What method of medication administration should have its 1st peak concentration in the blood in about 1 hour?

Benefits

First-pass metabolism, other variables associated with the gastrointestinal tract (e.g., pH, gastric emptying time) avoided195-197

Reduced side effects, minimization of drug concentration peaks and troughs in blood197,198

Ease of dose termination in case of untoward side effects

Delivery can be sustained and controlled over a prolonged period199,200

Direct access to the target site201

Convenient, painless administration195,196

Improved patient acceptance, adherence to therapy202-204

Ease of use—may reduce overall health treatment cost205,206

Provides a viable solution for treatment when oral dosing not feasible (e.g., in unconscious or nauseated patients)197

Phase 2 Reactions

Conjugation with glucuronic acid, sulfate, glutamine, glycine, or glutathione increases the water solubility of the xenobiotic and decreases its biological activity (Fig. 20-17). This is the true detoxification step, since phase 1 reactions often can convert inactive xenobiotics to toxic products.

Ethanol is either a metabolite or a xenobiotic, depending on the amount consumed. When consumed in excess, ethanol is detoxified by the cytochrome P-450 microsomal ethanol oxidizing system (MEOS). However, when consumed in lower amounts, ethanol can enter normal metabolic pathways. In this case, it is metabolized as if it were fat. Two enzymes, alcohol dehydrogenase (cytosol) and acetaldehyde dehydrogenase (mitochondrion), convert ethanol to acetate (Fig. 20-18). This increases the NADH to NAD+ ratio in the cytosol and the mitochondrion, which becomes a significant problem in the chronic alcoholic who neglects carbohydrate intake. The shift to fasting metabolism mobilizes free fatty acids to the liver, adding to the acetyl-CoA already produced from ethanol metabolism. As is the case in starvation and untreated diabetes when acetyl-CoA reaches very high levels for a sustained period, acetyl-CoA is shunted into production of ketones with resulting ketoacidosis. The situation is further complicated by the effect of the high NADH to NAD+ ratio on pyruvate. Pyruvate would normally be routed to oxalo-acetate for gluconeogenesis during inadequate carbohydrate intake, but instead it is shunted into lactate (Fig. 20-19). This not only produces lactic acidosis, but it leads to hypoglycemia as well.

PHARMACOLOGY

KEY POINT ABOUT LIVER METABOLISM OF XENOBIOTICS AND ETHANOL

Xenobiotics are nonnutritive chemicals that are metabolized in the liver in two phases: In phase 1 cytochrome P-450 adds a hydroxyl group to the foreign molecule, and in phase 2 conjugation enzymes add a water-soluble molecule like glycine that allows excretion in the urine or bile; xenobiotics include not only toxins and poisons but therapeutic drugs and ethanol.

Propafenone

Propafenone has weak β-adrenoceptor antagonist activity in addition to its class Ic action.

Pharmacokinetics

Lidocaine undergoes extensive first pass metabolism and is therefore only administered in an intravenous form. It has a short half-life of 3 hours and is metabolized to metabolites with weak class I antiarrhythmic properties: glycinexylidide and monoethylglycinexylidide. It is highly bound to α1-acid glycoprotein, which may be increased in heart failure, making the free active drug less readily available. On the other hand, reduced clearance and volume of distribution in heart failure result in higher levels of the active drug, requiring a dosage reduction. Therapeutic plasma lidocaine levels range between 1.5 to 5.0 μg/mL and should be monitored.

Pharmacokinetics

All TCAs undergo extensive first-pass metabolism in the liver, forming active metabolites that are partially responsible for the variable effective half-lives of these drugs (8–90 hours; see the compendium at the end of this chapter). There is considerable interindividual variability in the first-pass metabolism of most TCAs, leading to up to 40-fold differences in plasma concentrations of the parent drug. Dose titration is usually necessary to optimise the therapeutic response; this should be gradual over 1–2 weeks to minimise unwanted dose-related effects.

Ketamine

Ketamine is a non-competitive antagonist at NMDA receptors. It is similar in action to PCP (but shorter acting), with binding to the cation channel of NMDA receptor being responsible for its analgesic/dissociative and purported neuroprotective effects. It also enhances monoamine transmission resulting in significant sympathomimetic properties. It also has analgesic opioid receptor mediated effects. The induction of an anaesthetic state and subsequent hallucinations are thought to be due to inhibition of central and peripheral cholinergic transmission.

Ketamine shows marked first pass metabolism and is fairly ineffective when taken orally. More commonly and efficiently, ketamine is snorted or injected. It exhibits dose-related psychedelic effects, which show a linear relationship at low doses. Effects are highly sensitive to age, dose, route, sex and setting and include:

Rapid onset, short duration of action (1 hour), wide safety margin

Dissociative anaesthesia ‘somatosensory blockade’ (analgesia without anaesthesia): analgesia

Perceptual distortion/hallucinations/near death

Out-of-body experience

Sympathetic stimulation

Emergence phenomena

Cognitive impairment

Thought disorder/synaesthesia

Little effect on cough reflex

Hypersalivation.

At low doses, sought-after experiences are primarily stimulant and elevation of mood. Psychedelic effects commence at higher doses. The Harvard academic Timothy Leary described it as ‘the ultimate psychedelic journey’. Users describe entering the ‘K hole’ where they experience visits to God, aliens, their birth, past lives and the ‘experiences of evolution’ (Dillon et al 2003).

Detection by clinical examination relies on identifying mydriasis, tachycardia, elevated blood pressure, slurred speech, blunted affect, ataxia, delirium and nystagmus. Urine drug screens do not routinely detect it.

Adverse effects are short-lived (<5 h) and include: frightening hallucinations/out of body experiences; thought disorder; confusion; dissociation; chest pain; palpitations and tachycardia; nausea; stomach cramps; vomiting; difficulty with and burning on micturition; difficulty breathing; ataxia; temporary paralysis/inability to speak; blurred vision; no awareness of pain; derealization/depersonalization and amnesia. A psychotic picture that can briefly mimic schizophrenia can also be seen.

Management is by supportive monitoring (CVS) in a quiet, low-stimulation room with symptomatic treatment with benzodiazepines if needed. CVS excitation can sometimes be helped by using propranolol. Death is rare and usually only occurs when used in combination with alcohol and other respiratory depressants. Prolonged periods of immobility and unconsciousness may result in rhabdomyolysis. Chlorpromazine should be avoided (because of anticholinergic effects) and haloperidol is largely ineffective. One volunteer study found benefit from using lamotrigine.

Ketamine dependence has been described, with compulsive use a primary symptom. Although tolerance develops, there is no evidence for a withdrawal syndrome. Other risks associated with its use include accidents, trauma, risky sexual behaviour and cognitive impairment that appears to be persistent in heavy users.

Pharmacokinetics

Tramadol undergoes some first-pass metabolism after oral administration and has a bioavailability of 68%.9 It is O-demethylated by the cytochrome P450 enzyme CYP2D6 to the therapeutically active O-desmethyltramadol and N-demethylated by CYP34A to the inactive N-desmethyltramadol. O-desmethyltramadol is two to four times more potent than tramadol itself. A significant amount (10% to 30%) of tramadol is excreted unchanged in the urine. Whereas plasma protein binding is low (20%), its apparent volume of distribution is large (2.7l/kg), indicating considerable tissue uptake.126 The elimination half-life for tramadol is 6 hours and the active metabolite has a slightly longer half-life of 7.5 hours.

Drug Bioavailability

Following absorption, first-pass metabolism can reduce the total exposure of the body to drug. First-pass metabolism refers to any loss of the administered material by transmucosal or hepatic means after absorption and before reaching the systemic circulation, and this is shown schematically in Figure 3.

Bioavailability is a term used to describe the systemic availability of drug and can be defined as the rate and extent of appearance of unchanged drug in the systemic circulation following an extravascular (e.g., oral) dose. Experimentally, it is determined as the fraction of the maximal levels of drug present in the systemic circulation after an intravenous dose. It takes into account both absorption and metabolism and is dependent on area under the curve (AUC), peak concentration achieved (Cmax), and time to reach peak concentration (tmax). It is generally expressed as a percentage and is represented by eqn [1]:

[1]%Bioavailability=AUC1×Dose2AUC2×Dose1×100

where 1 refers to an oral dose and 2 refers to an intravenous dose.

The assessment of many PK parameters depends upon the accurate measurement of AUC. Although software is used routinely to do this, the calculations are straightforward and are based on the sum of trapezoid areas under the concentration versus time curve for each sampling interval (trapezoidal rule).

As pharmacological effect depends upon the quantity of unchanged drug reaching the target organ and its residence time, it is evident that changes in absorption and metabolism will lead to changes in bioavailability and therefore activity.

Relative bioavailability (bioequivalence) is the comparison of the rate and extent of drug appearance in the systemic circulation when one formulation is compared with another. When two or more formulations of the same drug produce statistically indistinguishable rates and extents of appearance they can be said to be bioequivalent.

Subarachnoid Haemorrhage

Most subarachnoid haemorrhages are caused by rupture of a saccular (or berry) aneurysm on an intracranial artery, usually on or close to the circle of Willis. These aneurysms are acquired during life and the cause is unknown, although there is an association with hypertension and conditions that increase cerebral blood flow, such as arteriovenous malformations. About 5% of all strokes are caused by subarachnoid haemorrhage. Sudden onset of a severe occipital headache is the most common presenting symptom, but focal neurological signs or progressive confusion and impaired consciousness can occur. Rebleeding is a significant cause of disability and death; early surgical intervention in survivors of the initial bleed reduces this risk. However, a more common cause of permanent neurological disability or later death is delayed cerebral ischaemia. This is produced by cerebral vasospasm, which develops in about 25% of cases, usually at least 3 days after the haemorrhage. The mechanism is poorly understood but involves activation of voltage-dependent L-type Ca2+ channels in intracranial arteries. It presents with confusion, decreased consciousness, and new focal neurological deficits.

Pre-Clinical Research

Pharmacokinetic work has been carried out on the rat, the pig, the rabbit and the cat after single i.v. injections Adam et al (1980). Studies of the effects of propofol anesthesia on drug distribution and metabolism have been investigated in dogs Perry et al (1991).