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.