By E. Gorok. The Rockefeller University.

Hypothyroidism-induced impairment of ing hypothyroidism with the classic symptoms of hy- linear growth can lead to dwarfism in which the limbs pothyroidism cheap persantine 100 mg visa. Decompensation into myxedema coma are disproportionately short in relation to the trunk may occur when the homeostatic mechanisms of the se- with the apparent bone age retarded in relation to verely hypothyroid patient are subject to a stressful pre- chronological age cheap persantine 100 mg with mastercard. The principal manifestation of tardation of mental development and growth) become myxedema coma is a deterioration of mental status (ap- manifest only in later infancy and are largely irre- athy, confusion, psychosis, but rarely coma). Consequently, early recognition and initiation mon clinical features include hypothermia, diastolic hy- of replacement therapy are crucial. In the absence of pertension (early), hypotension (late), hypoventilation, thyroid hormone therapy, the symptoms of infantile hy- hypoglycemia, and hyponatremia. If myxedema coma is pothyroidism include feeding problems, failure to suspected, the patient is usually admitted to an inten- thrive, constipation, a hoarse cry, and somnolence. In sive care unit for pulmonary and cardiovascular support 748 VII DRUGS AFFECTING THE ENDOCRINE SYSTEM and treated with intravenous T4 (or sometimes T3). The total thyroid hormone content of thyroid DRUGS USED IN THE TREATMENT glands and the ratio of T3 to T4 vary somewhat from OF HYPOTHYROIDISM one species to another. Thyroid USP preparations are therefore standardized on the basis of their iodine con- Levothyroxine Sodium tent. Thus, a Levothyroxine sodium (Levothroid, Synthroid, Levoxine) given preparation may satisfy the USP iodine assay re- is the sodium salt of the naturally occurring levorota- quirements and yet contain low amounts of T and T. It is the preparation of choice for Thyrar (a beef extract) and Armour Thyroid tablets (a maintenance of plasma T4 and T3 concentrations for pork extract) are evaluated by additional biological as- thyroid hormone replacement therapy in hypothyroid says to ensure consistent potency from one batch to an- patients. Since much of the T4 is deiodi- rified frozen porcine Tg preparation, is an attempt to nated to T3, it is usually unnecessary to use more ex- avoid the variability in desiccated thyroid prepara- pensive preparations containing both T4 and T3. It is also assayed and standardized for biological is to establish euthyroidism with measured serum con- potency. These two preparations have a higher ra- prove useful in removing the stimulatory effects of TSH tio of T to T than that found in human thyroid secre- 3 4 on the thyroid gland in the management of simple tion, so supraphysiological levels of T may occur in 3 nonendemic goiter, chronic thyroiditis, and TSH- the immediate postabsorptive period because of the dependent thyroid carcinoma. Liothyronine sodium (Cytomel) is the sodium salt of the naturally occurring levorotatory isomer of T3.

Slightly more women than men are affect- with Down syndrome 100 mg persantine free shipping, caused by an extra copy of chro- ed with AD buy persantine 25mg with mastercard, but this may be because women tend to live mosome 21. Other mutations on other chromosomes longer, leaving a higher proportion of women in the most have been linked to other early-onset cases. Potentially the most important genetic link was dis- The cost of caring for a person with AD is consider- covered in the early 1990s on chromosome 19. A gene able, and has been estimated at approximately $174,000 on this chromosome, called apoE, codes for a protein in- per person over the course of the disease. ApoE occurs with AD are cared for at home; the cost of extended in at least three forms—apoE2, apoE3, and apoE4. Compared to those without ApoE4, people Causes & symptoms with one copy are about three times as likely to develop late-onset AD, and those with two copies are almost four The cause or causes of AD are unknown. Despite this important link, not strong leads have been found through recent research, everyone with apoE4 develops AD, and people without it and these have also given some theoretical support to can still have the disease. AD affects brain cells, mostly those in brain regions There are several risk factors that increase a per- responsible for learning, reasoning, and memory. The most significant sies of persons with AD show that these regions of the one is age; older people develop AD at much higher rates brain become clogged with two abnormal structures— than younger ones. Another risk factor is having a family neurofibrillary tangles and senile plaques. No parts of neurons surrounding a group of brain proteins other medical conditions have been linked to an in- called beta-amyloid deposits. To date, none of these factors has Diagnosis been shown to cause AD or increase its likelihood. Further Diagnosis of AD is complex, and may require office research may yet turn up links to other environmental cul- visits to several different specialists over several months prits, although no firm candidates have been identified. While a confident provi- The symptoms of AD begin gradually, usually with sional diagnosis may be made in most cases after thor- short-term memory loss. Occasional memory lapses are ough testing, AD cannot be definitively diagnosed until of course common to everyone, and do not by them- autopsy examination of the brain for senile plaques and selves signify any change in cognitive function. Since there are both lost or disoriented on a walk around the neighborhood prescription and over-the-counter drugs that can cause becomes more likely as the disease progresses.

However order persantine 100 mg on line, most analeptic stimulants can be absorbed orally and have short dura- Clinical Uses tions of action buy 100mg persantine amex. The pharmacological effect of most of these compounds is terminated through hepatic metab- As indicated, most of the analeptic stimulants were olism rather than renal excretion of unchanged drug. Doxapram (Dopram) is sometimes used to counteract postanesthetic respiratory depression Mechanism of Action and as an aid in chronic obstructive pulmonary disease. Perhaps the most unifying concept concerning the mode Pentylenetetrazol (Metrazol) was used experimentally of action of these agents comes from studies of the - on rare occasions to “activate” the electroencephalo- aminobutyric acid (GABA) receptor–chloride ionophore gram. It has long been recognized that the in- studies as a tool for studying CNS mechanisms because hibitory action of many amino acid neurotransmitters it is a relatively specific glycine antagonist. Thus, GABA and other inhibitory amino acids ac- Adverse Effects tively promote an increase in chloride influx by activation of the chloride channel in the neuronal membrane. An in- Most of the CNS stimulants produce adverse reactions crease in chloride conductance generally leads to mem- that are extensions of their therapeutic effect. Convulsions produced by this class of is possible to ion-trap this weak organic base by acidify- agents (with the exception of strychnine) are usually ing the urine, thereby reducing its reabsorption in the tonic–clonic and are uncoordinated. Mechanism of Action The uncontrolled excitation that occurs after acci- dental or intentional strychnine ingestion (in the ab- There is good evidence that the facilitation of peripheral sence of normal inhibition) results in characteristic con- sympathetic nervous system transmission produced by vulsions. The possibility normally dominant, tonic extension of the body and all that amphetamines act indirectly (i. This hyperextension is known as monoamines) at monoaminergic synapses in the brain opisthotonos; at its extreme, it consists of a characteris- and spinal cord seems likely. However, amphetamine has tic posture in which the back is arched and only the effects beyond displacement of catecholamines; these in- back of the head and the heels are touching the surface clude inhibition of neuronal amine uptake, direct stimula- on which the victim is lying. Under the influence of strychnine, catecholamine action at certain subtypes of adrenocep- all sensory stimuli produce exaggerated responses. Interestingly, primary therapeutic consideration after strychnine poi- none of these actions explains the therapeutic benefit of soning is to prevent convulsions, which may be fatal.

The increase in GMP results in Endocardial–epicardial flow Radius or heart size vascular smooth muscle relaxation persantine 25 mg visa, possibly through in- Coronary collateral blood flow Systolic pressure hibition of calcium entry via L-type calcium channels discount persantine 100mg line, (afterload) decreased calcium release from the sarcoplasmic reticu- Large coronary artery diameter Diastolic pressure lum, or via an increase in calcium extrusion via a sar- (preload) colemmal Ca -adenosine triphosphatase (ATPase). Heart rate Contractility Absorption, Metabolism, and Excretion Nitroglycerin is a lipid-soluble substance that is rapidly ischemic areas has been documented in experimental an- absorbed across the sublingual or buccal mucosa. Its on- imals following nifedipine (Adalat, Procardia), diltiazem set of action occurs within 2 to 5 minutes, with maximal (Cardizem),verapamil (Calan), amlodipine (Norvasc), ni- effects observed at 3 to 10 minutes. Little residual activ- troglycerin (Nitrostat, Tridil, Nitro-Dur), or propranolol ity remains 20 to 30 minutes after sublingual adminis- (Inderal) administration. The plasma half-life of nitroglycerin, given ischemic areas also have been observed in experimental animals and humans after treatment with certain calcium entry blockers and organic nitrates. Nitroglycerin, When coronary vasospasm occurs, the balance be- Organic Nitrates tween oxygen supply and demand can be restored by re- lieving the spasm, thereby restoring normal coronary Extracellular N blood flow. In contrast, cal- cium entry blockers and long-acting nitrates have proved Membrane SH SH effective in the chronic therapy of coronary vasospasm. Cysteine Intracellular SPECIFIC ANTIANGINAL DRUGS S-Nitrosothiol, NO Organic Nitrates Soluble Guanylate Cyclase Organic nitrates have been used in the therapy of angina pectoris routinely for more than 140 years, and their use is increasingly favored in a variety of other Cyclic GMP cardiac conditions, such as decompensated congestive heart failure and acute myocardial infarction. Other common Ca organic nitrates are isosorbide mononitrate (Ismo), isosorbide dinitrate (Isordil, Sorbitrate) and pentaery- thritol tetranitrate (Peritrate). With the exception of ni- Vascular Smooth Muscle Relaxation troglycerin, which is a liquid having a high vapor pres- sure, these compounds are solid at room temperature. Proposed mechanism by which nitroglycerin and the organic nitrates produce relaxation in vascular smooth muscle. Mechanism of Vasodilator Action Nitrates induce endothelial cells to release NO or a nitrosothiol (endothelium-derived releasing factor, or EDRF). The mechanism of action of nitroglycerin and other or- EDRF activates the enzyme guanylate cyclase, which causes ganic nitrates is thought to involve an interaction with the generation of cyclic guanosine monophosphate (GMP), nitrate receptors that are present in vascular smooth producing a decrease in cytosolic free calcium. Isosorbide dinitrate and pentaerythritol tetrani- to reduce myocardial ischemia is still controversial (Fig. Although nitroglycerin dilates both peripheral ca- These compounds have a slower onset and slightly pacitance and resistance vessels, the effect on the ve- longer duration of action than sublingually or buccally nous capacitance system predominates.