Examples of Disease-Specific Drugs
Musculoskeletal System Pharmacology
While estrogen therapy is still used in the treatment of osteoporosis, there are a number of medication options presently being used. The current drug options for osteoporosis fall into four categories:17
Bisphosphonates (alendronate [Fosamax] and risedronate sodium [Actonel]). These are antiresorptive agents that decrease osteoclastic bone resorption. The results are decreased bone remodeling, indirectly increased bone mass, and a reduced risk of fractures.
Calcitonin (Miacalcin). This is a calcium lowering hormone secreted by the thyroid gland that exerts its effects by direct inhibition of osteoclast activity, and promotion of renal excretion of calcium and other minerals.
Selected receptor molecules (raloxifene hydrochloride [Evista]). This is a nonhormonal medication that acts as an estrogen agonist in bone to suppress bone remodeling without unfavorable stimulation of the estrogen receptors located on the breast tissue or the uterus.
Strontium Ranelate. A drug that offers the dual mechanisms of action of combining the antiresorptive effect with the anabolic effect of new bone formation.
The medications prescribed to treat gout usually depend on whether the patient produces too much uric acid or does not excrete uric acid properly. If the body produces too much uric acid, a drug such as allopurinol (Lopurin, Zyloprim) is used to slow uric acid production. In the case where the body does not excrete uric acid well, another drug such as probenecid (Benemid, Probalan) can be used.
Neurologic System Pharmacology
Selective Serotonin Reuptake Inhibitors
Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed psychotherapeutic agents. Serotonin is a neurotransmitter synthesized from the amino acid L-tryptophan. Synthesis is necessary in both the central and peripheral nervous systems because serotonin cannot cross the blood–brain barrier. Once synthesized, serotonin is either stored in neuronal vesicles or metabolized by monamine oxidase (MAO) to 5-hydroxyindoleacetic acid. The most serious drug-related adverse effect of SSRIs is the potential to produce serotonin syndrome (SS). SS, characterized by mental status changes, neuromuscular dysfunction, and autonomic instability, is thought to be secondary to excessive serotonin activity in the spinal cord and brain. Symptoms attributed to serotonin excess may include
Commonly prescribed SSRIs include sertraline (Zoloft), fluoxetine (Prozac), paroxetine (Paxil), and fluvoxamine (Luvox).
Monoamine Oxidase Inhibitors (MAOIs)29
Neurotransmitters are generally monoamines. When released into the synaptic space, neurotransmitters are either reabsorbed into the proximal nerve or destroyed by monoamine oxidase (MAO) in the synaptic cleft. The two types of MAO are MAO-A and MAO-B. MAO-A is found primarily in the liver and GI tract with some found in the monoaminergic neurons. MAO-A present in the liver is involved in the elimination of ingested monoamines, such as dietary tyramine. Circulating monoamines such as epinephrine, norepinephrine, and dopamine are inactivated when they pass through a liver rich in MAO-A. MAO-B, on the other hand, is found primarily in the brain and in platelets.
MAOIs act by inhibiting the activity of MAO preventing the breakdown of monoamine neurotransmitters (norepinephrine, serotonin, and dopamine) thereby increasing the available monamines available within the central nervous system (CNS).
The MAOI agents currently available in the United States include phenelzine sulfate (Nardil), tranylcypromine sulfate (Parnate), isocarboxazid (Marplan), and selegiline (specific for the MAO-B enzyme), all of which irreversibly bind to MAO.
Benzodiazepines (BZDs) are sedative/hypnotic agents that are used for a variety of situations, including seizure control, anxiety, alcohol withdrawal, insomnia, control of drug-associated agitation, as muscle relaxants (antispasticity agents), and as preanesthetic agents. They also are combined frequently with other medications for conscious sedation before procedures or interventions.
γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS. BZDs exert their action by potentiating the activity of GABA. They bind to a specific receptor on the GABAA receptor complex, which facilitates the binding of GABA to its specific receptor site. BZD binding causes increased frequency of opening of the chloride channel complexes with the GABAA receptor. The reversal potential for GABAA/chloride complexes is negative to threshold for generating an action potential. In this way, activation of the GABAA receptor/chloride pore is inhibitory.
Enhanced GABA neurotransmission results in sedation, striated muscle relaxation, anxiolysis, and anticonvulsant effects. Stimulation of peripheral nervous system (PNS) GABA receptors may cause decreased cardiac contractility, vasodilation, and enhanced perfusion.
Beta-blockers, for example, Propranolol, are a class of drugs used for various indications, including the management of cardiac arrhythmias, hypertension, cardioprotection after myocardial infarction, and to block the autonomic response in persons with social phobia.
Sedative/hypnotics are a group of drugs that cause CNS depression and are mainly used in the treatment of insomnia, but can also be used to treat anxiety, depression, and psychosis. BZDs, which are non-barbiturates (see above) are the most commonly used agents in this class.31 Although barbiturates produce a sedative-hypnotic effect, the associated rapid development of tolerance carries with it a high risk of physical and psychological dependence, withdrawal syndromes, and fatalities by overdose. For these reasons, barbiturates are not routinely prescribed. BZDs induce sleep by decreasing the number of arousals between the different stages of sleep thereby allowing for more continuous total sleep time. Most sedative/hypnotics stimulate the activity of GABA, the principal inhibitory neurotransmitter in the CNS. γ-Hydroxybutyric acid (GHB) is a sedative/hypnotic recently banned for sale to the public because of frequent abuse and serious adverse toxic effects. GHB is a neuroinhibitory neurotransmitter or neuromodulator in the CNS. It also appears to increase GABAB receptor activity and dopamine levels in the CNS. Three other types of medications act on the same receptor as BZDs and, therefore, share some of the same pharmacological properties. These include the following:
- Zolpidem. Zolpidem is used to treat insomnia, and is particularly effective in initiating sleep. Zolpidem can also be used as an anticonvulsant and muscle relaxant.
- Zaleplon. Zaleplon is effective in the treatment of insomnia where difficulty in falling asleep is the primary complaint. The side effects of zaleplon are similar to the side effects of BZDs, although with less next-day sedation.
- Zopiclone. Zopiclone is a non-BZD hypnotic agent used in the treatment of insomnia. In the United States, zopiclone is not commercially available, although its active stereoisomer, eszopiclone, is sold under the names Lunesta.
Mild toxicity of sedative/hypnotics resembles ethanol intoxication and can include excessive drowsiness, impaired psychomotor coordination, decreased concentration, and cognitive deficits.31 Moderate poisoning leads to respiratory depression and hyporeflexia. Severe poisoning leads to flaccid areflexic coma, apnea, and hypotension.
Occasionally, hyperreflexia, rigidity, clonus, and Babinski signs are present. Miosis is common, but mydriasis may be present with certain agents. The nonbarbiturates, such as methyprylon and glutethimide, more commonly present with mydriasis. Hypotension is usually secondary to vasodilation and negative cardiac inotropic effects.
The term narcotic specifically refers to any substance that induces sleep. In current practice, narcotic refers to any of the many opioids or opioid derivatives.
Activation of the opiate receptors results in the inhibition of synaptic neurotransmission in the CNS and PNS. Opioids bind to opiate receptors thereby inducing a postsynaptic response. The physiological effects of opioids are mediated principally through μ and κ receptors in the CNS and periphery. μ receptor effects include analgesia, euphoria, respiratory depression, and miosis. κ receptor effects include analgesia, miosis, respiratory depression, and sedation. Two other opiate receptors that mediate the effects of certain opiates include σ and δ sites. σ receptors mediate dysphoria, hallucinations, and psychosis; δ receptor agonism results in euphoria, analgesia, and seizures. The opiate antagonists (e.g., naloxone, nalmefene, naltrexone) antagonize the effects at all four opiate receptors.
Common classifications divide the opioids into agonist, partial agonist, or agonist–antagonist agents and natural, semisynthetic, or synthetic. Opioids decrease the perception of pain, rather than eliminate or reduce the painful stimulus. Inducing slight euphoria, opioid agonists reduce the sensitivity to exogenous stimuli. The GI tract and the respiratory mucosa provide easy absorption for most opioids.
Peak effects are generally reached in 10 minutes with the IV route, 10–15 minutes after nasal insufflation (e.g., butorphanol, heroin), 30–45 minutes with the IM (intramuscular) route, 90 minutes with the PO (by mouth) route, and 2–4 hours after dermal application (i.e., fentanyl). Following therapeutic doses, most absorption occurs in the small intestine. Toxic doses may delay absorption because of delayed gastric emptying and slowed gut motility.
Most opioids are metabolized by hepatic conjugation to inactive compounds that are excreted readily in the urine. Certain opiates (e.g., propoxyphene, fentanyl, and buprenorphine) are more lipid soluble and can be stored in the fatty tissues of the body. All opioids have a prolonged duration of action in patients with liver disease (e.g., cirrhosis) because of impaired hepatic metabolism. This may lead to drug accumulation and opioid toxicity. Renal failure also leads to toxic effects from accumulated drug or active metabolites (e.g., normeperidine).
Opioid toxicity characteristically presents with a depressed level of consciousness. Opiate toxicity should be suspected when the clinical triad of CNS depression, respiratory depression, and pupillary miosis are present. Drowsiness, conjunctival injection (redness of the white sclera of the eye), and euphoria are seen frequently. Other important presenting signs are ventricular arrhythmias, acute mental status changes, and seizures.
Examples of commonly prescribed opioids include codeine phosphate, Demerol, Dilaudid, Empirin with codeine, Subli-maze, Synalgos-DC, Talwin 50, propoxyphene, morphine, Hydrocodone, Lorcet, Lortab, Zydone, Hydrocet, Oxycontin (Oxycodone), Percodan (Percocet), Darvon (Darvocet), and Vicodin (Vicoprofen).
Tricyclic antidepressants (TCAs) are used in the treatment of depression, chronic pain, and enuresis (involuntary discharge of urine, especially while asleep). Patients with depression and those with chronic pain are at high risk for abuse, misuse, and overdosing of these drugs.
TCAs affect the cardiovascular, pulmonary, and GI systems, and the CNS. The toxic effects on the myocardium are related to the blocking of fast sodium channels, which involves the same mechanism as type IA antiarrhythmics (e.g., quinidine). The result is a slowing myocardium depolarization that leads to arrhythmia, myocardial depression, and hypotension. Hypotension also results from peripheral α-adrenergic blockade, which causes vascular dilatation. Inhibition of norepinephrine reuptake and subsequent depletion causes further hypotension. The effects on the pulmonary system include pulmonary edema, adult respiratory distress syndrome, and aspiration pneumonitis. The etiologies of the first two remain unclear, but the third, aspiration pneumonitis, is secondary to an altered mental status.
The anticholinergic effects of TCAs cause a slowing of the GI system, which results in delayed gastric emptying, decreased motility, and prolonged transit time.
CNS toxicity results from the anticholinergic effects and direct inhibition of biogenic amine reuptake. An excitation syndrome is the initial result and manifests as confusion, hallucinations, ataxia, seizures, and coma.
Examples of commonly prescribed TCAs include Amitriptyline, Clomipramine, Doxepin, Trimipramine, Desipramine, Nortriptyline, Protriptyline, Imipramine, Amoxapine (dibenzoxazepine), and Maprotiline (tetracyclic antidepressant).
Parkinson Disease and Parkinsonian Syndrome32
Parkinson disease (PD) is a progressive neurodegenerative disease affecting every 100–150 per hundred thousand individuals, or about 1% of those over 60 years of age, in the US population.33–35 PD is characterized clinically by tremor, bradykinesia, rigidity, and postural instability. The basal ganglia motor circuit modulates cortical output necessary for normal movement.
Levodopa, coupled with a peripheral decarboxylase inhibitor (PDI), remains the criterion standard of symptomatic treatment for PD. It provides the greatest antiparkinsonian benefit with the fewest adverse effects.
Dopamine agonists provide symptomatic benefit comparable to levodopa/PDI in early disease, but lack sufficient efficacy to control signs and symptoms by themselves in later disease.
Medications for PD usually provide good symptomatic control for 4–6 years. Whether levodopa has a toxic or protective effect in the brain with PD is unknown. As PD progresses, fewer dopamine neurons are available to store and release levodopa-derived dopamine. The patient's clinical status begins to fluctuate more and more closely in concert with plasma levodopa levels. Fluctuating levodopa-derived dopamine concentrations in association with advancing disease, therefore, may be responsible for development of motor fluctuations and dyskinesia.
In contrast to levodopa, the long-acting dopamine agonists (i.e., bromocriptine, pergolide, pramipexole, ropinirole, cabergoline) provide relatively smooth and sustained receptor stimulation.
The selection of medication depends in part on the nature and cause of the disability. If disability is due solely to tremor, a tremor-specific medication, such as an anticholinergic agent, is often used. Anticholinergic medications provide good tremor relief in approximately 50% of patients, but do not improve bradykinesia or rigidity. Because tremor may respond to one anticholinergic medication and not another, a second anticholinergic usually is tried if the first is not successful. These medications are usually introduced at a low dose and escalated slowly to minimize adverse effects, which include memory difficulty, confusion, and hallucinations. Adverse cognitive effects are relatively common, especially in the elderly.
If disability is due to a dopamine-responsive symptom such as bradykinesia, rigidity, decreased dexterity, slow speech, or shuffling gait, a dopaminergic medication (dopamine agonist or levodopa/PDI) are typically introduced. Symptomatic medications are started at a low dose, escalated slowly, and titrated to control symptoms. Most patients require symptomatic dopaminergic therapy to ameliorate bradykinesia and rigidity within 1–2 years after diagnosis.
For patients younger than 65 years, symptomatic therapy is normally initiated with a dopamine agonist and then add levodopa/PDI when the dopamine agonist alone no longer controls symptoms adequately. Dopamine agonists provide antiparkinsonian efficacy comparable to levodopa/PDI for 6–18 months or longer and may control symptoms adequately for several years.
For patients who are demented or those older than 70 years, who may be prone to adverse effects from dopamine agonists, and for those likely to require treatment for only a few years, physicians may elect not to use a dopamine agonist but depend on levodopa/PDI as the primary symptomatic therapy. For patients aged 65–70 years, a judgment is made based on general health and cognitive status.
Medications for Cerebrovascular Accidents
The ischemic cascade is a series of biochemical reactions that take place in the brain and other aerobic tissues after seconds to minutes of ischemia (inadequate blood supply; Table 9-3).36 Since the ischemic cascade is a dynamic process, the efficacy of interventions to protect the ischemic cascade also may prove to be time dependent.
Table 9-3 The Ischemic Cascade ||Download (.pdf)
Table 9-3 The Ischemic Cascade
Lack of oxygen causes the neuron's normal process for making ATP for energy to fail.
The cell switches to anaerobic metabolism, producing lactic acid.
ATP-reliant ion transport pumps fail, causing the cell to become depolarized, allowing ions, including calcium (Ca++), to flow into the cell.
The ion pumps can no longer transport calcium out of the cell, and intracellular calcium levels get too high.
The presence of calcium triggers the release of the excitatory amino acid neurotransmitter glutamate.
Glutamate stimulates AMPA receptors and Ca++-permeable NMDA receptors, which open to allow more calcium into cells.
Excess calcium overexcites cells and causes the generation of harmful chemicals like free radicals, reactive oxygen species, and calcium-dependent enzymes such as calpain, endonucleases, ATPases, and phospholipases. Calcium can also cause the release of more glutamate.
As the cell's membrane is broken down by phospholipases, it becomes more permeable, and more ions and harmful chemicals flow into the cell.
Mitochondria break down, releasing toxins, and apoptotic factors into the cell.
The caspase-dependent apoptosis cascade is initiated, causing cells to “commit suicide.”
If the cell dies through necrosis, it releases glutamate and toxic chemicals into the environment around it.
Toxins poison nearby neurons, and glutamate can overexcite them.
If and when the brain is reperfused, a number of factors lead to reperfusion injury.
An inflammatory response is mounted, and phagocytic cells engulf damaged but still viable tissue.
Harmful chemicals damage the blood–brain barrier.
Cerebral edema occurs because of leakage of large molecules like albumin from blood vessels through the damaged blood–brain barrier. These large molecules pull water into the brain tissue after them by osmosis. This “vasogenic edema” causes compression of and damage to brain tissue.
Theoretically, calcium channel blockers (e.g., nimodipine) should have the narrowest window of therapeutic opportunity, since calcium influx is one of the earliest events in the ischemic cascade.
Neuroprotectants affecting later events in the ischemic cascade include free-radical scavengers (e.g., tirilazad, citicoline) and neuronal membrane stabilizers (e.g., citicoline). Monoclonal antibodies against leukocyte adhesion molecules also are being evaluated as late neuroprotectants (e.g., enlimomab).
Anticoagulants are considered as potential treatments for cerebrovascular accidents (CVA). However, although heparin prevents recurrent cardioembolic strokes and may help inhibit ongoing cerebrovascular thrombosis, no definitive evidence exists to show that initiating anticoagulation reduces brain injury in acute ischemic stroke.
Anticoagulation drug treatment is not without risk. Overall, intracranial hemorrhage occurs in 1–4% of patients who receive an anticoagulant for TIA or acute stroke. Accordingly, uncontrolled hypertension, intracranial hemorrhage, and uncontrolled bleeding at another site are contraindications to anticoagulation.
Several new oral anticoagulant medications, including ximelagatran, are in the final stages of clinical trials for use in the prophylaxis of ischemic thromboembolic stroke. Once approved for use, the potential of such drugs in the arena of stroke treatment may be significant.
Many structures and processes are involved in the development of a seizure, including neurons, ion channels, receptors, glia, and inhibitory and excitatory synapses.37 The antiepileptic drugs (AEDs) are designed to modify these processes to favor inhibition over excitation in order to stop or prevent seizure activity. The AEDs can be grouped according to their main mechanism of action, although many of them have several actions and others have unknown mechanisms of action. The main groups are as follows.
The sodium channel blockade is the most common and the most well-characterized mechanism of currently available AEDs. AEDs that target these sodium channels prevent the return of the channels to the active state by stabilizing their inactive form. In doing so, repetitive firing of the axons is prevented. The presynaptic and postsynaptic blockade of sodium channels of the axons causes stabilization of the neuronal membranes, blocks and prevents posttetanic potentiation, limits the development of maximal seizure activity, and reduces the spread of seizures. AED examples include carbamazepine, oxcarbazepine, lamotrigine, zonisamide, and the hydantoins: phenytoin, fosphenytoin.
Anticonvulsants in mood disorders have four major effects:
- Increasing of the seizure threshold
- Decreasing the seizure duration
- Decreasing the neurometabolic response to an episode
- Decreasing the phenomena of amygdaloid kindling
Side Effects and Toxicity
AEDs can produce dose-related adverse effects, which include dizziness, diplopia, nausea, ataxia, and blurred vision. Rare idiosyncratic adverse effects include aplastic anemia, agranulocytosis, thrombocytopenia, and Stevens–Johnson syndrome. Asymptomatic elevation of liver enzymes is observed commonly during the course of therapy in 5–10% of patients. Rarely, severe hepatotoxic effects can occur.
GABA has two types of receptors:
- GABAA. GABAA receptor is stimulated and chloride channels open to allow the influx of negative ions (i.e., chloride). The GABAA receptors have multiple binding sites for BZDs, barbiturates, and others substances such as picrotoxins, bicuculline, and neurosteroids.
- GABAB. The GABAB receptor is linked to a potassium channel.
Direct binding to GABAA receptors can enhance the GABA system by blocking presynaptic GABA uptake, by inhibiting the metabolism of GABA by GABA transaminase, and by increasing the synthesis of GABA. The BZDs most commonly used for treatment of epilepsy are lorazepam, diazepam, clonazepam, and clobazam. The two barbiturates mostly commonly used in the treatment of epilepsy are phenobarbital and primidone.
Side Effects and Toxicity
The most common effect is sedation. Other adverse effects include dizziness, ataxia, blurred vision, diplopia, irritability, depression, muscle fatigue, and weakness.
At least four specific GABA-transporting compounds help in the reuptake of GABA; these carry GABA from the synaptic space into neurons and glial cells, where it is metabolized. Nipecotic acid and tiagabine (TGB) are inhibitors of these transporters; this inhibition makes increased amounts of GABA available in the synaptic cleft, which serves to prolong GABA-mediated inhibitory postsynaptic potentials (IPSPs).
Side Effects and Toxicity
The most common adverse effects include dizziness, asthenia, nervousness, tremor, depressed mood, and emotional lability. Diarrhea also was significantly more frequent among TGB-treated patients than placebo-treated patients. Other adverse effects included somnolence, headaches, abnormal thinking, abdominal pain, pharyngitis, ataxia, confusion, psychosis, and skin rash.
GABA Transaminase Inhibitor
GABA is metabolized by transamination in the extracellular compartment by GABA-transaminase (GABA-T). Inhibition of this enzymatic process leads to an increase in the extracellular concentration of GABA. Vigabatrin (VGB) inhibits the enzyme GABA-T.
Side Effects and Toxicity
The most common adverse effect is drowsiness. Other important adverse effects include neuropsychiatric symptoms, such as depression (5%), agitation (7%), confusion, and, rarely, psychosis. Minor adverse effects, usually at the onset of therapy, include fatigue, headache, dizziness, increase in weight, tremor, double vision, and abnormal vision.
Glutamate and aspartate are the most two important excitatory neurotransmitters in the brain. The glutamate system is a complex system with macromolecular receptors with different binding sites (i.e., AMPA, kainate, NMDA, glycine, metabotropic site).
Examples of glutamate blockers include topiramate and felbamate.
Side Effects and Toxicity
Common adverse effects include insomnia, weight loss, nausea, decreased appetite, dizziness, fatigue, ataxia, and lethargy. Polytherapy is associated with increases in adverse effects.
The term neuroleptic refers to the effects on cognition and behavior of antipsychotic drugs that reduce confusion, delusions, hallucinations, and psychomotor agitation in patients with psychoses.38 Also known as major tranquilizers and antipsychotic drugs, neuroleptic agents comprise a group of the following classes of drugs:
The adverse effects of neuroleptics are not confined to psychiatric patients. Neuroleptics also are used as sedatives, for their antiemetic properties, to control hiccups, to treat migraine headaches, as antidotes for drug-induced psychosis, and in conjunction with opioid analgesia.
The major tranquilizers have complex CNS actions that are incompletely defined. Their therapeutic action is thought to be primarily antagonism of central dopaminergic (D-2 receptor) neurotransmission, although they also have antagonist effects at muscarinic, serotonergic, α1-adrenergic, and H1-histaminergic receptors.
Although all antipsychotic preparations share some toxic characteristics, the relative intensity of these effects varies greatly, depending on the individual drug. Generally, all neuroleptic medications are capable of causing the following symptoms:
- Hypotension: Phenothiazines are potent α-adrenergic blockers that result in significant orthostatic hypotension, even in therapeutic doses for some patients. In overdose, the hypotension may be severe.
- Anticholinergic effects: Neuroleptic agent toxicity can result in tachycardia, hyperthermia, urinary retention, toxic psychosis, and hot dry flushed skin.
- Extrapyramidal symptoms: Alteration in the normal balance between central acetylcholine and dopamine transmission can produce dystonia, oculogyric crisis, torticollis, acute parkinsonism, akathisia, and other movement disorders. Chronic use of major tranquilizers is associated with buccolingual dysplasia (tardive dyskinesia, TD), parkinsonism, and akathisia.
- Neuroleptic malignant syndrome: All of the major tranquilizers have been implicated in the development of neuroleptic malignant syndrome (NMS)—a life-threatening derangement that affects multiple organ systems and results in significant mortality.
- Seizures: Most major tranquilizers lower the seizure threshold and can result in seizures at high doses and in susceptible individuals.
- Hypothermia: Certain major tranquilizers prevent shivering, limiting the body's ability to generate heat.
- Cardiac effects: Prolongation of the QT interval and QRS can result in arrhythmias.
- Respiratory depression: Hypoxia and aspiration of gastric contents can occur in children and in mixed overdose.
Spasticity is a motor disorder characterized by a velocity-dependent increase in tonic stretch reflexes with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex, as one component of the upper motor neuron syndrome (see Chapter 3).39,40
Two types of GABA receptors, called A and B types, are found on neurons in the brain and spinal cord (see “Antiepileptic Drugs”). The drugs used to reduce spasticity work as agonists or antagonists at these receptors.
The BZDs bind GABAA receptor complexes on neurons located in the brainstem and at the spinal cord level and increase the affinity of GABA for the GABAA receptor complex. This results in an increase in presynaptic inhibition and the reduction of monosynaptic and polysynaptic reflexes. These drugs may improve passive range of motion and reduce hyperreflexia, painful spasms, and anxiety. Diazepam has a half-life of 20–80 hours and forms active metabolites that prolong its effectiveness. The half-life of clonazepam ranges from 18 to 28 hours.
Sedation, weakness, hypotension, adverse GI effects, memory impairment, incoordination, confusion, depression, and ataxia may occur. Tolerance and dependency can occur, and withdrawal phenomena, notably seizures, have been associated with abrupt cessation of therapy.
Baclofen—Oral and Intrathecal Pump
Baclofen is a GABA agonist, and its primary site of action is the spinal cord, where it reduces the release of excitatory neurotransmitters and substance P by binding to the GABAB receptor. Studies show that baclofen improves clonus, flexor spasm frequency, and joint range of motion, resulting in improved functional status.
Adverse effects include sedation, ataxia, weakness, and fatigue.
Intrathecal baclofen is approved in the United States for the treatment of spasticity of spinal or cerebral origin. In children, intrathecal baclofen is particularly effective for the treatment of spasticity of the lower extremities. Complications of the procedure are relatively few and usually are limited to mechanical failures of the pump or the catheter. Adverse drug effects are usually temporary and can be managed by reducing the rate of infusion.
- Dantrolene sodium: Dantrolene sodium is useful for spasticity of supraspinal origin, particularly in patients with cerebral palsy or traumatic brain injury. It decreases muscle tone, clonus, and muscle spasm by acting at the level of the muscle fiber, affecting the release of calcium from the sarcoplasmic reticulum of skeletal muscle and thus reducing muscle contraction. It is, therefore, less likely than the other agents to cause adverse cognitive effects. Its peak effect is at 4–6 hours, with a half-life of 6–9 hours.
Adverse effects include generalized weakness, including weakness of the respiratory muscles, drowsiness, dizziness, weakness, fatigue, and diarrhea.
- Tizanidine. Tizanidine (Zanaflex) is a new and effective therapeutic option for the management of spasticity due to cerebral or spinal damage. The antispasticity effects of tizanidine are the probable result of inhibition of the H-reflex. It may also facilitate inhibitory actions of glycine and reduce the release of excitatory amino acids and substance P, and may have analgesic effects. When combined with baclofen, tizanidine presents the opportunity to maximize therapeutic effects and minimize adverse effects by reducing the dosages of both drugs.
Tizanidine hydrochloride is a short-acting drug with extensive first-pass hepatic metabolism to inactive compounds following an oral dose. The half-life is 2.5 hours with peak plasma level at 1–2 hours, and therapeutic and side effects dissipate within 3–6 hours. Therefore, use must be directed to those activities and times when relief of spasticity is most important.
Dry mouth, somnolence, asthenia, and dizziness are the most common adverse events associated with tizanidine. Liver function problems (5%), orthostasis, and hallucinations (3%) are rare tizanidine-related adverse events.
Cardiovascular System Pharmacology
Many cardiovascular medications have the potential to alter responses to both acute and chronic exercise in a predictable manner. Knowledge of how common drugs alter these responses can assist the clinician in assessing the safety and appropriateness of exercise and in determining the effectiveness of exercise training.41 Most medications that are prescribed for cardiovascular disease have either a direct or indirect effect on the heart or vascular system, including alteration of the myocardial oxygen consumption, peripheral blood flow, and cardiac preload or afterload.41 Medications may either increase or decrease exercise capacity, or alter the expected changes in heart rate and blood pressure that normally occur with an increase in activity or at rest (Table 9-4).41
Table 9-4 Effects of Medications on the Cardiovascular and Metabolic Responses to Exercise ||Download (.pdf)
Table 9-4 Effects of Medications on the Cardiovascular and Metabolic Responses to Exercise
Medications That Could Alter Response
Initiation/conduction of cardiac action potential
Increase by digitalis
Decreased by β-blockers
Effects on peripheral circulation
Venodilation or constriction: preload
Arterial vasoconstriction ordilation: afterload
Decrease by nitrates
Decrease by α1-antagonists
Decreased by diuretics
Myocardial oxygen consumption
Decreased by beta-blockers
Systolic wall tension
Decreased by nitrates
Distribution of cardiac output
Blood flow to active skeletal muscles
Blood flow to cutaneous vessels
Decreased by α1-antagonists
Decreased by α1-antagonists
Fatty acid mobilization and oxidation
Decreased by beta-blockers
Decreased by beta-blockers
α-Adrenergic Blocking Drugs (α1-Antagonists/Alpha-Blockers)
These drugs work through the autonomic nervous system (ANS) by blocking alpha-receptors. Alpha-receptors normally promote constriction of the arterioles. Blocking constriction promotes dilation of vessels and lowers blood pressure as well as reducing the work of the heart in some situations. Alpha-blocking drugs also inhibit the actions of norepinephrine that raises blood pressure as part of the fight-or-flight response. Alpha-blockers are usually prescribed along with other blood-pressure-lowering drugs, such as a beta-blocking drug and/or a diuretic. There are now several medications available that combine the effects of blocking both the beta- and alpha-receptors (Labetalol [Normo-dyne, Trandate]).
Examples of alpha-blockers include doxazosin (Cardura), prazosin (Minipress), and terazosin (Hytrin).
Possible Adverse Side Effects
Nausea and indigestion; these usually subside with long-term use. Less frequent effects are cold hands and feet, temporary impotence, and nightmares. Dizziness may occur initially or as the dosage is increased.
Angiotensin-Converting Enzyme Inhibitors
These drugs act to prevent production of a hormone, angiotensin II, which constricts blood vessels. They belong to the class of drugs called vasodilators—drugs that dilate blood vessels, an effective way to lower blood pressure and increase the supply of blood and oxygen to the heart and various other organs. In addition to dilating blood vessels, angiotensin-converting enzyme (ACE)-inhibiting medications may produce some beneficial effects indirectly by preventing the abnormal rise in hormones associated with heart disease, such as aldosterone. ACE inhibitors are widely used to treat high blood pressure, or hypertension, a major risk factor for cardiovascular disease. Used alone or in combination with other drugs, ACE inhibitors have also proved effective in the treatment of congestive heart failure.
Examples include benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec, Vasotec I.V.), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril erbumine (Aceon), quinapril (Accupril), ramipril (Altace), spirapril (no brand names listed), and trandolapril (Mavik).
Possible Adverse Side Effects
Common side effects are dizziness or weakness, loss of appetite, a rash, itching, a hacking, unpredictable cough, and swelling.
These drugs, which are potent medications, correct an irregular heartbeat (arrhythmia) and slow a heart that is beating too fast (tachycardia).
Examples of antiarrhythmic drugs include amiodarone (Cordarone), digoxin (Lanoxin), disopyramide phosphate (Nor-pace), flecainide (Tambocor), propafenone (Rhythmol), lidocaine (Xylocaine), mexiletine (Mexitil), procainamide (Procan SR, Pronestyl, Pronestyl SR), quinidine gluconate (Duraquin, Quinaglute Dura-Tabs, Quinalan Sustained-Release), quinidine sulfate (Quinidex Extentabs), and tocainide (Tonocard).
The most significant common side effects are weakening of heart contractions, worsening of some arrhythmias, weight loss, nausea, and tremors. Other less common effects are fever, rash, dry mouth, depressed white blood cell count, liver inflammation, confusion, loss of concentration, dizziness, and disturbances in vision. About 0.1–0.2% of patients suffer lung inflammation, a potentially serious side effect.
Anticoagulants, Antiplatelets, and Thrombolytics
These drugs are sometimes referred to as “blood thinners,” but this term is not truly accurate, as they inhibit the ability of the blood to clot—preventing clots from forming in blood vessels and from getting bigger. Anticoagulants, antiplatelet agents, and thrombolytics each have specific indications and uses. Any patient who has had a heart valve replaced with a mechanical valve requires lifelong oral anticoagulants in order to prevent clots from forming on the valve. Patients who develop atrial fibrillation may require anticoagulants; clot formation in the left atrium is a potential hazard of this rhythmic disturbance. Oral anticoagulants are prescribed for patients who develop thrombophlebitis, an inflammation of the veins in the legs or pelvis. One of the dangers of this condition is the development of blood clots that may travel to the lungs and cause pulmonary emboli. Lastly, some patients who have a serious heart attack involving the anterior surface of the heart are prescribed an anticoagulant to prevent clots from forming on the inner lining of the scar.
Heparin is an anticoagulant that is administered intravenously when rapid anticoagulation is necessary. All patients undergoing open-heart surgery are treated with heparin while their blood is being oxygenated by the heart–lung machine. At the end of the operation, medication is given to reverse the effects of heparin.
Aspirin is not an anticoagulant but has a profound effect on platelets—blood cells that stick together and cause clots to form. Because of aspirin's ability to inhibit the clotting action of platelets, it is designated as an antiplatelet and is frequently prescribed in patients who have recovered from a heart attack, in order to prevent clots from forming in the veins used for coronary bypass surgery.
The most recent and exciting classes of drugs that are useful for people with heart attacks are the thrombolytic drugs. These agents are given intravenously as soon as possible with the goal of dissolving the offending clot within a coronary artery before it causes permanent, debilitating damage. The three most commonly used thrombolytics are t-PA, streptokinase, and APSAC.
Examples of these drugs are acetylsalicylic acid or aspirin (Alka-Seltzer, Anacin, Ascriptin, Bayer, Bufferin, Easprin, Ecotrin, St. Josephs, Zorprin), dipyridamole (Persantine), and warfarin (Coumadin, Panwarfin).
Adverse effects are rare, but may include nausea, headache, flushing, dizziness or faintness, or rash.
These drugs probably reduce blood pressure by reducing cardiac output (or perhaps by blocking the production of angiotensin). Beta-blockers are also used to treat hypertension. Specifically, they block responses from the beta nerve receptors. This serves to slow down the heart rate and to lower blood pressure. Beta-blockers also block the effects of some of the hormones that regulate blood pressure. During exercise or emotional stress, adrenaline and norepinephrine are released and normally stimulate the beta-receptors—sensors that transmit messages to the heart to speed up and pump harder. By blocking the receptors, beta-blockers act to reduce heart muscle oxygen demands during physical activity or excitement, thus reducing the possibility of angina caused by oxygen deprivation.
Examples of these drugs are acebutolol (Sectral), atenolol (Tenormin), betaxolol (Betoptic, Betoptic S, Kerlone), bisoprolol (Zebeta), metoprolol (Lopressor), carteolol (Cartrol Oral, Ocupress Ophthalmic), labetalol (Normodyne, Trandate), levobetaxolol, levobunolol, metoprolol (Lopressor, Toprol XL), nadolol (Corgard), penbutolol (Levatol), pindolol (Visken), propranolol (Inderal), sotalol (Betapace AF, Betapace), timolol (Betimol, Blocadren, Timoptic-XE, Timoptic, Timoptic, OcuDose).
Lethargy and cold hands and feet because of reduced circulation may occur. These drugs may also cause nausea, nightmares or vivid dreams, and impotence.
Calcium plays a central role in the electrical stimulation of cardiac cells and in the mechanical contraction of smooth muscle cells in the walls of arteries. Calcium channel blockers are relatively new synthetic drugs that work by blocking the passage of calcium into the muscle cells that control the size of blood vessels. All muscles need calcium in order to contract; by preventing the muscles of the arteries from contracting, blood vessels dilate, allowing blood to flow through them more easily, and reducing blood pressure.
Examples of these drugs are diltiazem (Cardizem), nicardipine (Cardene), nifedipine (Procardia, Procardia XL), nimodipine (Nimotop), and verapamil (Calan, Isoptin, Verelan).
Excessively slow heart rate, low blood pressure, headache, swelling of ankle/feet, constipation, nausea, tiredness, dizziness, redness of face and neck, palpitations, and rash.
Like many drugs, digitalis was originally derived from a plant, in this case the foxglove. Digitalis has the primary effect of strengthening the force of contractions in weakened hearts and is also used in the control of atrial fibrillation. The most commonly used digitalis products are digoxin and digitoxin. The drug penetrates all body tissues and reaches a high concentration in the muscle of the heart. Its molecules bind with cell receptors that regulate the concentration of sodium and potassium in the spaces between tissue cells and in the bloodstream. These two minerals determine the level of calcium. Digitalis preparations act by increasing the amount of calcium supplied to the heart muscle and thus enhancing its contractions. Digitalis drugs also affect electrical activity in cardiac tissues. They control the rate at which electric impulses are released and the speed of their conduction through the chamber walls. These two actions determine the two major uses of digitalis drugs in heart disease—treatment of heart failure and control of abnormal heart rhythms. Digitalis may be given on a short-term basis in acute heart failure or over a long period of time to treat chronic heart failure. Digitalis drugs can be used to treat disturbances of the heartbeat, particularly the abnormally rapid contractions of the atria referred to as atrial or supraventricular arrhythmias (especially atrial fibrillation). The drugs restore the normal heartbeat either by interrupting the abnormal rhythm or by slowing down the rapid beats to a rate at which effective and coordinated heart contractions are possible.
Example of these drugs are digoxin (Lanoxicaps, Lanoxin).
Some side effects include tiredness, nausea, loss of appetite, and disturbances in vision.
Diuretics, commonly referred to as water pills, lower blood pressure by increasing the kidney's excretion of sodium and water, which in turn reduces the volume of blood. There are several types of diuretics, which are classified according to their site of action in the kidney.
- Thiazide diuretics work in the tubules (the structures that transport urine in the kidneys).
- Loop diuretics are more potent than the thiazide diuretics. They are so named because they work in the area of the kidney called the loop of Henle. They are usually prescribed when a thiazide diuretic proves insufficient or for patients with heart failure or compromised kidney function.
- Potassium-sparing diuretics work in the area of the kidney or distal tubule of the nephrons in the kidney where potassium is excreted. They prevent the excessive loss of potassium that sometimes occurs with the thiazides. They are most often given in conjunction with a thiazide or loop diuretics.
Examples of diuretics are chlorthalidone (Hygroton) and hydrochlorothiazide (Esidrix, Hydrodiuril, Oretic), and examples of potassium-sparing diuretics are amiloride (Midamor), spironolactone (Aldactone), and triamterene (Dyrenium).
Although uncommon, lethargy, cramps, rash, or impotence may occur. Some of these effects may be caused by a loss of potassium and may be avoided by including a potassium supplement or potassium-sparing agent in the regimen.
The oldest and most frequently used coronary artery medications are the nitrates. Nitrates are potent vein and artery dilators, causing blood to pool in the veins and the arteries to open up, thus reducing the amount of blood returning to the heart. This decreases the work of the left ventricle and lowers the blood pressure. Nitrates may also increase the supply of oxygenated blood by causing the coronary arteries to open more fully, thus improving coronary blood flow. Nitrates effectively relieve coronary artery spasm. They do not, however, appear to affect the heart's contractions.
Example of nitrates are nitroglycerin (Deponit NTG, Mini-tran, Nitro-Bid, Nitrogard, Nitroglyn, Nitrol, Nitrolingual, Nitrong, Nitrostat, Transderm-Nitro, Tridil) and isosorbide dinitrate (Dilatrate-SR, Iso-Bid, Isordil, Sorbitrate, Sorbitrate SA).
Headaches, flushing, and dizziness may occur.
Pulmonary System Pharmacology
The delivery of a drug to the lungs allows the medication to interact directly with the diseased tissue and reduce the risk of adverse effects, specifically systemic reactions, while also allowing for the reduction of dose compared to oral administration. The prescription of any pulmonary medication is founded on four basic goals42:
- Promotion of bronchodilation or relief of bronchoconstriction.
- Facilitation of the removal of secretions from the lungs.
- Improvement of alveolar ventilation or oxygenation.
- Optimization of the breathing pattern.
The relative importance of each of these goals depends on the specific disease process and the resultant respiratory problem.42
Most inhaled drugs are administered through a pressurized metered-dose inhaler. Dry pounder inhalers or breath-activated devices are delivery devices that scatter a fine powder into the lungs by means of a brisk inhalation. The other major drug delivery system for pulmonary problems is the nebulizer, a device that dispenses liquid medications as a mist of extremely fine particles in oxygen or room air so that is inhaled.
Bronchodilator agents are a group of medications that produce an expansion of the lumina of the airway passages of the lungs. The primary goal of bronchodilator therapy is to influence the ANS via two opposing nucleotides: cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP).42 cAMP facilitates smooth muscle relaxation and inhibits mast cell degranulation, resulting in bronchodilation.42 cGMP facilitates smooth muscle contraction and may enhance mast cell release of histamine and other mediators, resulting in bronchoconstriction.42 Bronchodilator agents, which either stimulate (sympathomimetics) or inhibit (sympatholytics) adrenergic receptors, are central to the symptomatic management of chronic obstructive pulmonary disease (COPD) and asthma (Table 9-5).
Table 9-5 Drugs that Have a Positive Influence on Bronchial Intralumenal Diameter ||Download (.pdf)
Table 9-5 Drugs that Have a Positive Influence on Bronchial Intralumenal Diameter
Mechanism of Action
Increases cyclic AMP, decreases intracellular calcium concentrations, thus relaxing smooth muscle
Tremor, palpitations, tachycardia, headache, nervousness, dizziness, nausea, hypertension
Methylxanthines (a substance found in coffee, tea, and chocolate)
Blocks the degradation of cyclic AMP.
Used for patients who do not respond to the standard asthma agents, and is occasionally used in the treatment of spinal cord injury
Agitation, tachycardia, headache, palpitations, dizziness, hypotension, chest pain, nausea, possibly diuresis
Blocks the decrease of cyclic AMP
Agitation, tachycardia, headache, palpitations, dizziness, hypotension, chest pain, nausea, possibly diuresis
Blocks parasympathetic stimulation, which prevents an increase in cyclic GMP, allowing cyclic AMP to increase; blocks the activity of the enzyme hosphodiesterase, which prevents the degradation of cyclic AMP
Central nervous system stimulation with low doses, depression with high doses; delirium, hallucinations, decreased gastrointestinal activity
Administered systemically or topically.
Blocks the release of arachidonic acid from airway epithelial cells, which in turn blocks production of prostaglandins and leukotrienes.
Decreases inflammatory response
Cushingoid appearance; obesity; growth suppression; hyperglycemia and diabetes, mood changes, irritability, or depression; thinning of skin; muscle wasting; osteoporosis; hypertension; and immunosuppression
Cromolyn sodium (extract of a Mediterranean plant)
Prevents influx of calcium ions into the mast cell, thus blocking the release of mediators responsible for bronchoconstriction
Used prophylactically to prevent exercise-induced bronchospasm and severe bronchial asthma via oral inhalation
Throat irritation, hoarseness, dry mouth, cough, chest tightness, bronchospasm
Ancillary Pulmonary Medications
In addition to bronchodilators, several other drug groups are frequently used in the treatment of respiratory disorders, including decongestants, antihistamines, antitussives, mucokinetics, respiratory stimulants and depressants, and paralyzing and antimicrobial agents.42
Antitussives are drugs that suppress an ineffective, dry, hacking cough by decreasing the activity of the afferent nerves or decreasing the sensitivity of the cough center. The stimulus to cough is relayed to the cough center in the medulla and then to the respiratory muscles via the phrenic nerve. The primary adverse effect of antitussive agents is sedation, although GI distress and dizziness may also occur.42
Decongestants are used to treat upper airway mucosal edema and discharge by binding with the alpha-1 receptors in the blood vessels of the mucosal lining of the upper airways thereby stimulating vasoconstriction.42 Primary side effects include headache, dizziness, nausea, nervousness, hypertension, and cardiac irregularities.42
Histamines play a role in the modulation of neural activity within the CNS and the regulation of gastric secretion by means of two types of receptors:
- H1-receptors. These are primarily located in vascular, respiratory, and GI smooth muscles and are specifically targeted for blockade by antihistamines in the treatment of asthma. H1-antagonist drugs decrease the mucosal congestion, irritation, and discharge caused by inhaled allergens. The adverse effects most often attributable to antihistamines include sedation, fatigue, dizziness, blurred vision, loss of coordination, and GI distress.
- H2-receptors. These act via G-proteins (guanine nucleotide binding proteins) to stimulate adenylate cyclase, the enzyme that synthesizes cAMP from adenosine triphosphate (ATP). Among the many responses mediated by these receptors are gastric acid secretion, smooth muscle relaxation, inotropic and chronotropic effects on heart muscle, and inhibition of lymphocyte function.
This class of drugs is responsible for promoting the mobilization and removal of secretions from the respiratory tract.42 There are four basic types of mucokinetics agents42:
- Mucolytics act by disrupting the chemical bonds in mucoid and purulent secretions, decreasing the viscosity of the mucus and promoting expectoration. The primary adverse effects of these drugs include mucosal irritation, coughing, bronchospasm, and nausea.
- Expectorants increase the production of respiratory secretions, thus facilitating their ejection from the respiratory tract.
- Wetting agents make expectoration easier for the patient and are delivered by either continuous aerosol or intermittent ultrasonic nebulization.
- Surface active agents (surfactant) lower the surface tension of the medium in which these are dissolved. They are primarily used to stabilize aerosol droplets thereby enhancing their efficacy as carrier vehicles for nebulized drugs.
Penicillins are the mainstay in the treatment of respiratory infections.42 First, second, and third generation cephalosporins are generally considered as alternatives to the penicillins, when penicillins are not tolerated by the patient or when they are ineffective.42
Oxygen should be considered a drug when it is breathed in concentrations higher than those found in the atmospheric air. The therapeutic administration of oxygen can elevate the arterial oxygen tension and increase the arterial oxygen content, improving peripheral tissue oxygenation. When used judiciously, oxygen therapy has few side effects.
Metabolic and Endocrine System
Physical therapists routinely treat patients who are diagnosed with diabetes mellitus (DM). People with DM are at increased risk of developing chronic complications related to ophthalmic, renal, neurological, cerebrovascular, cardiovascular, and peripheral vascular disease.43,44 The major classes of DM are insulin-dependent diabetes mellitus (IDDM), also known as type 1 DM, and noninsulin-dependent diabetes mellitus (NIDDM), also known as type 2 DM, and subclassed as obese or nonobese.45 Type 1 DM results from autoimmune beta cell destruction, whereas type 2 DM is related to deficiency in insulin production or a condition of insulin resistance. Malnutrition-related DM, gestational DM, and other types of DM associated with specific conditions complete the classification. By its action on carbohydrate, protein, and lipid metabolism, insulin exerts a dominant effect on the regulation of glucose homeostasis.45 Through various actions, insulin, a hormone which is secreted by the beta cells of the pancreas, lowers blood glucose by either suppressing glucose release from the liver, or by promoting uptake of glucose into peripheral tissues, especially muscle. Insulin also affects adipose tissue by activating lipogenesis (conversion of glucose into triglyceride).45 Glucagon, catecholamines, glucocorticoids, and growth hormone act in opposition to insulin by increasing blood glucose.
The classic intervention approach to DM is the triad of diet (weight management), exercise, and drug therapy.45 Patients with IDDM require insulin replacement, with diet and exercise completing the treatment plan, whereas patients with NIDDM are often managed by diet and exercise prior to any use of pharmacological agents.
Because patients with type 2 (NIDDM) diabetes have both insulin resistance and beta cell dysfunction, oral medication to increase insulin sensitivity is often given with an intermediate-acting insulin at bedtime or a long-acting insulin given in the morning or evening. The medications prescribed for DM have a variety of actions:
- Exenatide (Byetta) is an incretin-mimetic agent that mimics glucose-dependent insulin secretion and several other anti-hyperglycemic actions of incretins.
- Chlorpropamide (Diabinese) may increase insulin secretion from pancreatic beta cells.
- Tolbutamide (Orinase) increases insulin secretion from pancreatic beta cells.
- Tolazamide (Tolinase) increases insulin secretion from pancreatic beta cells.
- Acetohexamide (Dymelor) increases insulin secretion from pancreatic beta cells.
- Glyburide (DiaBeta, Micronase, PresTab, Glynase) increases insulin secretion from pancreatic beta cells.
- Glipizide (Glucotrol, Glucotrol XL) is second-generation sulfonylurea; stimulates insulin release from pancreatic beta cells.
- Repaglinide (Prandin) stimulates insulin release from pancreatic beta cells.
- Acarbose (Precose) delays hydrolysis of ingested complex carbohydrates and disaccharides and absorption of glucose; inhibits metabolism of sucrose to glucose and fructose.
- Miglitol (Glyset) delays glucose absorption in small intestine; lowers after-dinner hyperglycemia.
- Pioglitazone (Actos) improves target cell response to insulin without increasing insulin secretion from pancreas.
- Rosiglitazone (Avandia) is an insulin sensitizer; major effect in stimulating glucose uptake in skeletal muscle and adipose tissue.
- Pramlintide acetate (Symlin) is a synthetic analog of human amylin, a hormone made in beta cells; slows gastric emptying, suppresses after-dinner glucagon secretion, and regulates food intake.
Exercise has the effect of increasing glucose uptake of insulin-sensitive tissues by two mechanisms45:
- Increasing blood flow and thus enhancing glucose and insulin delivery to muscle.
- Stimulation of glucose transport by muscle contraction.
In a nondiabetic person, insulin levels fall during acute exercise and hepatic glucose production rises to meet the demands of the exercising muscle. In a diabetic patient, exercise lowers blood glucose concentration and transiently improves glucose tolerance during acute exercise. The metabolic response to exercise is based on the fitness level of the individual, the intensity and duration of the exercise, and timing of exercise in relation to insulin administration and meals.45
Additional benefits of exercise in a diabetic population include improved whole-body insulin sensitivity, improved glycemic control, reduction of certain cardiovascular risk factors, and an increase in psychological well-being.
Ergogenic aids is a term used to describe a broad category of topics including physiologic, pharmacologic, psychologic, and nutritional enhancement.46 The most common pharmacologic enhancement used by athletes are anabolic–androgenic steroids, a synthetic derivative of the male hormone testosterone. The more appropriate term “anabolic–androgenic steroids” is frequently shortened to anabolic steroids.
The use of anabolic steroids for nonmedical purposes has been in existence for over 50 years. These synthetic agents have a core steroid structure that gives them both anabolic (tissue building) and androgenic (masculinizing) effects, although physiologically these effects are inseparable.47 Anabolic steroids may be taken orally or parenterally. Orally ingested steroids are well absorbed from the stomach, excreted fairly rapidly from the body because of their short half-lives, are more toxic to the liver than injectable steroids, and are highly potent.46,48–50 Injectable steroids are characterized by delayed uptake from the body, slower excretion, increased detectability in drug tests for longer periods of time, less liver toxicity, and have less potency than oral steroids.46,48–50
Studies on the effects of anabolic steroids on muscle strength provide inconsistent results.46 Muscle strength increases will result from anabolic steroid use only if the following criteria are met46,51:
- The athlete must have been intensively trained in weightlifting immediately prior to the steroid regimen and must continue with intense weightlifting during the steroid regimen.
- The athlete must maintain a high protein, high calorie diet.
- Strength must be assessed with a single repetition, maximal-weight technique using the specific exercises with which the athlete trains, as opposed to single-joint, isolation-testing techniques.
Weight gain is commonly associated with anabolic steroid use. Whether these gains reflect muscle mass increases or fluid retention remains unclear.46
Although the potential benefits associated with anabolic steroid use remain questionable, the immediate and long-term side effects are well-established and include46
- increased risk of myocardial infarction and stroke;
- liver toxicity;
- significant decreases in plasma testosterone, testicular atrophy, impotence, prostate enlargement, decreased sperm counts, and a decrease in testosterone production from the testes;
- gynecomastia, characterized by a subareolar, button-like unilateral or bilateral plaque of tissue, and/or the development of breast tissue;
- increased musculotendinous injury;
- premature closure of the epiphysis in children, resulting in decreased adult height;
- alterations in lipid profiles—a significant rise in total serum cholesterol level and a decrease in high density lipoprotein (HDL); and
- alterations in mental status including, euphoria, aggressiveness, irritability, nervous tension, changes in libido, mania, depression (with withdrawal from steroids), and psychosis.
The phenylethylamine structure of amphetamines is similar to catecholaminergic, dopaminergic, and serotonergic agonists (biogenic amines), which may explain their actions, with the clinical presentation being dependent on the type of amphetamine used. For example, methamphetamine lacks much of the peripheral stimulant properties of amphetamine while still offering euphoric and hallucinogenic properties. These actions are similar to those of cocaine; however, while effects of cocaine last for 10–20 minutes, duration of amphetamine action is much longer, lasting as long as 10–12 hours.
The routes of amphetamine administration may be oral (ingestion), inhalation (smoke), or injection (IV). Oral use is associated with an approximate one-hour lag time before onset of symptoms, whereas inhaled and IV methods yield effects within a few minutes. Peak plasma concentrations occur within 5 minutes with IV use, 30 minutes with nasal or IM use, and 2–3 hours postingestion.
Amphetamine compounds cause a general efflux of biogenic amines from neuronal synaptic terminals (indirect sympathomimetics). They inhibit specific transporters responsible for the reuptake of biogenic amines from the synaptic nerve ending and presynaptic vesicles. Amphetamines also inhibit MAO, which degrades biogenic amine neurotransmitters intracellularly. The net effect is an increase of monoamine neurotransmitter release into the synapse. Physiological adaptation occurs through receptor or coupling down regulation; this tolerance and an accompanying psychological tolerance can lead to escalating use of the drug and increased toxicity. Chronic use can lead to a depletion of biogenic amine stores and a paradoxical reverse effect of the drug—a wash out.
Elevated catecholamine levels usually lead to a state of increased arousal and decreased fatigue. Increased dopamine levels at synapses in the CNS may be responsible for movement disorders, schizophrenia, and euphoria. Serotonergic signals may play a role in the hallucinogenic and anorexic aspects of these drugs.
Other serotonergic and dopaminergic effects may include resetting the thermal regulatory circuits upward in the hypothalamus and causing hyperthermia. The hyperthermia produced by amphetamines is similar to that of the SS.
Peripheral Nervous System
Catecholaminergic (sympathomimetic) effects of amphetamines include inotropic and chronotropic effects on the heart, which can lead to tachycardia and other dysrhythmias. The vasoconstrictive properties of the drugs can lead to hypertension and/or coronary vasospasm.
The serotonergic action of amphetamines on peripheral vasculature can lead to vasoconstriction, which is especially problematic in placental vessels. Animal studies have shown that serotonergic actions of amphetamines effect changes in plasma levels of oxytocin, somatostatin, gastrin, and cholecystokinin.
Patients with amphetamine intoxication often are identified by a change of mental status alone or associated with another injury and/or illness. These changes include disorientation, headache, dyskinesias, agitation, symptoms of stroke, cardiovascular signs and symptoms (chest pain, palpitations), GI problems (dry mouth, nausea and vomiting, diarrhea), genitourinary dysfunction (difficult micturition), and skin changes (diaphoresis, erythematous painful rashes, needle marks, infected deep ulcerations (ecthyma)).