Unit II

Chapter ... 7
Drugs used in the Therapy of Shock
♦ LEARNING OBJECTIVES ♦
After completing this chapter, reader should be able to:
• Discuss the general concepts associated with shock states, including physiologic response to shock, and
shock progression.
• Classify drugs and illustrate mechanism of action and ADR

7.1 INTRODUCTION
It is abnormal physiological state resulting from widespread and serious reduction of
tissue perfusion that if prolonged will lead to generalized impairment of cellular function.
• A life-threatening clinical syndrome of cardiovascular collapse characterized by:
o An acute reduction of effective circulating blood volume (hypotension).
o An inadequate perfusion of cells and tissues (hypoperfusion).
• If uncompensated, these mechanisms may lead to impaired cellular metabolism and
death.
• The clinical manifestations of shock are the result of stimulation of the sympathetic
and neuroendocrine stress responses, inadequate oxygen delivery, end-organ
dysfunction.
7.2 TYPES OF SHOCK
• Hypovolemic shock
• Cardiogenic shock
• Distributive shock
o Septic shock
o Neurogenic shock
o Anaphylatic shock
Management of Shock:
• Ionotrope: An agent that changes myocardial contractility.
• Vasopressor: An agent that increases blood pressure.
• Chronotrope: An agent that changes heart rate.
• Dromotrope: An agent that increases cardiac conduction velocity.

(7.1)
Pharmacology - II 7.2 Drugs used in the Therapy of Shock

Norepinephrine:
• Most widely used vasopressor.
• Potent α1 agonist causing vasoconstriction in tissue beds.
• Resultant increase in SVR causes rise in blood pressure.
• Standard dose: 4 mg in 50 ml (0.08 mg/ml).
Epinephrine:
• Nature’s vasopressor.
• Most commonly used during resuscitation cardiac arrest and anaphylaxis.
α1: Increases SVR.
β1: Increases HR and myocardial contractility.
β2: Bronchial smooth muscle relaxation.
Standard dose: 10 mg in 50 ml (0.2mg/ml).
Dopamine:
• Vasopressor agent.
• Use in cardiogenic and septic shock.
• Receptor stimulation depend on dose given.
Dobutamine:
• A synthetic cathecholamine.
• An inodilator.
• β1 stimulation: Increase HR and increase cardiac contractility.
• β2 mediated vasodilatation.
• Reduction in MAP is common with dobutamine.
• NE usually needed to offset vasodilatation.
Vassopressin:
• Peptide hormone released from posterior pituitary.
• Causes increase permeability of DCT and CT, increases water retention.(V2 receptor).
• V1 receptor present in the smooth muscle of a arteriolar wall and stimulation causes
smooth muscle contraction and vasoconstriction.
7.2.1 Hypovolemic Shock
Improper tissue perfusion as a result of severe loss of blood or other fluid from the body
or inadequate fluid intake, any of which decrease intravascular volume.
Causes of Hypovolemic Shock;
• Haemorragic (acute blood loss)
• Burns
• Excessive vomiting and diarrhea
Pharmacology - II 7.3 Drugs used in the Therapy of Shock

Pathophysiology of Hypovolemic shock

Hemorrhage from small venules and veins (50%)
↓
Decreased filling of right heart
↓
Decreased filling of pulmonary vasculature
↓
Decreased filling of left atrium and ventricle
↓
Left ventricular stroke volume decreases (Frank Starling )
↓
Drop in arterial blood pressure and tachycardia
↓
Poor perfusion to pulmonary arteries
↓
Cardiac depression and pump failure
Classsification of Hypovolemic Shock:
• Hemorrhagic: Trauma, gastrointestinal bleeding.
• Non-Hemorrhagic: external fluid loss, diarrhoea, vomiting, polyurea, fluid
redistribution, burns, anaphylaxis.
Signs and Symptoms:
• Anxiety, restlessness, altered mental state.
• Hypotension.
• A rapid, weak, thready pulse.
• Cool, clammy skin.
• Rapid and shallow respirations.
• Hypothermia.
• Thirst and dry mouth.
• Distracted look in the eyes.
Compensatory Mechanisms:
1. Adrenergic discharge.
2. Hyperventilation.
3. Vasoactive hormones Angiotensin, Vasopressin, Epinephrine.
4. Collapse.
5. Re-absorption of fluid from interstitial tissue.
6. Resorption of fluid from intracellular to extracellular space.
7. Renal conservation of body water and electrolyte.
Clinical Monitoring:
• Blood pressure
• Respiration
• Urine output
• Central venous pressure
Pharmacology - II 7.4 Drugs used in the Therapy of Shock

• ECG
• Swan-Ganz catheter
o cardiac output.
o mixed venous oxygen level.
o vascular pressure.
• Pulmonary artery wedge pressure.
Diagnosis:
• In management of trauma patients, understanding the patterns of injury of the
patient in shock will help direct the evaluation and management.
• Blood loss sufficient to cause shock is generally of a large volume (e.g. external,
intrathoracic, intra-abdominal, retroperitoneal, and long bone fractures).
• Diagnostic and therapeutic tube thoracotomy may be indicated in unstable patients
based on clinical findings and clinical suspicion.
• Chest radiographs, pelvic radiography, diagnostic ultrasound or diagnostic
peritoneal lavage.
MANAGEMENT:
Objectives:
(a) Increase Cardiac Output
(b) Increase Tissue Perfusion
The plan of action should be based on:
(a) Primary problem
(b) Adequate fluid replacement
(c) Improving myocardial contractility
(d) Correcting acid-base disturbances
• Resuscitation
• Immediate control of bleeding: Rest, Pressure Packing.
Operative Methods:
• Extracellular fluid replacement:
o Infusion of fluid is the fundamental treatment.
o Crystalloids, for initial resuscitation for most forms of hypovolemic shock.
o After the initial resuscitation, with up to several liters of crystalloid fluid, use of
colloids.
Drugs:
1. Sedatives
2. Chronotropic agents
3. Inotropic
7.2.2 Distributive Shock
• As in hypovolemic shock, there is an insufficient intravascular volume of blood.
• This form of "relative" hypovolemia is the result of dilation of blood vessels which
diminishes systemic vascular resistance.
• Examples of this form of shock:
1. Septic shock
2. Anaphylactic shock
3. Neurogenic shock
Pharmacology - II 7.5 Drugs used in the Therapy of Shock

1. Septic Shock: A type of distributive shock resulting from sepsis.

• Sepsis: An abnormal body wide inflammatory response to an infection that can
result in death.
Pathophysiology of Septic Shock:
Pathogenesis of septic shock
Exotoxin
TSST-1
Toxin-A

Nidus of infection Organism Gut release of

Abscess endotoxin
Pneumonia
Peritonitis Structural component
Pyelonephritis Teichoic acid antigen
Cellulitis Peptidoglycan
Endotoxin (LPS)

Plasma Monocyte-macrophage Endothelial cells Neutrophils

Complement Kinins Cytokines Selection, Icams Lysosomes

- TNF Renin-angiotensin system Oxygen free radicals
Coagulation - Interleukins Prostaglandins (superoxides)
- Extrinsic/intrinsic - Interferons Leukotrienes Granulocyte colony
pathways Platelet activating factor Prostacyclin stimulating factor
- Protein C; S Nitric oxide Thromboxane (G-CSF)
- TFPI Endothelin

Cellular dysfunction

Membrane
receptor Nucleus
Membrane
channel
Actin/myosin
Mitochondria lysosome
Cell death ? Apoptosis

Vasculature Organs Myocardium

- Vasodilation - Dysfunction - Depression
- Vasoconstriction - Metabolic abnormalities - Dilation
- Leukocyte aggregation
- Endothelial cell dysfunction

Shock

Refractory hypotension Multiple organ dysfunction Recovery

Death
Fig. 7.1: Pathogenesis of Septic Shock
Pharmacology - II 7.6 Drugs used in the Therapy of Shock

Clinical Signs:
• Hyperthermia
• Tachycardia
• Wide pulse pressure
• Low blood pressure (SBP < 90)
• Mental status changes
Treatment of Septic Shock:
• Fluid replacement.
• Supplemental oxygen.
• Antibiotics: Survival correlates with how quickly the correct drug given cover gram
positive and gram negative bacteria:
o Ceftriaxone 1 gram IV BD or
o Imipenem 1 gram IV TDS.
Add additional coverage for:
• Pseudomonas: Gentamicin or Cefepime.
2. Anaphylactic Shock:
It develops following exposure to:
• Allergen and cross links IgE on mast cells causing mediator release (release of
Histamine, Eicosanoids-LTs, PGs).
Clinical Presentation:
• Urticaria and angioedema.
• Bronchospasm.
• Hypertension and CV collapse.
Treatment:
Epinephrine is 1st line drug:
• Standard Dose: Inj. 0.5 ml (1:1000) IM.
• Repeat every 5-10 min if not improve.
• Inj. 0.5 ml (1: 10000),(1:100000) IV.
Antihistaminic:
• Diphenhydramine (H1) administered IV.
• Ranitidine (H2) administered IV.
• β2 agonist: Salbutamol.
• Corticosteroid: Hydrocortisone 200 mg IV followed by oral prednisolone for 3 days.
3. Neurogenic Shock:
Develops secondary to a sudden loss of ANS functions following spinal cord injury
resulting in vasomotor tone and impaired cellular metabolism.
Pharmacology - II 7.7 Drugs used in the Therapy of Shock

Features:
• Hypotension
• Bradycardia
• Poikilothermia
Management:
• Airway support.
• Fluid replacement.
• Dopamine (>10 mcg/kg/min).
• Ephedrine (12.5 - 25 mg IV every 3-4 hr).
• Atropine for bradycardia. (0.5 mg IV every 3 to 5 mins − 3 mg).
• Treatment of the underlying cause.
7.2.3 Cardiogenic Shock
A state of inadequate cardiac output despite of adequate intravascular volume ,
resulting in hypoxia.
• Cool, mottled skin
• Tachypnea
• Hypotension
• Altered mental status
• Narrowed pulse pressure
Causes of Cardiogenic Shock:
• Acute myocardial infarction
• Myocarditis
• Myocardial contusion
• Aortic or mitral stenosis
• Acute aortic insufficiency
Pathophysiology of Cardiogenic Shock:
• Often after ischemia, loss of LV function
• CO reduction = lactic acidosis, hypoxia
• Stroke volume is reduced
• Tachycardia develops as compensation
• Ischemia and infarction worsens
Treatment of Cardiogenic Shock:
• Aspirin, beta blocker, morphine, heparin
• If no pulmonary edema, IV fluid
• If pulmonary edema
• Dopamine – will ↑ HR and thus cardiac work
• Dobutamine – May drop blood pressure
• Combination therapy may be more effective
• Thrombolytics(streptokinase, rt-PA)
Pharmacology - II 7.8 Drugs used in the Therapy of Shock

7.3 TREATMENT OF SHOCK

Treatment of shock:
Always remember: BP = PVR × (SV × HR) - Identify which is the problem, and then fix it

CO

*Cardiogenic shock Distributive shock Hypovolemic shock Obstructive shock

Primary SV (due to PVR (profoundly) SV (due to Extrinsic compression of

problem contractility abnormal vasodilation) preload) heart preload, SV

Need to Need to Need to restore Need to relieve

contractility and PVR intravascular volume obstruction
PVR
Key
intervention Intravascular:
Inotropes Vasoconstrictors: Fluids:
-PE: Thrombolytics to
crystalloids: 2L bolus
destroy emoblus
Dobutamine Norepinephrine Epinephrine Valvular:
- Mechanical valve
If ineffective at obstruction: OR stat
Cardiac b1 1. Strong a1 restoring BP: Cardiac:
1. Strong a1 agonist
agonist agonist vasoconstriction, - Temponade: pericadio-
vasoconstriction, PVR centesis to drain effusion
PVR 2. Strong cardiac b1 Consider Change to blood Extravascular:
Force of myosin
2. Mild cardiac vaso- products: - tension pneumo: needle
power stroke ion agobnist
Explanation cardiac myocytes b1 agonist condstrictors - RBCs to restore decompression/chest
contractility, tube to remove intra-
contractivity to PVR O2 carrying.
SV and CO pleural air
SV and CO capacity
Contractility (strength of (inotropic) and HR 3. Strong b2 agonist
- FFP to restore
myocyte contraction) (chronotropic) Bronchodilation blood volume and Relieving ecternal
useful to treat clotting factors compression of heart
anaphylaxis) helps restore cardiac
Stroke volume
preload and SV
* For arrhythmias, treat the arrhythmia. For valvular dysfunction, send to the operating room (OR), stat

Fig. 7.2: Treatment of shock

QUESTIONS
1. Write a note on drugs used in the therapy of shock.