Antianginal Drugs

Angina pectoris is a clinical manifestation that results from coronary atherosclerotic heart disease. An acute anginal attack (secondary angina) is thought to occur because of an imbalance between myocardial oxygen supply and demand owing to the inability of coronary blood flow to increase in proportion to increases in myocardial oxygen requirements.This is generally the result of severe coronary artery atherosclerosis.Angina pectoris (variant,primary angina) may also occur as a result of vasospasm of large epicardial coronary vessels or one of their major branches. In addition,angina in certain patients may result from a combination of coronary vasoconstriction,platelet aggregation, plaque rupture, and an increase in myocardial oxygen demand (crescendo or unstable angina).

Antianginal drugs may relieve attacks of acute myocardial ischemia by increasing myocardial oxygen supply or by decreasing myocardial oxygen demand or both. Three groups of pharmacological agents have been shown to be effective in reducing the frequency, severity,or both of primary or secondary angina.These agents include the nitrates, -adrenoceptor antagonists,
and calcium entry blockers. To understand the beneficial actions of these agents,it is important to be familiar with the major factors regulating the balance between myocardial oxygen supply and demand.

THE THERAPEUTIC OBJECTIVES IN THE USE OF ANTIANGINAL DRUGS:-

The major therapeutic objectives in the treatment of angina are aimed at terminating or preventing an acute attack and increasing the patient’s exercise capacity. These objectives can be achieved by reducing overall myocardial oxygen demand or by increasing oxygen supply to ischemic areas.A decrease in myocardial oxygen demand can be attained through use of the organic nitrates,calcium entry blockers,and -adrenoceptor blocking agents. 

General Organization and Functions of the Nervous System

The nervous system is divided into two parts:the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain and spinal cord. The PNS consists of all afferent (sensory) neurons, which carry nerve impulses into the CNS from sensory end organs in peripheral tissues,and all efferent (motor) neurons, which carry nerve impulses from the CNS to effector cells in peripheral tissues.The peripheral efferent system is further divided into the somatic nervous system and the autonomic nervous system. The effector cells innervated by the somatic nervous system are skeletal muscle cells.The autonomic nervous system innervates three types of effector cells:(1) smooth muscle, (2) cardiac muscle, and (3) exocrine glands. While the somatic nervous system can function on a reflex basis, voluntary control of skeletal muscle is of primary importance. In contrast, in the autonomic nervous system voluntary control can be exerted, but reflex control is paramount.

Both somatic and autonomic effectors may be reflexly excited by nerve impulses arising from the same sensory end organs. For example, when the body is exposed to cold, heat loss is minimized by vasoconstriction of blood vessels in the skin and by the curling up of the body.At the same time,heat production is increased by an increase in skeletal muscle tone and shivering and by an increase in metabolism owing in part to secretion of epinephrine.

ANATOMIC DIFFERENCES BETWEEN THE SOMATIC AND AUTONOMIC NERVOUS SYSTEMS :-

Anatomical differences between the peripheral somatic and autonomic nervous systems have led to their classification as separate divisions of the nervous system.

.The axon of a somatic motor neuron leaves the CNS and travels without interruption to the innervated effector cell. In contrast, two neurons are required to connect the CNS and a visceral effector cell of the autonomic nervous system. The first neuron in this sequence is called the preganglionic neuron. The second neuron, whose cell body is within the ganglion,travels to the visceral effector cell;it is called the postganglionic neuron.

AUTONOMIC NERVOUS SYSTEM :-

The preganglionic neurons of the sympathetic nervous system have their cell bodies in the thoracic and lumbar regions of the spinal cord,termed the thoracolumbar division. The preganglionic neurons of the parasympathetic division have their cell bodies in the brainstem and in the sacral region of the spinal cord, termed the craniosacral division.The cranial part of the parasympathetic nervous system innervates structures in the head, neck, thorax, and abdomen (e.g., the stomach, part of the intestines, and pancreas.

Location of the Autonomic Ganglia :-

The sympathetic ganglia consist of two chains of 22 segmentally arranged ganglia lateral to the vertebral column. The preganglionic fibers leave the spinal cord in adjacent ventral roots and enter neighboring ganglia, where they make synaptic connections with postganglionic neurons.Some preganglionic fibers pass through the vertebral ganglia without making synaptic connections and travel by way of splanchnic nerves to paired prevertebral ganglia in front of the vertebral column, where they make synaptic connections with postganglionic neurons. In addition, some sympathetic preganglionic fibers pass through the splanchnic nerves into the adrenal glands and make synaptic connections on the chromaffin cells of the adrenal medulla.

Principles of Toxicology

         The discipline of toxicology considers the adverse effects of chemicals, including drugs, and other agents, such as biological toxins and radiation, on biological systems.

    Toxicity associated with drug action can generally be characterized as either an extension of the therapeutic effect, such as the fatal central nervous system (CNS) depression that may follow a barbiturate overdose,or as an effect that is unrelated to the therapeutic effect,such as the liver damage that may result from an acetaminophen overdose.

     This chapter focuses on the tissue response associated with the latter type of drug toxicity and on the toxicities associated with several important classes of nontherapeutic agents.

    The target organ for the expression of xenobiotic toxicity is not necessarily the tissue or organ in which the drug produces its therapeutic effect,nor is it necessarily the tissue that has the highest concentration of the agent. For example, lead accumulates in bone but produces no toxicity there; certain chlorinated pesticides accumulate in adipose tissue but produce no local adverse effects.

     Drugs such as acetaminophen cause necrosis in the centrilobular portion of the liver at a site of the monooxygenase enzymes that bioactivate the analgesic.

      It is necessary to distinguish between the intrinsic toxicity of a chemical and the hazard it poses.While a chemical may have high intrinsic toxicity, it may pose little or no hazard if exposure is low.In contrast,a relatively nontoxic chemical may be quite hazardous if exposure is large or the route of exposure is not physiological.

 

MANIFESTATIONS OF TOXICITY:-

Organ Toxicity:-  

  The events that initiate cell death are not completely understood. The common final stages of necrotic cell death are disruption of normal metabolic processes and ensuing inability to maintain intracellular electrolyte homeostasis.If the insult is severe or prolonged enough, the cell will not regain normal function. At the same time, other cells show apoptotic cell death, characterized by cell shrinkage,cleavage of DNA between nucleosomes,and formation of apoptotic bodies.Some chemicals are metabolized to reactive products that bind to cellular macromolecules. If such binding impairs the function of crucial macromolecules,cell viability is lost. How severely organ function will be impaired depends on the reserve capacity of that organ.The ultimate outcome will depend on the affected organ’s regenerative capacity and response to damage.

Pulmonary Toxicity:-

Inhaled gases,solid particles,or liquid aerosols may deposit throughout the respiratory system, depending on their chemical and physical properties.The large surface area of the respiratory passages and alveolar region and the large volume of air delivered to that area (approximately 6–7 L/minute in a young man) provide great opportunity for interaction between inhaled materials and lung tissue.

Exposure of the lungs to xenobiotics may result in a number of disease conditions including bronchitis, emphysema, asthma, hypersensitivity pneumonitis, pneumoconiosis, and cancer. During repair, damaged lung alveolar epithelium may be replaced by fibrous tissue that does not allow for gas exchange, which intensifies the damage caused by the initial lesion.

Hepatotoxicity:-

The blood draining the stomach and small intestine is delivered directly to the liver via the hepatic portal vein, thus exposing the liver to relatively large concentrations of ingested drugs or toxicants. Hepatic exposure to agents that undergo bioactivation to toxic species can be significant.

          Hepatic necrosis can be classified by the zone of the liver tissue affected. Xenobiotics, such as acetaminophen or chloroform,that undergo bioactivation to toxic intermediates cause necrosis of the cells surrounding the central veins (centrilobular) because the components of the cytochrome P450 system are found in those cells in abundance.At higher doses or in the presence of agents that increase the synthesis of cytochrome P450 (inducers), the area of necrosis may incorporate the midzonal area (midway between the portal triad and central vein).Cells around the portal triad are exposed to the highest concentrations; necrosis occurs with direct-acting agents.

     A single large dose of a hepatotoxin may cause liver necrosis yet resolve with little or no tissue scarring. Continued exposure to the toxic agent, however, can result in hepatic cirrhosis and permanent scarring.

Nephrotoxicity:-

The kidneys are susceptible to toxicity from xenobiotics  because they too have a high blood flow.Cells of the tubular nephron face double-sided exposure, to agents in the blood on the basolateral side and in the filtered urine on the luminal side. Proximal tubule cells are generally the site of nephrotoxicity,since these cells have an abundance of cytochrome P450 and can transport organic anions and cations from the blood into the cells,thereby concentrating these chemicals manyfold. 

General Organization and Functions of the Nervous System

GENERAL ORGANIZATION AND FUNCTIONS OF THE NERVOUS SYSTEM:-

                      The nervous system is divided into two parts:the central nervous system (CNS) and the peripheral nervous system (PNS). The CNS consists of the brain and spinal cord.The PNS consists of all afferent (sensory) neurons, which carry nerve impulses into the CNS from sensory end organs in peripheral tissues,and all efferent (motor) neurons, which carry nerve impulses from the CNS to effector cells in peripheral tissues.The peripheral efferent system is further divided into the somatic nervous system and the autonomic nervous system. The effector cells innervated by the somatic nervous system are skeletal muscle cells.The autonomic nervous system innervates three types of effector cells:
(1) smooth muscle
(2) cardiac muscle
(3) exocrine glands.

While the somatic nervous system can function on a reflex basis, voluntary control of skeletal muscle is of primary importance. In contrast, in the autonomic nervous system voluntary control can be exerted, but reflex control is paramount.

Both somatic and autonomic effectors may be reflexly excited by nerve impulses arising from the same sensory end organs. For example, when the body is exposed to cold, heat loss is minimized by vasoconstriction of blood vessels in the skin and by the curling up of the body.At the same time,heat production is increased by an increase in skeletal muscle tone and shivering and by an increase in metabolism owing in part to secretion of epinephrine.

ANATOMIC DIFFERENCES BETWEEN THE SOMATIC AND AUTONOMIC NERVOUS SYSTEMS:-

                      Anatomical differences between the peripheral somatic and autonomic nervous systems have led to their classification as separate divisions of the nervous system. 

.   The axon of a somatic motor neuron leaves the CNS and travels without interruption to the innervated effector cell. In contrast, two neurons are required to connect the CNS and a visceral effector cell of the autonomic nervous system. The first neuron in this sequence is called the preganglionic neuron. 

   The second neuron, whose cell body is within the ganglion,travels to the visceral effector cell;it is called the postganglionic neuron.

AUTONOMIC NERVOUS SYSTEM :-

The preganglionic neurons of the sympathetic nervous system have their cell bodies in the thoracic and lumbar regions of the spinal cord,termed the thoracolumbar division. The preganglionic neurons of the parasympathetic division have their cell bodies in the brainstem and in the sacral region of the spinal cord, termed the craniosacral division.The cranial part of the parasympathetic nervous system innervates structures in the head, neck, thorax, and abdomen (e.g., the stomach, part of the intestines, and pancreas). 

Location of the Autonomic Ganglia:-

The sympathetic ganglia consist of two chains of 22 segmentally arranged ganglia lateral to the vertebral column. The preganglionic fibers leave the spinal cord in adjacent ventral roots and enter neighboring ganglia, where they make synaptic connections with postganglionic neurons.Some preganglionic fibers pass through the vertebral ganglia without making synaptic connections and travel by way of splanchnic nerves to paired prevertebral ganglia in front of the vertebral column, where they make synaptic connections with postganglionic neurons. In addition, some sympathetic preganglionic fibers pass through the splanchnic nerves into the adrenal glands and make synaptic connections on the chromaffin cells of the adrenal medulla.

         Because sympathetic ganglia lie close to the vertebral column, sympathetic preganglionic fibers are generally short. Postganglionic fibers are generally long, since they arise in vertebral ganglia and must travel to the innervated effector cells. 

Contemporary Bioethical Issues in Pharmacology and Pharmaceutical Research

BIOMEDICAL ETHICS IN PHARMACOLOGY: AN INTRODUCTION AND FRAMEWORK :-

The relationship between physicians, scientists, and the pharmaceutical industry is a mutually advantageous one that is fraught with ethical complexity. Seemingly straightforward questions, such as whether a physician ought to enroll patients in a drug trial, which drug to prescribe when any one of several may be effective,and how to stay abreast of new drugs while remaining objective, become difficult when examined closely. This chapter provides a conceptual framework for bioethical analysis,presents some cases that illustrate ethical problems,and delineates some guidelines for consideration. 

      

        Bioethics is the study of ethical issues associated with providing health care or pursuing biomedical research. Most approaches to bioethics in the United States are secular in nature and presuppose no particular religious or theological perspective.While one’s religious beliefs may play an important role in determining personal morality,the broader endeavor of bioethical analysis attempts to be devoid of any particular religious perspective.Similarly,bioethical analysis stands independent of legal analysis.Although the law is often a consideration in bioethical decision making,laws in themselves do not determine the morality of an action.Laws are supposed to reflect a societal consensus on issues and are established to set a minimum standard of behavior. 

    Thus, while religion and law provide guidelines for acceptable actions, religious beliefs, and knowledge of the law are frequently insufficient to guide moral action, in the realm of health care. Solving problems that arise in the scientific and clinical contexts requires knowledge of ethical principles and the methodology for applying them.

BIOMEDICAL ETHICS AND CLINICAL RESEARCH :-

For more than 50 years, scientists, physicians, bioethicists, and the media have focused on a variety of issues in research with human subjects,or clinical research.In 1948, in response to the atrocities perpetrated by Nazi experimentation, the Nuremberg Code was developed to set forth guidelines for the acceptable conduct of scientific research.In 1964 the World Medical Association adopted the Declaration of Helsinki, which specifically guides physicians in biomedical research. These documents specify basic moral guidelines ultimately founded on concerns for autonomy,beneficence,and justice.

            

 The guidelines require the following::-

    • Subjects must give voluntary consent before being enrolled in any study after being fully advised of the           study’s aims, methods, benefits, risks,and discomforts.

    • Proposed studies must have sufficient scientific merit to warrant their risks.

    • Studies must be designed to avoid all unnecessary physical and mental suffering.

    • Potential benefits to subjects must outweigh risks to subjects.

    • Researchers must ensure subjects’ privacy and confidentiality.

    • Subjects must have the right to withdraw from the study at any time.

    • Researchers are obligated to stop the study if continuation is likely to result in injury to subjects.

The guidelines further require that research on human subjects be conducted by qualified individuals and that most clinical research be reviewed by an independent committee, which is generally an institutional review board.

Drug Research and Development:-

                                                           Pharmacology, unlike some other basic science disciplines, has a unique status when it comes to potential conflicts of interest. The pharmaceutical industry combines a desire for discovery and development with profit-motivated marketing and sales goals. Although scientists and physicians share the desire for drug discovery and development and are motivated by the desire to contribute to scientific advancement and improved patient care, pharmaceutical companies are simultaneously under strong commercial pressures. Pharmaceutical companies are therefore willing to offer financial incentives to physician–researchers who conduct studies, recruit patients, or are helpful in product development and testing. In some cases, this financial support may compromise professional judgment in conducting,analyzing,or reporting research.