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I first thought that this is because of prolonged depolarisations. However, I am not sure anymore, because after reading PubChem, the only possible pathways are are Choline agonist. So I would say that succinylcholine cause myorelaxation by some cholino-receptor agonists. I do not think it is about depolarisation and how long it is.
How can succinylcholine cause myorelaxation?
Succinycholine, as its name might suggest, is a cholinergic agonist indeed. It acts on the neural plate of skeletal muscles, where it activates the muscle cholinergic receptors.
Phase 1 block due to succinylcholine thus occurs by activating so many receptors at once, that the whole muscle gets desensitized and therefore paralyzed. A corollary of that is that muscle will twitch during activation, thus accounting for the reason why people twitch shortly before becoming paralyzed after a succinycholine iv injection. This phase 1 block will resolve in 2-5 minutes.
Now an interesting phenomenon is that if you go on stimulating the muscle with more cholinergic agonists (for example, a second iv dose of succinylcholine), you may end up provoking endocytosis and degradation of the cholinergic receptors. This is called phase 2 block, and in contrast to phase 1, it will take at least several hours to resolve. This is why we never use a second dose in the clinics, except in very special cases. You can also read about it all on wikipedia
Pseudocholinesterase deficiency and malignant hyperthermia are pharmacogenetic disorders recognized in the 1960s the latter is discussed elsewhere (see Chapter 41 ). Butyrylcholinesterase (BChE) or pseudocholinesterase is the enzyme that hydrolyzes neuromuscular blocking agents such as succinylcholine and mivacurium, as well as ester local anesthetic agents. Deficient activity of the enzyme leads to prolonged apnea from succinylcholine and is caused by several factors, including genetic variants that affect the function of the enzyme. 335 More than 30 variants of the gene (BChE, 3q26.1-q26.3) have been described of which the two most common are the A (atypical) (209A>G, Asp70Gly) and the K (Kalow) variants (1615G>A, Ala539Thr). 336 The homozygosity incidence for the A variant is 3 : 1000 in Caucasians but may be as great as 1 : 175 individuals in some ethnicities in Iraq, Iran, and South India. 337,338 The BChE activity is decreased by 70% in A homozygotes and about 30% in the K homozygotes. Duration of apnea after 1.0 to 1.5 mg/kg of succinylcholine increases from 5 to 10 minutes in homozygous normal to 10 to 20, 20 to 35, and 35 to 60 minutes in heterozygous one abnormal gene, heterozygous two abnormal gene, and homozygous abnormal gene accordingly (see also Chapter 7 ). 339
Inherited pseudocholinesterase deficiency can be caused by mutations in the BCHE gene . This gene provides instructions for making the pseudocholinesterase enzyme , known as butyrylcholinesterase. This enzyme is made by the liver and circulates in the blood. It is involved in breaking down (metabolizing) choline ester drugs. Mutations that cause pseudocholinesterase deficiency either impair the function or production of butyrylcholinesterase. This impairs the body's ability to effectively metabolize choline ester drugs, leading to the abnormally prolonged effects of these drugs. 
Acquired pseudocholinesterase deficiency is not inherited and cannot be passed to the next generation. This form of the condition is caused by impairment of the enzyme's function due to factors such as kidney or liver disease, malnutrition, major burns, cancer , or certain drugs.  
Factors Modifying Drug Effect and Dosage | Pharmacodynamics
This article throws light upon the five major factors modifying drug effect and dosage. The factors are: 1. Physiological Factors 2. Genetic Factors 3. Pathological Factors 4. Environmental Factors 5. Therapeutic Factors.
Factor # 1. Physiological Factors:
Absolute dose of a drug varies with species as different species are of different sizes, and the amount of drug has to be in proportion to the size of the target species. Assuming the weight of an average adult dog as 12 kg, the sizes of doses for various species would be:
Dog 1 cat 1/6 sheep 5/2 goat 4 horse 25 cattle 30, and buffalo 40
However, size differences amongst breeds of a given species need consideration. For instance, the size of an adult Pekingese dog (about 4 kg body wt.) is about 1/15 of Great Dane and 1/18th of Saint Bernard. Similarly, the size of a pony (about 225 kg) is 1/3rd of a draft horse. The size of an average Indian sheep (about 30 kg) is 1/5th of the size of British breed Lincoln.
It is customary to express drug doses in terms of dose rate this tends to obviate the afforested problem. It is more logical to assume that the size of the dose would be in relation to the surface area of the species, than to their body weights. The assumption is sound so for as it concerns to the role of basal metabolic rate in affecting the effective drug concentrations in the body.
Heat production per unit surface area in species of varying sizes (such as mouse, rabbit, dog, man pig and horse) has been found to be around 1000 KCal/ m 2 . The relative surface area ratios are handy in approximating dose of one species to that of another. The ratios are.
Mouse 100 g, 1 rat 200 g, 7 guinea pig 400 g, 12.25 rabbit 1.5 kg, 27.8 cat 2 kg, 29.7 monkey 4 kg, 64.1 dog 12 kg, 124.2 and man 70 kg, 387.9
It has been suggested that the large differences in effective dosages that exist among species depends more on such species differences that modify pharmacokinetic behaviour of drugs than on such species differences that modify the sensitivity of target systems i.e. pharmacodynamics factors.
Hence factors that modify pharmacological pattern of drugs assume greater significance in modifying drug response since a given pharmacological effect would generally appear at a similar blood level in all species. Generally, man is assumed to be six times as sensitive as dog, and ten times as sensitive as rat to the drug effects.
Domestic animals too exhibit varying sensitivity to some drugs (Table 4.1) therefore, dose rates vary with species. Ruminants are very sensitive to sedative effects of xylazine than cat, dog and horse, while birds appear to be least sensitive. Species-dependent variation in dose rates of succinylcholine are related to varying amounts of pseudochloinesterase in blood of different species ruminants contain negligible amounts of the enzyme than other species particularly pig.
The variation affects duration of neuromuscular blockade produced by succinylcholine in different species. The drug produced only a transient paralysis in pig that too at higher dose rate (2mg/kg) whereas 100-fold lesser dose rate in cattle produces recumbency for 15 minutes.
The extent of drug absorption following oral administration varies with species owing to their peculiar gut conditions. The absorption of drugs per os is generally fast and complete in monogastrics (cat, dog and pig), variable in both rate and extent in horse, and comparatively slow and incomplete in ruminants. This may affect onset as well as duration of action of orally administered drugs in ruminants and horses. The bioavailability of sodium salicylate is higher in dog and swine than in horse or goat.
Data complied from different sources * Dog may require lesser (0.3 -0.5 mg/kg) than cat
*t1/2 is dose-dependent (zero-order kinetics **absorption factor main contributor to dosage-interval choice (absorption t1/2 about 3 hours in cow)
Similarly bioavability of chloramphenicol is higher in cats followed by dog and pig lesser in horse and least in goat. Rumenoreticular flora inactivate orally given chloramphenicol by reduction, and cardiac glycosides by hydrolysis Acidic pH of rumen favours accumulation of organic bases such as trimethoprim, alkaloidal drugs,narcotic analgesics, antihistamines and phenothiazine neuroleptics.
These drugs undergo high ionization at acidic pH that consequently leads to their reduced rate of diffusion from rumen to systemic circulation (this process of accumulation of organic bases into rumen has been called ion-trapping). This alters apparent volumes of distribution of basic drugs in ruminants.
Hepatic potential for drug detoxification also varies with species thereby affecting drug effects. Ruminants particularly sheep and goat have higher oxidative microsomal enzyme activity compared to that in human or dog while large zoo cats appear to be relatively deficient in this activity.
Thus pentobarbitone is ultra-short acting (15 to 30 min t1/2 0.8 hr) in sheep it is short acting in dog (duration of action about 200 min, t1/2 4.5 hr) and very long acting in large zoo cats where the effect may last for 6 to 7 days. Frequency of drug administration may also vary with species in relation to different rates of elimination (Table 4.2).
The dosage interval of aspirin recommended for human, cow or dog would have poisonous effect in a cat. Large dosage interval for aspirin therapy in cat is related to their inability to inactivate the salicylate by glucuronidation due to deficiency of hepatic glucuronyl transferase activity.
In fact, drugs requiring glucuronidation for inactivation of parent drug or its metabolite such as paracetamol, morphine, salicylates, chloramphenicol, chloral hydras, pentobarbitone, diazepam, meprobamate and nortriptyline are either long-acting or toxic for cats.
High toxicity of phenolics in cats is largely due to rapid cutaneous absorption as well as defective glucuronidation process in cats. Phenylbutazone is given less frequently in human than horse or dog (Table 4.2). Elimination kinetics of aspirin in cats man and dogs, and of phenylbutazone in horses and dogs is zero order t1/2 varying with dose-rate.
Drug effects may vary qualitatively or quantitatively among species due to variations in physiology or pharmacodynamics features (Table 4.3). Characteristic qualitative variations are seen with emetics, morphine and histamine. Carnivores and primates are quite responsive to central acting, (morphine, apomorphine) or local-acting (zinc sulfate, copper sulfate) emetics owing to possession of well-developed emetic reflexes dogs being 740-2800 times more sensitive to morphine and apomorphine than cats.
Ruminants and horses do not respond to either due to lack of efficient vomiting reflexes. Rodents are also non-responders to emetics as they lack emetic centre. Pig and chicken respond only to local-acting emetics, but not to central-acting emetics. Varying pharmacodynamics features are responsible for some variations in drug effects in various species (Table 4.3).
Apart from these variations, certain species respond quite unusually to certain drug effects. For example, rat heart is resistant to cardiac glycosides alloxan fails to induce diabetes mellitus in guinea pig procaine is lethal to parakeet, and horses are more sensitive to its neurotoxic effects than other species particularly cattle, and penicillin is 100 to 1000 times more toxic to guinea pig than to the mouse.
Very young (neonatal) and very old (geriatic) human and animals require low dosage compared to those required by adults. This is predominantly related to liver and kidney function impairments in newborns and geriatic animals. Neonates have under-developed and inefficient hepatic microsomal enzyme systems (oxidation, reduction and glucuronidation processes inefficient) the capacity approaches adult level in most species in a month.
Geriatic animals and human have reduced liver function related to reduction in liver mass, decreased hepatic blood flow and decreased microsomal enzyme activity particularly cytochrome p-450 mono-oxygenase system. Similarly, reduced renal function in neonates is related to reduction in GFR and inefficient renal tubular carrier mediated excretion mechanism ruminants acquire renal function maturity (adult type) very quickly (1-2 weeks) compared to most other species (1-2 months).
In geriatic animals reduced renal function is related to reduction in GFR with or without accompanying renal degenerative changes. These organ dysfunctions in neonates and geriatic animals tend to raise t1/2 of most drugs particularly those requiring hepatic inactivation (salicylate, pentobarbitone and chloramphenicol) or renal excretion (penicillin-G, ampicillin and oxytetracycline) or both (trimethoprim, sulfadoxine and sulfadimethoxine).
Doses of such drugs are reduced in neonates and geriatic animals. Elimination half-life of such drugs particularly in newborns have been found mostly 2.4 fold higher than in corresponding adult species. Half-life of chloramphenicol in piglets is nearly 7-fold more than in the adults. These factors tend to make newborns (and also geriatic animals) more susceptible to drug effects and drug toxicity.
For example, pentobarbitone is long-acting (20 hours or more) in young calves than adult cattle (t1/2 0.8 hr) due to deficient hepatic oxidative microsomal system. Chloramphenicol is more toxic to piglets and human infants (gray baby syndrome due to cardiovascular collapse) than adults due to deficient glucuronidation in liver LD50 of pentobarbitone in neonatal rats is 1/3rd that of adults.
Another physiological parameter that changes with age in total body water it is greater in newborns (86-70%) that in adults (58-55%). Accordingly, water soluble drugs have to be given in decreasing dose rates with advancing with postnatal age.
The decline in total body water continues into old age. Immune system in newborns and very old animals is also inefficient thus, bacteriostatic drugs that require efficient immune system for maximum antibacterial effects are less effective in these age groups than in adults.
Hence, bactericidal drugs are preferred in these age groups. Drug sensitivity may also vary with age. Children are less responsive to atropine, and more responsive to morphine than adults. Morphine is 4 times more potent in 2-week old rats than in 4-week old rats. Brain receptor density (dopaminergic and cholinergic) has also been reported to decrease with age in rats.
Sex is not usually a major factor in altering drug effect or drug dosage. Males and females behave, most often, similarly to drug effects. Sex influences have been largely studied in rats (males tend to metabolize drugs faster than females) hexobaribital is more effective in females, red-squill is more toxic to females (twice), and contrarily schradan and oxy-de-meton-methyl pesticides are more toxic to males.
Alteration in drug sensitivity is presumably related to varying activities of hepatic microsomal enzymes affected variously by androgens and estrogens. Females require slightly lower dose than males presumably due to their smaller size and/ or decreased metabolic activity.
For example, dose of tribromoethanol is lesser in woman (75 mg/kg) than in men (100 mg/kg). Women show decreased oxidation of estrogens and benzodiazepines relative to men. Females tend to have relatively higher percentage of adipose tissue, and oxidation rates of drugs are slower in adipose tissue than in skeletal muscle.
These factors tend to affect drug dosage. Opiates such as morphine tend to depress man and excite woman prior to sedation ephedrine frequently produces restlessness and subjective tremors of the extremities in woman and seldom in man females metabolize aspirin slower than males and are more liable to adverse effects, and women respond less to anti-depressants than men.
In horses, t1/2 of glyceryl guaiacolate (central muscle relaxant) is somewhat higher in stallions than in mares. Phenothiazine neuroleptics particularly acepromazine tend to cause priapism (penile prolapse) in stallion this effect cannot be expected in mares. Drug effect and dosage also vary with stage of reproduction in females.
A drug safe otherwise may cause embryo toxicity, teratogenicity, abortion or delayed parturition if used during sensitive periods of reproductive cycle in females. The tissue response may vary with stage of reproductive cycle for example, adrenaline contracts pregnant cat uterus but relaxes that of virgin cat.
Iv. Circadian Rhythms:
Circadian (Latin: circa = about diem = day) rhythms occur in many physiological and many biochemical functions that alter drug dosage and drug effect. This includes variations in hepatic drug metabolizing enzymes, altered neuronal activity, altered drug distribution or even changes in hormonal profiles and in central receptor density.
For example, lesser doses of hypnotics and more doses of stimulants are required to elicit the respective effects when given at evening hours than otherwise clonidine produces more depression in blood pressure and spontaneous motor activity in rats when given during dark cycle than when given during light cycle, and gentamicin induced ototoxicity in rats is more when the drug is given during diurnal rest than when given during nocturnal activity.
Factor # 2. Genetic Factors:
Genetic factors or pertinently intra-species genetic variations are responsible for alterations in drug dosage and/or drug effect. These may be related to gene-related alterations in drug metabolism or alterations in tissue/receptor sensitivity. These variations can lead to genetic tolerance, intolerance or idiosyncratic-reactions in susceptible individuals.
Genetic tolerance renders individuals less responsive to normal/ or higher dosage intolerance makes individuals to respond excessively to normal or lower dosage, and idiosyncratic/ reaction refer to qualitatively or quantitatively abnormal reaction to a single dose of drug that may endanger patient survival (the phenomenon is called idiosyncrasy).
Thus, individuals within a given species may react variably to drug effect and drug dosage. These variations may pertain to breeds, races, strains or even to some individuals in a given population.
The basic mechanism for the variation pertains to DNA mutation that alters protein synthesis or leads to altered protein structure thereby affecting the concerned enzyme or receptor activity, or their binding affinity towards the drug. Role of genetic factors in altering drug response has been studied mainly in humans.
Breed differences may affect dosage or drug effect. Greyhound dogs require lesser doses of thiobarbiturates than other (due to their lean constitution) due to limited redistribution of these anesthetics into adipose tissue and often show prolonged sleeping time with thiopental sodium. Brachycephalic canine breeds (Bull-dog, Pekingse, Boxers & Pug) may develop syncope associated with high vagal activity (leading to SA nodal blockade) following acepromazine administration.
Brahman cattle are more sensitive to depressant effects of xylazine than other breeds. Some strains of rabbit are tolerant to atropine or belladonna over dosage due to high activity of atropine- esterase that hydrolyses the drug.
Certain strains of sheep develop neurotoxicity due to deficiency of esterase required for inactivation of haloxon organophosphate anthelmintic. Some sheep are very sensitive to toxic effects of carbon- tetrachloride, and get easily poisoned than others. Some equine breeds are more susceptible to gastrointestinal toxicity with phenylbutazone.
One of the important pharmacogenetic alterations that has been observed in widely related species is malignant hyperthermia. It has been observed in horses, cattle, pig, dog, cat, chicken, deer, and humans. Incidence is very high in pig, and somewhat low in human (1: 20,000). This occurs following exposure of susceptible individuals to drugs such as halothane methoxyflurane, succinylcholine and others.
The defect is attributed to impaired Ca ++ binding inside skeletal muscle fibres drug exposure causing excessive release of Ca ++ into myoplasm which consequently increases muscular activity, glycogenolysis and heat production thereby leading to hyper-pyrexia and other effects with fatal consequences. In humans several pharmacogenetic defects have been recognized.
There are fast and slow acetylators owing to variations in hepatic and jejunal acetyltransferase activity resistance to warfarin a mediated anticoagulant effect due to reduced binding affinity of hepatic vitamin K epoxide reductase that normally activates vitamin K hemolytic anemia in response to oxidant drugs or oxidant drug metabolites due to either deficient glucose-6-phosphate dehydrogenase or glutathione synthetase in RBCs porphyria in response to certain drugs (barbiturates, sulfa-drugs, griseofulvin, oral contraceptives and others) due to increased delta-ALA synthetase activity prolonged apnea with succinylcholine due to atypical pseudo-cholinesterase in plasma high hepatotoxicity with drugs such as paracetamol and nitrofurantoin due to deficient hepatic glutathione synthetase increased ethanol toxicity due to atypical alcohol dehydrogenase activity.
Factor # 3. Pathological Factors:
Several pathological states particularly those affecting liver, kidney or altering body fluid pH and electrolytes are known to affect drug, effects and drug dosage. Organic or systemic alterations can markedly alter pharmaco-kinetics and/or pharmacodynamics of a drug in affected species. Liver disorders affect mainly disposition, and thereby altering effective drug concentration and drug effect (s) the impairments could involve.
(i) Impaired activity of hepatic drug-metabolizing enzymes leading to decreased biotransformation of drugs such as tolbutamide, diazepam, pentobarbitone, propranolol, morphine, chloral hydras, digi-toxin, warfarin, phenytoin, procainamide and others drug effects are either increased or decreased depending on whether hepatic influence activates or inactivates the drug.
(ii) Impaired biliary excretion of drugs this can affect mainly those drugs that are excreted significantly by this route e.g. nafcillin, erythromycin, corticosteroids, cefoperazine, doxycycline and glucuronide conjugates of chloramphenicol and morphine.
(iii) Reduced synthesis of plasma proteins (mainly albumin) with which drugs are bound as ‘storage depot’ this would increase free drug concentration of drugs significantly if drug- protein binding is normally very high e.g. warfarin, phenylbutazone, indomethacin, propranolol, digitoxin, & sulfisoxazole (binding above 65-70% in mammalian species),
(iv) reduced hepatic blood flow drugs with high hepatic extraction ratio are affected most (e.g. lidocaine, verapamil, propranolol nitroglycerine and amitriptyline) than those with low extraction ratio (e.g. benzodiazepines, procainamide and theophylline).
Renal disorders can lead to slower excretion of drugs with obvious consequences. Drugs wholly or largely excreted by the kidneys would be affected most e.g., aminoglycosides, penicillin’s, cephalosporins except cefoperazine, tetracyclines except doxycycline, nitrofurantoin, methenamine, digoxin, barbiturates, procainamide, 5-fluorocytosine and methotrexate. Potentially toxic drugs affected by renal impairment include gentamicin, kanamycin, cephaloridine, cephalothin, digoxin and sulfonamides.
There are additional diseased states that modify drug effect.
These may be summarized in a tabulated form:
Factor # 4. Environmental Factors:
I. Ambient Conditions:
Ambient conditions can affect pharmacokinetic profile of many drugs. Drug effects including toxicity can vary with seasons, ambient temperature and with change in altitude. High altitude with low atmospheric pressure reduces the potential of body to oxidize drugs, as low oxygen is available in the system.
High ambient temperature has been reported to cause procaine toxicity in puppies, due to its rapid absorption owing to vasodilation. Ethanol toxicity is increased in winter as excessive vasodilation (skin) caused by ethanol leads to excessive heat loss (hypothermia) on exposure to cold. Carbon tetrachloride toxicity in sheep (or cattle) is higher in winter due to decreased rate of elimination under cold conditions.
Low ambient temperature can increase duration of anesthesia and toxicity with anesthetics that lower body temperature such as chloral hydras, alpha-chloralose and barbiturates. Insulin-induced convulsions (hypoglycemic) in mice occur more readily in winter than in summer.
Antiduretic response in rats with ADH is greater in spring and summer, and the variability in response is least in winter. The rabbit uterus is more sensitive to oestrogen in spring than in autumn or early winter. High ambient temperatures favour accomplishment of rapid anaesthesia with inhalant volatile anaesthetics when used by open method as high temperature increases vapour pressure of aneasthetics and also increase the respiratory rate.
Ii. Dietary Factors:
Apart from the fact that food interferes with the absorption of orally administered drugs particularly in ruminant species, a dietary component may also alter the absorption or activity of some drugs. In general drug absorption is better when gut is empty more important factors in omnivores and carnivores than in herbivores such as ruminants where rumen is always filled with food.
Food is known to interfere and reduce the absorption of drugs such as astemizole, captopril, pencil amine, many antibiotics, including erythromycin, pencillins (except pencillin-V potassium & amoxicillin) and tetracyclines (except doxycycline and minocycline).
High fat or oil intake is known to increase absorption of griseofulvin, and increase hepatotoxic action of carbon tetrachloride. Use of tea infusion can interfere with absorption of alkaloidal drugs notably ephedrine and codeine. tannins cause precipitation of alkaloids.
Vitamin C and copper ions are known to enhance iron absorption by reducing ferrous form to ferric state for quicker absorption and assimilation, clover, kale, lucerne, crushed beet tops and concentrates (high protein intake) are known to increase carbon tetrachloride toxicity in sheep. Phytic acid present in many whole grain cereals notably oat-meal and corn may interfere with absorption of calcium and iron.
Oxalic acid or oxalates (present in some plants) chelate Ca ++ in the gut and reduce its absorption. Ingestion of raw egg white containing heat-labile avidin can interfere with absorption of biotin by forming complexes.
If tyramine rich foods (such as cheese, alcoholic beverages, concentrated yeast extracts, broad bean pods and pickled herring) are taken while on treatment with MAO inhibitors (such as phenelzine, pargyline, isoniazid, tranylcyproamine, isocarboxazid) hypertensive crises can ensue as noradrenaline released by tyramine is not inactivated due to inhibition of MAO (monoamine oxidase).
Factor # 5. Therapeutic Factors:
I. Route of Drug Administration:
Dose may vary with the route of administration. The general ratio that correlate various drug doses with respect to routes have been given, Oral 1 rectal 2 subcutaneous 1/2 to 1/8 intramuscular 1/2 to 1/3 intra-peritonial 1/4 or More intra-tracheal 1/4 to 1/20 intravenous 1/4 to 1/50.
As evident ratio ranges vary depending upon the nature of drug, and type of factors that influence its passage into systemic circulation as governed by the local conditions at the site of drug administration.
The ratio does imply that, in general, the rapidity of achieving effective systemic drug concentration, and drug effect are in the following decreasing order: i.v. (no absorption required) i.p. (high absorptive surface available) i.m. (better absorption due to high blood circulation) s.c. (low and delayed absorption due to less vascularity) and p.o. (absorption affected by gut factors, and systemic availability affected by drug passage through liver i.e. first passage metabolism).
The bioavailability of a drug after i.v. administration is 100%, assumed to be approaching 100% when given i.m. or i.p., and frequently less than 100% when given p.o. Thus, gut factors are major determinants of drug dosage, and drug effect (s). This assumes varying importance with respect to different species.
As a consequence, chloramphenicol and cardiac glycosides are more effective when given parentrally in ruminants than when given orally rumen flora inactivate chloramphenicol (by reduction) and cardiac glycosides (by hydrolysis).
In general, drugs inactivated by gastric pH (e.g. acid-labile penicillins such as penicillin-G, methicillin and carbencillin), gut-proteolytic enzymes (e.g. insulin, vasopressin, oxytocin and other peptide drugs except tripeptide TRH), intestinal mucosal enzymes (e.g. glyceryl trinitrate, hydrolysed levodopa, decarboxylated and isoprenaline, sulfated) or significantly lost while passing through the liver (first-pass effect) (e.g. propranolol, guanethidine, isoprenaline and most opioids such as morphine) are much less effective when given orally than when used parentrally. To cite an example, oral dose of pencillin-G is 4.5 times more than that required for intra-muscular use.
The quality of drug effect may strikingly vary with route. For example, procaine or lidocaine infiltrated into the vicinity of nerve would produce local anesthetic effect, and when given intravenously produce an anti-arrhythmic effect cocaine applied topically to conjunctiva produces topical anesthetic effect, and when given parentrally produces euphoria (sense of well-being) magnesium sulfate applied locally to swollen joints reduces swelling (osmotic lymphogogue), given orally acts as a cathartic (osmotic) and when injected parentrally produced depression of CNS L cardiac activity, and skeletal muscle relaxation (effect of magnesium ions).
Ii. Frequency of Drug Administration:
This factor can significantly alter (increase or decrease) immediate or consequent drug effect (s) including toxic reactions which may or may not be the normal effect (s) of the drugs. Several phenomena are recognized such as acquired tolerance (including desentstization, refractoriness or ‘down- regulation) sensitization super-sensitivity resistance hypersensitivity or drug- allergies and cumulative action.
Tolerance may be defined as the reduction in response to the drug after repeated administration. It is either intrinsic i.e. naturally-occurring (see Genetic factors) or as is relevant in present context, acquired during repeated exposure to the drug. For example, an individual may not be sedated by 1 g of diazepam with constant use when only 5-10 mg produce sedation on first exposure to the drug.
Acquired tolerance can develop to opioids, CNS depressants, organic nitrates or to diuretics (e.g. acetazolamide). Cross-tolerance refers to the state that repeated administration of drugs in a given category confers tolerance not only to the drug being used but also to other drugs that bear structural and/or functional resemblance (pharmacodynamics) with the given drug.
For example, cross- tolerance exists between LSD, mescaline and psilocybin and between alcohol, barbiturates, benzodiazepines and sedative – antihistamines.
Tolerance to some effects develop slowly (e.g. GIT effects of opioids like heroin) or quite rapidly (e.g. ‘euphoric’ effect with heroin).
The mechanism involved in the development of acquired tolerance are manifold, but can be summarized as:
(i) Changes in the disposition of the drug with its repeated use, that reduce effective drug concentration in the system this has been called pharmacokinetic tolerance or dispositional tolerance e.g. barbiturates induce hepatic microsomal enzymes to inactivate the drugs alcohol increases its own rate of excretion by suppressing ADH release opioids alter their own biotransformation, and morphine gets (deposited in skeletal muscles (non-target site).
(ii) Changes in the target system that render the system least responsive here cells have adapted to the presence of the drug this has been also called as pharmaco-dynamic tolerance, or sometimes true tolerance.
(iii) Biochemical alterations produced by the drug on repeated use oppose its own effect e.g. carbonic anhydrase – inhibitor diuretics such as acetazolamide. This has been sometimes referred to as refractoriness.
(iv) Repeated administration causes depletion of an intrinsic mediator of drug response e.g. organic bases such as polymyxin-B, bradykinin or substance P (all potent), morphine, d-tubocurarine and succinylcholine cause histamine depletion from mast-cells (not from other sites), their repeated exposure evokes diminishing response similarly, tyramine, ephedrine amphetamine cause depletion of noradrenaline from adrenergic nerve terminals that normally mediate their actions partly (ephedrine, amphetamine) or wholly (tyramine).
This phenomenon is quite rapidly developing, and results with frequency of administration spanned at closer time intervals so that the body is not given enough time to replenish the mediator stores. The phenomenon is sometimes called as tachyphylaxis (i.e. rapidly developing acquired tolerance).
Desensitization or ‘Down-regulation’ refers to a steadily decreasing response to the repeated use to receptor agonists to the same dose of drug owing to drug-induced reduction in receptor density or efficiency of receptor coupling to signal transduction pathways. This can develop within the course of drug therapy, ‘Down-regulation’ phenomenon has been observed with bronchodilator β2-adrenoceptor agonists such as salbutamol, and with synthetic GnRH agonists.
Super sensitivity or ‘Up-regulation’ refers to an increase in drug response following repeated administration of a receptor antagonist due to increase in the density of the receptors or their signal-to-effect coupling that improves tissue response. This is usually observed following rapid withdrawal of the drug from the system. This has been observed with adrenergic blocking agents such as propranolol.
Sensitization refers to an increase in response with repetition of the same dose of the drug. This is also called reverse tolerance. This has been observed with cocaine and amphetamine. For example, rates given repeated cocaine show improvement in spontaneous motor activity and conditioned responses over several days.
Cumulative action refers to the action of a drug which results when its rate of elimination or inactivation is slow compared to that of administration the full and final response being the result of summation of two or more doses. The effect produced is called cumulative effect or chronic over-dosage effect.
For example, repeated administration of digitalis cardiac glycosides when frequency of drug administration is not in tune with the rate of its elimination from the body leads to digitalis mediated toxicity frequent exposure of sheep to copper salts leads to accumulation of copper in the body, which when exceeds the limit is released into circulation to produce hemolytic anemia repeated administration of vitamin A can lead to its excessive storage in liver that can produce hypervitaminosis A repeated exposure to carbon-tetrachloride can lead to carbon-tetrachloride toxicity and repeated exposure to lead salts can lead to lead poisoning (plumbism). Hypersensitivity or ‘anaphylaxis’ refers to an abnormal immunological reaction initiated by previous exposure to the drug against the drug-generated antigen.
The differential characteristics of this response are:
(i) Previous exposure to drug within a weak (5-7 days),
(ii) Reaction mediated by antigen-antibody (Ag-Ab) interaction,
(iii) Reaction precipitating dose is lower than therapeutic dose, and
(iv) Abnormal effects are not related to pharmacological effects of the drug. This is a form of drug-allergy, and is known as Type-I Immunological reaction.
This has been observed with many drugs notably pencillins protein hormones, cephalosporins, corticosteroids, levamisole, nitro furans and isoniazid.
The underlying mechanism is uniform, and includes step-wise:
(i) Drug or its metabolite complexes with an endogenous protein fragment to form an antigen,
(ii) The antigen generates reaginic antibodies (IgE type),
(iii) The antibodies localize on the surface of mast cells and basophils,
(iv) The interaction of the antibodies with the fresh antigen (following repeated exposure) lead to release of mediators of inflammation from the sensitized cells (mediators include vasoactive amines, bradykinin, prostaglandins, leukotrienes, chemotactic factors etc.), and
(v) The mediators produce localized and generalized reactions (bronchoconstricion and cardiovascular collapse) with possible fatal consequences.
Type-II immunological reaction occurs when Ag and Ab (IgG, IgM or IgA type) interaction occurs at the surface of blood cells (RBCs, neutrophils and thrombocytes) or directly with soluble Ag (e.g. insulin and its neutralizing antibodies) or even with other components of the body (e.g. myo-neural receptors) leading to cytotoxicity (hemolysis, neutropenia and thrombocytopenia or insulin deficiency as the case may be.
Type-III immunological reaction results when Ag-Ab complexes get deposited in microvasculature with ckonsequent danger (e.g. vasculitis, serum sickness etc.). Delayed hypersensitivity or contact allergic dermatitis is Type-IV immunological reaction to repeated exposure of drugs that is mediated by T-cell lymphocytes or activated macrophages with consequent cytotoxicity.
Resistance is a form of acquired tolerance exhibited by uneconomic cells (e.g. cancer cells) or species (bacteria, protozoa, helminths, insects, rodents etc.) which renders them less responsive to chemotherapeutic agents or pesticides.
Acquired resistance can be transmitted to other un-exposed species (mainly bacteria) by conjugation, transformation or transduction processes. The underlying mechanisms governing resistance vary from drug to drug, and with type of uneconomic cell or species (Table 4.4).
Iii. Pharmaceutical Factors:
Drug dosage and drug effects are also affected by the type of drug formulation or dosage form. The same drug with same amount through the same route but with different drug dosage formulations may produce varying concentrations of the drug in the system with consequent alterations in response. This phenomenon has been referred to as bio-in-equivalence, therapeutic in-equivalence or pharmaceutical in-equivalence.
The factors responsible for this in-equivalence are various, such as:
(i) The nature of excipients used in drug formulations,
(ii) Particle size of the active drug components,
(iii) Degree of compression used while preparing solid drug formulations, and/or
(iv) Type of interaction drug molecules undergo while on storage.
The particle size affects the absorption rate of drugs such as digoxin, griseofulvin, nitrofurantoin, oxytetracycline, ampicillin, aspirin, phenothiazine, spironolactone and chloramphenicol palmitate finer particles are better absorbed than coarser ones.
The nature of excipient (vehicle) has been reported to affect bioavailability of tetracyclines, phenobarbitone, phenylbutazone, phenytoin and others. Pharmaceutical in-equivalence has been observed with parentral formulations of drugs such as chloramphenicol, oxytetracycline, diazepam and iron dextran. These factors remain largely unpredictable in therapeutic practice.
Iv. Drug-Drug Interactions:
One of the most important factors that would affect drug effects are those that result from simultaneous use of two or more drugs in therapeutic practice. One drug may alter the dose or the effect (s) of another drug when the two are used concurrently, these are called drug interactions Consequences of such interactions are:
(i) An increase in response to one or both drugs,
(ii) A decrease in response to one or both drugs, or
(iii) An abnormal alteration in response to one or both drugs.
Drug-interactions are of two types:
(i) Pharmacokinetic Interactions:
Those interactions in which one drug alters the pharmacokinetics of a second drug thereby affecting the concentration (and effect) of one or of both drugs in the system. (Table 4.5)
(ii) Pharmaco-dynamic Interactions:
Those in which there is no alteration in either drug’s pharmacokinetics but there is an alteration in biological response to one or both drugs. (Table 4.6).
Certain terms have been used to refer to certain types of drug- interactions such as addition, potentiation (sometimes also called synergism, atnagonism (chemical, physiological or pharmacological) and physico-chemical incompatibility.
Two drugs are said to be additive if combined effect produced by them when used together is not more than sum of their individual effects. If R (A) is a the response produced by drug (A), and R (B) that of drug (B), then
The phenomenon is called addition. This is shown mainly by CNS depressants, and congener drugs that act through the same type of receptors (see Table 4.6 for examples).
Potentiative or Synergistic:
Two drugs are said to be potentiative or synergistic if combined effect is more than the sum of their individual effects one drug may be inactive, less active or active for the concerned effect. It may be written as,
The phenomenon is called potentiation or synergism. The phenomenon may refer to enhancement of desirable or undesirable effects (See Table 4.5 and Table 4.6 for examples).
It refers to the phenomenon wherein two drugs used simultaneously or one after another produce effect that is less than the sum of their individual effects one drug may or may not have to concerned effect when used alone. It may be designated as
It may be due to the drugs directly interacting with each other (chemical antagonism), or due to drugs acting through different receptors to activate physiologically opposite effects (physiological antagonism)or due to one drug blocking the effect of another drug by acting on the same type of receptor (pharmacological antagonism).
Pharmacological antagonism may be competitive, when antagonism is reversible by increasing concentration of the agonist (one that activates the receptor e.g. noradrenaline and phentolamine or alpha-adrenergic receptors.
It may be irreversible pharmacological antagonism such that antagonist (one that blocks the receptor) cannot be dislodged from the receptor sites (e.g. noradrenaline and phenoxybenzamine with respect to alpha-adrenergic receptors).
Physico-chemical incompatibility refers to state wherein combination of two or more drugs leads to alteration of physical state of drugs (e.g. precipitation or gel-formation) or of chemical state (s) of drugs (e.g. neutralization or chelation). This happens when either drugs are mixed together before administration or when administration of one drug is immediately followed by another drug.
Such combinations reduce intended drug effect (s), and may prove dangerous if there is precipitate formation (e.g. calcium chloride + sodium bicarbonate) or gel- formation (e.g. sodium sulfonamides + calcium gluconate).
A general rule that would reduce or avoid such a drug interaction is as follows:
“Never mix a cationic drug with an anioin drug unless there is some definite reason to use them”. Cationic drugs can be recognized by their salt formulations such as sulfates, hydrochlorides, phosphates, acetates, citrates, lactobionates, succinates or tartrates. Anionic drugs can be recognized by their salt preparations such as sodium, potassium, ammonium or calcium.
Cationic drugs include atropine, aminoglycosides, local anesthetics, lincosamides, polymyxins, macrolides, chlorpromazine and promethazine. Anionic drugs include sulfonamides, pencillins, cephalosporins, heparin, EDTA, and barbiturates. Drugs within either category (anionic or cationic) can be mixed unless otherwise stated.
The Medically Compromised Patient
Atypical Plasma Cholinesterase
Atypical plasma cholinesterase is another pharmacogenetic disorder. Two commonly used drugs—succinylcholine, a short-acting, depolarizing muscle relaxant used during intubation in general anesthesia, and the ester local anesthetics, such as procaine, chloroprocaine, tetracaine, and propoxycaine—are metabolized by the enzyme plasma cholinesterase. A form of this enzyme, called atypical plasma cholinesterase, is found in 1 in 2820 persons. 83 Patients with atypical plasma cholinesterase are unable to metabolize these drugs at a normal rate and are therefore more likely to exhibit clinical signs and symptoms of (1) prolonged clinical activity and/or (2) drug overdose. When the paralytic agent succinylcholine is administered, the clinical duration of muscular relaxation in these patients is considerably prolonged beyond the usual 5 minutes. In cases in which an ester local anesthetic has been administered, elevated blood levels, which increase the risk of drug overdose, are noted. Clinical duration of action (pain control) is not prolonged when local anesthetics are administered to these patients. Patients with atypical plasma cholinesterase are considered ASA 2 risks.
Amide local anesthetics are recommended in these patients. Vasopressors are not contraindicated. Ester local anesthetics should be avoided in patients with atypical plasma cholinesterase however, if they must be administered, the smallest effective volume is recommended.
Oral, IM, and inhalation sedation are recommended without specific contraindications. IV sedation is recommended with the warning that succinylcholine not be administered to these patients.
Outpatient general anesthesia may be administered if succinylcholine is not administered to these patients. It is prudent, however, to consider hospitalization of these patients if general anesthesia is required.
Alcuronium is a non-depolarizing skeletal muscle relaxant agent, also known as a competitive muscle relaxant Dollery (1999) . It was used as an adjunct to general anesthesia for muscle relaxation, for neuromuscular blockade in mechanically ventilated patients in intensive care, and for endotracheal intubation. It has been withdrawn from the US and UK markets as it was used infrequently and was inferior to comparable muscle relaxants. Reports of prolonged paralysis particularly in renal dysfunction also occurred. The reader is encouraged to refer to records for currently marketed muscle relaxants, pancuronium, vecuronium, cisatracurium, mivacurium, rocuronium, rapacuronium, and pipecuronium, for more information. Overall there is little current published literature on alcuronium.
Cyclodextrin-based synthetic hosts
In order to circumvent the side-effects of the anticholinesterases and the anticholinergic agents, a new approach has been developed to reverse residual neuromuscular block. Chemical encapsulation or chelation of the neuromuscular blocking agent in the plasma by an exogenous host molecule, which would promote dissociation of the agent from its site of action thus antagonizing neuromuscular block, has been attempted. Cyclodextrins have been used as the host molecule as they have a well defined lipophilic cavity for host–guest complex formation, are water soluble, very stable, and have few side-effects. The complex formed is excreted in the urine. Org 25969 has been shown to antagonize 90% rocuronium-induced neuromuscular block within 3 min, producing 90% recovery of muscle function.
See multiple choice questions 123–127.
The following list includes the most common signs and symptoms in people with neuromyelitis optica spectrum disorders (NMOSD). These features may be different from person to person. Some people may have more symptoms than others and symptoms can range from mild to severe. This list does not include every symptom or feature that has been described in this condition.
- Inflammation of the optic nerve (optic neuritis)
- Temporary vision loss
- Inflammation of the spinal cord (acute transverse myelitis)
- Abnormal sensations
- Weakness in the arms and legs
- Bladder and bowel control problems
- Episodes of nausea and vomiting
This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.
Neuromuscular Blocking Drugs and Reversal Agents
B. Depolarizing neuromuscular block (also called phase I block ) is often preceded by muscle fasciculation. During partial neuromuscular block, depolarizing block is characterized by (a) decrease in twitch tension, (b) no fade during repetitive stimulation (tetanic or TOF), and (c) no posttetanic potentiation ( Fig. 12-2 ).
V. Pharmacology of Succinylcholine
A. Structure–Activity Relationships for Succinylcholine
1. Succinylcholine is a long, thin, flexible molecule composed of two molecules of acetylcholine linked through the acetate methyl groups ( Fig. 12-3 ).
2. Like acetylcholine, succinylcholine stimulates cholinergic receptors at the neuromuscular junction and at nicotinic (ganglionic) and muscarinic autonomic sites, opening the ionic channel in the acetylcholine receptor.
B. Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics of Succinylcholine
1. Succinylcholine has an elimination half-life of 47 seconds (95% confidence interval of 24 to 70 seconds), and the dose of succinylcholine causing on average 95% suppression of twitch height (the ED 95 ) is approximately 0.3 mg/kg.
2. The usual dose of succinylcholine required for tracheal intubation in adults is 1.0 mg/kg (results in complete suppression of response to neuromuscular stimulation in approximately 60 seconds).
3. In patients with genotypically normal butyrylcholinesterase activity, time to recovery to 90% muscle strength following administration of 1 mg/kg succinylcholine ranges from 9 to 13 minutes.
4. The short duration of action of succinylcholine is due to its rapid hydrolysis by butyrylcholinesterase (plasma cholinesterase) to succinylmonocholine and choline.
a. There is little or no butyrylcholinesterase at the neuromuscular junction.
b. Butyrylcholinesterase influences the onset and duration of action of succinylcholine by controlling the rate at which the drug is hydrolyzed in the plasma before it reaches, and after it leaves, the neuromuscular junction.
C. Factors Affecting Butyrylcholinesterase Activity
1. Butyrylcholinesterase is synthesized by the liver and found in the plasma.
2. Butyrylcholinesterase is responsible for metabolism of succinylcholine, mivacurium, procaine, chloroprocaine, tetracaine, cocaine, and heroin. Neuromuscular block induced by succinylcholine or mivacurium is prolonged when there is a significant reduction in the concentration or activity of butyrylcholinesterase.
3. Neostigmine (and to a lesser degree edrophonium) causes a profound decrease in butyrylcholinesterase activity. Even 30 minutes after administration of neostigmine, the butyrylcholinesterase activity remains about 50% of control values.
D. Genetic Variants of Butyrylcholinesterase
1. Neuromuscular block induced by succinylcholine or mivacurium can be significantly prolonged if the patient has an abnormal genetic variant of butyrylcholinesterase.
2. The dibucaine number reflects quality of cholinesterase enzyme (ability to hydrolyze succinylcholine) and not the quantity of the enzyme that is circulating in the plasma.
a. In case of the usual butyrylcholinesterase genotype (E 1 u E 1 u ), the dibucaine number is 70 or higher, whereas in individuals homozygous for the atypical gene (E 1 a E 1 a ) (frequency in general population of 1 in 3,500), the dibucaine number is less than 30.
b. In individuals with the heterozygous atypical variant (E 1 u E 1 a ) (frequency in general population of 1 in 480), the dibucaine number is in the range of 40 to 60.
c. In individuals with the homozygous atypical genotype (E 1 a E 1 a ), the neuromuscular block induced by succinylcholine or mivacurium is prolonged to 4 to 8 hours, and in individuals with the heterozygous atypical genotype (E 1 u E 1 a ), the period of neuromuscular block induced by succinylcholine or mivacurium is about 1.5 to 2 times that seen in individuals with the usual genotype (E 1 u E 1 u ).
3. Phase II block may appear after prolonged or repeated administration of succinylcholine and has characteristics similar to nondepolarizing neuromuscular blockers (edrophonium or neostigmine do not consistently result in adequate antagonism of neuromuscular blockade). The alternative is to keep the patient adequately sedated and maintain artificial ventilation until the TOF ratio has recovered to 0.9 or more.
E. Side Effects of Succinylcholine
a. Sinus bradycardia, junctional rhythm, and even sinus arrest may follow administration of succinylcholine. Cardiac dysrhythmias are most likely to occur when a second dose of succinylcholine is administered approximately 5 minutes after the first dose. Atropine is effective in treating or preventing bradycardia.
b. In contrast to actions at cardiac muscarinic cholinergic receptors, the effects of succinylcholine at autonomic nervous system ganglia may produce ganglionic stimulation and associated increases in heart rate and systemic blood pressure.
a. The administration of succinylcholine is associated with approximately 0.5 mEq/dL increase in the plasma potassium concentration in healthy individuals, which is well tolerated and generally does not cause dysrhythmias. (Patients with renal failure are no more susceptible to an exaggerated hyperkalemic response.)
b. Succinylcholine has been associated with severe hyperkalemia in patient conditions associated with upregulation of extrajunctional acetylcholine receptors (e.g., hemiplegia or paraplegia, muscular dystrophies, Guillain-Barré syndrome, and burn).
3. Increased Intraocular Pressure
a. Succinylcholine usually causes an increase in intraocular pressure (peaks at 2 to 4 minutes after administration and returns to normal by 6 minutes).
b. The use of succinylcholine is not widely accepted in open eye injury (when the anterior chamber is open) even though succinylcholine has not been shown to cause adverse events.
4. Increased Intragastric Pressure . Administration of succinylcholine does not predispose to regurgitation in patients with an intact lower esophageal sphincter because the increase in intragastric pressure does not exceed the “barrier pressure.”
5. Increased Intracranial Pressure . The potential for succinylcholine to increase intracranial pressure can be attenuated or prevented by pretreatment with a nondepolarizing neuromuscular blocker.
a. Postoperative skeletal muscle myalgia, which is particularly prominent in the skeletal muscles of the neck, back, and abdomen, can occur after administration of succinylcholine, especially to young adults undergoing minor surgical procedures that permit early ambulation. Myalgia localized to neck muscles may be perceived as pharyngitis (“sore throat”) by the patient and attributed to tracheal intubation by the anesthesiologist.
b. Muscle pain occurs more frequently in patients undergoing ambulatory surgery, especially in women, than in bedridden patients.
c. Myalgia may best be prevented with muscle relaxants, lidocaine, or nonsteroidal antiinflammatory drugs. However, myalgias following outpatient surgery occur even in the absence of succinylcholine.
7. Masseter Spasm . An increase in tone of the masseter muscle may be an early indicator of malignant hyperthermia, but it is not consistently associated with malignant hyperthermia.
VI. Pharmacology of Nondepolarizing Neuromuscular Blockers ( Tables 12-1 to 12-3 )
Summary – Depolarizing vs Nondepolarizing Neuromuscular Blockers
Depolarizing and nondepolarizing neuromuscular blockers are two types of neuromuscular blocking drugs or skeletal muscle relaxants. Depolarizing neuromuscular blockers are non-competitive for the acetylcholine binding sites of the receptors. In contrast, nondepolarizing neuromuscular blockers are competitive for the binding sites in the receptors. Thus, this is the key difference between depolarizing and nondepolarizing neuromuscular blockers. Moreover, as a result of the action of depolarizing blockers, depolarization of the muscle takes place while due to the action of nondepolarizing blockers, depolarization does not occur.
1. Gulenay, Michael, and Josephin Mathai. “Depolarizing Neuromuscular Blocking Drugs”. Ncbi.Nlm.Nih.Gov, 2020, Available here.
2. “Neuromuscular-Blocking Drug”. En.Wikipedia.Org, 2020, Available here.
1. “Succinylcholine 1(cropped)” By Mark Oniffrey – Own work (CC BY-SA 4.0) via Commons Wikimedia
2. “Doxacurium” By Fvasconcellos – Own work (Public Domain) via Commons Wikimedia