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Pharmacology

Pharmacodynamics

Pharmacodynamics is the study of what drugs do to the body and how they do it.

Dose-Response Relationships

- Basic Features of the Dose-Response Relationship:  The dose-response relationship is graded instead of all-or-nothing (as dose increases, response becomes progressively larger).

- Maximal Efficacy and Relative Potency

- Maximal Efficacy: the largest effects that a drug can produce

- Relative Potency:  Potency refers to the amount of drug that must be given to elicit an effect.

- Potency is rarely an important characteristic of a drug.

- Potency of a drug implies nothing about its maximal efficacy.
 

Thiazide diuretics

Chlorothiazide, Hydrochlorothiazide

Mechanism(s) of Action

1.    Block facilitated Na/Cl co-transport in the early distal tubule. This is a relatively minor Na absorption mechanism and the result is modest diuresis 

2.    Potassium wasting effect 

a.    Blood volume reduction leads to increased production of aldosterone 
b.    Increased distal Na load secondary to diuretic effect 
c.    a + b = increase Na (to blood) for K (to urine) exchange which produces indirect K wasting

3.    Increase distal Ca re-absorption (direct effect) 

o    causes an increase in plasma calcium.This is unimportant NORMALLY but makes thiazides VERY inappropriate choice for hypercalcemic patients.

4.    Anti-diuretic effect in nephrogenic diabetes insipidus patients secondary to depletion of Na and Water. 

Toxicity
 
•    Electrolyte imbalance (particularly hypokalemia) ,Agranulocytosis , Allergic reactions 
•    Hyperuricemia , Thrombocytopenia 
 

Neurophysiology

Nerve fibers exhibit wide range of sensitivity to nerve blockade-in order of increasing resistance to block are the sensations of pain, cold, warmth, touch, pressure, proprioception and motor function

Nerve Fibers:

Types

Size

Speed

Occurrence

A (α)

20 µm

80 - 120

Myelinated (Primarily for muscular activity).

β

8 - 15 µm

 

Myelinated (Touch and pressure)

γ

4 - 8 µm

 

Myelinated (Muscle spindle tone)

δ

3 - 4 µm

10-15

Myelinated (Pain and temperature sensation)

B

4 µm

10-15

Myelinated (Preganglionic autonomic)

C

1-2 µm

1 - 2

Unmyelinated (Pain and temperature sensation)

 

Myelinated = faster conducting

Unmyelinated = slower conducting

- Small non-myelinated fibers (C- pain fibers) and smaller myelinated pre-ganglionic B fibers are more readily blocked than are larger myelinated fibers responsible for muscle activity and touch [A-alpha and A-beta].

- Clinically, a person would notice complete lack of sensation to a pinprick, while at the same time still be able to move their fingers.

Valproic acid: broad spectrum (for most seizure types)


Mechanism: blocks Ca T currents in thalamic neurons (prevents reverberating activity in absence seizures), ↓ reactivation of Na channels (in tonic/clonic seizures; prolongs refractory periods of neurons, prevents high frequency cell firing)


Side effects: very low toxicity; common = anorexia, N/V; at high doses inhibits platelet function (bruising and gingival bleeding); rarely see idiosyncratic hepatotoxicity


Drug interactions: induces hepatic microsomal enzymes (↓ effectiveness of other drugs), binds tightly to plasma proteins so displaces other drugs

Neomycin

used as a topical preparation

Neomycin is not absorbed from the gastrointestinal tract, and has been used as a preventative measure for hepatic encephalopathy and hypercholesterolemia. By killing bacteria in the intestinal tract, it keeps ammonia levels low and prevents hepatic encephalopathy, especially prior to GI surgery. It is not given intravenously, as neomycin is extremely nephrotoxic (it causes kidney damage), especially compared to other aminoglycosides.

Rofecoxib

Inhibit prostacyclin(PGI2) in vascular  endothelium , letting TXA2 act freely and  promote platelet aggregation. 

used in the treatment of osteoarthritis, acute pain conditions, and dysmenorrhea

Higher incidence of cardiovascular thrombotic  events.

Not used due to increase risk of heart attack, stroke

Class III Potassium Channel Blockers

Prolong effective refractory period by prolonging Action Potential

Treatment: ventricular tachycardia and fibrillation, conversion of atrial fibrillation or flutter to  sinus rhythm, maintenance of sinus rhythm
– Amiodarone (Cordarone) – maintenance of sinus rhythm
– Bretylium (Bretylol) 
– Ibutilide (Corvert) 
– Dofetilide (Tykosyn) 
– Sotalol (Betapace) 

 

 Amiodarone 
- Has characteristics of sodium channel blockers, beta blockers, and calcium channel blockers 
- Has vasodilating effects and decreases systemic vascular resistance 
- Prolongs conduction in all cardiac tissue 
- Decreases heart rate 
- Decreases contractility of the left ventricles 

Class III - Adverse Effects 
- GI- Nausea vomiting and GI distress 
- CNS- Weakness and dizziness
- CV-Hypotension, CHF, and arrhythmias are common. 
- Amiodarone associated with potentially fatal Hepatic toxicity, ocular abnormalities and serious cardiac arrhythmias. 

Drug – Drug Interactions
These drugs can cause serious toxic effects if combined with digoxin or quinidine. 
 

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