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. 

Drug Metabolism

The clinical responses to drug administration can be greatly influenced both by the chronological age of the patient and by the relative maturity of the particular organ system that is being targeted.Human development follows a continuum of time-related events. There are unique therapeutic differences and concerns associated with the treatment of the very young and the elderly patient. Age-dependent changes in body function are known to alter the pharmacokinetic parameters that determine each compound’s duration of action, extent of drug–receptor interaction, and the drug’s rates of absorption, distribution, metabolism, and excretion. This chapter discusses some of these principles and the cautions that must be considered when treating these particular patient populations.

Directly and Indirectly Acting Cholinomimetics

These are example of  cholinomimetics drugs:-
1.Acetylcholine
2.Ambenonium
3.Bethanechol
4.Carbachol
5.Demecarium
6.Donepezil
7.Echothiophate
8.Edrophonium
9.Galanthamine
10.Isofluorophate
11.Methacholine
12.Neostigmine
13.Physostigmine
14.Pilocarpine
15.Pralidoxime
16.Pyridostigmine
17.Rivastigmine
18.Tacrine


       Cholinomimetic drugs can elicit some or all of the effects that acetylcholine (ACh) produces. This class of drugs includes agents that act directly as agonists at cholinoreceptors and agents that act indirectly by inhibiting the enzymatic destruction of endogenous ACh (i.e.,cholinesterase inhibitors).
   
       The directly acting cholinomimetics can be subdivided into agents that exert their effects primarily through stimulation of muscarinic receptors at parasympathetic neuroeffector junctions (parasympathomimetic drugs) and agents that stimulate nicotinic receptors in autonomic ganglia and at the neuromuscular junction. This chapter focuses on the parasympathomimetic drugs and cholinesterase inhibitors.

Muscarinic Receptors and Signal Transduction:-

      Classical studies by Sir Henry Dale demonstrated that the receptors activated by muscarine, an alkaloid isolated from the mushroom Amanita muscaria, are the same receptors activated by ACh released from parasympathetic nerve endings,from which the general notion that muscarinic agonists have parasympathomimetic properties was born.

  

       All muscarinic receptors are members of the seven transmembrane domain, G protein–coupled receptors, and they are structurally and functionally unrelated to nicotinic ACh receptors. Activation of muscarinic receptors by an agonist triggers the release of an intracellular G-protein complex that can specifically activate one or more signal transduction pathways. Fortunately, the cellular responses elicited by odd- versus evennumbered receptor subtypes can be conveniently distinguished.

       Activation of M1, M3, and M5 receptors produces an inosine triphosphate (IP3) mediated release of intracellular calcium, the release of diacylglycerol (which can activate protein kinase C),and stimulation of adenylyl cyclase. 

        These receptors are primarily responsible for activating calcium-dependent responses, such as secretion by glands and the contraction of smooth muscle.

Activation of M2 and M4 receptors inhibits adenylyl cyclase,and activation of M2 receptors opens potassium channels. The opening of potassium channels hyperpolarizes the membrane potential and decreases the excitability of cells in the sinoatrial (SA) and atrioventricular (A-V) nodes in the heart. The inhibition of adenylyl cyclase decreases cellular cyclic adenosine monophosphate (cAMP) levels,which can override the opposing stimulation of adenylyl cyclase by β-adrenoceptor agonists. 

Adrenoceptor Antagonists

It is also called β‐blockers drugs .Most common example of 阝-blockers that are following:-
1.Acebutolol
2.Atenolol
3.Betaxolol
4.Bucindolol
5.Carteolol
6.Carvedilol
7.Doxazosin
8.Esmolol
9.Labetalol
10.Medroxalol
11.Metoprolol
12.Nadolol
13.Phenoxybenzamine
14.Phentolamine
15.Pindolol
16.Prazosin
17.Propranolol
18.Terazosin
19.Timolol
20.Tolazoline
21.Trimazosin

ADRENOCEPTORS:-

                                     Drugs that produce responses by interacting with adrenoceptors are referred to as adrenoceptor agonists or adrenergic agonists. 

        Norepinephrine and isoproterenol are examples of such compounds. Agents that inhibit responses mediated by adrenoceptor activation are known as adrenoceptor antagonists, adrenergic antagonists, or adrenergic blocking agents. Prazosin and propranolol are examples of receptor-blocking drugs. 

         The pharmacology of the adrenoceptor antagonists is described in this chapter. Norepinephrine is released from the varicosities of the postganglionic sympathetic nerves during neural activity and interacts with the adrenoceptors of the effector organ, producing the characteristic response of the effector. 

       This occurs because norepinephrine has an affinity for the receptors and possesses intrinsic activity; that is, it has the capacity to activate the receptors. Circulating catecholamines and other directly acting adrenomimetic drugs also interact with these receptors. 

      The adrenergic blocking agents also have an affinity for the adrenoceptors. The antagonists, however, have only limited or no capacity to activate the receptors; that is,they have little or negligible intrinsic activity.The blocking drugs compete with adrenomimetic substances for access to the receptors.

     Thus,these agents reduce the effects produced by both sympathetic nerve stimulation and by exogenously administered adrenomimetics. This action forms the basis for their therapeutic and investigational use.

     Competition for receptors, hence receptor antagonism, is governed by the law of mass action; that is, the interaction between drug and receptor depends on the concentration of drug in the vicinity of the receptor and the number of receptors present. Because agonist and antagonist have an affinity for the same receptors, the two substances compete for binding to the receptors.

CLASSIFICATION OF BLOCKING DRUGS:-

   An α-receptor is one that mediates responses for which the adrenomimetic order of potency is epinephrine greater than or equal to norepinephrine greater than isoproterenol, and that is susceptible to blockade by phentolamine and phenoxybenzamine. It follows from this definition that phentolamine and phenoxybenzamine are called α-adrenoceptor antagonists or α-blocking agents. 

A β-receptor mediates responses for which the adrenomimetic order of potency is isoproterenol greater than epinephrine greater than or equal to norepinephrine, and this receptor is susceptible to blockade by propranolol.Propranolol is,therefore,called a β-adrenoceptor antagonist or β-blocking agent.

β -Receptor Subtypes :-

The two main types of β-receptors have been given the designations β1 and β2.Among the responses mediated by β1-receptors is cardiac stimulation, whereas β2 receptor stimulation mediates bronchodilation and relaxation of vascular and uterine smooth muscle. These findings are significant,since a number of both agonists and antagonists have some degree of selectivity for either β1- or β2-receptors. 

α -Receptor Subtypes:-

                                      There are differences between the receptors on nerves (presynaptic receptors) and those on effector cells. Furthermore, some α-agonists and antagonists exhibit selectivity for one of these receptor types.

Pharmacokinetics

           Pharmacokinetics is the description of the time course of a drug in the body, encompassing absorption, distribution, metabolism, and excretion. In simplest terms, it can be described as what the body does to the drug.

           Pharmacokinetic concepts are used during drug development to determine the optimal formulation of a drug, dose (along with effect data),and dosing frequency. For drugs with a wide therapeutic index (difference between the minimum effective dose and the minimum toxic dose), knowledge of the drug’s pharmacokinetic properties in that individual patient may not be particularly important.
For example, nonsteroidal antiinflammatory drugs,such as ibuprofen,have a wide therapeutic index, and thus knowledge of the pharmacokinetic parameters in a given individual is relatively unimportant, since normal doses can vary from 400 to 3200 mg per day with no substantial difference in acute toxicity or effect.
       However,for drugs with a narrow therapeutic index,knowledge of that drug’s pharmacokinetic profile in an individual patient has paramount importance.
     
       If there is little difference between the minimum effective dose and the toxic dose, slight changes in a drug’s pharmacokinetic profile, or even simply interindividual differences, may require dosage adjustments to minimize toxicity or maximize efficacy.For example, the blood concentrations of the antiasthmatic drug theophylline must usually be maintained within the range of 10–20 g/mL. At concentrations below this, patients may not obtain relief of symptoms, while concentrations above 20 g/mL can result in serious toxicities,such as seizures,arrhythmias,and even death. Thus, a drug’s pharmacokinetic profile may have important clinical significance beyond its use in drug development.

      

⇒ DRUG CONCENTRATION–TIME PROFILES AND BASIC PHARMACOKINETIC PARAMETERS:-

                               The time course of a drug in the body is frequently represented as a concentration–time profile in which the concentrations of a drug in the body are measured analytically and the results plotted in semilogarithmic form against time.

          Drug concentrations are measured in samples typically taken from the brachial vein, since this vein is readily accessible, since sampling results in minimal patient discomfort and since obtained values reflect the concentrations of drug in the bloodstream. Concentrations in the blood may not be identical to concentrations at the site of action, such as a receptor,but one hopes they serve as a surrogate that correlates in a proportional manner. 

         .The concentrations of drug in the blood decline over time according to the elimination rate of that particular drug. More commonly, drug is given via extravascular routes (e.g., orally), so absorption and distribution must occur, and therefore it will take some time before maximum concentrations are achieved.

        An additional parameter that can be determined from a concentration–time profile is the half-life of the drug, that is, the time it takes for half of the drug to be eliminated from the body. 

        Half-life determination is very useful,since it can readily be used to evaluate how long a drug is expected to remain in the body after termination of dosing, the time required for a drug to reach steady state (when the rate of drug entering the body is equal to the rate of drug leaving the body),and often the frequency of dosing.

⇒ADDITIONAL PHARMACOKINETIC PARAMETERS:-

➝Bioavailability:-

                           Bioavailability (designated as F) is defined as the fraction of the administered drug reaching the systemic circulation as intact drug.Bioavailability is highly dependent on both the route of administration and the drug formulation. For example, drugs that are given intravenously exhibit a bioavailability of 1, since the entire dose reaches the systemic circulation as intact drug. However, for other routes of administration, this is not necessarily the case. 

        Subcutaneous, intramuscular, oral, rectal, and other extravascular routes of administration require that the drug be absorbed first,which can reduce bioavailability. The drug also may be subject to metabolism prior to reaching the systemic circulation, again potentially reducing bioavailability.For example,when the -blocking agent propranolol  is given intravenously, F = 1, but when it is given orally,F = ~0.2,suggesting that only approximately 20% of the administered dose reaches the systemic circulation as intact drug

      Two types of bioavailability can be calculated, depending on the formulations available and the information required.The gold standard is a calculation of the absolute bioavailability of a given product compared to the intravenous formulation (F = 1). The absolute bioavailability of a drug can be calculated as:

                                             

      =where the route of administration is other than intravenous (e.g., oral, rectal). For calculation of absolute bioavailability, complete concentration-time profiles are needed for both the intravenous and other routes of administration.   

 

Clearance:-

                  Clearance is a pharmacokinetic parameter used to describe the efficiency of irreversible elimination of drug from the body. More specifically,clearance is defined as the volume of blood from which drug can be completely removed per unit of time (e.g., 100 mL/minute). 

  

       Clearance can involve both metabolism of drug to a metabolite and excretion of drug from the body.For example, a molecule that has undergone glucuronidation is described as having been cleared, even though the molecule itself may not have left the body. 

    

      Clearance of drug can be accomplished by excretion of drug into the urine,gut contents,expired air,sweat,and saliva as well as metabolic conversion to another form.However,uptake of drug into tissues does not constitute clearance. 

      Because clearance estimates the efficiency of the body in eliminating drug, the calculation of clearance can be especially useful in optimizing dosing of patients.  

      Since this parameter includes both the volume of distribution and the elimination rate,it adjusts for differences in distribution characteristics and elimination rates among people, thus permitting more accurate comparisons among individuals. 

       However, as stated earlier, by far the easiest clearance parameter to estimate is that of apparent (oral) clearance, since it does not require intravenous administration,yet this parameter can be profoundly affected by bioavailability of the drug.

Volume of Distribution:-

        Vd relates a concentration of drug measured in the blood to the total amount of drug in the body. This mathematically determined value gives a rough indication of the overall distribution of a drug in the body.For example, a drug with a Vd of approximately 12 L (i.e., interstitial fluid plus plasma water) is probably distributed throughout extracellular fluid but is unable to penetrate cells. In general, the greater the Vd, the greater the diffusibility of the drug.

The volume of distribution is not an actual volume, since its estimation may result in a volume greater than the volume available in the body (~40 L in a 70-kg adult).Such a value will result if the compound is bound or sequestered at some extravascular site. 

Adrenomimetic Drugs

=The adrenomimetic drugs mimic the effects of adrenergic sympathetic nerve stimulation on sympathetic effectors; these drugs are also referred to as sympathomimetic agents.

=The adrenergic transmitter norepinephrine and the adrenal medullary hormone epinephrine also are included under this broad heading.

= The adrenomimetic drugs are an important group of therapeutic agents that can be used to maintain blood pressure or to relieve a life-threatening attack of acute bronchial asthma.

=They are also present in many overthe-counter cold preparations because they constrict mucosal blood vessels and thus relieve nasal congestion.

Classification of Adrenomimetic drugs:-

⇨There are many drugs that are given bellow:-

⇾Albuterol 

⇾Amphetamine

⇾Dobutamine 

⇾Dopamine 

⇾Ephedrine 

⇾Epinephrine 

⇾Isoproterenol 

⇾Metaraminol 

⇾Methoxamine 

⇾Norepinephrine 

⇾Phenylephrine 

⇾Terbutaline 

CHEMISTRY:-

= The adrenomimetic drugs can be divided into two major groups on the basis of their chemical structure: the catecholamines and the noncatecholamines. The catecholamines include norepinephrine, epinephrine, and dopamine,all of which are naturally occurring,and several synthetic substances, the most important of which is isoproterenol (isopropyl norepinephrine).

=The L-isomers are the naturally occurring forms of epinephrine and norepinephrine and possess considerably greater pharmacological effects than do the D-isomers. Throughout most of the world, epinephrine and norepinephrine are known as adrenaline and noradrenaline, respectively. 

=Noncatecholamine adrenomimetic drugs differ from the basic catecholamine structure primarily by having substitutions on their benzene ring.

MECHANISM OF ACTION :-

=Many adrenomimetic drugs produce responses by interacting with the adrenoceptors on sympathetic effector cells. 

=The effect of a given adrenomimetic drug on a particular type of effector cell depends on the receptor selectivity of the drug,the response characteristics of the effector cells,and the predominant type of adrenoceptor found on the cells. 

 

=The interaction of compounds with these adrenoceptors initiates a chain of events in the vascular smooth muscle cells that leads to activation of the contractile process. Thus, norepinephrine and epinephrine, which have high affinities for α-adrenoceptors, cause the vascular muscle to contract and the blood vessels to constrict. Since bronchial smooth muscle contains β2-adrenoceptors,the response in this tissue elicited by the action of 2β-adrenoceptor agonists is relaxation of smooth muscle cells.

= Epinephrine and isoproterenol, which have high affinities for β2-adrenoceptors,cause relaxation of bronchial smooth muscle. Norepinephrine has a lower affinity for β2-adrenoceptors and has relatively weak bronchiolar relaxing properties.

=Adrenomimetic drugs can be divided into two major groups on the basis of their mechanism of action. Norepinephrine, epinephrine, and some closely related adrenomimetics produce responses in effector cells by directly stimulating α- or β-adrenoceptors and are referred to as directly acting adrenomimetic drugs.

=Many other adrenomimetic drugs, such as amphetamine,do not themselves interact with adrenoceptors,yet they produce sympathetic effects by releasing norepinephrine from neuronal storage sites (vesicles). The norepinephrine that is released by these compounds interacts with the receptors on the effector cells.

.=These adrenomimetics are called indirectly acting adrenomimetic drugs. The effects elicited by indirectly acting drugs resemble those produced by norepinephrine.

=An important characteristic of indirectly acting adrenomimetic drugs is that repeated injections or prolonged infusion can lead to tachyphylaxis (gradually diminished responses to repeated administration).

=This is a result of a gradually diminishing availability of releasable norepinephrine stores on repeated drug administration. The time frame of the tachyphylaxis will vary with individual agents. 

=The actions of many indirectly acting adrenomimetic drugs are reduced or abolished by the prior administration of either cocaine or tricyclic antidepressant drugs (e.g., imipramine).

= These compounds can block the adrenergic neuronal transport system and thereby prevent the indirectly acting drug from being taken up into the nerve and reaching the norepinephrine storage vesicles. Lipophilic drugs (e.g.,amphetamine),however, can enter nerves by diffusion and do not need membrane transport systems. 

Drug Metabolism and Disposition in Pediatric and Gerontological Stages of Life

The clinical responses to drug administration can be greatly influenced both by the chronological age of the patient and by the relative maturity of the particular organ system that is being targeted.Human development follows a continuum of time-related events. There are unique therapeutic differences and concerns associated with the treatment of the very young and the elderly patient. Age-dependent changes in body function are known to alter the pharmacokinetic parameters that determine each compound’s duration of action, extent of drug–receptor interaction, and the drug’s rates of absorption, distribution, metabolism, and excretion. This chapter discusses some of these principles and the cautions that must be considered when treating these particular patient populations.

DRUG DISPOSITION IN PEDIATRIC PATIENTS :-

                                                                                           In spite of recent advances in this area, knowledge of the disposition and actions of drugs in children is limited.This lack of information has made drug therapy for them difficult and dangerous.There are two major obstacles to clinical drug studies in children.One is an ethical issue,the inability to obtain true informed consent. The second obstacle is inherent to children; they grow and change rapidly.Drug studies must be performed on children at each stage of their development to determine appropriate usage for all patients. 

To study drug disposition in children it is most informative to divide them into five age groups: preterm infants, term infants from birth through the first month of life, children 1 month to 2 years of age, children 2 to

12 years of age, and children 12 to 18 years of age. Tanner staging of sexual maturation may more appropriately break down this latter group.Children that are Tanner stages I,II,and III are appropriately considered children;those who are Tanner stages IV and V are considered adults. 

Preterm infants, especially those near the limits of viability (24 weeks’ gestation),have glomerular filtration rates approximately one-tenth that of a term newborn. Because of limitations on tubular reabsorption, they have increased urinary loss of filtered substances. Glucuronidation pathways appear after 20 weeks of gestation and so are limited in extremely premature infants. 

At birth, term infants can metabolize and eliminate drugs. For most patients these systems did not function during fetal life and therefore even at birth are not very efficient. outlines the time required for maturation of some of the systems used in drug absorption and elimination.

The period from 1 month to 2 years of age is a time of rapid growth and maturation. By the end of this period,most systems function at adult levels.Paradoxically, between 2 and 12 years of age drug clearance greatly increases and often exceeds adult levels. Half-lives are shorter and dosing requirements are frequently greater than for adults.

From 12 to 18 years of age sex differences start to appear. These differences are often associated with a decreased drug absorption and elimination in the female as opposed to the male. Females have less gastric acidity and an increased gastric emptying time. Estrogens decrease hepatic cytochrome P450 content and therefore may decrease metabolism of some drugs via phase I pathways. Cyclic changes in glomerular filtration are noted during the menstrual cycle.

Absorption:-

                    Oral absorption of drugs is influenced by gastric acidity and emptying time. Gastric acid is rarely found in the

stomach of infants at less than 32 weeks’ gestation.Acid initially is secreted within the first few hours after birth, reaching peak levels within the first 10 days of life.It decreases during the next 20 days of extrauterine life. Gastric acid secretion approaches the lower limits of adult values by 3 months of age. The initiation of acid secretion is often delayed in infants with delayed initiation of oral feedings, such as extreme preemies and those with anomalies of the gastrointestinal tract. 

Drug Absorption and Distribution

Unless a drug acts topically (i.e., at its site of application), it first must enter the bloodstream and then be distributed to its site of action.The mere presence of a drug in the blood,however,does not lead to a pharmacological response.To be effective, the drug must leave the vascular space and enter the intercellular or intracellular spaces or both.The rate at which a drug reaches its site of action depends on two rates: absorption and distribution.Absorption is the passage of the drug from its site of administration into the blood; distribution is the delivery of the drug to the tissues.To reach its site of action, a drug must cross a number of biological barriers and membranes, predominantly lipid. Competing processes, such as binding to plasma proteins, tissue storage,metabolism,and excretion (Fig.3.1),determine the amount of drug finally available for interaction with specific receptors

PROPERTIES OF BIOLOGICAL MEMBRANES THAT INFLUENCE DRUG PASSAGE :-

                      Although some substances are translocated by specialized transport mechanisms and small polar compounds may filter through membrane pores, most foreign compounds penetrate cells by diffusing through lipid membranes. 

 =A smaller component consists of glycoproteins or lipoproteins that are embedded in the lipid matrix and have ionic and polar groups protruding from one or both sides of the membrane.

= This membrane is thought to be capable of undergoing rapid local shifts,whereby the relative geometry of specific adjacent proteins may change to form channels, or pores.

=The pores permit the membrane to be less restrictive to the passage of low-molecularweight hydrophilic substances into cells.

= In addition to its role as a barrier to solutes,the cell membrane has an important function in providing a structural matrix for a variety of enzymes and drug receptors.The model depicted is not thought to apply to capillaries.

Physicochemical Properties of Drugs and the Influence of pH:-

=The ability of a drug to diffuse across membranes is frequently expressed in terms of its lipid–water partition coefficient rather than its lipid solubility per se.

=This coefficient is defined as the ratio of the concentration of the drug in two immiscible phases: a nonpolar liquid or organic solvent (frequently octanol),representing the membrane; and an aqueous buffer, usually at pH 7.4, representing the plasma.The partition coefficient is a measure of the relative affinity of a drug for the lipid and aqueous phases. 

=Increasing the polarity of a drug, either by increasing its degree of ionization or by adding a carboxyl, hydroxyl, or amino group to the molecule, decreases the lipid–water partition coefficient. 

=Alternatively, reducing drug polarity through suppression of ionization or adding lipophilic (e.g.,phenyl or t-butyl) groups results in an increase in the lipid–water partition coefficient. 

Metabolism and Excretion of Drugs

⇒Both metabolism and excretion can be viewed as processes responsible for elimination of drug (parent and metabolite) from the body. Drug metabolism changes the chemical structure of a drug to produce a drug metabolite, which is frequently but not universally less pharmacologically active. Metabolism also renders the drug compound more water soluble and therefore more easily excreted.

Drug excreation

⇒Drug metabolism reactions are carried out by enzyme systems that evolved over time to protect the body from exogenous chemicals. The enzyme systems for this purpose for the most part can be grouped into two categories: phase I oxidative or reductive enzymes and phase II conjugative enzymes. Enzymes within these categories exhibit some limited specificity in relation to the substrates acted upon; a given enzyme may interact with only a limited number of drugs.Some nonspecific hydrolytic enzymes, such as esterases and amidases, have not received much research attention. The focus of this discussion therefore is on phase I and phase II reactions and the enzymes that carry out these                                                                             processes.

MEtabolism of drugs

⇒The cytochrome P450 (CYP450) enzyme superfamily is the primary phase I enzyme system involved in the oxidative metabolism of drugs and other chemicals.These enzymes also are responsible for all or part of the metabolism and synthesis of a number of endogenous compounds,such as steroid hormones and prostaglandins. 

⇉Substrate Specificity of the CYP Enzymes፦

                                                                 CYP3A4 is thought to be the most predominant CYP isoform involved in human drug metabolism, both in terms of the amount of enzyme in the liver and the variety of drugs that are substrates for this enzyme isoform.

⇒This isoform may account for more than 50% of all CYP-mediated drug oxidation reactions,and CYP3A4 is likely to be involved in the greatest number of drug–drug interactions. The active site of CYP3A4 is thought to be large relative to other isoforms, as evidenced by its ability to accept substrates up to a molecular weight of 1200 (e.g., cyclosporine). 

⇒This active site size allows drugs with substantial variation in molecular structure to bind within the active site.However,the fact that two drugs are metabolized predominantly by CYP3A4 does not mean that coadministration will result in a drug–drug interaction, since drugs can bind in different regions of the CYP3A4 active site, and these binding regions may be distinct.In fact,it is believed that two drugs (substrates) can occupy the active site simultaneously,with both available for metabolism by the enzyme.

✱Regulation of the CYP Enzymes ፦

CYP450 enzymes can be regulated by the presence of other drugs or by disease states.This regulation can either decrease or increase enzyme function, depending on the modulating agent. These phenomena are commonly referred to as enzyme inhibition and enzyme induction,respectively.

1.Enzyme Inhibition፦

                                Enzyme inhibition is the most frequently observed result of CYP modulation and is the primary mechanism for drug–drug pharmacokinetic interactions. The most common type of inhibition is simple competitive inhibition, wherein two drugs are vying for the same active site and the drug with the highest affinity for the site wins out.

=A second type of CYP enzyme inhibition is mechanism-based inactivation (or suicide inactivation).In this type of inhibition, the effector compound (i.e., the inhibitor) is itself metabolized by the enzyme to form a reactive species that binds irreversibly to the enzyme and prevents any further metabolism by the enzyme. 

                     

 2.Enzyme Induction ፦          

                                   Induction of drug-metabolizing activity can be due either to synthesis of new enzyme protein or to a decrease in the proteolytic degradation of the enzyme.Increased enzyme synthesis is the result of an increase in messenger RNA (mRNA) production (transcription) or in the translation of mRNA into protein. Regardless of the mechanism,the net result of enzyme induction is the increased turnover (metabolism) of substrate.

☆CONJUGATIVE ENZYMES: PHASE II REACTIONS ፦

⇒Phase II conjugative enzymes metabolize drugs by attaching (conjugating) a more polar molecule to the original drug molecule to increase water solubility, thereby permitting more rapid drug excretion.This conjugation can occur following a phase I reaction involving the molecule, but prior metabolism is not required. The phase II enzymes typically consist of multiple isoforms, analogous to the CYPs, but to date are less well defined.

 

✱Glucuronosyl Transferases፦

⇒Glucuronosyl transferases (UGTs) conjugate the drug molecule with a glucuronic acid moiety,usually through establishment of an ether, ester, or amide bond. 

Glucuronosyl Transferases 

⇒Typically this conjugate is inactive, but sometimes it is active. For example, UGT-mediated conjugation of morphine at the 6- position results in the formation of morphine-6-glucuronide,which is 50 times as potent an analgesic as morphine.

✱N-Acetyltransferases፦

⇒As their name implies, the N-acetyltransferase (NAT) enzymes catalyze to a drug molecule the conjugation of an acetyl moiety derived from acetyl coenzyme A. 

N-Acetyltransfrases

⇒The net result of this conjugation is an increase in water solubility and increased elimination of the compound.The NATs identified to date and involved in human drug metabolism include NAT-1 and NAT-2.Little overlap in substrate specificities of the two isoforms appears to exist. 

Mechanisms of Drug Action

DYNAMICS OF DRUG–RECEPTOR BINDING፦ 

 The drug molecule, following its administration and passage to the area immediately adjacent to the receptor surface (sometimes called the biophase), must bond with the receptor before it can initiate a response. Resisting this bond formation is a random thermal agitation that is inherent in every molecule and tends to keep the molecule in constant motion. Under normal circumstances, the electrostatic attraction of the ionic bond, which can be exerted over longer distances than can the attraction of either the hydrogen or van der Waals bond,is the first force that draws the ionized molecule toward the oppositely charged receptor surface. This is a reasonably strong bond and will lend some stability to the drug–receptor complex. 

DOSE–RESPONSE RELATIONSHIP ፦

To understand drug–receptor interactions, it is necessary to quantify the relationship between the drug and the biological effect it produces.Since the degree of effect produced by a drug is generally a function of the amount administered, we can express this relationship in terms of a dose–response curve. Because we cannot always quantify the concentration of drug in the biophase in the intact individual, it is customary to correlate effect with dose administered.

The principles derived from dose–response curves are the same in animals and humans. However, obtaining the data for complete dose–response curves in humans is generally difficult or dangerous.We shall therefore use animal data to illustrate these principles.

Mechanisms of Drug Action

☆THE CHEMISTRY OF DRUG–RECEPTOR BINDING ፦     

⇨Biological receptors are capable of combining with drugs in a number of ways, and the forces that attract the drug to its receptor must be sufficiently strong and long-lasting to permit the initiation of the sequence of events that ends with the biological response. Those forces are chemical bonds, and a number of types of bonds participate in the formation of the initial drug–receptor complex.

⇨The bond formed when two atoms share a pair of electrons is called a covalent bond. It possesses a bond energy of approximately 100 kcal/mole and therefore is strong and stable; that is, it is essentially irreversible at body temperature. Covalent bonds are responsible for the stability of most organic molecules and can be broken only if sufficient energy is added or if a catalytic agent that can facilitate bond disruption,such as an enzyme,is present.Since bonds of this type are so stable at physiological temperatures, the binding of a drug to a receptor through covalent bond formation would result in the formation of a long-lasting complex. 

⇨The formation of an ionic bond results from the electrostatic attraction that occurs between oppositely charged ions.The strength of this bond is considerably less (5 kcal/mole) than that of the covalent bond and diminishes in proportion to the square of the distance between the ionic species.Most macromolecular receptors have a number of ionizable groups at physiological pH (e.g., carboxyl, hydroxyl, phosphoryl, amino) that are available for interaction with an ionizable drug. 

Mechanisms of Drug Action

           ➤A fundamental concept of pharmacology is that to initiate an effect in a cell, most drugs combine with some molecular structure on the surface of or within the cell. This molecular structure is called a receptor.The combination of the drug and the receptor results in a molecular change in the receptor,such as an altered configuration or charge distribution,and thereby triggers a chain of events leading to a response.
           ➞ This concept applies not only to the action of drugs but also to the action of naturally occurring substances,such as hormones and neurotransmitters.Indeed,many drugs mimic the effects of hormones or transmitters because they combine with the same receptors as do these endogenous substances.
           ➞It is generally assumed that all receptors with which drugs combine are receptors for neurotransmitters,hormones, or other physiological substances.

           ➞ Thus, the discovery of a specific receptor for a group of drugs can lead to a search for previously unknown endogenous substances that combine with those same receptors.For example, evidence was found for the existence of endogenous peptides with morphinelike activity.A series of these peptides have since been identified and are collectively termed endorphins and enkephalins .

 ☆DRUG RECEPTORS AND BIOLOGICAL RESPONSES∶➞ 

         ➞ Although the term receptor is convenient, one should never lose sight of the fact that receptors are in actuality.

➞molecular substances or macromolecules in tissues that combine chemically with the drug. Since most drugs have a considerable degree of selectivity in their actions, it follows that the receptors with which they interact must be equally unique.

➞Thus,receptors will interact with only a limited number of structurally related or complementary compounds. The drug–receptor interaction can be better appreciated through a specific example.

➞The end-plate region of a skeletal muscle fiber contains large numbers of receptors having a high affinity for the transmitter acetylcholine. 

➞Each of these receptors, known as nicotinic receptors, is an integral part of a channel in the postsynaptic membrane that controls the inward movement of sodium ions.

➞.The acetylcholine combines with the receptors and changes them so that channels are opened and sodium flows inward. 

➞The more acetylcholine the end-plate region contains, the more receptors are occupied and the more channels are open.When the number of open channels reaches a critical value, sodium enters rapidly enough to disturb the ionic balance of the membrane,resulting in local depolarization. 

➞The local depolarization (end-plate potential) triggers the activation of large numbers of voltage-dependent sodium channels, causing the conducted depolarization known as an action potential.

➞The action potential leads to the release of calcium from intracellular binding sites.