1. Fluid Compartments
1. intracellular fluid compartment - within the cells themselves
2. extracellular fluid compartment - outside the cells
• plasma - fluid portion of the blood (3 L)
• interstitial fluid - fluid bathing all cells and tissues of body (15 L)

2. Fluid Composition
1. nonelectrolytes - no electrical charge (glucose)
2. electrolytes - dissociate into ions (NaCl)
3. milliequivalents per liter (mEq/L) - measure of number of charges in 1 liter of solution
• concentration of ion (mg/L)
• mEq/L = -------------------------------------- X # charges per ion
• atomic weight of ion
3. Extracellular vs. Intracellular Fluids
1. extracellular - high Na+ and high Cl-
2. intracellular - low Na+ and low Cl-
4. Fluid Movement between Compartments
1. plasma -> interstitial -> plasma & lymphatics
2. Oxygen, glucose -> into cells
3. Carbon Dioxide, nitrogenous wastes -> out of cells
4. ECF <===> ICF depends on NaCl in the ECF

1. Overview of Water Balance
1. intake - 90% ingested water; 10% metabolic water
2. output - 60% urine; 28% lungs/skin; 12% sweat/feces
3. water need - trigger thirst & release of ADH

2. The Thirst Mechanism
• decrease in plasma volume OR increase in osmolarity -----> excitation of hypothalamic thirst center -----> sensation of thirst

3. Regulation of Water Output
1. obligatory water loss - lungs, sweat, feces
2. regulation of water - kidneys (ADH -> Na+)
4. Disorders of Water Balance
1. dehydration - water loss > water intake
• bleeding, burns, sweating, diuretics
2. hypotonic hydration - too much water or Na+
3. edema - accumulation of water in interstitial space

1. Sodium (Na+) - 90% of solutes in the ECF; most important and prevalent of all electrolytes
2. Aldosterone - released by adrenal cortex (renin-angiotensin)
1. released in response to:
• a. decrease in blood pressure
• b. decreased osmolality of filtrate
• c. sympathetic stimulation of juxtoglomerular cells
2. function - increase Na+ reabsorption at distal tubule
• a. water will follow if ADH makes the distal tubule permeable to water
3. Baroreceptors
1. located in carotid arteries and aorta
2. respond to changes in stretch due to blood pressure
• blood pressure increases ------> hypothalamic stimulation ------> sympathetics to kidneys decrease ------> increased GFR (water removed)
• blood pressure decreases (same path as above) ----> ----> ----> lower GFR (water retained)
4. Antidiuretic Hormone (ADH)
1. released from the posterior pituitary
2. responds to osmoreceptors in the hypothalamus
• decrease in osmo of ECF ------> decreased release of ADH ------> less permeability of distal tubule to water ------> more water released into urine
• increase in osmo of ECF ------> increased release of ADH ------> more permeability of distal tubule to water ------> less water released into urine

5. Atrial Natriuretic Factor (ANF)
1. released by cell of heart atria under high B.P.
2. reduces blood pressure and blood volume by INHIBITING nearly all events that promote vasoconstriction and Na+/water retention."
6. Steroid Hormones
1. estrogen - increases resorption of Na+ in distal convoluted tubule
2. glucocorticoids (cortisol) - increases resorption of Na+ in the distal tubules

1. Importance of K+
1. K+ is primary CATION (+) in within cells
2. K+ abnormalities cause changes in Resting Mem Pot (neurons, cardiac muscle especially)
2. Renal Control of K+ Levels
1. 10-15% constantly lost in urine
2. most resorption occurs in Proximal Tubule
3. regulation - changing amount SECRETED into urine in the collecting tubules
• low K+ ----> less secretion (intercalated cells in collecting tube can reabsorb more)
• high K+ ----> more secretion
3. Factors Controlling K+ Secretion
1. tubule cell intracellular K+ level - when low, secrete less; when high, secrete more
2. aldosterone level - K+ secreted: Na+ reabsorbed
• increase aldosterone -> more K+ secretion
• decrease aldosterone -> less K+ secretion
3. 3. pH - K+ and H+ compete for antiport with Na+
• lower pH (high H+) -> less K+ secretion
• higher pH (low H+) -> more K+ secretion

1. Importance of Ca++
1. bone is the "reservoir" of most Ca++ in the form of Calcium Phosphate (Ca++ with PO4-2)
2. primary physiological roles:
• at the muscle and neuron synapse
• essential for blood clotting process
• very critical in heart rhythms
2. Ca++ Regulation: Parathyroid Hormone (PTH) & Calcitonin
1. parathyroid hormone (PTH) - chief control when Ca++ begin to DECREASE too low
• bones - Ca++ and PO4-2 release to blood
• small intestine - activates Vitamin D which is essential for Ca++ resorption
• kidneys - Ca++ reabsorbed (but PO4-2 excreted)
2. calcitonin (thyroid gland) - released when Ca++ begins the INCREASE too high
• inhibits Ca++ release from bone, increases actual formation of Calcium Phosphate in bone

Drug Toxicities
Agranulocytosis	- Clozapine
Aplastic Anemia	- Chloramphenicol - NSAIDs - Benzene
Atropine-like Side Effects	- Tricyclics
Cardiotoxicity	- Doxorubicin - Daunorubicin
Cartilage Damage in children	- Fluoroquinolones (Ciprofloxacin & Norfloxacin)
Cinchonism	- Quinidine
Cough	- ACE Inhibitors
Diabetes Insipidus	- Lithium
Disulfiram-like effect	- Metronidazole - Sulfonylureas (1st generation)
Extrapyramidal Side Effects	- Antipsychotics (Thioridazine, Haloperidol, Chlorpromazine)
Fanconi’s Syndrome	- Tetracycline
Fatal Hepatotoxicity (necrosis)	- Valproic Acid - Halothane - Acetaminophen
Gingival Hyperplasia	- Phenytoin
Gray Baby Syndrome	- Chloramphenicol
Gynecomastia	- Cimetidine - Azoles - Spironolactone - Digitalis
Hemolytic Anemia in G6PD-deficiency	- Sulfonamides - Isoniazid - Aspirin - Ibuprofen - Primaquine
Hepatitis	- Isoniazid
Hot Flashes, Flushing	- Niacin - Tamoxifen - Ca++ Channel Blockers
Induce CP450	- Barbiturates - Phenytoin - Carbamazepine - Rifampin
Inhibit CP450	- Cimetidine - Ketoconazole
Interstitial Nephritis	- Methicillin - NSAIDs (except Aspirin) - Furosemide - Sulfonamides
Monday Disease	- Nitroglycerin Industrial exposure  tolerance during week  loss of tolerance during weekend  headache, tach, dizziness upon re-exposure
Orange Body Fluids	- Rifampin
Osteoporosis	- Heparin - Corticosteroids
Positive Coombs’ Test	- Methyldopa
Pulmonary Fibrosis	- Bleomycin - Amiodarone
Red Man Syndrome	- Vancomycin
Severe HTN with Tyramine	- MAOIs
SLE-like Syndrome	- Procainamide - Hydralazine
Tardive Dyskinesia	- Antipsychotics (Thioridazine, Haloperidol, Chlorpromazine)
Tinnitus	- Aspirin - Quinidine

GH sequence it is 191 AA – large polypeptides

Growth hormone:

Long arm chromosome 17 – GH –hCS cluster : There are five genes for GH - two are important

1. Normal GH (22K): 75% of circulating GH

2. hGH –V (20K): 10% of circulating GH

3,4,5 hCS (HPL) –supplies fetal need in absence of GH-N leads to normal growth of embryo even if GH genes are defective.

Chorio somato mamotrope hormone L, A and B (transcription factor).

Pit-1 binds to promoter region of gene there is no GH if it is absent.

Pit-1(tissue specific protein transcription factor) binds to promotor region of gene = mRNA = pre hormone = removal of signal peptide = active hormone

GH also has homology to prolactin: The three cousins: HGH, HPL and Prolactin

Plasma level, Binding, Metabolism:

GH binding protein (GHBP): binds GH in plasma protecting from degradation.

GHBP is equivalent to extracellular portion of GH receptor: about 50% of total is bound

Metabolism takes place in liver, 1/2t: 6-20min

Molecular Action:

Binds to receptor –member of cytokine receptor superfamily:

Dimerization of receptor (must bind two receptors) leads to activation JAK2 = self phosphorlyation = phosphorylation of STAT 1,3 and 5 ( STAT proteins are transcription factors) which then enter nucleus to DNA and lead to gene transcription. No receptor = Laron syndrome.

Pit-1 involved in creation of GH and STAT is involved in post-receptor defects

HORMONES ALWAYS HAVE RECEPTOR AND POSTRECEPTOR ACTION

After JAK there is downstream action activation of IRS1, IGF1 and others, Tyrosine phosphatases cut of the reaction, GH receptor induced by insulin and estrogen and repressed by fasting (both insulin and GH are phosphorlated and phosphorlates others).

REMEMBER: dimmerization, STAT and series of activation

GH leads to dimmarization activates JAK2 then tyrosine on JAK is phosphorlated leads to phosporlation of other proteins.

JAK2 ---- transcription factor stat activates G protein and genes

Series of events:

GHRH and Somatostatin have opposing effects, when one increases the other decreases. Hypothalamus receives stimulus form the brain such as neuroepi, seratonine, etc, effected by stress and sleep. Glucose and FFA also work on hypothalamus. Somatomedin= IGF-1

IGF-1 works on pituitary and hypothalamus this is the long loop

GHRH has a negative feedback to hypothalamus this is ultra-short loop

GH has negative feedback on hypothalamus this is short loop

Regulation of GH secretion – very important:

• Pituitary GHRH: Specific GHRH receptor 1. AC &CAMP + 2. PLC &DAG + IP3

• GHRELIN –GHRP found in stomach and hypothalamus (first found in rat stomach), other (hottest hormone – in research)

GH secretagogues

• Somatostatin (GHIH): 5 receptors (dec CAMP and intracellular calcium)

• Secretion of GH dependent on S/GHRH – one inc. the other dec. opposing action

• Opposing effects on IC (intracellular) Ca+ levels GHRH inc and GHIH drops IC Ca+ levels – then Pit 1 action inc or decreased

• GH = IGF 1 = negative feedback to GH

Nutrition and GH secretion: High protein meal ( Arginine), hypoglycemia and low FFA increase & hyperglycemia and high FFA decrease secretion

GH protects you from hypoglycemia

Obesity: inhibits - Leptin (167 AA) polypeptide secreted from adipose cell. Most people are resistant to leptin, thus does not control appetite any longer

Malnutrition: inhibits IGF 1 upgrading GH, lack of feedback

LOTS of regulation of GH

• Stress (fever, exercise, surgery ) – shuts off sex hormones

• Sex hormones (E & A) – women have higher GH than men

• Neuronal: Dopamine, norepi, serotonin all increase GHRH responses, AcH drops SS.

• Alpha adrenergic stimuli inc and B adrenergic stimuli diminish response of GH

• Excess steroids drop GH (inhibit growth)

Endocrinologist used to examine boys GH levels by giving them estrogen and beta blocker at the same time and check levels.

Pulsatile secretion GH

• About 10 pulses daily: GH levels low 50% of day – in order to measure GH you must show that it is not responsive to stimulus, give insulin cause a drop in glucose levels and then give FFA

• Low in 95% of samples in elderly & obese

• Highest in puberty

• 50% drop in GH level every 7 years

• Regular nocturnal peak 1 hr after stage 3 or 4 sleep.

GH secretion : Higher in childhood than adulthood peak during puberty, low before birth because you have IGF-2 and HPL instead.

GH Action:

• Production of IGF -1

• Enhances lipolysis and lipid oxidation (correct for low FFA)

• Enhanced protein synthesis (muscle growth / steroid)

• Antagonism of insulin action

• Phosphorous, sodium and water retention

• Enhance renin and aldosterone (cause sodium and water retention)

• Suppression ANF (arterial naturatic factor – drop sodium)

• Inc 1,25(OH)2 Vit D = inc Ca absorption gut (for bone growth by increasing active vitamin D and Ca++ retention).

• Need normal levels of GH for pancreatic development but too much GH = antagonism to insulin

• Increases cardiac muscle size and contractility and CO

• Sensitizes gonads to LH and FSH promoting pubertal sexual development

• Leads to tumor growth in excess – colonic polyps

IGF 1 (Somatomedin) - Its like “and Abraham beget Isaac”

If you were to treat Jaws from James Bond you will give him somatostatin to stop GH and measure IGF-1 levels, there is a new drug that interferes with dimmarization of GH receptor.

Liver major site of syntheses but other organs produce as well

• GH stimulates IGF 1 (Structurally related to Proinsulin but have unique C chain).IGF -1 levels in plasma change with levels of GH.

• IGF-1 levels correlate with progression of pubertal growth

• 6 binding proteins (IGFBP 3 most significant and also GH mediated)

• IGF receptor similar to IR

• Fasting & insulin deficiency drops IGF 1 (inc GH)

• Growth promoting effects mostly accounted for by IGF 1.

• Cortisol and large doses estrogens diminish IGF -1 (GH antagonism)

• Be prepared for developments: is it tissue IGF or plasma IGF which leads to growth?? Open area in progress!

Structure of Proinsulin that is similar to IGF-1, insulin receptor has two alpha and two beta chains and will cross react with IGF-1. Large amounts of IGF-1 can cause hypoglycemia.

IGF-1 Pathology

• Acromegaly - activity of disease correlates with IGF – 1 levels

• Pituitary dwarfism – low IGF levels

• Laron syndrome: Abnormal IGF receptor with low IGF and high circulating GH levels

• Anorexia Nervousa: high GH and low IGF

IGF-2

• Also similar to proinsulin as is IFG 1

• mRNA found in liver, cartilage and others

• Receptor is a monomer (binds IGF 1)

• IGF -2 less affected by GH and regulates growth in fetus,

• Found in trophoblast cells and enhances placental growth

• In excess can stimulate insulin receptor and cause hypoglycemia

Next slide was a depiction of IGF-2 sequence it is alpha, beta, and C chain

Prolactin: in hypothalamus dopamine will shut off prolactin and somatostatin. TRH leads to production of TSH and prolactin (influences gonads and mammary glands). Overproduction shuts of THRH and leads to infertility.

Prolactin receptor works on DNA leads to gene expression. Prolactin is higher during sleep and highest in the morning, patient must get up two hours before giving blood for checking prolactin levels.

Factors for PROL secretion:

Increase physiological: pregnancy, nursing, nipple stimulation, exercise, stress and sleep.

Increase Pharmacological: TRH, estrogen, dopamine antagonist, opioids, monoamine oxidase inhibitors, verapamil.

Increase pathological: Hypothyroidism and pituitary tumors increase prolactin secretion.

Decrease pathological: hypopituitarism and pseudo-hypoparpthyroidism

During pregnancy there is a 50% increase in the size of pituitary for increased prolactin production.

GH sequence it is 191 AA – large polypeptides

Growth hormone:

Long arm chromosome 17 – GH –hCS cluster : There are five genes for GH - two are important

1. Normal GH (22K): 75% of circulating GH

2. hGH –V (20K): 10% of circulating GH

3,4,5 hCS (HPL) –supplies fetal need in absence of GH-N leads to normal growth of embryo even if GH genes are defective.

Chorio somato mamotrope hormone L, A and B (transcription factor).

Pit-1 binds to promoter region of gene there is no GH if it is absent.

Pit-1(tissue specific protein transcription factor) binds to promotor region of gene = mRNA = pre hormone = removal of signal peptide = active hormone

GH also has homology to prolactin: The three cousins: HGH, HPL and Prolactin

Plasma level, Binding, Metabolism:

GH binding protein (GHBP): binds GH in plasma protecting from degradation.

GHBP is equivalent to extracellular portion of GH receptor: about 50% of total is bound

Metabolism takes place in liver, 1/2t: 6-20min

Molecular Action:

Binds to receptor –member of cytokine receptor superfamily:

Dimerization of receptor (must bind two receptors) leads to activation JAK2 = self phosphorlyation = phosphorylation of STAT 1,3 and 5 ( STAT proteins are transcription factors) which then enter nucleus to DNA and lead to gene transcription. No receptor = Laron syndrome.

Pit-1 involved in creation of GH and STAT is involved in post-receptor defects

HORMONES ALWAYS HAVE RECEPTOR AND POSTRECEPTOR ACTION

After JAK there is downstream action activation of IRS1, IGF1 and others, Tyrosine phosphatases cut of the reaction, GH receptor induced by insulin and estrogen and repressed by fasting (both insulin and GH are phosphorlated and phosphorlates others).

REMEMBER: dimmerization, STAT and series of activation

GH leads to dimmarization activates JAK2 then tyrosine on JAK is phosphorlated leads to phosporlation of other proteins.

JAK2 ---- transcription factor stat activates G protein and genes

Series of events:

GHRH and Somatostatin have opposing effects, when one increases the other decreases. Hypothalamus receives stimulus form the brain such as neuroepi, seratonine, etc, effected by stress and sleep. Glucose and FFA also work on hypothalamus. Somatomedin= IGF-1

IGF-1 works on pituitary and hypothalamus this is the long loop

GHRH has a negative feedback to hypothalamus this is ultra-short loop

GH has negative feedback on hypothalamus this is short loop

Regulation of GH secretion – very important:

• Pituitary GHRH: Specific GHRH receptor 1. AC &CAMP + 2. PLC &DAG + IP3

• GHRELIN –GHRP found in stomach and hypothalamus (first found in rat stomach), other (hottest hormone – in research)

GH secretagogues

• Somatostatin (GHIH): 5 receptors (dec CAMP and intracellular calcium)

• Secretion of GH dependent on S/GHRH – one inc. the other dec. opposing action

• Opposing effects on IC (intracellular) Ca+ levels GHRH inc and GHIH drops IC Ca+ levels – then Pit 1 action inc or decreased

• GH = IGF 1 = negative feedback to GH

Nutrition and GH secretion: High protein meal ( Arginine), hypoglycemia and low FFA increase & hyperglycemia and high FFA decrease secretion

GH protects you from hypoglycemia

Obesity: inhibits - Leptin (167 AA) polypeptide secreted from adipose cell. Most people are resistant to leptin, thus does not control appetite any longer

Malnutrition: inhibits IGF 1 upgrading GH, lack of feedback

LOTS of regulation of GH

• Stress (fever, exercise, surgery ) – shuts off sex hormones

• Sex hormones (E & A) – women have higher GH than men

• Neuronal: Dopamine, norepi, serotonin all increase GHRH responses, AcH drops SS.

• Alpha adrenergic stimuli inc and B adrenergic stimuli diminish response of GH

• Excess steroids drop GH (inhibit growth)

Endocrinologist used to examine boys GH levels by giving them estrogen and beta blocker at the same time and check levels.

Pulsatile secretion GH

• About 10 pulses daily: GH levels low 50% of day – in order to measure GH you must show that it is not responsive to stimulus, give insulin cause a drop in glucose levels and then give FFA

• Low in 95% of samples in elderly & obese

• Highest in puberty

• 50% drop in GH level every 7 years

• Regular nocturnal peak 1 hr after stage 3 or 4 sleep.

GH secretion : Higher in childhood than adulthood peak during puberty, low before birth because you have IGF-2 and HPL instead.

GH Action:

• Production of IGF -1

• Enhances lipolysis and lipid oxidation (correct for low FFA)

• Enhanced protein synthesis (muscle growth / steroid)

• Antagonism of insulin action

• Phosphorous, sodium and water retention

• Enhance renin and aldosterone (cause sodium and water retention)

• Suppression ANF (arterial naturatic factor – drop sodium)

• Inc 1,25(OH)2 Vit D = inc Ca absorption gut (for bone growth by increasing active vitamin D and Ca++ retention).

• Need normal levels of GH for pancreatic development but too much GH = antagonism to insulin

• Increases cardiac muscle size and contractility and CO

• Sensitizes gonads to LH and FSH promoting pubertal sexual development

• Leads to tumor growth in excess – colonic polyps

IGF 1 (Somatomedin) - Its like “and Abraham beget Isaac”

If you were to treat Jaws from James Bond you will give him somatostatin to stop GH and measure IGF-1 levels, there is a new drug that interferes with dimmarization of GH receptor.

Liver major site of syntheses but other organs produce as well

• GH stimulates IGF 1 (Structurally related to Proinsulin but have unique C chain).IGF -1 levels in plasma change with levels of GH.

• IGF-1 levels correlate with progression of pubertal growth

• 6 binding proteins (IGFBP 3 most significant and also GH mediated)

• IGF receptor similar to IR

• Fasting & insulin deficiency drops IGF 1 (inc GH)

• Growth promoting effects mostly accounted for by IGF 1.

• Cortisol and large doses estrogens diminish IGF -1 (GH antagonism)

• Be prepared for developments: is it tissue IGF or plasma IGF which leads to growth?? Open area in progress!

Structure of Proinsulin that is similar to IGF-1, insulin receptor has two alpha and two beta chains and will cross react with IGF-1. Large amounts of IGF-1 can cause hypoglycemia.

IGF-1 Pathology

• Acromegaly - activity of disease correlates with IGF – 1 levels

• Pituitary dwarfism – low IGF levels

• Laron syndrome: Abnormal IGF receptor with low IGF and high circulating GH levels

• Anorexia Nervousa: high GH and low IGF

IGF-2

• Also similar to proinsulin as is IFG 1

• mRNA found in liver, cartilage and others

• Receptor is a monomer (binds IGF 1)

• IGF -2 less affected by GH and regulates growth in fetus,

• Found in trophoblast cells and enhances placental growth

• In excess can stimulate insulin receptor and cause hypoglycemia

Next slide was a depiction of IGF-2 sequence it is alpha, beta, and C chain

Prolactin: in hypothalamus dopamine will shut off prolactin and somatostatin. TRH leads to production of TSH and prolactin (influences gonads and mammary glands). Overproduction shuts of THRH and leads to infertility.

Prolactin receptor works on DNA leads to gene expression. Prolactin is higher during sleep and highest in the morning, patient must get up two hours before giving blood for checking prolactin levels.

Factors for PROL secretion:

Increase physiological: pregnancy, nursing, nipple stimulation, exercise, stress and sleep.

Increase Pharmacological: TRH, estrogen, dopamine antagonist, opioids, monoamine oxidase inhibitors, verapamil.

Increase pathological: Hypothyroidism and pituitary tumors increase prolactin secretion.

Decrease pathological: hypopituitarism and pseudo-hypoparpthyroidism

During pregnancy there is a 50% increase in the size of pituitary for increased prolactin production.

Adrenergic agonists, its important to know what the systemic effects of various vasoconstricors are.

Phenylephrine (a pure alpha agonist): doesn’t act on beta-receptors at all

Epinephrine (alpha, beta-1, beta-2 agonist): hydroxylated para position on the ring, epinephrine is a catecholamine. Dose concentration matters; low dose means that the concentration is below the alpha threshold. With respect to alpha-1, beta-1 and beta-2 receptors, epinephrine acts differently based on how much is present. If it is “below the alpha threshold” there is no alpha response (beta response only). If the epinephrine concentration is above the alpha threshold, alpha, beta-1 and beta-2 are activated, but the beta-2 response is masked because alpha and beta-1 are stronger.

Norepinephrine, levarterenol (Levophed) (alpha, beta-1 agonist; little beta-2): the structure lacks a terminal methyl group on the nitrogen. There is a small amount of beta-2 activation, mostly alpha and beta-1 are activated. When norepinephrine is marketed, it is called Levarterenol (Levophed).

Levonordefrin (Neo-Cobefrin): Syntetic vasoconstrictor, usually formulated with carbocaine. A methyl group is attached to the carbon chain. Levonordefrin has similar effects to epinephrine, but greater alpha/ beta-2 specificity and is 1/5 as potent for alpha (that’s why its used in 1:20,000 concentration).

These are alpha and beta agonists. The therapeutic effect is from the local stimulation of alpha-1 receptors, which causes local vasoconstriction of skin and mucosa; blood vessels in skeletal muscles do not have these receptors.

Of great concern to dentists are the systemic effects of vasoconstrictors. Stimulation of beta-receptors causes vasodilation of skeletal muscle (beta-2) and stimulation of the heart (beta-1). A general rule is that alpha-1 causes constriction of muscles, and beta-2 causes muscles to relax. Also, beta-1 affects the heart, beta-2 and alpha-1 affect the blood vessels.

The results of vasoconstrictors’ systemic effects are as follows:

-Decreased peripheral resistance (beta-2 receptor)

-increased heartrate/ tachycardia (beta-1 receptor)

-increased heart contractility (positive inotropic effect) (not mediated by receptors)

-for epinephrine (at “low dose” rate), mean blood pressure is unchanged (systolic BP increases [beta-1 receptor], diastolic BP decreases [beta-2 receptor]).

-for the other vasoconstrictors, mean BP increases (because there are less beta-2 effects)

-Cardiac output (C.O.) increases

-bronchodilation (beta-2)

Beta-1 effects also increase the irritability of the myocardium, thus increasing the danger of arrhythmia and fibrillation.

In summary:

-The net beta effect is good for counteracting cardiovascular depression of LA’s, but we don’t want too much beta stimulation due to cardiac irritability.

-Pure alpha agonists (phenylephrine) have no direct cardiac effects, but raises peripheral resistance and blood pressure, causing a reflex bradycardia of long duration; therefore we see hypertension and bradycardia. Also, a pure alpha agonist can cause too much vasoconstriction and produce tissue necrosis; thus, pure alpha agonists are generally not desirable.

(from Perusse, Goulet & Turcotte, Oral Surg. Oral Med. Oral Path. (1992) 74, 679)… just in case you were wondering

*It is essential that you know this list!

1. Absolute Contraindications:

   1. Heart Disease

      1. unstable angina

      2. recent m.i. (within 6 mos., get a med consult)

      3. recent coronary artery bypass surgery

      4. refractory arrhythmias

      5. untreated/ uncontrolled severe HTN

      6. untreated/ uncontrolled congestive heart failure

   2. Uncontrolled hyperthyroidism: thyroid hormones cause an increased beta-receptor response, will get high cardiovascular load and can lead to heart failure

   3. Uncontrolled Diabetes: epinephrine antagonizes insulin

   4. Sulfite sensitivity: metabolism of vasoconstrictors yields sodium metasulfite.

   5. Steroid-dependent asthma: because of sensitivity to sulfites

   6. Pheochromocytoma: lots of epi from tumor growth, don’t want to add more.

2. Relative Contraindications:

   1. Pts taking the following drugs: (** #’s 1-3 have effects on the heart)

      1. Tricyclic antidepressants: block amine pump; increase BP, HR and sympathetic tone

      2. Phenothiazine antipsychotics: block alpha receptors so you don’t get beta response (dec. BP)

      3. MAO inhibitors: MAO breaks down catecholamines, when MAO is inhibited the vasoconstrictors cant get broken down as well.

      4. Nonselective beta-blockers (ie. propranolol): you’d get alpha response, severe HTN and reflex bradycardia

      5. L-dopa (for Parkinson’s disease): L-dopa is metabolized to dopamine, acts on heart beta-receptors

   2. Cocaine abusers: cocaine blocks the amine pump, causing increased adrenergic responses.

3. Precautions:

   1. Recent Stroke: if within 6 mos., get a med consult before giving vasoconstrictor

In general, vasoconstrictors reduce the toxic risk of a local anesthetic, as previously discussed. However, if the LA is accidentally injected into a blood vessel, epinephrine can actually increase the toxic risk. Cardiac stimulation induced by epinephrine accelerates the spread of LA to the CNS. This may increase the LA toxicity as much as twofold!!!

The American and NY Heart Associations: For pts at cardiac risk, you may give a maximum of 0.04 mg (40 g) epinephrine.

How much is that? One 1.8 cc cartridge of 1:100,000 epinephrine contains 18 g epinephrine. So 40 g epinephrine is contained in about 2 cartridges.

Question of whether or not to use vasoconstrictor:

Don’t if the pt’s MD forbids it.

If the MD does not permit epinephrine, then you may NOT use levonordefrin either.

It is often said that a pt is likely to suffer more adverse effects from endogenously-released epinephrine due to pain if the LA wears off, than from a vasoconstrictor given to prolong the duration of anesthesia. However, this assessment is difficult to quantify. It has been shown that at resting levels, the epinephrine from 1 carpule can approximately double the amount of systemic epinephrine.

The bottom line: if there is any question as to whether or not to use vasoconstrictor, call the pt’s MD and discuss it. If you can’t use a vasoconstrictor, stay on top of the pain situation by giving more frequent injections.

-Unintentional injection of LA into a blood vessel can cause systemic effects, as can the rapid absorption of large amounts of LA (occasionally).

-Anesthesiologist must take special precautions against systemic toxicity. Time is critical for tx of systemic toxicity. Must have CPR training and working oxygen source, along with other equipment, including a defibrillator and suction device. Drugs such as succinylcholine, diazepam or thiopental, vasopressors, and atropine should be in syringes with needles attached. Pulse and BP should be taken before the block.

-the administration of LA requires 3 precautions to avoid systemic toxicity:
1) aspiration,
2) adequate test doses,
3) slow administration of full dose in fractional amounts.

-If blood is found on aspiration, move the needle to another place, but a clear aspiration does not necessarily ensure a safe injection. The possibility of systemic toxicity still exists.

-Epinephrine response consists of an increase in BP and pulse, circumoral pallor, palpitations and nervousness. Pts on beta-adrenergic blocking drugs may not respond to epinephrine with increased HR, but will usually have an increased BP.

-Slow injection technique while monitoring the pt is essential for the quick detection of systemic effects, also you must be careful not to move the needle into a blood vessel after a safe aspiration.

-Systemic toxicity after an intravascular injection will usually occur within 1-2 minutes, 5 or more minutes may elapse if rapid tissue absorption is the cause of systemic effects (for spinal block specifically, or also for dental injections? I don’t know… )

-If untreated, convulsions with hypoxia, hypercarbia and acidosis may result. Respiratory abnormalities including apnea may occur. The hypoxia and acidosis cause myocardial contractions from the direct effects of the LA, and may result in cardiac arrhythmias, asystole, or ventricular fibrillation. Prior to convulsions, the pt may display any or all of a plethora of signs: slurred or incoherent speech, restlessness, nervousness, dizziness, blurred vision, tinnitis, and or drowsiness.

-Pts with LA-induced convulsions developed rapid hypoxia, hypercarbia, and acidosis within a minute. Oxygen consumption and carbon dioxide production are greatly increased during LA convulsions, thus immediate and effective ventilation with oxygen is essential to avoid cardiac arrest.

-Tx of systemic toxicity:
1.) Establish and maintain an airway;
2) immediately administer 100% oxidation (may prevent convulsions);
3) if necessary, use drugs to control convulsions;
4) if cardiac arrest occurs despite other procedures, CPR must be initiated and continued as necessary.

Prilocaine hydrochloride (Citanest)

Prilocaine is similar in action to Lidocaine and Mepivacaine, but slightly less potent and less toxic than Lidocaine, with slightly longer duration of action (pKa= 7.9). Metabolism is unusual in that de-alkylation is not required as a first step (its already a secondary amine); it’s usually a first step in the degradation of LA’s, but not in this case.

Prilocaine can cause cyanosis due to production of methemoglobin (oxidized form of hemoglobin in which ferrous is converted to ferric iron, and O2 binding affinity is drastically reduced). Should not be used in cases where oxygenation is critical, eg. pregnancy. Should not be used in conjunction with other drugs that may induce formation of methemoglobin (eg. acetaminophen or phenacetin). Its important to know that Prilocaine comes in a 4% solution both without vasoconstrictor and with vasoconstrictor (1:200,000 epinephrine).


Bupivacaine hydrochloride (Marcaine, Sensorcaine)

the structure is similar to Mepivacaine, but the methyl is replaced by C4H9, which makes it more hydrophobic and more potent. Bupivacaine is 4x as potent and toxic as Mepivacaine. The dental preparation is 0.5% solution with 1:200,000 epinephrine. Bupivacaine is the only long-acting LA currently available (others have been pulled from the market for financial reasons).

Etidocaine hydrochloride (Duranest)

The name Duranest indicates that it’s a long duration product. Etidocaine has just been pulled from the market however.

Articaine hydrochloride (Septocaine)

The structure of Articaine is not drawn on the handout, and I can’t draw it here. Just know that it is an amide LA with a thiophene rign instead of a benzene ring, and has a methyl side-group attached to the thiophene ring by an ester bond (although it has an ester bond, it is still considered an amide!!). There is a Sulfur in the thiophene ring, be careful with pts who are allergic to sulfur.
Articaine comes in 1.7 ml carps, just to be different.

Body clearance is about 20 minutes (t ½) , compared to 90-120 minutes for Lidocaine.

Remember: Articaine is a 4% solution, so you should inject less than half of what you would if you were using Lidocaine.

H1-Receptor Antagonists

Diphenhydramine (Benadryl) and Promethazine (a phenothizine) and Pyrilamine (an ethylenediamine) are all effective local anesthetics theoretically,

The anesthetic concentration in topical agents is much higher than in injectable solutions; it can be as high as 20%!!

Cocaine hydrochloride is the best topical ever, but not available anymore for obvious reasons.
Benzocaine is not a weak base, but neutral (always in B form, never BH+)
Dyclonine hydrochloride (Dyclone) is a ketone!!

The LA’s toxic potential is related to its potency. Remember Mepivacaine and Lidocaine specifically, as related to Procaine. Mepivacaine is 2 times as potent as Procaine, and 2 times as toxic. Lidocaine is 4 times as potent as Procaine, and 2 times as toxic.

The maximum adult dose (MRD) is:

400mg Mepivacaine (without vasoconstrictor)

300mg Lidocaine (without vasoconstrictor)

1. Procaine hydrochloride (Novocain)

Procaine has a quick onset and short duration because it is rapidly hydrolyzed by the body's esterases (since Procaine is an ester).

2. Propoxycaine hydrochloride (Ravocaine)

Propoxycaine is more potent because there is a more hydrophobic group on the ring as compared to Procaine. Typically, if a structure is more hydrophobic it will be more potent... it will also probably be more toxic and have increased duration, and you may get binding to plasma proteins.

3. Tetracaine hydrochloride (Pontocaine)

This is no longer available for injection in dentistry due to toxic potential, but is still used for spinal anesthesia and in Oral Surgery.

Lidocaine hydrochloride (Xylocaine, Octocaine, Alphacaine)

Its very important to be able to recognize this molecule. The maximum systemic blood level after injection occurs at 10 minutes without vasoconstrictor, and at 60 minutes with vasoconstrictor... so you must be alert for toxic responses of your injection up to one hour after injection

Metabolism of Lidocaine

Lidocaine (2-diethylaminoacet-2',6'-xylidide) is broken down to several endproducts that are eventually excreted by the kidneys (KNOW THE ENDPRODUCTS!!):

-acetate

-ethylaminoacetic acid (monoethyl glycine) (MX or GX)

-4-hydroxy-2,6-DMA

-N-hydroxy-2,6-DMA

-2-amino-3-methyl-benzoic acid

*also, know each "in-between" product as outlined on this page and p.9 or the "regular handout"

Some pts experience sedation with lidocaine, probably due to the MEGX and MX metabolites; some metabolites are thus active!

Lidocaine is the only amide LA that can be used also as a topical anesthetic.

MRD for Lidocaine (2% Xylocaine)

The Maximum Recommended Dose (MRD) for normal, healthy adults (NOT elderly or young children or very sick pts) is:

-"Plain" (Lidocaine without epi): 4.5mg/kg (2.0 mg/lb) with a 300 mg MAXIMUM

DOSAGE regardless of weight (8 carps)

-Lidocaine with 1:100,000 epi: 7.0 mg/kg (3.2 mg/lb) with a 500 mg MAXIMUM

DOSAGE regardless of weight (14 carps)

(The Council on Dental Therapeutics recommends never going over 8 carps, regardless of the MRD values for lidocaine with epi).

**You must know MRD and be able to convert to mg and carpule equivalents... remember that there are different MRDs for lidocaine with and without epinephrine.

The benefit of Mepivacaine is that there is no apparent cross allergenicity with other amide LA’s or with ester LA’s.

Dental use for infiltration and block: 3% solution without vasoconstrictor; 2% solution with vasoconstrictor (1:20,000 levonordefrin [Neo-Cobefrin]). The vasoconstrictor is 5x more concentrated than the typical epinephrine dose (1:20,000 vs. 1:100,000) but levonordefrin has about 1/5 the potency of epinephrine, so it evens out.

The Mepivacaine without a vasoconstrictor is found in 3% concentration, so has 30 mg/ml. The MRD is 3.0 mg/lb (6.6 mg/kg). It is recommended that 5 carps is “usually adequate” although 400 mg is the maximum dosage permissible (regardless of body weight). According to studies, there has been no improvement in safety of Mepivacaine when a vasoconstrictor is present.

MRD for normal, healthy adults 2% carbocaine (Mepivacaine) with 1:20,000 neocobefrin (Levonordefrin)

The Mepivacaine with vasoconstrictor is found in 2% concentration, so has 20 mg/ml. The MRD is 3.0 mg/lb (6.6 mg/kg). It is recommended that 5 carps is “usually adequate” although 400 mg is the maximum dosage permissible (regardless of body weight).

The manufacturer has recently discontinued 2% Mepivacaine with levonordefrin.

Endometrial hyperplasia: is an important cause of abnormal uterine bleeding, a result of a variety of disordered glandular and stromal growth patterns. Although endometrial hyperplasia per se is benign, hyperplasia in which there are atypical changes in cells (cellular atypia) are precancerous lesions. Similar to endometrial adenocarcinoma, hyperplasia is associated with hyperestrogenism.

Endometrial proliferative progression: endometrial patterns following unopposed oestrogen action

Weakly proliferative > Normal proliferative> Disordered proliferative

> Adenocarcinoma > Hyperplasia (> atypia)

Disordered proliferative endometrium: a focal change in which the total volume of the endometrium is not markedly increased; associated with…

• Mild Increase in gland : stroma ratio

• Glands may show some dilatation, budding, branching or irregularities of shape

• Mitoses are not as common as in normal proliferative endometrium

Classification: histologically there are two general categories of hyperplasia:

1. Low grade hyperplasias include:

   • Simple hyperplasia (cystic or mild hyperplasia), in which benign hyperplastic glands become cystically dilated (lined by tall columnar epithelium)

   • Complex hyperplasia (adenomatous), in which glands of varying sizes and shape may show budding and branching with marked crowding of glands (clusters - back to back)

[Note: terms simple or complex refers to the degree and nature of glandular proliferation]

2. High grade hyperplasias include:

• Atypical hyperplasia, in which the glandular complexity is accompanied by cellular atypia of the hyperplasic epithelium; cells lose polarity, enlarged nuclei, increased mitoses etc.

All these types produce abnormal uterine bleeding, but only atypical hyperplasia is associated with a significant frequency of progression to carcinoma.

Related risks: of progression to carcinoma…

Simple hyperplasia without atypia: minimal risk

Complex hyperplasia without atypia: <2%>

Simple hyperplasia with atypia: <10%>

Complex hyperplasia with atypia: 25-80% risk

Endometrial carcinoma: is a disease of older women (peak incidence is 55-65 years); about 80% of cases are found in women past the menopause and only 3% of cases occur in women under 40 years of age.

Risk factors: an increased incidence is associated with:

• Obesity

• Diabetes

• Hypertension

• Infertility

Most endometrial carcinomas follow on endometrial hyperplasia and can be related to the action of oestrogens.

[However there is also a group of well-differentiated tumours occurring in older women, which cannot be related to oestrogen and which have a worse prognosis.]

Morphology:

Grossly: endometrial carcinoma presents either as:

• A localized polyploidy tumour

• A diffuse spreading lesion involving the entire endometrial surface.

Histologically: most endometrial carcinomas are adenocarcinomas; biologically the:

• Less aggressive tumours include well differentiated carcinomas closely resembling normal endometrial glands (endometrioid), with squamous, secretory or mucinous differentiation.

• More aggressive neoplasms are poorly differentiated carcinomas, including clear cell carcinomas and papillary serous carcinomas.

Prognosis: depends on the state of the disease…

Stage	Extent	5 year survival
I	Confined to corpus uteri itself Ia. Limited to endometrium and superficial myometrium Ib. Invades to >1/2 myometrium	90%
II	Invades cervix	30-50%
III	Extended outside uterus but within pelvis	<20%
IV	Outside pelvis directly or metastasis or involves bladder and rectal mucosa.	<20%