Opioid Analgesics

Introduction:

Morphine, the prototypical opioid agonist, has long been known to relieve severe pain with remarkable efficacy. The opium poppy is the source of crude opium from which Sertürner in 1803 isolated morphine, the pure alkaloid, naming it after Morpheus, the Greek god of dreams. It remains the standard against which all drugs that have strong analgesic action are compared. These drugs are collectively known as opioid analgesics and include not only the natural and semisynthetic alkaloid derivatives from opium but also synthetic surrogates, other opioid-like drugs whose actions are blocked by the nonselective antagonist naloxone, plus several endogenous peptides that interact with the different subtypes of opioid receptors.

Basic Pharmacology of the Opioid Analgesics:

Source Opium, the source of morphine, is obtained from the poppy, Papaver somniferum and P album. After incision, the poppy seed pod exudes a white substance that turns into a brown gum that is crude opium. Opium contains many alkaloids, the principle one being morphine, which is present in a concentration of about 10%. Codeine is synthesized commercially from morphine. Classification & Chemistry Opioid drugs include full agonists, partial agonists, and antagonists. Morphine is a full agonist at the (mu)-opioid receptor, the major analgesic opioid receptor. In contrast, codeine functions as a partial (or "weak") -receptor agonist. Other opioid receptor subtypes include (delta) and (kappa) receptors. Simple substitution of an allyl group on the nitrogen of the full agonist morphine plus addition of a single hydroxyl group results in naloxone, a strong -receptor antagonist. Some opioids, eg, nalbuphine, are capable of producing an agonist (or partial agonist) effect at one opioid receptor subtype and an antagonist effect at another. The activating properties of opioid analgesics can be manipulated by pharmaceutical chemistry; in addition, certain opioid analgesics are modified in the liver, resulting in compounds with greater analgesic action. Chemically, the opioids derived from opium are phenanthrene derivatives and include four or more fused rings, while most of the synthetic opioids are simpler molecules.

Opioid Receptor Subtypes, Their Functions, and Their Endogenous Peptide Affinities.

Receptor Subtype Functions Endogenous Opioid Peptide Affinity (mu) Supraspinal and spinal analgesia; sedation; inhibition of respiration; slowed gastrointestinal transit; modulation of hormone and neurotransmitter release Endorphins > enkephalins > dynorphins (delta) Supraspinal and spinal analgesia; modulation of hormone and neurotransmitter release Enkephalins > endorphins and dynorphins (kappa) Supraspinal and spinal analgesia; psychotomimetic effects; slowed gastrointestinal transit Dynorphins > > endorphins and enkephalins

Endogenous Opioid Peptides

Opioid alkaloids (eg, morphine) produce analgesia through actions at receptors in the central nervous system (CNS) that contain peptides with opioid-like pharmacologic properties. The general term currently used for these endogenous substances is endogenous opioid peptides.

Three families of endogenous opioid peptides have been described in detail: the endorphins, the pentapeptide enkephalins methionine-enkephalin (met-enkephalin) and leucine-enkephalin (leu-enkephalin), and the dynorphins. The three families of opioid receptors have overlapping affinities for these endogenous peptides.

The endogenous opioid peptides are derived from three precursor proteins: prepro-opiomelanocortin (POMC), preproenkephalin (proenkephalin A), and preprodynorphin (proenkephalin B). POMC contains the met-enkephalin sequence, -endorphin, and several nonopioid peptides, including adrenocorticotropic hormone (ACTH), beta-lipotropin, and melanocyte-stimulating hormone. 

Preproenkephalin contains six copies of met-enkephalin and one copy of leu-enkephalin. Leu- and met-enkephalin have slightly higher affinity for the (delta) than for the mu-opioid receptor. Preprodynorphin yields several active opioid peptides that contain the leu-enkephalin sequence. These are dynorphin A, dynorphin B, and and neoendorphins. The endogenous peptides endomorphin-1 and endomorphin-2 also possess many of the properties of opioid peptides, notably analgesia and high-affinity binding to the receptor. Endomorphin-1 and -2 selectively activate central and peripheral -opioid receptors but much about them remains unknown, including the identity of their preproendomorphin gene. Both the endogenous opioid precursor molecules and the endomorphins are present at CNS sites that have been implicated in pain modulation. Evidence suggests that they can be released during stressful conditions such as pain or the anticipation of pain and diminish the sensation of noxious stimuli. Whether acupuncture releases endogenous opioid peptides is under investigation.

In contrast to the analgesic role of leu- and met-enkephalin, an analgesic action of dynorphin A—through its binding to (kappa) opioid receptors—remains controversial. Dynorphin A is also found in the dorsal horn of the spinal cord, where it may play a critical role in the sensitization  of nociceptive neurotransmission. Increased levels of dynorphin can be found in the dorsal horn after tissue injury and inflammation. This elevated dynorphin level is proposed to increase pain and induce a state of long-lasting hyperalgesia. The pronociceptive action of dynorphin in the spinal cord appears to be independent of the opioid receptor system but dependent on the activation of the bradykinin receptor. Moreover, dynorphin A can bind and activate the N -methyl-D-aspartate (NMDA) receptor complex, a site of action that is the focus of intense therapeutic development.

Recently, a novel receptor-ligand system homologous to the opioid peptides has been found. The principle receptor for this system is the G protein-coupled orphanin opioid-receptor-likesubtype 1 (ORL1). Its endogenous ligand has been termed nociceptin by one group of investigators and orphanin FQ by another group. This ligand-receptor system is currently known as the N/OFQ system. Nociceptin is structurally similar to dynorphin except for the absence of an N-terminal tyrosine; it acts only at the ORL1 receptor, now known as NOP. The N/OFQ system is widely expressed in the CNS and periphery, reflecting its equally diverse biology and pharmacology. As a result of experiments using highly selective NOP receptor ligands, the N/OFQ system has been implicated in both pro- and anti-nociceptive activity as well as in the modulation of drug reward, learning, mood, anxiety, and cough processes, and of parkinsonism.

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Posted in: CNS acting drugs,opoid analgesics

Functional Organization of Autonomic Activity

Autonomic function is integrated and regulated at many levels, from the CNS to the effector cells. Most regulation uses negative feedback, but several other mechanisms have been identified. Negative feedback is particularly important in the responses of the ANS to the administration of autonomic drugs.

Central Integration:

At the highest level—midbrain and medulla—the two divisions of the ANS and the endocrine system are integrated with each other, with sensory input, and with information from higher CNS centers, including the cerebral cortex. These interactions are such that early investigators called the parasympathetic system a trophotropic one (ie, leading to growth) used to "rest and digest" and the sympathetic system an ergotropic one (ie, leading to energy expenditure), which is activated for "fight or flight." Although such terms offer little insight into the mechanisms involved, they do provide simple descriptions applicable to many of the actions of the systems. For example, slowing of the heart and stimulation of digestive activity are typical energy-conserving and storing actions of the parasympathetic system. In contrast, cardiac stimulation, increased blood sugar, and cutaneous vasoconstriction are responses produced by sympathetic discharge that are suited to fighting or surviving attack.

Direct Effects of Autonomic Nerve Activity on Some Organ Systems. Autonomic Drug Effects Are Similar But Not Identical.

Organ Effect of Sympathetic Activity Parasympathetic Activity Action1   Receptor2   Action Receptor2   Eye    Iris radial muscle Contracts 1   . . . . . .   Iris circular muscle . . . . . . Contracts M3     Ciliary muscle [Relaxes] Contracts M3   Heart    Sinoatrial node Accelerates 1, 2   Decelerates M2     Ectopic pacemakers Accelerates 1, 2   . . . . . .   Contractility Increases 1, 2   Decreases (atria) M2   Blood vessels    Skin, splanchnic vessels Contracts . . . . . .   Skeletal muscle vessels Relaxes 2   . . . . . . [Contracts] . . . . . . Relaxes3   M3   . . . . . .   Endothelium (drug effect) Releases EDRF4   M3, M55   Bronchiolar smooth muscle  Relaxes 2   Contracts M3   Gastrointestinal tract    Smooth muscle     Walls Relaxes 2,6 2   Contracts M3       Sphincters Contracts 1   Relaxes M3     Secretion . . . . . . Increases M3   Genitourinary smooth muscle    Bladder wall Relaxes 2   Contracts M3     Sphincter Contracts 1   Relaxes M3     Uterus, pregnant Relaxes 2   . . . . . . Contracts Contracts M3     Penis, seminal vesicles Ejaculation Erection M Skin    Pilomotor smooth muscle Contracts . . . . . .   Sweat glands . . . . . .     Eccrine Increases M . . . . . .     Apocrine (stress) Increases . . . . . . Metabolic functions    Liver Gluconeogenesis 2,   . . . . . .   Liver Glycogenolysis 2,   . . . . . .   Fat cells Lipolysis 3   . . . . . .   Kidney Renin release 1   . . . . . .

At a more subtle level of interactions in the brain stem, medulla, and spinal cord, there are important cooperative interactions between the parasympathetic and sympathetic systems. For some organs, sensory fibers associated with the parasympathetic system exert reflex control over motor outflow in the sympathetic system. Thus, the sensory carotid sinus baroreceptor fibers in the glossopharyngeal nerve have a major influence on sympathetic outflow from the vasomotor center. This example is described in greater detail in the following text. Similarly, parasympathetic sensory fibers in the wall of the urinary bladder significantly influence sympathetic inhibitory outflow to that organ. Within the ENS, sensory fibers from the wall of the gut synapse on both preganglionic and postganglionic motor cells that control intestinal smooth muscle and secretory cells.

Integration of Cardiovascular Function:

Autonomic reflexes are particularly important in understanding cardiovascular responses to autonomic drugs. The primary controlled variable in cardiovascular function is mean arterial pressure.  Changes in any variable contributing to mean arterial pressure (eg, a drug-induced increase in peripheral vascular resistance) evoke powerful homeostatic  secondary responses that tend to compensate for the directly evoked change. The homeostatic response may be sufficient to reduce the change in mean arterial pressure and to reverse the drug's effects on heart rate. A slow infusion of norepinephrine provides a useful example. This agent produces direct effects on both vascular and cardiac muscle. It is a powerful vasoconstrictor and, by increasing peripheral vascular resistance, increases mean arterial pressure. In the absence of reflex control—in a patient who has had a heart transplant, for example—the drug's effect on the heart is also stimulatory; that is, it increases heart rate and contractile force. However, in a subject with intact reflexes, the negative feedback response to increased mean arterial pressure causes decreased sympathetic outflow to the heart and a powerful increase in parasympathetic (vagus nerve) discharge at the cardiac pacemaker. This response is mediated by increased firing by the baroreceptor nerves of the carotid sinus and the aortic arch. Increased baroreceptor activity causes the changes mentioned in central sympathetic and vagal outflow. As a result, the net effect of ordinary pressor doses of norepinephrine in a normal subject is to produce a marked increase in peripheral vascular resistance, an increase in mean arterial pressure, and a consistent slowing of heart rate. Bradycardia, the reflex compensatory response elicited by this agent, is the exact opposite of the drug's direct action; yet it is completely predictable if the integration of cardiovascular function by the ANS is understood.

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Nonadrenergic, Noncholinergic (NANC) Neurons

It has been known for many years that autonomic effector tissues (eg, gut, airways, bladder) contain nerve fibers that do not show the histochemical characteristics of either cholinergic or adrenergic fibers. Both motor and sensory NANC fibers are present. Although peptides are the most common transmitter substances found in these nerve endings, other substances, eg, nitric oxide synthase and purines, are also present in many nerve terminals. Capsaicin, a neurotoxin derived from chili peppers, can cause the release of transmitter (especially substance P) from such neurons and, if given in high doses, destruction of the neuron.

The enteric system in the gut wall  is the most extensively studied system containing NANC neurons in addition to cholinergic and adrenergic fibers. In the small intestine, for example, these neurons contain one or more of the following: nitric oxide synthase (which produces nitric oxide; NO), calcitoningene-related peptide, cholecystokinin, dynorphin, enkephalins, gastrin-releasing peptide, 5-hydroxytryptamine (serotonin), neuropeptide Y, somatostatin, substance P, and vasoactive intestinal peptide (VIP). Some neurons contain as many as five different transmitters.

The sensory fibers in the nonadrenergic, noncholinergic systems are probably better termed "sensory-efferent" or "sensory-local effector" fibers because, when activated by a sensory input, they are capable of releasing transmitter peptides from the sensory ending itself, from local axon branches, and from collaterals that terminate in the autonomic ganglia. These peptides are potent agonists in many autonomic effector tissues.

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Autonomic Receptors

Historically, structure-activity analyses, with careful comparisons of the potency of series of autonomic agonist and antagonist analogs, led to the definition of different autonomic receptor subtypes, including muscarinic and nicotinic cholinoceptors, and alpha, beta, and dopamine adrenoceptors. Subsequently, binding of isotope-labeled ligands permitted the purification and characterization of several of the receptor molecules. Molecular biology now provides techniques for the discovery and expression of genes that code for related receptors within these groups

Major Autonomic Receptor Types.

Receptor Name Typical Locations Result of Ligand Binding Cholinoceptors    Muscarinic M1   CNS neurons, sympathetic postganglionic neurons, some presynaptic sites Formation of IP3 and DAG, increased intracellular calcium     Muscarinic M2   Myocardium, smooth muscle, some presynaptic sites; CNS neurons Opening of potassium channels, inhibition of adenylyl cyclase   Muscarinic M3   Exocrine glands, vessels (smooth muscle and endothelium); CNS neurons Like M1 receptor-ligand binding     Muscarinic M4   CNS neurons; possibly vagal nerve endings Like M2 receptor-ligand binding     Muscarinic M5   Vascular endothelium, especially cerebral vessels; CNS neurons Like M1 receptor-ligand binding     Nicotinic NN   Postganglionic neurons, some presynaptic cholinergic terminals Opening of Na+,K+ channels, depolarization     Nicotinic NM   Skeletal muscle neuromuscular end plates Opening of Na+,K+ channels, depolarization   Adrenoceptors    Alpha1   Postsynaptic effector cells, especially smooth muscle Formation of IP3 and DAG, increased intracellular calcium     Alpha2   Presynaptic adrenergic nerve terminals, platelets, lipocytes, smooth muscle Inhibition of adenylyl cyclase, decreased cAMP   Beta1   Postsynaptic effector cells, especially heart, lipocytes, brain; presynaptic adrenergic and cholinergic nerve terminals, juxtaglomerular apparatus of renal tubules, ciliary body epithelium Stimulation of adenylyl cyclase, increased cAMP   Beta2   Postsynaptic effector cells, especially smooth muscle and cardiac muscle Stimulation of adenylyl cyclase and increased cAMP. Activates cardiac Gi under some conditions.     Beta3   Postsynaptic effector cells, especially lipocytes; heart Stimulation of adenylyl cyclase and increased cAMP1   Dopamine receptors    D1 (DA1), D5   Brain; effector tissues, especially smooth muscle of the renal vascular bed Stimulation of adenylyl cyclase and increased cAMP   D2 (DA2)   Brain; effector tissues, especially smooth muscle; presynaptic nerve terminals Inhibition of adenylyl cyclase; increased potassium conductance D3   D3 Brain Inhibition of adenylyl cyclase D4     D4   Brain, cardiovascular system Inhibition of adenylyl cyclase

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The primary acetylcholine receptor subtypes were named after the alkaloids originally used in their identification: muscarine and nicotine, thus muscarinic and nicotinic receptors. In the case of receptors associated with noradrenergic nerves, the use of the names of the agonists (noradrenaline, phenylephrine, isoproterenol, and others) was not practicable. Therefore, the term adrenoceptor is widely used to describe receptors that respond to catecholamines such as norepinephrine. By analogy, the term cholinoceptor denotes receptors (both muscarinic and nicotinic) that respond to acetylcholine. In North America, receptors were colloquially named after the nerves that usually innervate them; thus, adrenergic (or noradrenergic) receptors and cholinergic receptors. The general class of adrenoceptors can be further subdivided into alpha-adrenoceptor, beta-adrenoceptor, and dopamine-receptor types on the basis of both agonist and antagonist selectivity and on genomic grounds. Development of more selective blocking drugs has led to the naming of subclasses within these major types; for example, within the alpha-adrenoceptor class, alpha₁ and alpha₂ receptors differ in both agonist and antagonist selectivity.

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Posted in: Autonomic drugs