Megaloblastic anaemia: caused most commonly by a deficiency of vitamin B₁₂ or folate, features…

• Abnormally large erythroid precursors (megaloblasts) whose nuclear maturation lags behind the cytoplasmic maturation

• Ineffective erythropoiesis (death of megaloblasts in the marrow) associated with compensatory hyperplasia

• Prominent anisocytosis (variability in cell size), a reflection of ineffective erythropoiesis, including abnormally large and oval red cells (macro-ovalocytes)

• Abnormal granulopoieses yielding giant metamyelocytes and hyper-segmented neutrophils (up to 6 lobes)

Pathophysiology:

Vitamin B₁₂ and folic acid are essential coenzymes in the DNA synthetic pathway. A deficiency of these nutrients results in deranged or inadequate synthesis of DNA, but the synthesis of RNA and proteins is unaffected. Therefore, cytoplasmic enlargement and maturation occur without concomitant nuclear maturation.

In addition to affecting red cell precursors, a deficiency of vitamin B₁₂ and folate affects all rapidly dividing cells, including all myeloid cells and the mucosal epithelium of the GIT.

The anaemia results from:

• Ineffective erythropoiesis

• Production of abnormal erythrocytes that are susceptible to accelerated haemolysis

Ineffective granulopoiesis and thrombopoiesis as well as premature destruction may also affect granulocyte and platelet precursors, giving rise to pancytopenia.

Vitamin B₁₂ deficiency:

Vitamin B₁₂ is absorbed through the ilium, facilitated by intrinsic factor (IF) secreted by parietal cells of the stomach; absorption is limited to 2-3mg daily (the body requires only 1mg B₁₂ daily).

The ultimate source of this vitamin is dietary animal products. The daily requirements are approximately supplied by a normal western diet 10-30mg daily, but not by strict vegetarian diet excluding all animal produce.

A deficiency of vitamin B₁₂ may result from:

• Pernicious anaemia: (1 in 10 000) an autoimmune disorder that damages gastric parietal cells and the production of IF

• Gastrectomy, which leads to loss of IF

• Resection of the ilium (preventing absorption of IF- B₁₂ complex)

• Malabsorption syndromes

• Increased requirements (e.g. pregnancy)

• Inadequate diet; uncommon because the body has large reserves

Folate deficiency:

Natural folates are largely absorbed through the upper small intestine after deconjugation and bony stores are sufficient for only about 4 months.

Daily requirement of folate is 0.1-0.2mg; normal mixed diet contains 0.2-0.3mg.

A deficiency of folate may result from:

• Inadequate dietary intake (poor quality, poverty, synthetic without added folate)

• Malabsorption through the proximal small bowel (e.g. gluten induced enteropathy, jejunal resection)

• Increased requirements (transfer of folate to the foetus in pregnancy)

Dispositional (metabolic) tolerance – Pharmacokinetic. Less drug gets to the site of action due to metabolism or distribution change. Continuous use.

Pharmacodynamic (functional) tolerance – Decreasing effects cannot be explained by change in metabolism or distribution. Same amount of drug gets to site of action, but changes in tissues or cells result in decreased response to drug. Doing interval is important. Continuous use.

Behavioral tolerance – Individual learns to compensate for effects of drug. Occurs with occasional use.

Degree of tolerance – Depends on doing interval, dose level, type of tolerance, and duration of treatment.

Requirements for production of physical dependence – Dose interval (continuous), dose level (sufficient depression of function), duration of treatment. Shorter-acting drugs have more intense withdrawl symptoms upon termination of administration.

Opioid tolerance – High degree of cross-tolerance. No tolerance to miosis, constipation, or excitatory effects. Withdrawal symptoms include lacrimation, rhinorrhea, sneezing, yawning, other muscarinic effects, and kicking movements. Opioid withdrawl is not life-threatening, except in newborns. Methadone and clonidine (autonomic symptoms) are used to suppress withdrawl symptoms during detoxification. Ultra-rapid opiate detoxification has been attempted with naltrexone. Maintenance therapy is administered using methadone orally. Acetylmethadol is also used for maintenance therapy as it is long-acting. Buprenoprhine (partial agonist) may be able to substitute for opiates and blocks the euphoria of opiates. Treatment of neonatal withdrawl involves methadone and diazepam in some cases. Clonidine is also used.

CNS depressant tolerance – The lethal dose (death by respiratory depression) is not much greater in addicts than in non-tolerant individuals. Tolerance develops to the psychic and motor effects but not to the respiratory depressing effects. Withdrawal from these agents is much more severe and life-threatening than withdrawal from opiates. Symptoms of withdrawal include hyperexcitability that can progress to seizures and status epilepticus. Abrupt withdrawal of short-acting agents can be fatal. A common approach to treatment of withdrawal us to suppress withdrawal with pentobarbital or Phenobarbital and then gradually reduce the dose. Diazepam is given to substitute for short-acting benzodiazepines and then gradually withdrawn.

I. THE AUTONOMIC NERVOUS SYSTEM (ANS)

A. The ANS regulates the activity of smooth muscle, cardiac muscle and certain glands.

B. It generally works without conscious control-it is involuntary.

C. The ANS is regulated primarily by the hypothalamus.

D. It has a major role in maintaining homeostasis in the human body.

E. The ANS contains both sensory and motor neurons.

II. TYPES OF NEURONS IN THE ANS

A. General Visceral Sensory Neurons-makeup the input portion of the ANS.

1. These carry impulses from the internal organs and joints to the CNS.

2. These neurons are involved in:

a. Monitoring CO₂ levels in the blood

b. Detecting stretch of organs and blood vessels

c. Pain and nausea sensations from damaged viscera

d. Monitoring fullness of the urinary bladder

B. General Visceral Motor Neurons-these carry impulses to cardiac muscle, smooth muscle and

some glands.

1. Responses produced by these neurons include:

a. Changing pupil size in the eye

b. Dilating blood vessels

c. Adjusting the rate and force of the heartbeat

d. Movements in the GI tract

e. Secretion of most glands

2. 2 Divisions of the Motor Portion of the ANS

a. The Sympathetic Division

b. The Parasympathetic Division

3. The sympathetic and parasympathetic divisions are distinguished by:

a. Their specific origin sites

1) Parasympathetic fibers emerge from the brain and sacral portion of the

spinal cord (referred to as Craniosacral).

2) Sympathetic fibers originate in the Thoracolumbar region of the spinal cord.

b. The lengths of their fibers

1) Parasympathetic fibers tend to have long preganglionic and short

postganglionic fibers. The opposite is true of sympathetic fibers.

c. Location of their ganglia

1) Most parasympathetic ganglia are located in the visceral effector

organs; whereas, sympathetic ganglia lie near the spinal cord.

4. Most organs of the body receive impulses from both divisions of the motor portion of

the ANS. This is referred to as Dual Innervation.

a. In general, the above 2 divisions have opposing effects on a particular effector.

5. Anatomy of Motor Pathways in the ANS

a. Autonomic motor pathways always contain 2 neurons that occur in succession.

The first neuron has its cell body in the CNS; the second extends to effectors

in the body (which includes cardiac and smooth muscle and glands).

1) Preganglionic Neuron-in the CNS. These contain a preganglionic axon

that synapses with the second motor neuron of the ANS. These

neurons usually contain thin nerve fibers that are lightly myelinated.

2) Postganglionic Neuron-extends to effectors in the body. Nerve fibers

in these neurons are extremely thin and are never myelinated.

3) An autonomic ganglion separates the 2 neurons. Autonomic ganglia

are motor ganglia.

III. THE PARASYMPATHETIC DIVISION OF THE ANS

A. This division regulates those activities that conserve and regulate body energy during times of

rest and recovery. This is an energy conservation-restoration system.

B. It dominates over sympathetic impulses in the digestive glands and G.I. Tract.

1. This ensures that food is digested and nutrients absorbed.

C. SLUD Responses-are associated with the parasympathetic division of the ANS.

1. These responses are salivation, lacrimation, urination, and defecation. These (except for lacrimation) are associated with digestion. Under extreme stress or fear, one may lose control over these responses. These responses are sometimes referred to as D Responses-digestion, defecation, diuresis (urination).

D. Major Parasympathetic Neurons are associated with:

1. The oculomotor nerves-to help position the lens and eyeballs for focusing.

2. The facial nerves-especially those that regulate the lacrimal glands and salivary glands.

3. The glossopharyngeal nerves

4. The vagus nerves

5. The pelvic nerves

IV. SYMPATHETIC DIVISION OF THE ANS

A. This division prepares the body for emergency situations. It is primarily concerned with

processes that expend energy. This division generally increases body temperature.

B. It acts to counteract parasympathetic effects within the body.

C. It regulates E Situations: excitement, emergency, exercise, and embarrassment.

D. It produces “Fight or Flight Responses.”

E. This division innervates many of the visceral organs and visceral structures in the superficial

portion of the body.

F. Table 14.2

V. A FEW EFFECTS OF THE SYMPATHETIC AND PARASYMPATHETIC DIVISION OF THE ANS

A. Effector Sympathetic Parasympathetic

1. Sweat glands Increases secretion Decreases secretion

2. Blood vessels Dilates Constricts

3. Bronchial action Increases respiration Decreases respiration

4. Liver Increases glycogen release Decreases glycogen release

5. Adrenal glands Increases activity Decreases activity

VI. NEUROTRANSMITTERS IN THE ANS

1. Neurotransmitters released by neurons in the ANS

1. Postganglionic autonomic fibers in the sympathetic division of the ANS release

Norepinephrine onto visceral effectors (See Table 14.3).

2. Postganglionic autonomic fibers in the parasympathetic division of the ANS release

acetylcholine as their primary neurotransmitter.

B. Neurotransmitter Receptors associated with the ANS

1. Cholinergic Receptors-bind acetylcholine. 2 Types of cholinergic receptors include:

a. Nicotinic Receptors-which are located on motor end plates of skeletal muscle

cells, all ganglionic neurons (both sympathetic and parasympathetic) and the

hormone-producing cells of the adrenal medulla.

b. Muscarinic Receptors-found on effector cells stimulated by postganglionic fibers.

2. Adrenergic Receptors-these generally receive norepinephrine.

a. 2 Classes of these: alpha and beta receptors.

3. Drug effects on these receptors-in textbook.

VII. HOMEOSTATIC IMBALANCES OF THE ANS

A. Hypertension

B. Raynaud’s disease