DANIL HAMMOUDI.MD

USMLE 1 REVIEW

A drug attribute that is proportional to receptor affinity: potency

Increasing doses are required to produce a specific magnitude of response: tolerance

A drug that increases the median effective dose (ED₅₀) of an agonist but does not change the maximal response: Competitive antagonist
	Rapidly reversible decline in the response to an agonist drug during drug exposure: Desensitization
		A condition that occurs when receptors are up-regulated: Supersensitivity

Most drugs bind reversibly to receptors.
Receptor affinity for a drug determines its potency, which is the dose or concentration required to produce a defined response.
The maximal response obtained with a drug is an indication of its efficacy.
Full agonists produce 100% of the maximal response, whereas partial agonists produce less than 100%.
Competitive or surmountable antagonists increase the median effective dose (ED₅₀) of an agonist but do not change its maximal response, whereas noncompetitive antagonists reduce the maximal response.
Tolerance occurs when increasing doses are required to elicit a specified response.
It may be caused by down-regulation of receptors, in which the number of receptors declines over a relatively long period of drug exposure, or by desensitization, which is an acute response that occurs during a short period of drug exposure.
Both down-regulation and desensitization may lead to tolerance, whereas the up-regulation of receptors may cause supersensitivity.

A middle-aged woman complains of an uncomfortable feeling in her chest. Her radial pulse is fast and irregular, and an electrocardiogram (EKG) shows a normal QRS complex that is not accompanied by distinct P waves. What is the most likely diagnosis?

This patient is most likely experiencing atrial fibrillation.
During atrial fibrillation, an excessive number of impulses are travelling in the atria in all directions, in effect cancelling one another out.
Therefore, P waves, which reflect atrial depolarization, are not seen on the electrocardiogram (EKG).
In atrial fibrillation, the QRS complexes are normal, but appear at irregular intervals because of the random arrival of waves of depolarization at the atrioventricular node.
The overall heart rate may be as high as 150 beats per minute. P waves are seen in both first-degree heart block, which is manifested on the EKG as an increased PR interval, and second-degree heart block (although not every P wave elicits a QRS complex). In third-degree heart block, the P waves are regular but there is no relationship between the P waves and the QRS complex.
In ventricular fibrillation, the QRS complex is widened and bizarre in appearance because the arrhythmia does not employ the specialized conducting system of the heart.
Because the ventricles are operating independently of the atria, there is no constant relationship of the P wave to the QRS complex.

Alcohol amnestic disorder (Korsakoff syndrome) is the result of long-term alcohol abuse.

Thyroid peroxidase catalyzes many of the steps involved in thyroid hormone synthesis.

However, it does not affect the active transport of iodide from plasma into the follicle cell (i.e., iodine trapping).

This is an energy-requiring process that is increased by thyroid-stimulating hormone (TSH) and by increasing availability of extracellular iodide.

Its action

Oxidation of iodide to organic iodine
3-iodination of tyrosine residues contained in thyroglobulin
5-iodination of monoiodinated tyrosine residues contained in thyroglobulin
Coupling of two diiodotyrosines to yield thyroxine (still in linkage with thyroglobulin) and alanine

Human thryoid peroxidase (TPO) is the primary enzyme involved in thyroid hormone synthesis. The immunological measurements of TPO and of specific antibodies against TPO have been of great value in the screening and monitoring of Hashimoto's thyroiditis and other thyroid diseases

Once in the follicular cell, iodide is converted into iodine by the enzyme thyroid peroxidase, which uses hydrogen peroxide (H2O2) as a cofactor. Thyroid peroxidase catalyzes the incorporation of iodide molecule onto both the 3 and/or 5 positions of the phenol rings of tyrosines found in the very large glycoprotein called thyroglobulin. Thyroglobulin has a molecular weight of about 660,000. Thyroid peroxidase also appears to couple iodinated tyrosine rings to iodinated phenol rings which it obtains from other iodinated tyrosine residues within the protein. Thyroglobulin contains approximately 300 carbohydrate residues and 5500 amino acids, including 140 tyrosine residues. Of these 140 tyrosines, but only two to five of these tyrosines are converted into either T₄ or T₃! The entire thyroglobulin protein with its thyroid hormones is stored in the lumen of the thyroid follicle cell. As mentioned concerning TSH (thyroid stimulatory hormone, p43), TSH stimulates enzymatic degradation of thyroglobulin to effect release of the thyroid hormones. T₄ is formed exclusively in the thyroid and secreted. In contrast, 80% of T₃ found circulating in the blood is derived from metabolism of T₄ in peripheral tissues, especially the liver and kidney.

The autoimmune disease myasthenia gravis, characterized by muscle weakness, is ten times more likely to strike people with Graves' disease. Grave's disease itself is characterized by the presence of antibodies to the receptors which recognize thyroid-stimulating hormone (TSH). In Hashimoto's thyroiditis, antibodies are found to the thyroid specific protein, thyroid peroxidase. With the new discovery of the iodide transporter, the search is on for antibodies to the transporter which may be implicated in various forms of thyroid disease.

Through the action of thyroid peroxidase, thyroid hormones accumulate in colloid, on the surface of thyroid epithelial cells. Remember that hormone is still tied up in molecules of thyroglobulin - the task remaining is to liberate it from the scaffold and secrete free hormone into blood. Thyroid peroxidase, which is located on the apical side of the follicular epithelium, catalyzes organification and coupling

Thyroid hormones are excised from their thyroglobulin scaffold by digestion in lysosomes of thyroid epithelial cells. This final act in thyroid hormone synthesis proceeds in the following steps:

Thyroid epithelial cells ingest colloid by endocytosis from their apical borders - that colloid contains thyroglobulin decorated with thyroid hormone. Colloid-laden endosomes fuse with lysosomes, which contain hydrolytic enzymes that digest thyroglobluin, thereby liberating free thyroid hormones. Finally, free thyroid hormones apparently diffuse out of lysosomes, through the basal plasma membrane of the cell, and into blood where they quickly bind to carrier proteins for transport to target cells.
Increased TBG	Decreased TBG
Estrogens, oral contraceptives, tamoxifen, raloxifene	Androgens, danazol
Pregnancy	Anabolic steroids
Newborn state	Large doses of glucocorticoids
Acute/chronic active hepatitis; hepatoma	Cirrhosis
Acute intermittent porphyria	Nephrotic syndrome, severe hypoproteinemia
Opiates: heroin, methadone	Chronic renal failure
Clofibrate	Severe systemic illness, especially CHF
5-fluorouracil, mitotane	Active acromegaly
HIV infection	L-asparaginase
Pancreatic neuroendocrine tumors can increase TBPA	Colestipol plus niacin, slow-release nicotinic acid
Congenital increase in TBG	Congenital decrease in TBG

Thyroid peroxidase antibodies.

This anti-thyroid peroxidase (TPO) is an auto antibody to an integral part of thyroid cell microsomal membrane, and is a confirmation test for a diagnosis of Hashimoto's thyroiditis. Also sometimes called thyroid antimicrosomal antibody. Present in significant titers in Hashimoto's thyroiditis and Grave's disease.

Thyroid, antimicrosomal antibody (thyroid peroxidase), immunofluorescence

Total T4 (T4):

The T4 test measure the concentration of Thyroxine in the serum. This includes both bound and free hormone. Only the free hormone, about 0.05% of the total, is biologically active. Anything which affects levels of thyroid binding globulin (TBG), albumin, or thyroid binding prealbumin (transthyretin) will affect the total thyroxine but not the free hormone. Estrogens and acute liver disease will increase thyroid binding, while androgens, steroids, chronic liver disease and severe illness can decrease it.

Free T4 (FT4):

The FT4 measures the concentration of free thyroxine, the only biologically active fraction, in the serum. The free thyroxine is not affected by changes in concentrations of binding proteins such as TBG and thyroid binding prealbumin. Thus such conditions as pregnancy, or estrogen and androgen therapy do not affect the FT4.

Total T3 (T3):

The TOTAL T3 test measures the concentration of triiodothyronine in the serum. The T3 is increased in almost all cases of hyperthyroidism and usually goes up before the T4 does. Thus the T3 is a more sensitive indicator of hyperthyroidism than the Total T4. In hypothyroidism the T3 is often normal even when the T4 is low. The T3 is decreased during acute illness and starvation, and is affected by several medications including Inderal, steroids and amiodarone. This test measures both bound and free hormone. Only the free hormone is biologically active, but is only 0.5% of the total. Anything which effects thyroid binding globulin (TBG), or albumin will effect the total Triiodothyronine but not the free.

Resin T3 Uptake:

The Resin T3 Uptake is used to assess the binding capacity of the serum for thyroid hormone. This is used to help determine if the Total T4 is reflecting the free T4, or if abnormalities in binding capacity are responsible for changes in T4 values. This test is only useful in conjunction with Total T4 or Total T3. In the Resin T3 Uptake test, labeled hormone is added to the patient's serum. If there is an increase in binding capacity, more labeled hormone will be bound to the binding proteins and thus less will be left free in the serum. The free labeled hormone in the serum is measured and usually reported as a percent of the total labeled hormone added. If a patient has a high total T4, it may be due to overproduction of thyroid hormone (Hyperthyroidism) or to an excess of one of the thyroid binding proteins, usually Thyroid Binding Globulin (TBG). If the high Total T4 is secondary to high TBG, the Resin T3 will be low, otherwise it will be normal or elevated. Another way of putting this is that if the Total T4 or Total T3 deviates from normal in one direction and the Resin T3 Uptake deviates in the opposite direction, then the abnormality is due to changes in binding capacity, otherwise it is secondary to a true change in thyroid function (i.e. Hyper or Hypothyroidism). Thus if the binding capacity is increased because of high estrogens, the free labeled hormone will be decreased and the Resin T3 uptake will be decreased. The T4 Uptake is a similar test.

sTSH (TSH):

The high sensitivity thyroid stimulating hormone (sTSH or TSH) assay measures the concentration of thyroid stimulating hormone in the serum. In normal individuals, this is usually between 0.3 and 5.0 mU/ml. TSH is under negative feed back control by the amount of free thyroid hormone (T4 and T3) in the circulation and positive control by the hypothalamic thyroid releasing hormone (TRH). Thus in the case of thyroid hormone deficiency the TSH level should be elevated. A value greater than 20 mU/ml is a good indicator of primary failure of the thyroid gland. A value of between 5 and 15 is a borderline value which may require more careful evaluation. If the hypothyroid state is due to failure of the pituitary gland (TSH) or the hypothalamus (TRH), the values for TSH may be low, normal or occasionally in the borderline range. Thus a TSH above 15 is very good evidence for primary hypothyroidism and a value below 5 is very good evidence against primary hypothyroidism. The presence of low Free T4 with a TSH of less than 10 strongly suggests a pituitary or hypothalamic etiology for the hypothyroidism (secondary hypothyroidism). The TSH alone cannot be used to screen for secondary hypothyroidism and usually requires a measurement of thyroid hormone levels to be adequately interpreted.

Because high levels of free thyroid hormone will suppress TSH levels, in almost all case of hyperthyroidism the TSH values will be less than 0.3 and usually less the 0.1 mU/L. Though TSH is a very effective tool to screen for hyperthyroidism, the degree of suppression of TSH does not always reflect the severity of the hyperthyroidism. Therefore a measurement of free thyroid hormone levels is usually required in patients with a suppressed TSH level. If the Free T4 is normal, the free T3 should be checked as it is the first hormone to increase in early hyperthyroidism.

TSH levels can also be effectively used to follow patients being treated with thyroid hormone. High TSH levels usually indicates under-treatment, while low values usually indicate over-treatment. Again, abnormal TSH values should be interpreted with the measurement of free thyroid hormone before modifying therapy because serum thyroid hormone levels change more quickly than TSH levels. Thus patients who have recently been started on thyroid hormone, or who have been noncompliant until shortly before an office visit may have normal T4 and T3 levels, though their TSH levels are still elevated.

TSH levels may be affected by acute illness and several medications, including dopamine and glucocorticoids.

Antithyroid Antibodies:

Antithyroid antibodies often are associated with and play a role in thyroid diseases. The antibodies of most clinical importance are the Antithyroid Microsomal (measured by the Antithyroid Peroxidase assay and also referred to as anti TPO antibodies), the Antithyroglobulin and the Thyroid Simulating Immunoglobulin. The Antithyroid Microsomal Antibodies are usually elevated in patients with Autoimmune Thyroiditis (Hashimoto’s Thyroiditis) and may be used to help predict which patients with subclinical hypothyroidism (Normal Free T4 and elevated TSH) will go on to develop overt hypothyroidism. Antithyroglobulin antibodies may also be elevated in patients with autoimmune thyroiditis, but this is less frequent and to a lesser degree. Thyroid Stimulating Immunoglobulins are associated with Grave’s Disease and are the likely cause of the hyperthyroidism seen in this condition. These antibodies attach to the thyrotropin (TSH) receptor in the thyroid gland and activate it. While Antithyroid Microsomal Antibody levels are usually highest in Autoimmune Thyroiditis, and Thyroid Simulating Immunoglobulins are highest in Grave’s Disease, each may be present the both diseases, as well as in family members without clinical disease. There are several other less common antibodies associated with autoimmune thyroid disease but they are usually not measured in the clinical setting.

Reverse T3:

Reverse T3 (RT3) is formed when T4 is deiodinated at the 5 position (T3 is formed from deiodination of the 5’ position). RT3 has little or no biological activity and serves as a disposal path for T4. During periods of starvation or severe physical stress, the level of RT3 increases while the level of T3 decreases. In hypothyroidism both RT3 and T3 levels decrease. Thus RT3 can be used to help distinguish between hypothyroidism and the changes in thyroid function associated with acute illness (Euthyroid Sick Syndrome).

TPOAb

The presence of thyroid peroxidase autoantibodies (TPOAb) in the serum serves as an excellent marker for autoimmune thyroid disease, whether it be Graves’ hyperthyroidism or chronic autoimmune thyroiditis (Hashimoto’s thyroiditis). Detectable levels of TPOAb, which are directed toward the thyroid peroxidase enzymes, are present in more that one half of patients with active autoimmune thyroid disease. Recent studies suggest that TPOAbs are prevalent in about 93 percent of Hashimoto’s patients, and as high as 73 percent of Graves' Disease patients. TPO autoantibodies have also been shown to be nearly 100 percent associated with postpartum thyroiditis patients. Elevations in TPOAb values alone, or in conjunction with minimally abnormal TSH values, appear to serve as a predictor of future autoimmune thyroid disease.

TgAb

Autoimmune thyroid disease describes conditions in which the body’s immune system turns on itself and produces antibodies to its own tissues. These autoantibodies attack and destroy the tissues resulting in associated diseases. Autoantibodies to thyroglobulin (TgAb) are one type of thyroid autoantibody. TgAb levels are elevated in 80 percent of Hashimoto’s Thyroiditis patients, and in 30 percent of Graves’ Disease patients. Multiple thyroid autoantibodies are often found in a patient’s serum; only 2.5 percent of TgAb positive patients were found to be TPOAb negative in one study.

The TgAb assay is particularly useful in the monitoring of serum thyroglobulin levels in thyroid cancer patients after treatment, as TgAbs can confound the measurement of serum thyroglobulin. Determination of TgAb concentration is critical for proper evaluation.

TRAb

Tests designed to measure circulating TSH receptor autoantibodies (TRAb) have been developed as an outgrowth of research studies aimed at elucidating the etiology of thyrotoxic Graves' disease. There are two major categories of TRAb: TSAb and TBAb. Thyroid-stimulating antibody (TSAb), which is an analogy to TSH, is known to cause hyperthyroidism in Graves’ disease. Thyroid blocking antibody (TBAb), which inhibits the binding of TSH and the biologic actions of both TSH and TSAb, results in hypothyroidism and has been found in some patients with Hashimoto’s Thyroiditis. Receptor binding assays may be useful in pregnancy, where transplacental passage of blocking or stimulating autoantibodies may result in fetal or neonatal thyroid dysfunction. This is particularly important in those cases where fetal or neonatal thyroid dysfunction has been encountered in a previous pregnancy.

Use of anabolic steroids is associated with an increase in all of the following characteristics EXCEPT : spermatogenesis

Anabolic steroids are derivatives of testosterone and have significant androgen effects. In addition to decreased bone resorption and increased muscle mass, libido, and sebaceous gland secretion (acne), the increase in circulating androgen suppresses normal secretion of luteinizing hormone (LH) from the anterior pituitary. Decreased LH levels results in decreased spermatogenesis because of decreased Leydig cell secretion of testosterone.

Urinary retention in a post-surgical patient without outflow obstruction.

Bethanechol

Increasing dyspnea in an older woman with emphysema: Ipratropium

Dysuria due to benign prostatic hypertrophy in an older male. Terazosin

Prophylaxis of migraine headache in a young woman who has had frequent attacks during the past several months.: propanolol

Anaphylactic shock, characterized by immediate hypersensitivity reactions, bronchoconstriction, and hypotension, is best treated with epinephrine, which acts as a physiological antagonist of histamine released from mast cells during anaphylaxis.

Urinary retention in post-surgical patients can be relieved with a cholinoreceptor agonist such as bethanechol, which increases contraction of the detrusor muscle, leading to micturition.

Dyspnea associated with emphysema may be improved with the administration of the muscarinic antagonist ipratropium, which is given as an aerosol and is poorly absorbed from the lungs due to its quaternary ammonium structure.

The urinary obstruction due to benign prostatic hypertrophy may be partly relieved with an alpha-adrenergic blocker such as terazosin, because increased sympathetic tone may contribute to the obstruction of contracting prostatic muscle, even though tissue hypertrophy is the primary problem.

Patients with frequent migraine headaches may benefit from a course of therapy with the adrenergic beta blocker propranolol, which presumably acts by a central mechanism to prevent the occurrence of such headaches.

Skeletal muscle fibers can be divided into two major groups; fast and slow, based on the speed of their adenosine triphosphatase (ATPase) activity.

All fast fibers have fast ATPase.

However, fast fibers can be further subdivided based on their ability to sustain contractions.

Some fatigue more quickly, have less myoglobin (which makes them white), and have fewer mitochondria and capillaries.

The fatigue-resistant fast fibers have a reddish color due to more myoglobin, and they have more mitochondria and capillaries.

The slow fibers are similar to the fatigue-resistant fast fibers except they have slower ATPase activity.

Bromocriptine = ergot alkaloids

potent dopamine-receptor agonist used for hyperprolactinemia ,infertility, and Parkinson disease

inhibits prolactin release

Alkaloids that have alpha-adrenergic blocking activity, a direct stimulating action on smooth muscle, especially that of the uterus

Ergonovine: Is highly selective in stimulating uterine muscle contractions

Ergotamine: Its vasoconstrictive effect enables termination of acute migraine headache

Methysergide: A serotonin antagonist/partial agonist used for migraine prophylaxis

Bromocriptine is a potent dopamine-receptor agonist and is used to activate pituitary dopamine receptors to mediate inhibition of prolactin secretion. It is also used in Parkinson disease.
Ergonovine, ergotamine, and methysergide are all partial agonists at serotonin 5-HT₂ receptors, and act to constrict most blood vessels.

Ergonovine has the most selective effect on uterine smooth muscle and is usually preferred for obstetric uses, including control of postpartum hemorrhage, partly because of its lower toxicity in this setting.

Ergotamine is usually preferred for terminating acute migraine attacks. Methysergide has been used for prophylaxis of migraine, despite its extensive chronic toxicity.

The ergot alkaloids are serotonin antagonists with affinity for dopamine and norepinephrine binding sites as well. Though the combination of actions is considered an advantage in light of the rather complicated pathophysiology of the disorder, the effectiveness of serotonin antagonism is primarily limited to the aura phase of classic migraine, and rebound is a problem with all of the ergot products.

Ergot Alkaloids

Overview:
- Ergot alkaloids -- produced by Claviceps purpurea, a grain (rye, especially) fungus
- This fungus synthesizes many biologically active agents including:
  - acetylcholine
  - histamine
  - tyramine and
  - many unique ergot alkaloids -- which effect:
    - alpha-adrenergic receptors
    - dopamine receptors
    - serotonin receptors
- Ergot poisoning (ergotism, St. Anthony's fire)-- symptoms:
  - dementia
  - florid hallucinations
  - persistent vasospasm (gangrene may develop)
  - uterine muscle stimulation (may cause abortion in pregnancy)
  - Ergot poisoning specific manifestations depend on the alkaloids mixture

Chemistry and pharmacokinetics:
- Two Major Families:
  - Tetracyclic Ergoline Nucleus: Examples --
    - lysergic acid diethylamide (LSD)
    - ergonovine
    - methysergide (Sansert)
    - 6-methylergoline
    - lysergic acid
  - Peptide alkaloids: Examples --
    - ergotamine
    - alpha-ergocryptine
    - bromocriptine (Parlodel)
- Ergot alkaloids -variably absorbed from the GI tract
- Absorption following oral administration: improved by caffeine
- Bromocriptine (Parlodel): well absorbed from the GI tract
- Metabolism:
  - extensively metabolized

Pharmacodynamics:
- Mechanism of Action:
  - Targets: several receptor types
    - agonist effects
    - partial agonist effects
    - antagonist effects
    - Pre- and post-synaptic sites

Ergot Alkaloids	Alpha-adrenergic receptor	Dopamine receptor	Serotonin receptor (5 HT₂)	Uterine smooth muscle stimulation
Bromocryptine	-	+++	-	0
Ergonovine	+	+	- (partial agonist)	+++
Ergonovine	-- (partial agonist)	0	+ (partial agonist)	+++
LSD	0	+++	--	+
Methysergide	+/0	+/0	--- (partial agonist)	+/0

-- {based on Table 16-6,Burkhalter, A, Julius, D.J. and Katzung, B. Histamine, Serotonin and the Ergot Alkaloids (Section IV. Drugs with Important Actions on Smooth Muscle), in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p 279.}

Organ Systems:
- CNS:
  - hallucinogenic-- LSD:
    - peripheral (5 HT₂) serotonin receptor peripheral antagonist
    - behavioral effects: agonist presynaptic or postsynaptic 5 HT₂ effects.
  - Dopamine Receptor Interactions:
    - Extrapyramidal system
    - Prolactin release regulation:
      - bromocriptine (Parlodel) and pergolide (Permax)}specificity for pituitary dopamine receptors
        
        suppression of pituitary prolactin secretion: by activating regulatory dopamine receptors
        Bromocriptine (Parlodel) and pergolide (Permax) are competitive with dopamine and other dopamine agonists (apomorphine) before the these binding sites

Vascular Smooth Muscle:
- Ergotamine (unrelated compounds) are mainly vasoconstricting.
  - Vasoconstriction: partially blocked by alpha adrenergic receptor blocking drugs--
    - suggesting vasoconstriction by ergot alkaloids may be due to partial agonist effects at alpha adrenergic receptors
  - Vasoconstriction: long-lasting--
    - alpha adrenergic receptor effects
    - 5 HT receptor-mediated effects
  - Vasoconstriction: differential vascular sensitivity to ergot alkaloids
    - most sensitive: cerebral arteriovenous anastomotic vessels to:
      1. ergotamine
      2. dihydroergotamine
      3. sumatriptan (Imitrex)
    - Antimigraine specificity: mediated by neuronal or vascular serotonin receptors
  - Most-common drugs used for migraine treatment:
    - ergotamine
    - ergonovine
    - methysergide (Sansert)
  - Overdosage (ergotamine and related agents)
    - Severe, long-lasting vasospasm --

not reversible by alpha-antagonists
not reversible by serotonin antagonists

Uterine Smooth Muscle
- Stimulant action: involves serotonergic, alpha-adrenergic, and other effects
- Uterine sensitivity changes during pregnancy (possibly due to progressively increasing numbers of alpha₁ receptors
- Small doses: rhythmic uterine contraction and relaxation
- Larger doses: substantial, prolonged contractions
- Ergonovine: more uterine selective (agent of choice for obstetric uses)

Other Smooth Muscle:
- Bronchiolar smooth muscle: no effect
- Gastrointestinal smooth muscle: variable sensitivity {nausea, diarrhea, and vomiting -- occurs with variability in required dosage probation impatient}
  - Mechanism of Action:

1. activation of gastrointestinal serotonin receptors

2. CNS emetic centers

Ergot Alkaloids: Clinical Pharmacology

Migraine
- Clinical Presentations:
  - Often accompanied by brief aura (visual scotomas, hemianopia, beach abnormalities
  - Severe, throbbing, usually unilateral headache (few hours to a few days in duration)
  - Familial disease:
    1. more common in women
    2. onset: early adolescence; less common in older patients
    3. Migraine associated with stress
    4. Headache frequency: Range -- to or more per week to once a year
- Migraine Pathophysiology:
  - Vasomotor mechanism -- inferred from:
    1. increased temporal artery pulsation magnitude
    2. pain relief (by ergotamine) occurs with decreased artery pulsations
  - Migraine attack associated with (based on histological studies):

sterile neurogenic perivascular edema
inflammation (clinically effective antimigraine medication reduce perivascular inflammation)

Serotonin involvement (evidence for):
1. Throbbing headache: associated with decreased serum and platelet serotonin
2. Presence of serotonergic nerve terminals at meningeal blood vessels
3. Antimigraine drugs influence serotonergic neurotransmitter
4. Some migraine chemical triggers may work through serotonin pathways, i.e. decreasing estrogen (associated with the menstrual cycle) and increased prostaglandin E₁.

Drug Treatment (migraine):
- Ergotamine: best results when drug administered prior to the attack (prodromal phase) -- less effective as attack progresses
  1. Ergotamine may be combined with caffeine; caffeine promotes ergot alkaloid absorption
  2. Vasoconstriction associated with excessive ergotamine use may be long-lasting and potentially severe.
  3. Ergotamine: availableby oral, IV,or intramuscular routes of administration
- Dihydroergotamine (IV administration mainly): may be appropriate for intractable migraine (nasal or oral formulations dihydroergotamine are being assessed)
- Sumatriptan (Imitrex): alternative to ergotamine for acute migraine treatment; not recommended for patients with coronary vascular disease risk.
  1. formulations: subcutaneous injection, oral, nasal spray
  2. selective serotonin-receptor agonist (short duration of action)
  3. probably more effective than ergotamine for management of acute migraine attacks (relief: 10 to 15 minutes following nasal spray)
  4. subcutaneous injection: relief within two hours for 70% -- 80% of patients
- New Triptans:
  1. Zolmitriptan--more rapid onset than oral sumatriptan (Imitrex)
  2. Naratriptan--
    - slower onset; longer half-life
  3. Rizatriptan-- more rapid onset than oral sumatriptan
- Analgesics:-- may be sufficient for model/moderate migraine
  1. Aspirin
  2. Aspirin combination (Fiorinal --aspirin + caffeine + butalbital)
  3. Acetaminophen
  4. Acetaminophen combinations (Midrin-- acetaminophen + isometheptene + dichloralphenazone)
  5. Excedrin Migraine: acetaminophen + aspirin +caffeine
  6. Oral opioids: usual systemic opioid adverse effects
  7. Butorphanol nasal spray --opioid agonist-antagonist
    - effective for moderate/severe migraine; psychiatric reactions/drug abuse have been reported
- Drug-Drug interactions:
  1. A triptan should not be used within one-day following another triptan or any ergotamine-containing drug (vasoconstriction may be additive)
  2. Ergot derivatives should not be taken or until 24 hours or more following a triptan
  3. "Serotonin Syndrome": weakness, hyperreflexia, incoordination following use of a selective serotonin reuptake inhibitor (SSRIs) with a triptan
  4. All triptans except naratriptan are contraindicated in patients taking MAO inhibitors (or within two weeks of discontinuation of MAO inhibitors)
Migraine Prophylaxis:
- Ergonovine
- Methysergide (Sansert)
  1. effective in about 60% of patients
  2. 40%: frequency of toxicity
  3. NOT effective in treating an active migraine attack or even preventing an impending attack.
  4. Methysergide toxicity:
    - retroperitoneal fibroplasia
    - subendocardial fibrosis
    - The side effects are the basis of recommending a 3-4 week drug holiday every six months
- Propranolol (Inderal) -- prophylaxis- Most common for continuous prophylaxis
  1. propranolol (Inderal) and timolol (Blocadren) FDA approval for this indication
  2. note all beta-blockers: contraindicated in asthmatics
  3. best established drug for migraine attack prevention.
- Amitriptyline (Elavil, Endep) -- prophylaxis-- most frequently used among the tricyclic antidepressants
- Valproic acid (Depakene, Depakote) --effective in decreasing migraine frequency; FDA approval for this indication;
- Nonsteroidal antiinflammatory drugs (NSAIDs) -- naproxen sodium; flurbiprofen -- used for attack prevention and aborting acute attack

Hyperprolactinemia:(amenorrhea, infertility inwomen, galactorrhea)
- may be caused by:
  - prolactin-secreting anterior pituitary tumors
  - centrally-acting anti-dopaminergic drugs (antipsychotic drugs)
- Drug treatment: hyperprolactinemia
  - Bromocriptine (Parlodel) -- very effective
    1. occasional postpartum cardiotoxicity
  - Pergolide (Permax): lactation suppression
Postpartum Hemorrhage:
- Ergot Derivatives: used to control late uterine bleeding (NEVER given before delivery, given before delivery an increase in internal and fetal mortality occur)
- Ergot alkaloids cause uterine contractions (prolonged, powerful spasms, unlike natural labor)
Ergot Toxicity:
- Most common:
  - gastrointestinal -- diarrhea, vomiting, nausea
    1. Mechanism of Action:

1. medullary vomiting center stimulation

2. activation of gastrointestinal serotonergic receptors

Use of methysergide (Sansert) (prophylactic migraine agent) any limited by GI toxicities

Other toxicities:
- Vasospasm -- overdosage with drugs such as: ergotamine and ergonovine
- Dangerous toxic effect
- gangrene, possible amputation
  1. most vasospastic reactions involves the extremities
  2. Bowel infarction (secondary to mesenteric artery vasospasm) may also occur
- Serious vasospastic reactions may be reversible by high-dose nitroprusside or nitroglycerin
Chronic toxicities:
- Methysergide (Sansert): -- retroperitoneal fibroplasia, subendocardial fibrosis, fibroplastic changes in the pleural cavity.
  1. Slowly developing
  2. Presenting symptoms:

1. hydronephrosis (ureter obstruction)

2. cardiac murmur (valve deformation)

Methysergide (Sansert) CNS effects {stimulation/loose nations}

Contraindications for Ergot Alkaloids Use:
- Presence of vascular or collagen disease

The effects of therapeutic doses of dobutamine could be most effectively opposed by the administration of labetalol

Dobutamine is a synthetic catecholamine that stimulates alpha, beta1 and beta2 adrenergic receptors. The effects of this drug include positive inotropic effects with minimal changes in chronotropic activity or systemic vascular resistance. For these reasons, dobutamine is useful ain the management of CHF when an increase in heart rate is not desired.

Stimulates beta-1 receptors (in the heart), increasing cardiac function, CO, and SV, with minor effects on HR. Decreases afterload reduction although SBP and pulse pressure may remain unchanged or increase (due to increased CO). Also decreases elevated ventricular filling pressure and helps AV node conduction. Onset: 1-2 min. Peak effect: 10 min. t1/2: 2 min. Therapeutic plasma levels: 40-190 ng/mL. Metabolized by the liver and excreted in urine.

Contraindications: Idiopathic hypertrophic subaortic stenosis.

Special Concerns: Safe use during childhood or after AMI not established.

Side Effects: CV: Marked increase in HR, BP, and ventricular ectopic activity precipitous drop in BP, premature ventricular beats, anginal and nonspecific chest pain, palpitations. Hypersensitivity: Skin rash, pruritus of the scalp, fever, eosinophilia, bronchospasm. Other: Nausea, headache, SOB, fever, phlebitis, and local inflammatory changes at the injection site.

Overdose Management: Symptoms: Excessive alteration of BP, anorexia N&V, tremor, anxiety, palpitations, headache, SOB, anginal and nonspecific chest pain, myocardial ischemia, ventricular fibrillation or tachycardia. Treatment: Reduce the rate of administration or discontinue temporarily until the condition stabilizes. Establish an airway, ensuring oxygenation and ventilation. Initiate resuscitative measures immediately. Treat severe ventricular tachyarrhythmias with propranolol or lidocaine.

Additional Drug Interactions: Concomitant use with nitroprusside causesCO andPAWP.

Although dobutamine is usually characterized as a selective b₁ adrenoceptor agonist, it also produces significant stimulation of a₁ and b₂ receptors.

In the vasculature, the opposing effects of a₁ and b₂ stimulation tend to cancel each other out, and the observed effect of dobutamine appears to be cardiac stimulation.

In fact, an a₁ receptor-mediated inotropic effect supplements the b₁-mediated inotropic and chronotropic activity, resulting in a preferential increase in cardiac force.

For this reason, the drug has less effect on heart rate and vascular resistance than other catecholamines.

Labetalol would oppose the effects of dobutamine by blocking both a and b adrenoceptors.

Indications: Dobutamine is a positive inotrophic drug, resulting in increased myocardial contracture, thus improving cardiac output.

Uses: Dobutamine is used primarily in congestive heart failure associated with poor cardiac output.

Adverse Reactions

Dobutamine may cause hypotension secondary to it's beta-2 properties. Tachycardia may result from Dobutamine's beat-1 properties, do not permit the heart rate to increase by 10% of it's original rate. Dobutamine may cause an increase in ventricular ectopy.

congenital spherocytosis, which is an autosomal dominant disease with an increased prevalence in people of Northern European extraction. Congenital spherocytosis is an example of an intrinsic hemolytic anemia with extravascular hemolysis. The intrinsic abnormality is a membrane defect in spectrin, which decreases the amount of red blood cell membrane resulting in a low surface-to-volume ratio and spherocyte formation. Spherocytes are trapped in the splenic cords because they are not flexible enough to enter through the narrow openings into the sinusoids. Stagnation in the cords results in the red blood cell release of lactic acid, which decreases pH and decreases glycolysis. Reduced glycolysis results in less adenosine triphosphate formed; therefore, the spherocytes have difficulty in extruding sodium and using glucose. Macrophages in the splenic cords remove the spherocytes, resulting in an extravascular hemolytic anemia. Anemia, splenomegaly, and jaundice (indirect hyperbilirubinemia) are a common triad. A family history of splenectomy or gallstones at an early age from increased bilirubin metabolism (calcium bilirubinate stones) is strongly suggestive of spherocytosis. Patients usually have a normocytic anemia with a corrected reticulocyte count greater than 3%. Spherocytes are small, round cells with no central pallor. Because they have less membrane, the hemoglobin concentration is increased, which is reflected by an increased mean corpuscular hemoglobin concentration. The osmotic fragility test is the confirmatory test for spherocytosis. This test documents increased susceptibility of the spherocytes to hemolysis in hypotonic saline solutions when compared with normal cells. For example, spherocytes begin hemolyzing at 0.65%, whereas normal red blood cells begin hemolyzing at 0.50%. Splenectomy is the treatment of choice. Patients should receive Pneumovax before splenectomy to protect the patient against Streptococcus pneumoniae sepsis. Spherocytes remain in the peripheral blood after splenectomy, but do not hemolyze in the absence of a spleen.
An abnormal hemoglobin electrophoresis with a patient history of gallbladder disease may occur in sickle cell disease. However, the patient is white and the spleen is enlarged rather than autosplenectomized.
A positive direct Coombs test indicates the presence of an autoimmune hemolytic anemia. Spherocytes are present in autoimmune hemolytic anemia, but most patients have a history of another autoimmune disease (e.g., systemic lupus erythematosus).
An abnormal Schilling test is noted in B₁₂ deficiency. It is a defect in DNA synthesis, which is not normally associated with splenomegaly and an increased incidence of gallstones.
An increased urine for hemosiderin is noted in chronic intravascular hemolysis. Spherocytosis is an extravascular hemolysis.

Drugs can lower intraocular pressure either by reducing the formation of aqueous humor or increasing the outflow of aqueous humor.
Atropine and other muscarinic blockers can cause acute angle-closure glaucoma by relaxing the iris sphincter muscle so as to cause mydriasis. As the sphincter relaxes, it occludes the trabecular meshwork in patients with a narrow angle between the iris and cornea, leading to a precipitous rise in intraocular pressure.
Pilocarpine can be used to reduce intraocular pressure in patients with chronic open-angle glaucoma. Pilocarpine contracts the meridianal fibers of the ciliary muscle , thereby increasing tension on the trabecular meshwork at the angle of the iris and cornea and opening the spaces through which aqueous humor drains into Schlemm's canal. Epinephrine reduces the intraocular pressure in patients with open-angle glaucoma, primarily by causing vasoconstriction and "decongestion" in the trabecular area so that aqueous humor drains out more easily. The end result is much the same as that obtained with pilocarpine.
Timolol, a b-adrenoceptor blocker, acts on the ciliary process to inhibit the production of aqueous humor, thereby lowering intraocular pressure.
Carbonic anhydrase inhibitors, such as acetazolamide, act to block the formation of bicarbonate required for aqueous humor secretion by the ciliary body thereby lowering intraocular pressure.

The anterior chamberis the area bounded in front by the cornea and in back by the lens, and filled with aqueous.

The aqueousis a clear, watery solution in the anterior and posterior chambers.

The arteryis the vessel supplying blood to the eye.

The canal of Schlemmis the passageway for the aqueous fluid to leave the eye.

The choroid, which carries blood vessels, is the inner coat between the sclera and the retina.

The ciliary bodyis an unseen part of the iris, and these together with the ora serrata form the uveal tract.

The conjunctivais a clear membrane covering the white of the eye (sclera).

The corneais a clear, transparent portion of the outer coat of the eyeball through which light passes to the lens.

The irisgives our eyes color and it functions like the aperture on a camera, enlarging in dim light and contracting in bright light. The aperture itself is known as the pupil.

The lenshelps to focus light on the retina.

The maculais a small area in the retina that provides our most central, acute vision.

The optic nerveconducts visual impulses to the brain from the retina.

The ora serrataand the ciliary body form the uveal tract, an unseen part of the iris.

The posterior chamberis the area behind the iris, but in front of the lens, that is filled with aqueous.

The pupilis the opening, or aperture, of the iris.

The rectus medialisis one of the six muscles of the eye.

The retinais the innermost coat of the back of the eye, formed of light-sensitive nerve endings that carry the visual impulse to the optic nerve. The retina may be compared to the film of a camera.

The sclerais the white of the eye.

The veinis the vessel that carries blood away from the eye.

The vitreousis a transparent, colorless mass of soft, gelatinous material filling the eyeball behind the lens.

Atropine

Name	Atropine Sulfate
Class	Anticholinergic Agent
Description	Atropine sulfate (a potent parasympatholytic), inhibits actinos of acetylchoine at postganglionic parasympathetic neuroeffector sites. Small doses inhibit salivary and bronchial secretions, moderate doses dilate pupils and increase heart rate. Large doses decrease GI motility, inhibit gastric acid secretion, and may block nicotininic receptor sites at the automomic ganglia and at the neuromuscular junction. Blocked vagal effects result in positive chronotropy and positive dromotropy (limited or no inotropic effect). In emergency care, it is primarily used to increase the heart rate in life-threatening bradycardias.
Onset	Rapid
Duration	2-6 hours
Indications	Hemodynamically significant bradycardia Asystole PEA Organophosphate poisoning (drug of choice) Bronchospastic pulmonary disorders
Contraindications	Tachycardia Hypersensitivity Unstable cardiovascular status in acute hemorrhage with myocardial ischemia Narrow angle glaucoma
Adverse Reactions	Tachycardia Paradoxical bradycardia when pushed slowly or when used at doses less than 0.5mg Palpitations, dysrhythmias, headache, dizziness, nausea/vomiting, flushed and dry skin, allergic reations. Anticholinergic effects (dry mouth/nose, photophobia, vlurred vision, urine retention)
Drug Interactions	Use with other anticholinergics may increase vagal blockade. Potential adverse effects when administered in conjunction with digitalis, cholinergics, neostigmine. The effects of atropine may be enhanced by antihistamines, procainamide, quinidine, antipsychotics, antidepressants, and benzodiazepines.
Supplied	Various injection preparations. For emergency situations, atropine is usually supplied in prefilled syringes containing 1.0 mg in 10 ml of solution.
Dose/Administration	Bradydysrhythmias Adult: 0.5 – 1.0 mg IV, may be repeated at 5 min intervals for desired response (max 0.03-0.04mg/kg) Pediatric: 0.02 mg/kg IV, IO, ET(diluted to 3-5ml). Min dose 0.1mg; max single dose fo 0.5 mg for a child and 1.0 mg for an adolescent; may be repeated in 5 minutes for a max total fo 1.0 mg for a child and 2.0 mg for an adolescent. Asystole Adult: 1.0 mg IV, ET, (1-2 mg diluted to a total of 10ml); may be repeated every 3-5 minutes (max 0.03 – 0.04mg/kg) Pediatric: unknown efficacy PEA: Adult: 1 mg IV (if bradycardic), repeat every 3-5 minutes, max 0.03 – 0.04mg/kg. Pediatric: unknown efficacy Anticholinesterase Poisoning Adult: 2 mg IV push every 5-15 minutes to dry secretions. No max dose. Pediatric: 0.05 mg/kg/dose (usual dose 1-5 mg) IV, may be repeated in 15 minutes.
Special Consideration	Pregnancy Safety: Category C Follow ET administration with several positive pressure ventilations.

Dobutamine (Dobutrex)
Class	Sympathomimetic
Description	Dobutamine is a synthetic catecholamine that stimulates alpha, beta1 and beta2 adrenergic receptors. The effects of this drug include positive inotropic effects with minimal changes in chronotropic activity or systemic vascular resistance. For these reasons, dobutamine is useful ain the management of CHF when an increase in heart rate is not desired.
Onset	1-2 min; peak after 10 min
Duration	10 – 15 min
Indications	Inotropic support for patients with left ventricular dysfunction
Contraindications	Tachydysrhythmias Severe hypotension
Adverse Reactions	Headache Dose-related tachydysrhythmias Hypertension PVCs
Drug Interactions	Beta adrenergic antagonists may blunt inotropic response Sympathomimetics and phosphodiesterate inhibitors may exacerbate dysrhythmia responses. Incompatible with sodium bicarbonate and furosemide.
Supplied	10 ml (25mg/ml)
Dose/Administration	Adult: Dilute 250mg in 250 ml. Usual dose is 2-2 mcg/kg/min IV, based on inotropic effect. Pediatric: Dilute 6mg/kg to create a 100 ml solution; infuse at 5-10 ml/hr (5-10 mcg/kg/min) IV/IO, titrated to desired effect
Special Consideration	Pregnancy Safety: Not well established Administer via an infusion pump to ensure precise flow rates. May be administered through a Y-site with concurrent dopamine, lidocaine, nitroprusside, and potassium chloride infusions. Blood pressure should be closely monitored. Increases in heart rate of more than 10% may induce or exacerbate myocardial ischemia. Lidocaine should be readily available

Name	Dopamine (Inotropin)
Class	Sympathomimetic
Description	Dopamine is chemically related to epinephrine and norepinephrine. It acts primarily on alpha 1, beta 1 adrenergic receptors in dose-dependant fashion. At low doses ("renal doses"), dopamine has a dopaminergic effect that causes renal, mesenteric, and cerebral vascular dilation. At moderate doses ("cardiac doses"), dopamine has beta 1and alpha-adrenergic effect, causing enhanced myocardial contractility, increased cardiac output, and a rise in blood pressure. aT high doses ("vasopressor doses"), dopamine has an alpha-adrenergic effect, producing peripheral arterial and venous constriction. Dopamine is commonly used in the treatment of hypotension associated with cardiogenic shock.
Onset	2-4 minutes
Duration	10-15 minutes
Indications	Hemodynamically significant hypotension in the absence of hypovolemia.
Contraindications	Tachydysrhythmias VF Hypovolemia Patients with pheochromocytoma
Adverse Reactions	Dose-related tachydysrhythmias Hypertension Increased myocardial oxygen demand
Drug Interactions	May be deactivated by alkaline solutions (sodium bicarbonate and furosemide) MAO inhibitors and bretylium may potentiate the effect of dopamine Sympathomimetics and phosphodiesterase inhibitors exacerbate dysrhythmia response.
Supplied	200 mg/5ml, 400 mg/5 ml prefilled syringes and ampules for IV infusion
Dose/Administration	Adult: Dilution to a concentration of 800 to 1600 mcg/ml; begin infusion at 1-5 mcg/kg/min, titrated to effect. Final dosage range of 5-20 mcg/kg/min is recommended. Dopaminergic response: 1-2 mcg/kg/min Beta Adrenergic response: 2-10 mcg/kg/min Alpha Adrenergic response: 10 – 20 mcg/kg/min Pediatric: dilute 6mg/kg in solution to a total of 100 mg; begin infusion at 10 mcg/kg/min IV/IO, titrate to effect (max 20 mcg/kg/min)
Special Consideration	Pregnancy Safety: Not well established Infuse through large, stable vein to avoid the possibility of extravasation injury. Use infusion pump to ensure precise flow rates. Monitor for signs of compromised circulation.

Name	Epinephrine (Adrenalin)
Class	Sympathomimetic
Description	Epinephrine stimulates alpha, beta₁ and beta₂ adrenergic receptors in dose-related fashion. It is the initial drug of choice for treating bronchoconsriction and hypotension resulting from anaphylaxis as well as all forms of cardiac arrest. It is useful in management of reactive airway disease, but beta adrenergic agents are often used initially due to convenience and oral inhalation route. Rapid injection produces a rapid increase in blood pressure, ventricular contractility, and heart rate. In addition, epinephrine causes vasoconstriction in the arterioles of the skin, mucosa, and splanchic areas, and antagonizes the effects of histamine.
Onset	(SQ) 5-10 minutes (IV, ET) 1-2 minutes
Duration	5-10 minutes
Indications	Bronchial asthma Acute allergic reaction All forms of cardiac arrest Profound symptomatic bradycardia
Contraindications	Hypersensitivity Hypovolemic shock Coronary insufficiency Hypertension
Adverse Reactions	Headache, nausea, restlessness Weakness, dysrhythmias, hypertension Precipitation of angina pectoris
Drug Interactions	MAO inhibitors and bretylium may potentiate the effect of epinephrine Beta adrenergic antagonists may blunt inotropic response. Sympathomimetics and phosphodiesterase inhibitors may exacerbate dysrhythmia response. May be deactivated by alkaline solutions (sodium bicarbonate, Furosemide)
Supplied	1mg/ml (1:1,000) 0.1mg/ml (1:10,000) ampule and prefilled syringes
Dose/Administration	Cardiac Arrest: Adult: 1mg IV or 2 – 2 ½ times the IV dose via ET, repeat every 3-5 minutes. Class IIB regimes: Intermediate: 2-5 mg IV every 3-5 minutes Escalating: 1 mg – 3mg – 5 mg (3 minutes apart) High: 0.1mg/kg IV every 3-5 minutes Pediatric: IV/IO 0.1ml/kg (1:10,000), doses as high as 0.2mg/kg may be effective. ET dose is 0.1 ml/kg (1:1,000) diluted to 3-5 ml Repeated at (IV/IO/ET) 0.1ml/kg (1:1,000) every 3-5 minutes Anaphylactic Reaction Adult: (Mild reaction) 0.3-0.5ml (1:1,000) SQ (Moderate to Severe): 1-2 ml (1:10,000) slow IV Pediatric: (Mild) 0.01ml/kg SQ (Moderate to Severe): 0.05 – 0.5 mcg/kg/min infusion Infusion Adult: Mix 1mg ampule in 500 ml (2mcg/ml); infuse at 2-10 mcg/min titrated to response Pediatric: Dilute 0.6 mg/kg to create a 100 ml solution; begin infusion at 1ml/hr (0.1mcg/kg/min); adjust every 5 minutes for effect.
Special Consideration	Pregnancy Safety: Category C Do not use prefilled syringes for epinephrine infusions Syncope has occurred following epinephrine administration to asthmatic children. May increase myocardial oxygen demand

Which of the following tissue or cell types is most dependent on insulin to facilitate the entry of glucose? Adipose

Glucose enters adipose cells via the insulin-dependent GLUT-4 glucose transport protein.
Insulin stimulates the movement of a cytoplasmic pool of GLUT-4 molecules to the membrane and thus increases facilitated diffusion of glucose into the cells.
Glucose uptake into liver cells and pancreatic beta cells is mediated by GLUT-2 transport proteins,
glucose uptake by red blood cells is mediated by the GLUT-1 transport protein.
Neither of these proteins is insulin dependent.
The sodium-dependent reabsorption of glucose in the renal tubules is mediated by a different transport protein (Na⁺-glucose cotransporter) that is not insulin dependent.

A patient with elevated levels of

plasma phenylalanine,
phenyllactate,
phenylacetate, and phenylpyruvate,
but a normal level of tetrahydrobiopterin

is most likely to be genetically deficient in the enzyme

· phenylalanine hydroxylase

Phenylketonuria (PKU) is a genetic disease caused by a deficiency of the enzyme phenylalanine hydroxylase. This deficiency causes the level of phenylalanine to become elevated. The excess phenylalanine is converted to phenyllactate, phenylacetate, and phenylpyruvate, compounds that are normally not produced in significant amounts. If tetrahydrobiopterin is present in normal amounts, the enzymes dihydrobiopterin reductase and dihydrobiopterin synthetase must be functioning normally.

Some variants of PKU are caused by a deficiency in tetrahydrobiopterin production. In these variants, tyrosine hydroxylase, tryptophan hydroxylase, and phenylalanine hydroxylase are all inhibited because of the lack of their required cofactor. These variants have the symptoms of PKU but, in addition, cannot synthesize adequate amounts of melanin, the catecholamines, and serotonin.

Which drug cause what?

Throat and bronchial irritation, cough, wheezing, and gastroenteritis Nedocromil

Oral candidiasis: Beclomethasone

Insomnia, nervousness, anorexia, nausea, and headache: Theophylline

Tachycardia and muscle tremor Pirbuterol

· Although b₂ agonists (pirbuterol), muscarinic antagonists (ipratropium), and methylxanthines (theophylline) may all cause tachycardia, it is most commonly observed with inhaled or systemic b₂ agonists. Skeletal muscle tremor is also most common with b₂agonists, whereas ipratropium is more likely to cause urinary retention and blurred vision.

· Theophylline often produces noticeable central nervous system effects, including anorexia, nervousness, insomnia, headache, and seizures, as serum concentrations increase. Gastrointestinal symptoms are also prominent with milder theophylline overdose, whereas seizures are usually associated with higher serum levels. Cromolyn and nedocromil cause almost no serious systemic side effects, but airway irritation may produce coughing and wheezing, and gastroenteritis may occur in some patients.

· Inhaled corticosteroids (beclomethasone) are also remarkably nontoxic but often predispose the patient to oropharyngeal candidiasis.

Bronchodilators

Albuterol inhaled – short acting. This is the standard, most common inhaled asthma medication that is used by virtually all asthmatics. It comes as an inhaler and as a solution to put into a nebulizer machine. Common brand names include Ventolin. They usually give relief within 5 – 15 minutes. They can be used every 3 – 4 hours to treat an asthma attack.
Xopenex. This is an exciting new form of albuterol, available in nebulizer form, and hopefully soon as an inhaler. It is much more potent than regular albuterol, which means that much lower doses can be used to achieve bronchodilation, with less side effects. It also does not become less effective with prolonged use (years) as is sometimes the case with plain albuterol. As of 2000, it is only approved down to age 12, but safety studies are being conducted as young as age two.
Albuterol oral liquid. This works like the inhaler, but the medication is swallowed, gets absorbed into the bloodstream, and then travels to the lungs where it can work. This is an advantage for infants, with whom using an inhaler can be quite difficult. However, the oral liquid causes more side effects (discussed below). They can be used every 6 – 8 hours.
Long-acting bronchodilators (brand name Serevent). These are designed to be more of a maintenance medicine (discussed below), but also deserve mention here. It is just like the albuterol inhaler but has two main differences. It doesn't start working for 30 minutes. It therefore won't "rescue" your child immediately from wheezing. It lasts much longer (up to 12 hours). It is therefore generally used twice daily more as a maintenance or preventative medication (see below) to keep wheezing from starting, but it can also be helpful to use for a few days during a persistence attack to decrease the need for the shorter-acting albuterol inhaler. It only comes as an inhaler, not for a nebulizer machine.
Theophilline. This works similarly to albuterol but is a very different medication. It comes only in tablets. It has considerably more side effects and therefore is used very rarely in children. It is mostly used in the hospital to control very severe asthma attacks.