Insulin
Insulin is only given parenterally (subcutaneous or IV) Various preparations have different durations of action 
 

Mechanism

bind transmembrane insulin receptor
activate tyrosine kinase
phosphorylate specific substrates in each tissue type
liver
↑ glycogenesis
store glucose as glycogen
muscle
↑ glycogen and protein synthesis
↑ K+ uptake 
fat
increase triglyceride storage

Clinical use

type I DM
type II DM
life-threatening hyperkalemia
increases intracellular K+
stress-induced hyperglycemia
 

Toxicity
hypoglycemia
hypersensitivity reaction (very rare)

Insulin Synthesis
first generated as preproinsulin with an A chain and B chain connected by a C peptide. 
c-peptide is cleaved from proinsulin after packaging into vesicles leaving behind the A and B chains

Class I Sodium Channel Blockers 

• Block movement of sodium into cells of the cardiac conducting system
• Results in a stabilizing effect and decreased formation and conduction of electrical impulses 
• Have a local anesthetic effect
• Are declining in use due to proarrhythmic effects and increased mortality rates 

• Na channel blockers - Class 1 drugs are divided into 3 subgroups 
• 1A. 1B, 1C based on subtle differences in their mechanism of action. 
• Blockade of these channels will prevent depolarization. 
• Spread of action potential across myocardium will slow and areas of  pacemaker activity is suppressed.

Class IA Sodium Channel Blockers 

• Treatment of: symptomatic premature ventricular contractions, supraventricular tachycardia, and ventricular tachycardia, prevention of ventricular fibrillation
– Quinidine (Cardioquin, Quinaglute) 
– Procainamide (Pronestyl, Procanbid) 
– Disopyramide (Norpace) 

• Quinidine – prototype 
• Low therapeutic index
• High incidence of adverse effects 

Class IB Sodium Channel Blockers 

• Treatment of: symptomatic premature ventricular contractions and ventricular tachycardia, prevention of ventricular  fibrillation
– Lidocaine (Xylocaine) 
– Mexiletine (Mexitil) 
– Tocainide (Tonocard) 
– Phenytoin (Dilantin) 

Side Effects: Lidocaine 
• Drowsiness • Paresthesias  • Muscle twitching • Convulsions  • Changes in mental status (disorientation, confusion) • Hypersensitivity reactions (edema, uticaria, anaphylaxis) 

Side Effects: Phenytoin (Dilantin)
• Gingival hyperplasia 
• Nystagmus 
• Ataxia, slurring of speech 
• Tremors 
• Drowsiness 
• Confusion 

• Lidocaine – prototype 
• Must be given by injection 
• Used as a local anesthetic 
• Drug of choice for treating serious ventricular arrhythmias associated with acute myocardial infarction, cardiac surgery, cardiac catheterization and electrical conversion 

Class IC Sodium Channel Blockers
• Treatment of: life-threatening ventricular tachycardia or fibrillation and supraventricular tachycardia unresponsive to other  drugs 

– Flecainide 
– Propafenone 

Adverse Effects 
• CNS - dizziness, drowsiness, fatigue, twitching, mouth numbness, slurred speech vision changes, and tremors that can progress to convulsions.
• GI - changes in taste, nausea, and vomiting. CV - arrhythmias including heart blocks, hypotension, vasodilation, and potential for cardiac arrest. 
• Other Rash, hypersensitivity reactions loss of hair and potential bone marrow depression. 

Drug-Drug Interactions
• Increased risk for arrhythmias if combined with other drugs that are know to cause arrhythmias- digoxin and beta blockers 
• Increased risk of bleeding if combined with oral anticoagulants. 

Drug Food Interactions
• Quinidine needs an acidic urine for excretion. Increased levels lead to toxicity 
• Avoid foods that alkalinize the urine- citrus juices, vegetables, antacid, milk products

Antiarrhythmic Drugs

Cardiac Arrhythmias 
Can originate in any part of the conduction system or from atrial or ventricular muscle.
Result from
– Disturbances in electrical impulse formation (automaticity) 
– Conduction (conductivity) 
– Both

MECHANISMS OF ARRHYTHMIA
ARRHYTHMIA – absence of rhythm
DYSRRHYTHMIA – abnormal rhythm

ARRHYTHMIAS result from:
1. Disturbance in Impulse Formation
2. Disturbance in Impulse Conduction
- Block results from severely depressed conduction
- Re-entry or circus movement / daughter impulse

Types of Arrhythmias

• Sinus arrhythmias 
– Usually significant only 
– if they are severe or  prolonged 

• Atrial arrhythmias 
– Most significant in the presence of underlying heart disease
– Serious: atrial fibrillation can lead to the formation of clots in the heart 

• Nodal arrhythmias 
– May involve tachycardia and increased workload of the heart or bradycardia from heart block 

• Ventricular arrhythmias 
– Include premature ventricular contractions (PVCs), ventricular tachycardia, and ventricular fibrillation 

Indications
• To convert atrial fibrillation (AF) or flutter to normal sinus rhythm (NSR) 
• To maintain NSR after conversion from AF or flutter 
• When the ventricular rate is so fast or irregular that cardiac output is impaired
– Decreased cardiac output leads to symptoms of decreased systemic, cerebral, and coronary circulation 
• When dangerous arrhythmias occur and may be fatal if not quickly terminated 
– For example: ventricular tachycardia may cause cardiac arrest 

Mechanism of Action 
• Reduce automaticity (spontaneous depolarization of myocardial cells, including ectopic pacemakers) 
• Slow conduction of electrical impulses through the heart
• Prolong the refractory period of myocardial cells (so they are less likely to be prematurely activated by adjacent cells 
 

Clavulanic acid is often combined with amoxicillin to treat certain infections caused by bacteria, including infections of the ears, lungs, sinus, skin, and urinary tract. It works by preventing bacterium that release beta-lactamases from destroying amoxicillin.

Histamine: 

Involved in inflammatory and anaphylactic reactions 
Local application causes swelling redness, and edema, mimicking a mild inflammatory reaction.

Large systemic doses leads to profound vascular changes similar to those seen after shock or anaphylactic origin.

Storage: widely distributed; in tissues, primarily in mast cells; in blood- in basophils, platelets; non-mast cell sites (epidermis, CNS, regenerating cells)

Histamine Stored in complex with:
Heparin
Chondroitin Sulfate
Eosinophilic Chemotactic Factor
Neutrophilic Chemotactic Factor
Proteases

Release: during type I (IgE-mediated) immediate hypersensitivity rxns, tissue injury, in response to some drugs
a.    Process: Fcε receptor on mast cell or basophil binds IgE, when Ag binds → ↑ PLC activity → histamine

Symptoms: bronchoconstriction, ↓ Pa, ↑ capillary permeability, edema

Action

H1 receptors are located mainly on smooth muscle cells in blood vessels and the respiratory and GI tracts. When histamine binds with these receptors producing the following effects.

-Contraction of smooth muscle in the bronchi and bronchioles producing bronchoconstraction.

-stimulation of vagus nerve endings to produce reflex bronchoconstraction and cough.

-Increased permeability of veins and capillaries, which allows fluid to flow into subcutaneous tissues and form edema (little lower blood pressure).

-Increased secretion of mucous glands. Mucosal edema and increased nasal mucus produce the nasal congestion characteristic of allergic rhinitis and the common cold.

-Stimulation of sensory peripheral nerve endings to cause pain and pruritus.

Histamine promotes vasodilation by causing vascular endothelium to release nitric oxide. This chemical signal diffuses to the vascular smooth muscle, where it stimulates cyclic guanosine monophosphate production, causing vasodilation.

H2-receptors present mostly in gastric glands and smooth muscle of some blood vessels. When receptors are stimulated, the main effects are increased secretion of gastric acid and pepsin, increased rate and force of myocardial contraction.

The H3-receptor functions as a negative-feedback mechanism to inhibit histamine synthesis and release in many body tissues. Stimulation of H3 receptors opposes the effects produced by stimulation of H1 receptors.

The H4- receptor is expressed in only a few cell types, and their role in drug action is unclear.

Drugs cause release of histamine: 

Many drugs can cause release of histamine in the body.
-Intracutaneouse morphine injection in humans produced localized redness, localized edema and a diffuse redness. This is due to release of histamine.

-I.V. inj of curare may cause bronchial constriction due to release of histamine.

-codeine , papaverine, meperidine (pethedine), atropine, hydralizine and sympathomimetic amines, histamine releases by these drugs may not be significant unless they are administered I.V in large doses

Pharmacological effects

-  If injected I.V. (0.1 mg of histamine) causes a sharp decline in the blood pressure, flushing of the face and headache. 
- There is also stimulation of gastric acid secretion. 
- If this injection is given to an asthmatic individual, there will be a marked decrease in vital capacity and a sever attack of asthma. 

Circulatory effects of histamine:

The two factors involved in the circulatory action of histamine are:
Arteriolar dilatation and
Capillary permeability
So it leads to loss of plasma from circulation

Effect on gastric secretion:
Histamine is a potent stimulant of gastric Hcl secretion. 

Miconazole

Miconazole is an  imidazole antifungal agent commonly used in topical sprays, creams and ointments applied to the  skin to cure fungal infections such as Athlete's foot and Jock itch. It may also be used internally to treat vaginal  yeast infection.

When used by a person taking the anticoagulant medication warfarin, Miconazole may cause an adverse reaction which can lead to excessive bleeding or bruising.