletine, tocainide, phenytoin

  • Weakly blocks Na+ channels in activated and inactivated states
    • Slightly ↓ rate of phase 0
    • Slightly ↓ AP duration
  • Preferentially acts on depolarized tissue
    • Ischemia, acidosis, fast stimulation rate
  • @ therapeutic doses does not alter electrical activity of normal tissue
  • Fast dissociation rate from channels
278
Q

Class IB

Indications

A

Acute suppression of ventricular arrhythmias.

Esp. after MI or cardioversion.

279
Q

Class IB

Side Effects and Interactions

A
  • Many CNS-related side effects
    • Tremor
    • Lightheadedness
    • Nausea of central origin
  • β-blockers may dec. lidocaine clearance
    • Must monitor levels
280
Q

Class IC

Names and Mechanism

A

Flecainide, Propafenone

  • Potent Na+ channel block
    • Very slow dissociation rate
  • Blocks Ito K+ current (Phase 1)
  • Marked effect on His/Purkinje system
  • Little effect on APD/ERP
  • EKG effects:
    • Significant QRS widening
    • May slightly prolong AP duration
  • Does not distinguish between normal and depolarized tissue
281
Q

Class IC

Indications

A
  • Life-threatening ventricular arrhythmias
  • Widely used to prevent recurrence of A. Fib
    • Flecainide only used in pts without significant LV disease or coronary heart disease
  • PSVT
282
Q

Class IC

Adverse Effects

A

Can be very pro-arrhythmic.

First dose usually given in the hospital so pt can be monitored.

283
Q

Class II

Antiarrhythmics

A

β-blockers

Propranolol, Sotalol, Acebutalol, Esmolol

  • Block sympathetic effects
  • Primarily affects SA and AV nodes
    • ↓ phase 4 depol in SA node
      • ↓ HR
    • ↓ AV nodal conduction
    • ↑ ERP of AV node
      • Can interrupt re-entry circuits
    • Slight prolongation of AV node AP
      • SNS slightly ↑ K+ currents
    • ↓ myocardial O2 consumption
      • Can ↓ risk of arrhythmia
  • See ↑ PR interval
284
Q

Class II

Indications

A

Shown to reduce arrhythmia-associated mortality.

  • Supraventricular arrhythmias
  • Control of ventricular rate in A. fib and A. flutter
  • Ventricular arrhythmias associated with re-entry circuits
  • Tachycardia induced by exercise or stress
285
Q

Class II

Adverse Effects

A
  • Bronchoconstriction
    • Use with cause in asthmatics
  • Sudden withdrawal can cause “rebound hypersensitivity”
286
Q

Class III

Mechanism

A
  • Block K+ channels
    • Prolong AP duration & ERP
  • Acts only on the repolarization phase
    • Conduction velocity is unaffected
    • Little effect on phase 0
287
Q

Class III Antiarrhythmics

Names

A
  1. Amiodarone
  2. Dronedarone
  3. Bretylium
  4. Sotalol
  5. Ibutilide
  6. Dofetilide
288
Q

Class III

Indications

A
  • Ventricular arrhythmias
  • Prophylactic control of V. tach
  • Amiodarone highly effective for recurrent A. Fib and A. Flutter
289
Q

Ibutelide (Convert)

&

Dofetilide (Tikosyn)

A

Pure Class III

(↑APD, ↑ERP)

  • Used for A. fib
  • Ibutelide IV
  • Dofetilide PO
290
Q

Sotalol

(Betapace)

A

Class III

  • D and L isomers
    • Both have class III activity
  • L-sotalol
    • β-blocker activity
  • Mainly used to maintain sinus rhythm after cardioversion
291
Q

Bretylium

A

Class III

  • Also blocks release of catecholamines from nerves after initial stimulation of release
  • Rarely used as an antiarrhythmic
292
Q

Amiodarone

(Cardarone, Pacerone)

A
  • Has actions from all 4 classes
  • Effects:
    • ↓ sinus rate
    • ↓ automaticity
    • Interrupt re-entry circuit
    • ⊖ inotrope
    • Vasodilator
  • Highly effective for reucrrent A. fib or A. flutter
  • Elimination half-life of 30-180 days
  • Many adverse effects ⇒ black box warning
    • Cardiac effects
    • Pulmonary fibrosis
    • Thyroid issues
    • Hepatonecrosis
    • Photodermatitis
  • Routine EKGs, CXR, LFTs, and thyroid panels are mandated
293
Q

Dronedarone

(Multaq)

A

Class III

  • Amiodarone analog
  • Much shorter half-life of 1-2 days
  • Does not have the pulmonary fibrosis or thyroid effects
  • Used for recurrent ventricular arrhythmias
294
Q

Class IV

Antiarrhythmics

A

Verapamil & Diltiazem

  • Calcium channel blockers
  • Mostly affects SA and AV nodes
    • ↓ SA node automaticity ⇒ ↓ HR
    • ↓ AV nodal conduction
    • Terminate AV re-entry
  • Avoid with β-blocker use
  • EKG: ↑ PR
295
Q

Class IV

Indications

A
  1. A. Fib (rate control)
  2. PSVT
296
Q

Class IV

Adverse Effects

A

Systemic effects ⇒ hypotension

297
Q

Adenosine

A
  • Opens K+ channels
    • Class IV-like
  • Indirectly inhibits Ca2+ channels and If
  • Mostly affects nodal tissues
    • ↓ SA firing rate
    • ↓ AV conduction
  • IV only w/ very short half life of 10-30 secs
  • Drug of choice for PSVT
  • Can be used as dx test for ventricular vs atrial cause of V tach
    • Will suprress atrial cause only
  • Effects reduced by adenosine receptor blockers
    • Caffeine and theophylline
298
Q

Magnesium IV

A
  • Weakly blocks ICa2+
  • Inhibits INa+ and If potassium channels
  • Indications
    • Used for torsades des pointes
    • Can be used to slow ventricular rate but not for PSVT
299
Q

Ivabradine

(Corlanor)

A
  • ⊗ If current in SA node
    • Responsible for phase 4 depolarization
  • ↓ HR
  • ↓ O2 demand
  • Indications:
    • CHF patients with tachycardia
    • Inappropriate sinus tachycardia
300
Q

Digoxin

A
  • ⊗ Na/K ATPase
  • Has vagomimetic actions
    • ↓ HR
    • ↓ AV nodal conductions
  • Used in A. Fib patients with heart failure
  • Can be proarrhythmic
301
Q

PSVT

Treatment

A
  • Acute
    • IV adenosine > verapamil or diltiazem
    • Carotid message
  • Chronic
    • Oral verapamil, diltiazem or β-blockers
302
Q

Atrial Fibrillation

Treatment

A
  • Rate Control
    • β-blocker or calcium channel blockers
    • Ventricular rate controlled by limiting rate of impulse propagation through AV node
    • Safety profile of rate-control drugs are better so try this first
  • Rhythm Control
    • Class III or Class IC agents
      • IC ⇒ flecainide or propafenone
      • III ⇒ amiodarone, dofetilide
    • Cardioversion
    • Suppress atrial automaticity to restore sinus rhythm
303
Q

Ventricular Tachycardias

Treatment

A
  • Acute
    • IV lidocaine
      • Drug of choice
    • IV amiodarone or flecainide also used
  • Recurrent
    • Oral amiodarone/dronedarone
304
Q

Antiarrhythmics

Effects on EKG

305
Q

Antiarrhythmics

Clinical Uses Summary

306
Q

CHF

Potential Interventions

A

3 basic therapeutic goals

  1. Improve myocardial contractility
    • Inotropic agents
  2. Reduce afterload
    • ACE inhibitors
    • Some vasodilators
  3. Reduce preload
    • Diuretics
    • Vasodilators
307
Q

Inotropic Agents

Mechanisms

A

Can increase cardiac contractility by:

  • ↑ resting Ca2+ levels
  • ↑ Ca2+ entry during an action potential
  • ↑ Ca2+ sensitivity of contractile apparatus
308
Q

Digitalis Compounds

Mechanism

A
  1. ⊗ Na/K ATPase
    • ↑ [Na+]intracellular ⇒ ↓ activity of Na/Ca exchanger ⇒ ↑ [Ca2+]intracellular ⇒ stronger contraction
  2. Vagomimetic actions
    • ∆ electrical activity of the heart
      • ↓ HR
      • ↓ AV nodal conduction
    • Reduces O2 demand
    • Allows more efficient filling
    • ↑ efficiency of failing heart
309
Q

Digitalis

Toxicity

A

Low therapeutic index ⇒ high risk of toxicity

Due to blockade of Na/K ATPase:

  • Cardiac manifestations
    • AV junctional rhythm
    • Premature ventricular depolarization
    • AV blockade
  • Extracardiac manifestations
    • Color vision abnormality
    • Disorientation
    • Gynecomastia
    • Anorexia
    • Nausea
    • Diarrhea
310
Q

Digitalis

Drug Interactions

A
  • Agents that ∆ renal clearance of digoxin ⇒ ↑ plasma digoxin levels ⇒ ↑ potential for toxicity
    • Ex. Quinidine
    • Digitoxin is cleared via hepatic system
  • Diuretics which cause hypokalemia ⇒ ↑ risk of toxicity for both digoxin and digitoxin
311
Q

Sympathomimetic Inotropes

(Treat CHF)

A

β-adreneric stimulation ⇒ ↑ cAMP

β1 ⇒ ⊕ inotropic & ⊕ chronotropic effects
β2 ⇒ peripheral vasodilation

312
Q

Dobutamine

CHF Treatment

A

β1 selective agonist

  • High inotropic effect
  • Low chronotropic effect
  • Not orally active
  • Shows desensitization
  • Limited to IV use for acute heart failure
313
Q

Dopamine

CHF Treatment

A

Used to treat acute heart failure.

  • At low doses
    • Release of NE at the heart
      • β1 adrenergic stimulation
    • Acts at dopamine receptors in the periphery
      • ⊗ peripheral NE release
        • Vasodilation
        • Enhanced renal and cerebral perfusion
  • At high doses
    • Direct α1 adrenergic activity
      • Vasoconstriction
314
Q

Norepi

CHF Treatment

A

Treatment of acute heart failure in cases where systolic pressure needs to be increased due to cardiogenic shock.

315
Q

Phosphodiesterase (PDE) Inhibitors

CHF Treatment

A

↑ cAMP levels

Avoids receptor desensitization.

  • Amrinone (Inocor)
    • Hepatotoxic
    • Induces nausea
    • Limited to short-term IV treatment for acute HF
  • Milrinone (Primacor)
    • PO was shown to have higher mortality rate than digitalis long term
    • Limited to IV treatment of acute HF
316
Q

Sympathomimetics

Receptor Sensitivity

317
Q

Diuretics

Mechanism

A

Reduce salt and water retention.

  • ↓ ventricular preload
  • ↓ edema
  • ↓ cardiac size
    • ↑ pumping efficiency
318
Q

Diuretics

CHF Treatment

A
  • Mild to moderate CHF
    • Dietary sodium restriction
    • Thiazide diuretic like hydrochlorotiazide
  • Severe CHF or when thiazide maxed out
    • Furosemide is diuretic of choice
319
Q

Spironolactone

CHF Treatment

A

Aldosterone antagonist

  • Aldosterone blockade can lead to significant reduction in mortality
  • Diuresis
  • Also inhibits other effects of aldosterone
    • Fibrosis of myocytes
    • Increased vascular sensitivity to Ang II
    • Inhibiton of NO release
  • Most common side affect ⇒ hyperkalemia
  • Also has weak progesterone receptor agonist and mixed estrogen agonist/antagonist activity
    • Breast enlargement in women
    • Gynecomastia in males
320
Q

Eplerenone

CHF Treatment

A

Aldosterone antagonist

  • Similar benefits to spironolactone
  • No progesterone/estrogen activity
    • Fewer side effects
321
Q

Vasodilators

CHF Treatment

A
  • Used to acutely reduce workload of failing heart
    • Arteriolar dilation ⇒ ↓ afterload
      • Use in pts w/ low ventricular output
      • Ex. hydralazine
    • Venodilation ⇒ ↓ preload
      • Use in pts w/ high filling pressures and pulmonary congestion
      • Ex. nitrates
  • Generally only used when other drugs haven’t worked
322
Q

BiDil

A

Isosorbide dinitrate + Hydralazine

  • For self-described African Americans with CHF
  • Hydralazine may potentiate effect of nitrate
    • Reduces tolerance
  • Appears effective
  • Does reduce mortality
323
Q

Nesiritide

(Natrecor)

A

Recombiant human B-type natriuretic peptide

  • Activates guanylate cyclase
    • Causes vasodilation
    • ↓ right atrial pressure
    • ↓ pulmonary capillary wedge prssure
  • May be an inc. in short-term mortality
  • Usefulness not proven
324
Q

ACEi and ARBs

CHF Treatment

A

Choice for chronic CHF.

Provides a significant improvement in cardiac function.

  • ↓ peripheral resistance ⇒ ↓ afterload
  • ↓ aldosterone secretion
    • ↓ salt and water retention ⇒ ↓ preload
  • ↓ circulating angiotensin levels
    • ↓ sympathetic activity
  • ↓ long term remodeling of the heart
325
Q

Neprilysin Inhibitors

A
  • Prevents Neprilysin degradation of vasoactive peptides
    • Natiuretic peptides
    • Bradykinin
  • Conteracts neurohormonal overactivation
    • ↓ vasoconstriction
    • ↓ volume loading
    • ↓ cardiac remodeling
  • Not shown to be effective alone
    • Neprilysin also breaks down Ang II so inhibition inc.
326
Q

Entresto

A

Neprilysin inhibitor sacubitril + ARB valsartan

  • Improved effects on morbidity and mortality
  • Used to reduce risk of cardiovascular death and hospitalization in chronic HF pts
327
Q

β-blockers

CHF Treatment

A
  • Certain β-blockers improves outcome of pts w/ mild CHF
  • May work by counteracting effects of excess SNS activation d/t low CO
  • Carvedilol
    • Nonselective β-blocker + some α-antagonist
    • Most effective
  • Metoprolol and Bisprolol
    • β1 selective
328
Q

Ivabradine

(Corlanor)

A

Block If in SA node ⇒ ↓ phase 4 depolarization ⇒ ↓ HR

Reduces hospitalizations associated with worsening heart failure and mortality.

329
Q

RAAS System

A
  • Renin
    • Protease made @ renal juxtaglomerular apparatus
  • Angiotensinogen
    • Plasma glycoprotein made by liver, kidney, brain, fat
  • Ang I
    • Formed by proteolysis of angiotensinogen by renin
    • Weak vasoconstrictor activity
  • Ang II
    • Formed by proteolysis of Ang I by ACE
    • Very potent vasoconstrictor
  • Ang III
    • Formed by aminopeptidase on Ang II
    • Weak vasoconstrictor activity
330
Q

Angiotensin Receptors

A
  • AT1
    • Gq ⇒ IP3/DAG system
    • Vasoconstriction
    • Mitogenic activity
    • Main clinical effector
  • AT2
    • Highest in fetus
    • Post-natal role unclear
331
Q

Bradykinin

A

Vasodilator peptide

Degraded by ACE

332
Q

Renin Secretion

Regulation

A

Renin release is rate-limiting step in Ang II formation.

Controlled by local renal mechanisms and CNS.

  • Renal vascular receptor
    • Dec. stretch ⇒ renin release
  • Macula densa
    • Dec. sodium delivery ⇒ renin release
  • SNS
    • NE ⇒ β1 ⇒ renin release
  • Ang II
    • Acts on juxtaglomerular cells to reduce renin release
333
Q

Ang II Actions

A
  • Blood pressure
    • Potent vasoconstrictor
  • Adrenal cortex
    • Simulates zona glomerulosa to release aldosterone
      • Inc. salt and water retention
  • CNS
    • CNS mediated pressor response ⇒ inc. SNS
    • Stimulates thirst
    • Stimulates ADH and ACTH release
  • Cell growth
    • Mitogen activity for vascular and cardiac muscle cells
334
Q

Aliskiren

(Tekturna)

A

Orally-active direct renin inhibitor

  • Not non-inferior to ACEi or ARBs
  • Induces reactive renin release
  • Not first-line therapy
  • Contraindicated in combo w/ ACEi or ARS in DM
335
Q

ACE inhibitors

Mechanism

A
  • ⊗ Ang I ⇒ Ang II
    • ↓ TPR ⇒ ↓ BP
    • Do not induce reflex sympathetic activation
      • Can use safely in pts w/ ischemic heart disease
  • ⊗ Bradykinin breakdown
    • Bradykinin has vasodilator activity
      • ↓ BP
    • Responsible for cough and rash
336
Q

ACE inhibitor

Classes

A

Pharmacokinetic classes:

  • Class I
    • Active as is
    • Captopril
  • Class II
    • Prodrugs
    • All except Captopril and Lisinopril
  • Class III
    • Water soluble, active as it, excreted unchanged by kidney
    • Lisinopril
337
Q

ACE inhibitor

Indications

A
  • HTN
    • Esp. in DM b/c doesn’t impair insulin sensitivity
  • CHF
    • Shown to reduce mortality
  • Diabetic nephropathy
  • Post MI
  • Type 2 DM
    • Lessens new microalbuminuria
338
Q

ACE Inhibitors

General Adverse Effects

A
  • Dry cough
  • Skin rash
  • Hypotension
  • Hyperkalemia
  • Acute renal failure
  • Teratogenesis
  • Angioedema
339
Q

Captopril Specific

Adverse Effects

A
  • Neutropenia
  • Loss of taste
  • Oral lesions
  • Proteinuria
340
Q

ACE Inhibitors

Contraindications

A

Share with ARBs and direct renin inhibitors.

  • Pregnancy
  • Severe renal failure
  • Hyperkalemia
  • Bilateral renal stenosis
  • Pre-existing hypotension
  • Severe aortic stenosis
  • Obstructive cardiomyopathy
341
Q

Angiotensin Receptor Blockers

(ARBs)

A

Losartan, Valsartan

  • Same effect on BP as ACEi
  • Fewer side effects
    • May have lower incidence of angioedema

1. HDS Cardiology (7 decks)

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