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Clinical Uses Phenobarbital is useful in the treatment of partial seizures and generalized tonic-clonic seizures effective ramipril 5 mg arteria 3d castle pack 2, although the drug is often tried for virtually every seizure type cheap ramipril 5mg mastercard pulse pressure stroke, especially when attacks are difficult to control discount 2.5mg ramipril amex heart attack the alias club remix. There is little evidence for its effectiveness in generalized seizures such as absence cheap 5 mg ramipril free shipping blood pressure medication numbness, atonic attacks, and infantile spasms; it may worsen certain patients with these seizure types. Some physicians prefer either metharbital (no longer readily available) or mephobarbital (especially the latter) to phenobarbital because of supposed decreased adverse effects. Pharmacokinetics, Therapeutic Levels, & Dosage For pharmacokinetics, drug interactions, and toxicity of phenobarbital, see Chapter 22. Documentation of effectiveness is best in febrile seizures, and levels below 15 mcg/mL appear ineffective for prevention of febrile seizure recurrence. The upper end of the therapeutic range is more difficult to define because many patients appear to tolerate chronic levels above 40 mcg/mL. Mechanism of Action Although primidone is converted to phenobarbital, the mechanism of action of primidone itself may be more like that of phenytoin. Clinical Uses Primidone, like its metabolites, is effective against partial seizures and generalized tonic-clonic seizures and may be more effective than phenobarbital. It was previously considered to be the drug of choice for complex partial seizures, but later studies of partial seizures in adults strongly suggest that carbamazepine and phenytoin are superior to primidone. Attempts to determine the relative potencies of the parent drug and its two metabolites have been conducted in newborn infants, in whom drug-metabolizing enzyme systems are very immature and in whom primidone is only slowly metabolized. Primidone has been shown to be effective in controlling seizures in this group and in older patients beginning treatment with primidone; older patients show seizure control before phenobarbital concentrations reach the therapeutic range. Pharmacokinetics Primidone is completely absorbed, usually reaching peak concentrations about 3 hours after oral administration, although considerable variation has been reported. Primidone has a larger clearance than most other antiseizure drugs (2 L/kg/d), corresponding to a half-life of 6–8 hours. Phenobarbital therefore accumulates very slowly but eventually reaches therapeutic concentrations in most patients when therapeutic doses of primidone are administered. During chronic therapy, phenobarbital levels derived from primidone are usually two to three times higher than primidone levels. Therapeutic Levels & Dosage Primidone is most efficacious when plasma levels are in the range of 8–12 mcg/mL. Concomitant levels of its metabolite, phenobarbital, at steady state usually vary from 15 to 30 mcg/mL. It is very important, however, to start primidone at low doses and gradually increase over days to a few weeks to avoid prominent sedation and gastrointestinal complaints. Toxicity The dose-related adverse effects of primidone are similar to those of its metabolite, phenobarbital, except that drowsiness occurs early in treatment and may be prominent if the initial dose is too large. Although it is effective in some patients with partial seizures, the drug causes aplastic anemia and severe hepatitis at unexpectedly high rates and has been relegated to the status of a third-line drug for refractory cases. A Felbamate has a half-life of 20 hours (somewhat shorter when administered with either phenytoin or carbamazepine) and is metabolized by hydroxylation and conjugation; a significant percentage of the drug is excreted unchanged in the urine. When added to treatment with other antiseizure drugs, felbamate increases plasma phenytoin and valproic acid levels but decreases levels of carbamazepine. In spite of the seriousness of the adverse effects, thousands of patients worldwide utilize this medication. Usual dosages are 2000–4000 mg/d in adults, and effective plasma levels range from 30 mcg/mL to 100 mcg/mL. In addition to its usefulness in partial seizures, felbamate has proved effective against the seizures that occur in Lennox-Gastaut syndrome. This appears to underlie 2+ the main mechanism of action, which is decreasing Ca entry, with a predominant effect on presynaptic channels. Clinical Uses Gabapentin is effective as an adjunct against partial seizures and generalized tonic-clonic seizures at dosages that range up to 2400 mg/d in controlled clinical trials. Open follow-up studies permitted dosages up to 4800 mg/d, but data are inconclusive on the effectiveness or tolerability of such doses. Some clinicians have found that very high dosages are needed to achieve improvement in seizure control. Gabapentin has also been promoted for the treatment of neuropathic pain and is now indicated for postherpetic neuralgia in adults at doses of 1800 mg and above. Pregabalin is approved for the adjunctive treatment of partial seizures, with or without secondary generalization; controlled clinical trials have documented its effectiveness. It is available only in oral form, and the dosage ranges from 150 to 600 mg/d, usually in two or three divided doses. Pregabalin is also approved for use in neuropathic pain, including painful diabetic peripheral neuropathy and postherpetic neuralgia. Absorption is nonlinear and dose-dependent at very high doses, but the elimination kinetics are linear. The half-life is relatively short, ranging from 5 to 8 hours; the drug is typically administered two or three times per day. Pregabalin, like gabapentin, is not metabolized and is almost entirely excreted unchanged in the urine. It is not bound to plasma proteins and has virtually no drug-drug interactions, again resembling the characteristics of gabapentin. Clinical Uses Lacosamide is approved as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalization in patients with epilepsy who are age 16–17 years and older. Clinical trials include three multicenter, randomized placebo-controlled studies with more than 1300 patients. In the open-label follow-up study, at dosages ranging from 100 to 800 mg/d, many patients continued lacosamide treatment for 24–30 months. The drug is typically administered twice daily, beginning with 50 mg doses and increasing by 100 mg increments weekly. Peak concentrations occur from 1 to 4 hours after oral dosing, with an elimination half-life of 13 hours. Lacosamide does not induce or inhibit cytochrome P450 isoenzymes, so drug interactions are negligible. Several phenyltriazines were developed, and though their antifolate properties were weak, some were active in seizure screening tests. Mechanism of Action Lamotrigine, like phenytoin, suppresses sustained rapid firing of neurons and produces a voltage- and use-dependent + blockade of Na channels. It appears likely that 2+ lamotrigine also inhibits voltage-gated Ca channels, particularly the N- and P/Q-type channels, which would account for its efficacy in primary generalized seizures in childhood, including absence attacks. Clinical Uses Although most controlled studies have evaluated lamotrigine as add-on therapy, it is generally agreed that the drug is effective as monotherapy for partial seizures, and lamotrigine is now widely prescribed for this indication. The drug is also active against absence and myoclonic seizures in children and is approved for seizure control in the Lennox-Gastaut syndrome. Although the risk of rash may be diminished by introducing the drug slowly, pediatric patients are at greatest risk, some studies suggest that a potentially life-threatening dermatitis will develop in 1–2% of pediatric patients. Pharmacokinetics Lamotrigine is almost completely absorbed and has a volume of distribution in the range of 1–1. The drug has linear kinetics and is metabolized primarily by glucuronidation to the 2-N-glucuronide, which is excreted in the urine. Lamotrigine has a half-life of approximately 24 hours in normal volunteers; this decreases to 13–15 hours in patients taking enzyme-inducing drugs.

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Drugs that are suffciently lipid soluble to be readily absorbed orally 3 Uptake by the liver and subsequent elimination in the bile ( are rapidly distributed throughout the body water compartments ( ) cheap ramipril 10 mg visa hypertension emergency treatment. Routes of administration the extracellular fuid purchase ramipril 10mg with amex hypertension and heart disease, whereas large volumes of distribution Drugs can be administered orally or parenterally buy cheap ramipril 10 mg on line blood pressure risks. Oral Most drugs are absorbed by this route and generic 10 mg ramipril fast delivery blood pressure medication in liquid form, because of its convenience, it is the most widely used. It is the benzylpenicillin, insulin) are destroyed by the acid or enzymes in the volume of blood or plasma cleared of drug in unit time. Clearance, but not t1/2, provides an indication of the ability • for continuous administration (infusion); of the liver and kidney to dispose of drugs. Ideally, in drug treatment, a steady-state plasma concentration (Cpss) is required within a known therapeutic range. A steady state will be Intramuscular and subcutaneous injections Drugs in aqueous solu- achieved when the rate of drug entering the systemic circulation tion are usually absorbed fairly rapidly, but absorption can be slowed (dosage rate) equals the rate of elimination. Sublingual F × dose and rectal administration avoids the portal circulation, and sublingual = Clp × Cp, average dosing interval preparations in particular are valuable in administering drugs subject to a high degree of frst-pass metabolism. The t1/2 value of a drug is useful in choosing a dosing interval that does not produce excessively high Distribution and excretion peaks (toxic levels) and low troughs (ineffective levels) in drug Distribution around the body occurs when the drug reaches the circula- concentration. The t1/2 (half-life) is the time taken for the concentration of drug in Bioavailability This is a term used to describe the proportion the blood to fall by half its original value (right, top graph). Bioavailability Measurement of t1/2 allows the calculation of the elimination rate is 100% following an intravenous injection (F = 1), but drugs constant (Kel) from the formula: are usually given orally, and the proportion of the dose reaching the systemic circulation varies with different drugs and also from 0 69. Excretion The exponential curve of plasma concentration (C ) against time (t) Renal excretion This is ultimately responsible for the elimination of p is described by: most drugs. Drugs appear in the glomerular fltrate, but if they are lipid soluble they are readily reabsorbed in the renal tubules by passive C = C e−Kelt diffusion. Metabolism of a drug often results in a less lipid-soluble p 0 compound, aiding renal excretion (see Chapter 4). By taking loga- The ionization of weak acids and bases depends on the pH of the rithms, the exponential curve can be transformed into a more conven- tubular fuid. Manipulation of the urine pH is sometimes useful in ient straight line (right, bottom graph) from which C0 and t1/2 can increasing renal excretion. Drug absorption, distribution and excretion 13 4 Drug metabolism Cytochrome Enzyme induction Some drugs increase enzyme Increase metabolism P-450-dependent synthesis (e. Oxidations are the most common reactions and these are catalysed 1 The drug is made more hydrophilic – this hastens its excretion by by an important class of enzymes called the mixed function oxidases the kidneys (right, ) because the less lipid-soluble metabolite is not (cytochrome P-450s). Other phase I reactions are reductions (middle left) and However, this is not always so, and sometimes the metabolites are as hydrolysis (bottom left). Prodrugs are inactive until ciently polar to be excreted rapidly by the kidneys are made more they are metabolized in the body to the active drug. For example, hydrophilic by conjugation with endogenous compounds in the liver levodopa, an antiparkinsonian drug (Chapter 26), is metabolized to (centre of fgure). This increases the rate of The liver is the main organ of drug metabolism and is involved in metabolism of the inducing drug and also of other drugs metabolized two general types of reaction. In contrast, drugs sometimes inhibit microsomal enzyme activity (top, ) and this increases the action of drugs metabolized by the same enzyme (top right, ). Phase I reactions These involve the biotransformation of a drug to a In addition to these drug–drug interactions, the metabolism of drugs more polar metabolite (left of fgure) by introducing or unmasking a may be infuenced by genetic factors (pharmacogenetics), age and functional group (e. Such drugs are metabo- may inhibit different forms of cytochrome P-450 and so affect the lized little, if at all, and the termination of their actions depends mainly metabolism only of drugs metabolized by that particular isoenzyme. However, most drugs are highly lipophilic and are Cimetidine inhibits the metabolism of several potentially toxic drugs often bound to plasma proteins. Erythromycin also tered at the renal glomerulus and the free drug readily diffuses back inhibits the cytochrome P-450 system and increases the activity of from the tubule into the blood, such drugs would have a very pro- theophylline, warfarin, carbamazepine and digoxin. In general, drugs are metabolized to more polar compounds, which are Genetic polymorphisms more easily excreted by the kidneys. The response to drugs varies between individuals Liver and, because the variations usually have a Gaussian distribution, it is The main organ of drug metabolism is the liver, but other organs, such assumed that the determinant of the response is multifactorial. However, some drug responses show discontinuous variation and, in Drugs given orally are usually absorbed in the small intestine and enter these cases, the population can be divided into two or more groups, the portal system to travel to the liver, where they may be extensively suggesting a single-gene polymorphism. For example, chlorpromazine is metabolized more in the intes- show exaggerated and prolonged responses to drugs such as pro- tine than by the liver. About 50% of the Microsomal mixed function oxidase system population acetylate isoniazid (an antitubercular drug) rapidly, whereas Many of the enzymes involved in drug metabolism are located on the the other 50% acetylate it slowly. Slow acetylation is caused by an smooth endoplasmic reticulum, which forms small vesicles when the autosomal recessive gene that is associated with decreased hepatic tissue is homogenized. There are various methods for calculat- These usually occur in the liver and involve conjugation of a drug or ing paediatric doses (see British National Formulary). The resulting In the elderly, hepatic metabolism of drugs may be reduced, but conjugates are almost always less active and are polar molecules that declining renal function is usually more important. However, not all enzymes subject to induction are micro- Occasionally, reactive products of drug metabolism are toxic to somal. However, these processes become saturated at high doses and the drug Enzyme inhibition is then conjugated with glutathione. These interac- depleted, then a reactive and potentially lethal hepatotoxic metabolite tions tend to occur more rapidly than those involving enzyme accumulates (Chapter 46). It formed and these block the Na+ channels ( ) preventing the genera- is often used in pregnancy to produce continuous epidural blockade tion of action potentials (lower half of fgure). Benzocaine is a neutral, water-insoluble local anaesthetic of small-diameter fbres are more sensitive than large fbres. Its only use is in surface anaesthesia for non-infamed differential block can be achieved where the smaller pain and tissue (e. The more toxic agents, tetracaine autonomic fbres are blocked, whereas coarse touch and movement and cocaine, have restricted use. Local anaesthetics vary widely in their potency, anaesthesia where its intrinsic vasoconstrictor action is desirable (e. The α-subunit has four identical anxiety and restlessness sometimes occur, presumably because central domains, each containing six membrane-spanning α-helices (S1–S6). Higher toxic doses cause twitching The 24 cylindrical helices are stacked together radially in the mem- and visual disturbances, whereas severe toxicity causes convulsions brane to form a central channel. Exactly how voltage-gated channels and coma, with respiratory and cardiac depression resulting from work is not known, but their conductance (gNa+) is given by medullary depression. Even cocaine, which has central stimulant prop- gNa+ = gNa+m3h, where gNa+ is the maximum conductance possible, erties unrelated to its local anaesthetic action, may cause death by and m and h are gating constants that depend on the membrane poten- respiratory depression. At the resting potential, most h-gates (blue) Cardiovascular system are open and the m-gates (yellow) are closed (closed channel).

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The discovery of a calcium channel in cardiac muscle was followed by the finding of several different types of calcium channels in different tissues (Table 12–4) cheap ramipril 10mg mastercard heart attack sam tsui chrissy costanza. Although the blockers currently available for clinical use in cardiovascular conditions are exclusively L-type calcium channel blockers cheap ramipril 5 mg fast delivery hypertension 2013, selective blockers of other types of calcium channels are under intensive investigation buy generic ramipril 5 mg online blood pressure medication used for withdrawal. Certain antiseizure drugs are thought to act order ramipril 2.5 mg amex heart attack from weed, at least in part, through calcium channel (especially T-type) blockade in neurons (see Chapter 24). Chemistry & Pharmacokinetics Verapamil, the first clinically useful member of this group, was the result of attempts to synthesize more active analogs of papaverine, a vasodilator alkaloid found in the opium poppy. Since then, dozens of agents of varying structure have been found to have the same fundamental pharmacologic action (Table 12–5). The calcium channel blockers are orally active agents and are characterized by high first-pass effect, high plasma protein binding, and extensive metabolism. Mechanism of Action The voltage-gated L-type calcium channel is the dominant type in cardiac and smooth muscle and is known to contain several drug receptors. Nifedipine and other dihydropyridines have been demonstrated to bind to one site on the α1 subunit, whereas verapamil and diltiazem appear to bind to closely related but not identical receptors in another region of the same subunit. Binding of a drug to the verapamil or diltiazem receptors allosterically affects dihydropyridine binding. These receptor regions are stereoselective, since marked differences in both stereoisomer-binding affinity and pharmacologic potency are observed for enantiomers of verapamil, diltiazem, and optically active nifedipine congeners. Blockade of calcium channels by these drugs resembles that of sodium channel blockade by local anesthetics (see Chapters 14 and 26). The drugs act from the inner side of the membrane and bind more effectively to open channels and inactivated channels. The result is a marked decrease in transmembrane calcium current, which in smooth muscle results in long-lasting relaxation (Figure 12– 3) and in cardiac muscle results in reduction in contractility throughout the heart and decreases in sinus node pacemaker * rate and atrioventricular node conduction velocity. Although some neuronal cells harbor L-type calcium channels, their sensitivity to these drugs is lower because the channels in these cells spend less time in the open and inactivated states. Smooth muscle responses to calcium influx through ligand-gated calcium channels are also reduced by these drugs but not as markedly. The block can be partially reversed by elevating the concentration of calcium, although the levels of calcium required are not easily attainable in patients. Block can also be partially reversed by the use of drugs that increase the transmembrane flux of calcium, such as sympathomimetics. Other types of calcium channels are less sensitive to blockade by these calcium channel blockers (Table 12–4). Therefore, tissues in which these other channel types play a major role—neurons and most secretory glands—are much less affected by these drugs than are cardiac and smooth muscle. Mibefradil is a selective T-type calcium channel blocker that was introduced for antiarrhythmic use but has been withdrawn. Potassium channels in vascular smooth muscle are inhibited by verapamil, thus limiting the vasodilation produced by this drug. Smooth muscle—Most types of smooth muscle are dependent on transmembrane calcium influx for normal resting tone and contractile responses. Vascular smooth muscle appears to be the most sensitive, but similar relaxation can be shown for bronchiolar, gastrointestinal, and uterine smooth muscle. In the vascular system, arterioles appear to be more sensitive than veins; orthostatic hypotension is not a common adverse effect. The reduction in peripheral vascular resistance is one mechanism by which these agents may benefit the patient with angina of effort. In general, the dihydropyridines have a greater ratio of vascular smooth muscle effects relative to cardiac effects than do diltiazem and verapamil. The relatively smaller effect of verapamil on vasodilation may be the result of simultaneous blockade of vascular smooth muscle potassium channels described earlier. Cardiac muscle—Cardiac muscle is highly dependent on calcium influx during each action potential for normal function. Impulse generation in the sinoatrial node and conduction in the atrioventricular node—so-called slow- response, or calcium-dependent, action potentials—may be reduced or blocked by all of the calcium channel blockers. Excitation-contraction coupling in all cardiac cells requires calcium influx, so these drugs reduce cardiac contractility in a dose-dependent fashion. This reduction in cardiac mechanical function is another mechanism by which the calcium channel blockers can reduce the oxygen requirement in patients with angina. Important differences between the available calcium channel blockers arise from the details of their interactions with cardiac ion channels and, as noted above, differences in their relative smooth muscle versus cardiac effects. Verapamil and diltiazem interact kinetically with the calcium channel receptor in a different manner than the dihydropyridines; they block tachycardias in calcium-dependent cells, eg, the atrioventricular node, more selectively than do the dihydropyridines. Skeletal muscle—Skeletal muscle is not depressed by the calcium channel blockers because it uses intracellular pools of calcium to support excitation-contraction coupling and does not require as much transmembrane calcium influx. Cerebral vasospasm and infarct following subarachnoid hemorrhage—Nimodipine, a member of the dihydropyridine group of calcium channel blockers, has a high affinity for cerebral blood vessels and appears to reduce morbidity after a subarachnoid hemorrhage. Nimodipine was approved for use in patients who have had a hemorrhagic stroke, but it has recently been withdrawn. Nicardipine has similar effects and is used by intravenous and intracerebral arterial infusion to prevent cerebral vasospasm associated with stroke. Verapamil as well, despite its lack of vasoselectivity, is used by the intra-arterial route in stroke. Some evidence suggests that calcium channel blockers may also reduce cerebral damage after thromboembolic stroke. Other effects—Calcium channel blockers minimally interfere with stimulus-secretion coupling in glands and nerve endings because of differences between calcium channel type and sensitivity in different tissues. Verapamil has been shown to inhibit insulin release in humans, but the dosages required are greater than those used in management of angina and other cardiovascular conditions. A significant body of evidence suggests that the calcium channel blockers may interfere with platelet aggregation in vitro and prevent or attenuate the development of atheromatous lesions in animals. However, clinical studies have not established their role in human blood clotting and atherosclerosis. Verapamil has been shown to block the P-glycoprotein responsible for the transport of many foreign drugs out of cancer (and other) cells (see Chapter 1); other calcium channel blockers appear to have a similar effect. Verapamil has been shown to partially reverse the resistance of cancer cells to many chemotherapeutic drugs in vitro. Animal research suggests possible future roles of calcium blockers in the treatment of osteoporosis, fertility disorders and male contraception, immune modulation, and even schistosomiasis. Toxicity The most important toxic effects reported for calcium channel blockers are direct extensions of their therapeutic action. Excessive inhibition of calcium influx can cause serious cardiac depression, including bradycardia, atrioventricular block, cardiac arrest, and heart failure.