Handbook of Pharmacology for the Anesthesiologists Lopamudra Chowdhury
INDEX
Page numbers followed by f refer to figure, fc refer to flowchart, and t refer to table.
A
Abciximab 192
Acetaminophen 72
side effect 73
toxicity 73
Acetic acid derivatives 69
Acetylation 18
Acetylcholine 13
action of 61
receptors for 9
Acetylcysteine 126
Acid-base
and electrolyte balance 72
imbalance 179
Adenosine 185, 186
monophosphate 120
cyclic 10
triphosphate 13, 18
Adrenal crisis, acute 231
Adrenaline 131, 132, 146, 150
Adrenergic receptors 8
Adrenocorticotropic hormone 78
Adverse drug reaction 19, 22
Aerosol 123
therapy 119
Agonist
antagonists 84
full 8
partial 8
Alcohol, acute ingestion of 208
Alcoholic beverages 46
Aldosterone 154
antagonist 162, 163
Alkaloids
atropine, natural 65t
natural 65
pilocarpine 1
Allergic reactions, drug-induced 22
Allopurinol 17
Alosetron 104
Alpha glucosidase inhibitors 208
Alprazolam 48, 52, 102, 228
Alteplase 193
Aluminum hydroxide 110, 114
Aluminum-toxicity 222
Alveolar concentration, minimum 25
Alveolar minute ventilation 218
Amantadine 198
American Thoracic Society 115
Amethocaine 91, 93
Amiloride 163
Amineptine 200
Amino acid sequence 16
Aminophylline 117
Aminosteroid 53
Amiodarone 186
Amitriptyline 201
Amlodipine 158, 174
felodipine 151
Ammonio steroid compounds 54
Amoxapine 201
Amrinone 132, 150
Analgesia 69
patient-controlled 77
stage of 27
Analgesics 76
centrally acting 78
Anaphylactic shock, treatment of 133
Anemia 222
Anesthesia 49, 225
clinical signs of 27
effects of 215
for hypertensive patients, management of 159
mechanism of 27
precautions during 184
stage of surgical 28
Anesthetic agent 40t
ideal 35
Anesthetic drugs, pharmacology of 221
Anesthetic implications 205
Anesthetize mucous membranes 90
Angina
drugs in 160
pectoris, worsening of 120
unstable 160
Angioedema 172
Angiotensin converting enzyme 153, 167
inhibitors 153, 166, 170
side effects of 171f
Angiotensin II receptor blockers 172
Angiotensin peptides 167
Angiotensin receptor blockers 151, 153
Angiotensinogen 166
Antacids 114
Antagonists, receptor 103
Antiadrenergic drugs 104, 109, 122, 155, 228
Antiarrhythmic drugs
classification of 185
efficacy of 186
Antiarrhythmics 178
Anti-asthma drugs, comparison of 117t
Anticholinergic drugs 67t, 228
in anesthesia 65
Anticholinesterases 63t
Anticoagulants agent 187
Anticonvulsant 49, 200
Antidepressants
atypical 200, 202
long-term effects of 201
mechanism of action of 200t
tricyclic 202
Antidiabetic agents 209t
Antidiabetic drugs 206
Antiemetics 205
Antiepileptic drugs 205
Antihistamines 128
Antihistaminics drugs 104
Antihypertensive 154t, 159t
action 151f
Anti-inflammatory drugs, nonsteroidal 68, 166
Antiplatelet agent 187
Antipsychotics, newer 228
Antipyresis 69
Antithyroid drugs 211
Antitussives 127
Anxiety 143
Apixaban 191
Apomorphine 196
Ardeparin 189
Argatroban 190
Arrhythmias 120
Arterial blood pressure 166
Arterial hypoxemia 180
Arterial pressure, mean 40, 131
Arylacetic acid derivatves 69
Ascites 225
Aspiration pneumonia 111
Aspirin 70, 191
therapy, high dose 208
Asthma
acute severe 125, 229
drugs in treatment of 115
grades of 116t
Atenolol 144, 156
acebutolol 151
Atherosclerosis 217
Athletic heart syndrome 180
Atracurium 53, 55
Atrial fibrillation 182
Atrial flutter 182
Atrial premature beat 181
Atrial septal defect 184
Atrioventricular heart block
second-degree 178
third-degree 179
Atropine 1, 67, 232
flush 66
methonitrate 65
sulfate 67
Attack, prevention of future 161
Autonomic ganglia 54, 155
B
Bambuterol 117, 120
Barbiturate 36, 46, 47, 49, 51, 228
anesthesia 230
Bartter syndrome 71
Beclomethasone dipropionate 117
Bendrofluazide 163
Benzocaine 90
Benzodiazepines 46, 47, 52, 107, 228, 232
newer 52
Benztropine 198
Benzylisoquinolines 53
Beta-blockers 140, 151, 152, 156, 166, 208, 233
actions of 142f
generation 141fc
mechanisms of action of 144
nonselective 140fc
selective 140fc
use of 144
Beta2-selective agonists, types of 119fc
Beta-endorphin 79
Betamethasone 15
Bifascicular heart block 179
Bioavailability 2
influence 4
Biotransformation 15
reactions 15
types 16
Bisoprolol 156
Bisphosphonates 228
Bivalirudin 190
Bladder 146
Blood glucose 207
level 210
monitoring 210t
Blood potassium level 210
monitoring 210t
Blood pressure
factors influencing 152fc
management protocol 153
Blood vessels 146
Blood-brain barrier 62, 195
Bradycardia, management of 132
Bradycardia-tachycardia syndrome 181
Bradykinesia 198
Brain 15
neonatal 220
Brainstem centers 101
Bromhexine 126
Bromide 46
Bronchial asthma
classification of drugs in 116
drugs for 115
Bronchodilators 116
mechanism of action of 118f
Budesonide 117
Bumetanide 163
Bupivacaine 88, 89, 91, 92
Buprenorphine 84
Bupropion 200
Buspirone 51
Butorphanol 84
C
Caffeine 17, 21, 120, 121
Calcium 18
carbonate 114
channel blockers 124, 138, 151, 153, 158, 173, 174t, 232
actions of 173t
channels, types of 173t, 174
Calmodulin 19
Cancers 217
Candesartan 172
Captopril 134, 157, 170
Carbamazepine 17
Carbidopa 195
Carbocisteine 126
Carbon dioxide 34
absorbent 216
Carcinogenesis 21
Cardiac arrest 232
Cardiac arrhythmia 60, 143
Cardiac dysrhythmia 178, 179
Cardiac glycosides 176, 176t
mechanism of action of 176fc
Cardiac insufficiency 129
Cardiac rhythm, disturbances of 180, 180fc
Cardiac surgery 182
Cardic output 40
Cardiovascular structure, alteration of 169
Cardiovascular system 24, 49, 218
drugs acting in 129
Catecholamine 180
types of 131fc
Catechol-o-methyltransferase 195, 197
Ceiling diuretics, high 162
Celiprolol 144
Cellular proteins 13
Central and autonomic nervous system 220
Central nervous system 12, 13, 46, 78, 146, 195, 202
action on 62, 65
drugs in 195
toxicity 215
type 14
Central venous pressure 131
Cerebral blood flow 40
Cerebral metabolic rate 40
Cervical cord injury, high 130
Chemical stability 4
Chlophedianol 128
Chloral hydrate 17, 46
Chloramphenicol 17
Chlordiazepoxide 46, 48
Chloroprocaine 91
Chlorpromazine 5, 198
Chlorthalidone 163
Cholinergic agents 65
Cilnidipine 175
Cimetidine 17
Cinnarizine 105
Cisapride 106
Cis-atracurium 53, 55
Citalopram 200
Clarithromycin 17
Clomipramine 201
Clonazepam 49, 52
Clonidine 45, 151
Clopidogrel 192
Clozapine 17
Coagulopathy 222
Cocaine 89, 92
Codeine 17, 78, 81, 82, 128
Colloidal bismuth 113
Concomitant disease 159
Congeners, uses of 84
Congestive heart failure 137, 138, 153
treatment of 138
Conn's syndrome 151
Conscious sedation 44
Coronary syndrome, acute 136
Coronary vessels, vasospasm of 160
Corticosteroids 102, 116, 208
Cortisol 15
Cough 126, 172
center 126
drugs in 126
inability to 95
Cromolyn sodium 123
Cushing's syndrome 17
Cyclizine 105
Cyclooxygenase 68, 69
inhibitors, nonselective 69
Cytochrome 16
Cytokines 68
D
Dabigatran etexilate 191
Dalteparin 189
Desflurane 31
Desirudin 190
Dexamethasone 102, 107
Dexloxiglumide 107
Dexmedetomidine 44, 45
Dextromethorphan 128
Diabetes, insulin in treatment of 206
Diabetic ketoacidosis 207
Diabetic patient
perioperative steps for 210
preoperative steps for 210
Diacylglycerol 11, 19
Dialysis disequilibrium syndrome 165
Diaphragm 126
Diazepam 44, 48, 49, 52, 205, 220, 226, 228
Diazoxide 157, 230
Dibucaine 91
Diclofenac 74
sodium 67
Dicyclomine 105
Dietary salt intake 166
Diflunisal 72
Digitalis 132, 186
toxicity 177
Digitoxin 176, 176t
Digoxin 114, 150, 176, 176t
pharmacokinetics of 177
therapy, disadvantages of 177
Dihydropyridines 174
Diligan 108
Diltiazem 158, 174, 186
Dipeptidyl peptidase 208
Diphenhydramine 232
Dipyridamole 192
Disopyramide 186
Disulfiram 17
Diuretics 151, 153, 154, 162, 162t
commonly used 163t
comparison of 162t
sites of action of 164f
Dobutamine 131, 132, 148, 150
Domperidone 67, 103, 108
Donepezil 61
Dopamine 131, 132, 147, 150, 198
agonists 198
receptor
agonists 196
distribution of 199
Dopexamine 131, 132
Doxacurium 53, 55
Doxazosin 156
Doxepin 201
Doxinate 108
Doxylamine 105, 108
Dronabinol 107
Droperidol 42
Drug 1, 42
absorption of 2
action, targets for 13
active principle of 1
administration, routes of 1, 2fc
agonism 8
types of 8fc
allergic reaction to 22
antagonism 6, 6fc, 7f
chemical 6
competitive 7, 7f
functional 7
irreversible 7
noncompetitive 7, 7f
pharmacokinetic 6
physiological 7
receptor block 6
reversible 7
application, routes of 2f
causes, sudden withdrawal of 143
centrally acting 152
commonly used 110t
for cough, classification of 126fc
interaction 86, 208
methods to ensure safety of 5
midazolam, bioavailability of 3f
names of 1
overdose, treatment of 232
pH of 4
properties of 1
reactions, allergic 20
risk-free 5
routes, determination of 1
safety profile of 4
solubility of 4
therapy 160, 218, 224, 226
Drug-drug interactions 20
D-tubocurarine 53
Ductus arteriosus, action on 70
Dynorphin A 79
Dysgeusia 172
Dyskinesia 196
Dyspepsia 114
Dyspnea, drugs for 128
E
Ebstein's anomaly 181, 184
Ecothiophate 61
Edrophonium 61
Effector cell 11
Emergency situations, management of 229
Enalapril 151, 157, 170
Enalaprilat 157, 230
Endocrinal changes 222
Endocrine
effects 142
system, drugs acting on 206
Endogenous opioid system 78
Enflurane 31, 205
Enoxaparin 189
Entonox 217
Enzymes 15
Ephedrine 120
Epidermal growth factor 8
Epidural anesthesia, complications of 95t
Epidural block 99
Epidural injection, therapeutic of 100
Epilepsy 205
Epinephrine 120
Eplerenone 163
Epoxide hydrolases 16
Erythromycin 17
Escitalopram 200
Eserine 61
Esmolol 144, 230
Esophageal ulceration 228
Eszopiclone 52
Ethacrynic acid 163
Ethanol 17
Ether anesthesia, based on 27
Etidocaine 92
Etomidate 38, 40, 205
Etorphine 79
Excitement, stage of 28
Exhaled gases 216
Extradural anesthesia, contraindications for 96
Extrapyramidal syndrome 199
Eye 22, 142
action on 62, 66
F
Famotidine 67, 110
Fat-soluble vitamins 114
Felodipine 174
Fenamates 69
Fentanyl 41, 42, 44, 67, 79, 83
Fibrinolytics agent 193, 187
Fire and explosion 215
Flecainide 186
Fluid
balance 219
therapy 130
Flumazenil 232
Fluoroquinolones 114
Fluoxetine 200
Flurazepam 48, 52
Flurbiprofen 75
Fluticasone propionate 117
Fluvoxamine 200
Fondaparinux 189
Formoterol 120
Fosinopril 170
Fracture reduction 217
Furosemide 163, 208
G
Ganglia, action on 62
Gantacurium 55
Gas effect, second 32
Gastric acid 66
secretion 109
reduction of 109
Gastric irritant 127
Gastrointestinal tract 5, 15, 106
action in 66, 70
General anesthetics 24
components of 25
history 24
physiological effects of 24
General pharmacology 1
Genetic polymorphism 17
Genleuton 123
Glaucoma 143
Glibenclaminde 209
Gliclazide 209
Glimeperide 209
Glipizide 209
Glomerular filtration rate 227
Glucocorticoids 17, 122
Glucose 219
absorption, decreases 209
Glucuronic acid 18
Glutathione conjugation 15
Glycemic goals, preoperative 206
Glyceryl trinitrate 134136
Glycine conjugation 18
Glycopyrrolate 67, 184
Glycoside 176
Glycosuria 209
G-protein 9
coupled receptor 8, 9, 11
activation of 9
Granisetron 67, 104, 108
Gravidox 108
Griseofulvin 17
Growth hormone 8
Guanethidine 151
Guanosine
diphosphate 10
triphosphate 9, 10
H
H2 antagonists 110
Halothane 29, 226
actions 29
hepatitis syndrome 30
Head injury, severe 130
Headache 95
Heart 12, 146
block
complete 132
unifascicular 178
failure
beta blockers in 144
vasodilators in 137
rate 40
Heliox 217
Helium 34
Hematological reactions, drug-induced 22
Heparin 187, 189, 232
antagonist 191
treatment 187
Hepatic disease 5
Hepatic metabolism 227
Hiccups 95
His-Purkinje conduction system 178
Histamine release 54
Hot water bath humidifier 217
Human insulins 206
Human liver, metabolism in 16
Humidification 215, 216
normal mechanics of 215
Humidifiers and nebulizer
advantages of 216t
disadvantages of 216t
Humidity, sources of 216
Hydralazine 134, 136, 151, 157, 230
Hydrochlorothiazide 151, 163
Hydrogen sulfide 34
Hydromorphone 79
Hyoscine 65t, 67, 105, 108
butylbromide 65
Hypercarbia 180
Hyperkalemia 60, 222
Hypermagnesemia 222
Hyperosmolar nonketotic coma 207
Hypersensitive reaction, acute 212
Hypertension 151, 180, 222
classification of 153t
drugs in 151, 152
Hypertensive crisis 229
Hyperthermia 180
malignant 231
Hypnotics 46
newer 50
Hypocalcemia 222
Hypoglycemia 208
Hypokalemia, acute 180
Hypotension 95
Hypothermia 25
Hypovolemia 129
Hypoxia, diffusion 33
I
Iatrogenic disease 5
Ibuprofen 17, 74
side effect 74
Idraparinux 189
Imipramine 201
Inadequate anesthesia 95
Indapamide 151, 163
Indomethacin 73, 114
Inflammatory bowel diseases 217
Inhalation
agents 221
anesthesia 218
side effect of 119
Inhalational anesthesia, principles of 27
Inhalational steroids 123
side effects of 123
Inhalers used, types of 119
Inhaling dry gases, effects of 215
Inositol triphosphate 11
Inotropic agents and vasoconstrictors 146
Insulin 8, 15
allergy 208
analogs 206
aspart 206
delivery devices 207
glulysine 206
infusion of 207
lispro 206
mixtures 206
resistance 208
secretagogues 209
sensitizers 209
soluble 210
therapy
complications of 208
methods of 207
types 206
Insulin-dependent diabetes, contraindicated in 143
Intercostal muscles 126
Intestine 5
Intracranial pressure 40
Intragastric pressure, increased 60
Intraocular pressure, increased 60
Intravenous
agents 221
anesthesia, total 42
anesthetic
agents 35, 42t
comparison of 36t
bioavailability of 2
bolus 188
Inverse agonists 8
Iodides 212
Ion-channel receptor 8, 13
Ionotropes 131
Ionotropic agents 150t
Ipratropium bromide 65, 117
Irbesartan 172
Iron 114
Ischemic heart disease 76, 143, 182
drugs in 160
Isoflurane 30
Isoprenaline 120, 132
Itopride 108
Itraconazole 114
J
Junctional premature beat 181
K
Kent's bundle 184
Ketaconazole 17
Ketamine 39, 40, 42, 205
Ketoconazole 114
Ketoprofen 75
Ketorolac 74
Kidney 15, 22, 225
action in 70
L
Labetalol 230
Labor, effects on 70
Lansoprazole 67, 110, 112
Laryngospasm, severe 230
Left bundle branch block 178
Lenegre's disease 179
Lepirudin 189
Leukopenia 112
Leukotriene antagonists 118
Leukotriene inhibitors, pathway of 124fc
Leukotriene pathway inhibitors 123
Leukotriene receptor antagonists 124
Levodopa 15, 195
adverse effects of 196
Levorphanol 79
Lidocaine 4, 89, 91, 186
Lignocaine 88, 92
Limb paresthesia 95
Lipopolysaccharides 129
Lipoxygenase inhibitors 123
Lisinopril 151, 157, 170
Lithium 208
Liver 5, 220
damage, allergic 22
disease 17
chronic 225
severe 5
dysfunction 225
Local anesthetics 87, 91t
comparison of characteristics of 92t
Loop diuretics 154, 162, 166
Lorazepam 49, 52, 102, 205, 226
Losartan 151
Lown-Ganong-Levine syndrome 184
Loxatidine 110
Lungs 5
M
Magnesium hydroxide 114
Malathion 61
Maprotiline 201
Marcaine 92
Mast cell stabilizers 123
Meclizine 105, 108
Medicine 1
Meglitinides 208
Melatonin congener 47
Meperidine 82
Mephentermine 149, 150
Mepivacaine 88
Mesalamine 72
Metabolic acidemia 220
Metabolic acidosis 222
Metabolic effects 142
Metabolism
bypass first-pass 6
first-pass 5
sites of first-pass 5
Metaprolol 17, 156
Metaraminol 149
Metformin 209
Methadone 79, 83
Methohexital 205
Methoxyflurane 17
Methylated xanthine alkaloids 120
Methylation 18
Methyldopa 151, 226
Methyl-morphine 82
Methylsalicylate 72
Methylxanthines 120
Metoclopramide 102, 108, 232
Metocurine 53, 55
Metolazone 163
Metoprolol 144
Metronidazole 17
Mexiletine 186
Mianserin 200
Midazolam 41, 42, 44, 52, 67
Midodrine 149
Migraine prophylaxis 143
Milk alkali syndrome 114
Milrinone 131, 132, 149
Minoxidil 137, 151, 157
Mirtazapine 200
Mitral valvular disease 182
Mivacurium 53, 55
Molecular weight heparin, low 188, 189
Monoamine oxidase inhibitors 67, 201, 203
Monooxygenases 16
Montelukast 124
sodium 117
Moricizine 186
Morphine 78, 79, 81
uses of 84
Mosapride 106, 108
Motilides 106
Moxonidine 151, 159
Mucokinetics 127
Mucolytics 126, 127
Muscarinic cholinergic receptors 9
Muscarinic receptor 8
antagonists 198
Muscle
relaxants 53, 55t
depolarizing 53
smooth 12
type receptor 14
Mutagenesis 21
Myalgia 60
Myasthenia gravis 63
Myocardial infarction 143
acute 129, 138, 160, 230
Myocardial ischemia, pathophysiology of 161f
Myocardial myofilament 219
Myoglobinuria 60
N
Nadolol 156
Nalbuphine 85
Nalmephine 86
Nalorphine 86
Naloxone 81, 85
Naltrexone 81, 85
Naproxen 75
Nateglinide 209
Nausea 25, 95, 101
drugs in 101
Nebivolol 144
Nebulizers 216, 217
Nedocromil sodium 123
Neostigmine 61, 63
Nephrotic syndrome 163
Nephrotoxicity 21
Nerve
growth factor receptor 8
stimulators 58
Neurodegenerative disorders 217
Neuromuscular block monitoring 57
Neuromuscular blockade 58
Neuromuscular monitoring 57f
New York Heart Association 144
Nicardipine 158, 174, 230
Nicotamide adenine dinucleotide phosphate 16
Nicotinic acetylcholine receptor 14f
Nicotinic cholinergic receptors 13
Nicotinic receptor 13
Nifedipine 134, 158, 174, 208
Nimodipine 174
Nitrates 160
Nitrazepam 49, 52, 228
Nitric oxide 34, 129
Nitroglycerin 230
Nitroprusside 151, 157
Nitrous oxide 32, 44
Nonbenzodiazepines 47
Noncovalent reactions 21
Nondepolarizing block, characteristics of 56
Nondepolarizing muscle 54
relaxants 53
Non-dihydropyridines 174
Nondrug regimen 152
Nonhemolytic jaundice, congenital 17
Nonopioids 128
Nonparoxysmal junctional tachycardia 182
Nonreceptor-mediated drug action 13
Nonsteroidal anti-inflammatory drugs
adverse effects of 77
pharmacokinetics of 70
Noradrenaline 131, 132, 147, 150
Norepinephrine reuptake inhibitors 200
Nortriphyline 201
Nuclear receptor 8
O
Obstructive lung disease, chronic 81
Obstructive pulmonary disease, chronic 66
Olsalazine 72
Omalizumab 124
Omeprazole 17
Ondansetron 67, 103, 108
Onium chlorofumarate, mixed 53
Opiates 128
Opioid 233
antagonists 85
centrally acting 78
clinical uses of 86
comparison of 81t
receptor 79
agonists, comparison of 79t
Oral anticoagulants, newer 191
Oral antidiabetic agents 208
classification 208
Oral glucocorticoids 122
Osmotic diuretics 164
Oxaprozin 75
Oxazepam 226
Oxeladin 128
Oxicams 69, 75
Oxide 52
Oxygen 34
delivery systems 214
head hood 214
incubator 214
therapy
advantages of 213
and humidification 213
clinical guidance for 214
evaluation of effectiveness of 214
hazards of 214
long-term 214
techniques of 213
P
Pain, prevention of 59
Palonosetron 104
Pancuronium 55
Pantoprazole 67, 110, 112
Paracetamol 17, 72, 226
Paraldehyde 46
Parenteral anesthetics 35
Parenteral anticoagulants 189
Parenteral glucocorticoids 122
Parkinson's disease 197
Parkinsonism, drugs in 195
Parnaparin 189
Paroxetine 200
Pentazocine 67, 81, 84
Peptic ulcer disease 109
classification 109
drugs in 109
Perindopril 170
Peripheral anticholinergic action 198
Peripheral nerves 12
Peripheral resistance, total 135
Pethidine 67, 81, 82
Pharmacodynamics, age-related changes in 227
Pharmacokinetics 54
age-related changes in 227
Pharyngeal demulcents 126, 127
Phenobarbitone 17, 51
Phenothiazines 114
Phentolamine 230
Phenylbutazone 17
Phenylephrine 148
Phenytoin
causes 205
decreases manifestations 17
Phenytoxin 17
Pheochromocytoma 143
Phosphodiesterase inhibitors 132, 166
Physostigmine 1, 61, 63, 232
Pioglitazone 209
Piperazines, tricyclic 199
Plasma 15
cholinesterase antagonism 59
protein 220
replacement fluid 130
Platelet
action on 70
inhibitors 191
Poisoning, chronic 17
Postspinal headache 98, 99
mechanism of 99
Postsuccinylcholine muscle pain 59
Potassium-sparing diuretics 154, 162, 163
Pramlintide 209
Pranlukast 124
Prasugrel 192
Prazosin 151, 156
Preanesthetic medications 67
Precordial discomfort 95
Preexcitation syndrome 183
Pregnidoxin 108
Prinzmetal's angina 143
Procainamide 186
Procaine 15, 88, 90, 91, 93
Prodrugs 16
Prokinetic agents 101, 105
Prolactin receptor 8
Proopiomelanocortin 78
Propafenone 186
Propanolol 156
Propidium 61
Propionic acid derivatives 69, 75
Propofol 37, 40, 42, 44, 205
Propranalol 4, 5, 144, 186, 230
Propylthiouracil 232
Prostaglandin 69
analogs 112
Protamine sulfate 191, 232
Protein 219
Proton pump inhibitors 67, 111
Prototype drug atropine, actions of 65
Protriptyline 201
Prucalopride 106
Pruritus 222
Pulmonary absorption collapse 215
Pulmonary edema 231
management 231
Pulmonary hypertension, drugs in 161
Pulmonary system 225
Pulmonary toxicity 215
Pump failure, treatment of 160
Pyrazolone derivatives 69
Pyridostigmine 61, 63
Pyrrolopyrole 69
Q
Quinidine 17, 186
Quinine 1
R
Rabeprazole 110, 112
Ramipril 157, 170
Ranitidine 67, 110
Rash 172
Reactions
covalent 21
type A 20
type B 20
Regional anesthesia 94, 96
advantages 94
characteristics of 94t
disadvantages 95
Remifentanil 83
Renal disease 5
Renal failure, chronic 222
Renal function 219
altered 168
dose calculation in impaired 224
Renin inhibitor, direct 153
Renin-angiotensin system
components of 166
effects of 168
functions of 168
mechanism of action of 168fc
pathophysiology of 166
Repaglinide 209
Respiratory changes 222
Respiratory components in neonate and adult 218t
Respiratory rate 40
Respiratory system 24, 49, 146, 218
Respiratory tract 66, 142
Restlessness 95
Reteplase 193
Retrolental fibroplasia 215
Reviparin 189
Reye's syndrome 71, 72
Rheumatic disease 72
Rifampicin 17
Right bundle branch block 178
Rivaroxaban 191
Rocuronium 55
Ropivacaine 91, 93
Roxatidine 110
Ryanodine 144
S
Salbutamol 117, 208
Salicylates 69, 226
Salicylic acid 72
Salmeterol 120
Saxagliptin 209
Scopolamine 184
Second messenger 18
Sedative 46
Sensitive potassium channels 13
Sensorcaine 92
Septic shock, treatment of 133
Serotonin
reuptake inhibitors, selective 200, 201
selective 200
transporter 201
Sertraline 200
Serum cholinesterase, low 59
Sevoflurane 32
Shock 129
anaphylactic 22, 129
cardiogenic 129, 132
compensatory mechanisms 130
hypovolemic 129
mechanisms responsible for 129
neurogenic 130
pathophysiology of 129
septic 129
treatment of 129, 130
types of 129
Sick sinus syndrome 175, 181, 182
Sincalide 107
Sinus
bradycardia 180
tachycardia 180
Sitagliptin 209
Skeletal muscle 54
relaxants 53
Skin 5
Smooth muscles, action on 66
Sodium
bicarbonate 114
cromoglycate 117
nitroprusside 134, 230
Sotalol 186
Spinal analgesia, drugs for 98
Spinal anesthesia
cephalad migration of 130
complications of 95t
prevention of hypotension to 96
total 100
treatment of hypotension to 96
Spinal block
analgesia in 98
high 95
Spinal over epidural anesthesia, disadvantages of 96
Spironolactone 163
Stable angina 160
Status asthmaticus, treatment of 125
Steroid 226
hormones 8
withdrawal, signs of 123
Streptokinase 193
Strophanthin G 176
Subarachnoid block, contraindications for 96
Succinylcholine 15, 54, 55
adverse effects of 60
apnea 58
Sucralfate 113
Sufentanil 79
Sugamadex 63
Sulfated glycosaminoglycan 187
Sulfonal 46
Sulfonylureas 208
Sulindac 73
Supraventricular tachycardia, paroxysmal 175, 181
Sweat glands and temperature, action on 66
Sympathomimetic
characteristics of 131t
drugs 180, 203
Systemic embolization, danger of 182
Systemic lupus erythematosus, drug-induced 22
Systemic steroids, side effects of 123
Systemic vascular resistance 225
Systolic blood pressure 147
T
Tachycardia 120
Tacrine 17, 61
Telmisartan 151, 172
Temazepam 52
Temperature regulation 220
Tenecteplase 193
Teratogenesis 21
Terazosin 151, 156
Testosterone 15
Tetracaine 91
Tetracyclines 114, 226
Thebaine 78
Theophylline 17, 208
Therapeutic gases 34
Thevetia 176
Thiazides 154, 162, 163, 208
Thiazolidinediones 208
Thienopyridine 192
Thioamides 211
Thiopentone 40, 51
Thoracic surgery 182
Thyroid
disorder 212
drugs in 211
storm 232
Thyrotoxicosis 143
Tianeptine 200
Ticlopidine 192
Tiotropium bromide 65
Tocainide 186
Tolbutamide 17
Tolmetin 74
Torsades de pointes, treatment of 132
Torsemide 163
Toxicity 215
Tramadol 67, 81, 83
Transmembrane enzyme 8
Transtracheal oxygen delivery 214
Trazodone 200
Triamterene 163
Trihexyphenidyl 198
Trimethaphan 230
Tubocurarine 55
U
Urethane 46
Urinary bladder, action on 66
Urokinase 193
Urticaria 111
V
Valsartan 172
Vasopressin antagonists 165
Vasopressor therapy 232
Vecuronium 14, 53, 55, 56, 63, 205
Ventricular failure, left 136
Ventricular fibrillation 183
Ventricular premature beats 182
appearance of 183
Ventricular tachycardia 183
Verapamil 158, 174, 175, 186
Vildagliptin 209
Vitamin
D 8, 15
K antagonists 190
Vomiting 25, 95, 101
drugs in 101
mechanism of 102f
W
Warfarin 17, 190, 233
Wolff-Parkinson-White syndrome 177, 181, 183, 185, 186
X
Xenon 33
Z
Zafirlukast 124
Zaleplon 47
Z-compounds 47
Zileuton 123
Zolpidem 47, 52
Zopiclone 47, 51
×
Chapter Notes

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General PharmacologyCHAPTER 1

 
SOME TERMINOLOGIES
The term pharmacon means drugs; logos means studies.
Pharmacology is a branch of medicine which deals with drugs.
 
Drug (WHO)
Drug is a chemical substance or biological product that is used or intended to be used to modify or explore physiological systems or pathological states for the benefit of the recipient.
Drug is called medicine when used in proper dosage form for safe administration. All medicines are drugs but all drugs are not medicines.
 
Active Principle of Drug
Chemical constituent present in the drug which is responsible for pharmacological effect of the drug, e.g. alkaloids pilocarpine, atropine, physostigmine, quinine, etc.
 
Names of Drug
A drug may be named in various ways: chemical, generic or nonproprietory, proprietory, e.g. chemical name—acetaminophen or 4-acetamidophenol generic/nonproprietory name—Paracetamol, proprietory/trade name—Calpol.
 
Determination of Drug Routes
Routes of drug administration is determined primarily by—
  • Properties of the drug, e.g. water or lipid solubility, degree of ionization, molecular weight, etc.
  • Therapeutic objectives, e.g. rapidity of onset of action, duration, site of action, etc.
  • Patient profile whether patient is conscious/unconscious, compliant/noncompliant, age of the patient, whether patient is vomiting/not vomiting (Flowchart 1.1 and Fig. 1.1).
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Flowchart 1.1: Routes of drug administration.
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Figure 1.1: Various routes of drug application.
 
BIOAVAILABILITY
It is the measure of the fraction of administered dose of a drug that reaches the systemic circulation in the unchanged form. Bioavailability (BA) is related to the rate and extent of absorption of a drug from its dosage form. Bioavailability of IV (intravenous) administered drug is 100% but it is not so, when administered orally. By plotting plasma concentrations of the drug vs time, one can measure area under the curve. This curve reflects the extent of absorption of the drug (Figs. 1.2A and B). So, bioavailability of a drug administered orally is the ratio of area under the curve calculated for oral administration compared with the area under the curve calculated for intravenous (IV) injection (Fig. 1.3).
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Bioavailability of an orally administered drug can be assessed by the following (expressed as %):
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Figures 1.2A and B: Bioavailability of drug midazolam.
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Figure 1.3: Diagram comparing BA of various routes.
AUC: area under the curve; IV: intravenous; BA: bioavailability
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Significance
  • Variation in bioavailability affects drugs with narrow safety margin, toxicity may be precipitated.
  • It influences the therapeutic efficacy of drugs, specially antibiotics.
  • Enteric coated tablets are used to increase bioavailability of drugs destroyed by enzymes in GIT. Hence, route of administration and dosage form to be decided accordingly.
 
Factors that Influence Bioavailability
  • First-pass hepatic metabolism—Drug absorbed from GIT enters portal circulation, before entering systemic circulation. If it is partly metabolized by the hepatic enzymes the amount of unchanged drug reaching systemic circulation is decreased, e.g. propranolol, lidocaine have high first pass hepatic metabolism.
  • Solubility of drug—Hydrophilic drugs are poorly absorbed. Again extremely hydrophobic substitutes too are not absorbed because they are insoluble in aqueous body fluids.
  • Chemical stability—Some drugs are destroyed in the GIT by degradative enzymes.
  • pH of the drug—Some drugs are unstable at gastric pH.
  • Properties of the drug and dosage form—Particle size, salt form, crystal polymorphism and presence of excipients (binders and dispersing agents) can influence rate of dissolution.
  • Presence of food or other drugs—These influence the absorption of the drug.
  • GI motility—It affects drug absorption hence bioavailability.
Two related drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentration. Two similar drugs which are bioequivalent may not be therapeutically equivalent.
 
Safety Profile of a Drug
A drug can be termed “risk free” if the precise action of the drug is known by the physician; drug was used correctly in appropriate dose and for appropriate indication; drug had biological selectivity or administered by selective targeted delivery.
Route
Bioavailability (%)
Characteristics
Intravenous (IV)
100
Most rapid onset
Intramuscular (IM)
75 ≤ 100
Injection may be painful
Subcutaneous (SC)
75 ≤ 100
Injection may be painful
Oral
5 <100
Significant first-pass metabolism
Rectal
30 to <100
Less first-pass metabolism than oral
Inhalation
5 to <100
Rapid onset
Transdermal
80 to <100
Slow onset
5
The criteria of a risk-free drug is never achieved because—
  • Drugs are not usually selective.
  • If the action is selective, its action may be extended to other sites.
  • Prolonged administration of a drug can lead to functional (receptor modification) and organic (iatrogenic disease) changes.
  • Genetic variability may induce unpredictable responses.
  • Need for dosage monitoring and adjustment.
  • Physiological variables like age, sex, pregnancy, lactation affect disposition of a drug.
  • Pathological variability, e.g. renal or hepatic disease also influences drug level.
  • Ignorant and casual prescribing may be responsible for iatrogenic disease conditions.
 
Methods to Ensure Safety of Drug
  • Target-oriented drug delivery.
  • Therapeutic dose monitoring.
  • Pharmacovigilance of adverse drug reactions (ADR).
  • Proper information to the patient regarding the usage details.
  • It is advisable not to prescribe a drug about which the prescriber is not fully conversant.
 
First-pass Metabolism
Most of the drugs administered orally, after absorption from the gastro-intestinal tract (GIT), enters the portal circulation first before reaching the systemic circulation. As the drug gains access to the liver via the portal circulation, it is exposed to the drug metabolizing enzymes (also in the intestinal wall) of the liver and a considerable fraction of the administered dose is metabolized. This metabolism is called first-pass metabolism.
 
Sites of First-pass Metabolism
(a) Intestine, (b) liver (mainly), (c) skin, (d) lungs.
The extent of first-pass metabolism differs for different drugs and is an important determinant of oral bioavailability. Consequences of first-pass metabolism—
  1. Oral dose required is higher than sublingual or parenteral route.
  2. There is marked individual variation in bioavailability, depending on the extent of metabolism.
  3. Oral bioavailability is increased in severe liver disease.
  4. Oral bioavailability is increased if another drug competing with it in first-pass metabolism is administered concurrently, e.g. chlorpromazine and propranolol.
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Examples
Examples of drugs with high first-pass metabolism—isoprenaline, lignocaine, hydrocortisone, testosterone, propranolol, nitroglycerin and verapamil, etc.
Hence, these drugs with high first pass metabolism should either be given in high oral dose or preferably oral administration should be avoided. Routes which bypass first-pass metabolism are preferred.
 
Routes which Bypass First-pass Metabolism
  • Parenteral → IV, IM, SC and routes like intravenous intramuscular, or subcutaneous.
  • Sublingual.
  • Transdermal.
  • Topical.
 
DRUG ANTAGONISM
When one drug decreases or inhibits the action of the other, they are said to be antagonists. The types of antagonism may be classified according to mechanism as—(a) chemical antagonism, (b) pharmacokinetic antagonism, (c) antagonism by receptor block and (d) physiological antagonism—e.g. insulin and glucose on blood glucose level.
 
Chemical Antagonism
Condition where two substances combine in solution, as a result of which the effect of active drug is lost, e.g. thiopentone + succinylcholine → precipitate. Drug chemical interaction leads to drug inactivation formation.
 
Pharmacokinetic Antagonism
In this antagonism, antagonist effectively reduces the concentration of active drug at the site of action, either by affecting drug absorption, increasing the rate of metabolism or increasing the rate of renal excretion of the active drug.
 
Antagonism by Receptor Block
It is of two types; competitive and noncompetitive. In competitive receptor antagonism. Drug reception is blocked by antagonist either reversibly or irreversibly (Flowchart 1.2 and Fig. 1.4).
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Flowchart 1.2: Antagonism of drug.
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zoom view
Figures 1.4A and B: Diagram of drug antagonism. (A) Competitive; (B) Noncompetitive.
 
Competitive Antagonism
  • Antagonist binds with the same receptor as the agonist.
  • Antagonist resembles chemically with the agonist.
  • Intensity of response depends on the concentration of both agonist and antagonist.
Reversible antagonism: The antagonist has affinity for the same receptor as the agonist but lacks efficacy.
  • Parallel shift of the agonist log dose concentration-effect curve without any decrease in the maximal response.
  • Rate of dissociation of the antagonist molecule is sufficiently high.
  • New equilibrium is rapidly established on addition of the agonist.
Irreversible antagonism: The antagonist bears high affinity to the receptor and binds with strong covalent bonds so that it cannot be detached easily.
  • Antagonism is not surmountable.
  • Antagonist dissociates very slowly.
  • No change in antagonist occupancy takes place when agonist is applied.
  • Reactive grouping of drug binds covalently to receptor.
 
Noncompetitive Antagonism
  • Chemical structure of the antagonist is not similar to that of the agonist and binds to an allosteric site.
  • Binds to another site of receptor.
  • Does not resemble the agonist.
  • Flattening of agonist drug response curve (DRC).
  • Maximum response is suppressed.
  • Response depends on concentration of antagonist.
 
Physiological/Functional Antagonism
The two drugs act on different receptors or by different mechanisms but have opposite effects on the same physiological function, e.g. glucagon and insulin on blood sugar level, ACE inhibitor and thiazide diuretic on serum potassium level.
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zoom view
Flowchart 1.3: Types of drug agonism.
 
DRUG AGONISM (FLOWCHART 1.3)
  • Full agonists: Agonists which can produce maximum effects and have high efficacy.
  • Partial agonists: Agonists which produce submaximal effects and have intermediate efficacy.
  • Inverse agonists: It shows selectivity for the receptor but produces effect opposite to that of an agonist. Hence shows affinity but negative efficacy.
Agonists on binding to receptors initiate changes in cell function, to bring about various effects. Potency of an agonist depends on two parameters—
  • Affinity: Ability to bind to receptors.
  • Efficacy: Ability to initiate changes that bring about effects.
According to the two state model, agonists show selectivity for the activated state of the receptor while antagonists show no selectivity.
Drugs act on various types of receptors:
  • G-protein coupled receptor (GPCR)—e.g. adrenergic, muscarinic receptors (cholinergic).
  • Ion-channel receptor—e.g. nicotinic (cholinergic), GABAA, 5HT3, receptors.
  • Transmembrane enzyme linked receptor—e.g. insulin, epidermal growth factor, nerve growth factor receptor.
  • Transmembrane JAK–STAT binding receptor e.g. growth hormone, prolactin receptor.
  • Nuclear receptor—e.g. steroids hormones, vitamin D.
 
G-protein Coupled Receptor
The G-protein coupled receptors are also known as metabotropic receptors or seven transmembrane spanning (heptahelical) receptors. They are membrane receptors that are coupled to intracellular effector system via G-protein. They constitute the largest family and include receptors for many hormones and slow transmitters.
G-protein coupled receptor (GPCR) consists of a single polypeptide chain of up to 1100 residues; the characteristic structure comprises seven transmembrane α-helices, with extracellular N-terminal domain of varying length and an intracellular C-terminal domain.
G-protein coupled receptor (GPCR) are divided into 3 distinct families. They share the same heptahelical structure but differ in other respects, e.g. length of the N-terminus—location of the agonist binding domain.
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  • Family A: Related to rhodopsin, most monoamine and neuropeptide receptors. It is by far the largest.
  • Family C: The smallest, its main members being the metabotropic glutamate receptors and the Ca+2 sensitizing receptors.
  • Family B: Secretin/glucagon receptor family. Receptors for peptide hormones including secretin, glucagon, calcitonin.
Examples: Muscarinic cholinergic receptors, adrenoceptors, chemokine receptors, neuropeptide receptors. The first G-protein coupled receptor (GPCR) to be fully characterized was the β-adrenoceptor which was cloned in 1986. So far, G-protein coupled receptor (GPCR) cannot be obtained in crystalline form, so powerful techniques of X-ray crystallography cannot yet be used to define the molecular structure of the receptors in detail.
The long third cytoplasmic loop is the region of the molecule that couples to the G-protein. Usually a particular receptor subtype couples selectively with a particular G-protein, swapping parts of the cytoplasmic loop between different receptors alters their G-protein selectivity. For small molecules such as nor adrenaline the ligand binding domain appears to reside not on the extracellular N-terminal region but buried in the cleft between the α-helical segments within the membrane. Peptide ligands such as substance P, bind more superficially to the extracellular loops.
Though activation of G-protein coupled receptor (GPCR) is normally the consequence of agonist binding, it can occur by other mechanism.
  • Rhodopsin activated by light induced cis-trans isomerization.
  • Thrombin initiates a variety of cellular response by binding to a GPCR.
  • β-adrenoceptor—mutations in the third intracellular loop or simply overexpression of the receptor, result in constitutive receptor activation.
Inactivation occurs by desensitization involving phosphorylation after which the receptor is internalized and degraded to be replaced by newly synthesized protein. One of the intracellular loops is larger than the others and interacts with the G-protein. The G-protein is a membrane protein compromising three subunits (α, β, γ), the α subunit possessing guanosine triphosphate (GTP) ase activity. The α subunits of G-proteins differ in structure.
Coupling of the α-subunit to an agonist occupied receptor causes the bound guanosine diphosphate (GDP) to exchange with intracellular guanosine triphosphate (GTP), The α-GTP complex then dissociates from the receptor and from the βγ subunit complex and interacts with a target protein (target 1). The βγ complex may also activate a target protein (target 2). Guanosine triphosphate (GTP) ase activity of the α–subunit is increased when the target protein is bound, leading to hydrolysis of the bound guanosine triphosphate (GTP) to guanosine diphosphate (GDP), where upon the α-subunit reunites with the βγ complex.
 
MUSCARINIC CHOLINERGIC RECEPTORS
Two classes of receptors for acetylcholine are recognized—muscarinic and nicotinic. The muscarinic receptors are G-protein coupled receptor (GPCR) and are selectively stimulated by muscarine and blocked by atropine (Fig. 1.5).
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zoom view
Figures 1.5A to D: Diagram of G-protein coupled receptor (GPCR).
GDP: guanosine diphosphate; GTP: guanosine triphosphate; cAMP: cyclic adenosine monophosphate
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  • Sites: These receptors are primarily present on autonomic effector cells in periphery—heart, blood vessels, eye, smooth muscles, glands of GI, respiratory and urinary tract and sweat glands.
  • CNS: Preganglionic nerve fibers, ganglia—modulatory role.
  • History: Muscarinic receptors were characterized initially by analysis of the responses of cells and tissues in the periphery and the CNS. Differential effects of two muscarinic antagonists, bethanechol and MeN-A 343 on the tone of esophageal sphincter led to the initial designation M1 and M2 (effector cell) by Goyal and Rattan 1978. Subsequently, radiological binding studies definitively revealed distinct populations of antagonist binding sites.
  • Types: By pharmacological as well as molecular cloning techniques, muscarinic receptors have been divided into 5 subtypes—M1, M2, M3, M4 and M5. The first 3 subtypes have been functionally characterized but responses mediated by M4 and M5 subtypes are not well defined.
 
M1 Receptors
  • Main locations—CNS: cortex, hippocampus and corpus striatum, autonomic ganglia, gastric and salivary gland and enteric nerves.
  • Receptor type— G-protein coupled receptor (GPCR).
 
Mechanism of Action
The muscarinic receptors are G-protein coupled receptor (GPCR) having characteristic membrane domains. The M1 and M3 subtypes function through Gq protein and activate membrane bound phospholipase C (PLC); generating inositol triphosphate (IP3) and diacylglycerol (DAG) which in turn release Ca+2 intracellularly, causing depolarization, glandular secretion and raise smooth muscle tone.
 
Functional Response
  1. Increase in cognitive function (learning and memory)
  2. Increase in seizure activity
  3. Decrease in dopamine release and locomotion
  4. Increase in depolarization of autonomic ganglia
  5. Increase in secretions.
 
M2 Receptors
 
Main Locations
Widely expressed in CNS and heart, also in visceral smooth muscle and autonomic nerve terminals.
 
Receptor Type
G-protein Coupled Receptor (GPCR)
Mechanism of action: The M2 and M4 receptor opens k+ channels (through βγ subunits of regulatory protein Gi) and inhibits adenylyl cyclase (through α subunit of Gi) resulting in hyperpolarization, decrease in pacemaker 12activity, slowing of conduction and decreased force of contraction in heart. Increased production of cyclic guanosine monophosphate (cGMP) and release of eicosanoids can also occur in certain tissues by activation of muscarinic receptors.
 
Functional Response
  • Heart: Sinoatrial node (SA) node → slowed spontaneous depolarization and hyperpolarization, decrease in heart rate (HR). Atrioventricular node (AV node) → decrease in conduction velocity, atrium → decrease in refractory period, decrease in contraction.
  • Smooth muscles: Increase in contraction.
  • Peripheral nerves: Neural inhibition and decrease in ganglionic transmission.
  • Central nervous system (CNS): Neural inhibition, increase in tremor, hypothermia and analgesia.
 
M3 Receptors
 
Site of Location
Widely expressed in CNS, abundant in smooth muscles and glands, vascular endothelium, iris, and ciliary muscle.
 
Mechanism of Action and Receptor as M1
Functional response—gastric and salivary secretion, GI smooth muscle contraction, vasodilation, ocular accommodation, increase in body weight, fat deposits, increase in food intake, and inhibition of dopamine release.
 
M4 Receptors
 
Site of Location
Vagal nerve endings, CNS—cortex and hippocampus, striatum.
 
MOA and Receptor
As M2.
 
Action
Increase in locomotion, facilitation of dopamine release.
 
M5 Receptors
 
Site of Location
Central nervous system (CNS), substantia nigra [Mechanism of action (MOA) as M3], vascular endothelium of cerebral vessels.
 
Action
Dilatation of cerebral arteries and arterioles, facilitates dopamine release, augmentation of drug seeking behavior and reward.
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ION CHANNEL RECEPTORS
These cell surface receptors enclose ion selective channels (for Na+, K+, Ca+2 and Cl) within their molecules. Agonist binding opens the channel and causes depolarization/hyperpolarization/changes in cytosolic ionic composition depending on the ion that flows through.
Examples of ion channel receptors are nicotinic cholinergic receptors, GABAA receptor, glycine receptors, NMDA (n methyl D-aspartate), 5HT3 receptors.
The receptor is usually a pentameric protein. In addition to the intra- and extracellular segments, the receptor has four membrane spanning domains, in each of which, amino acids (AA) chain traverses the width of the membrane six times. The subunits are arranged round the channel like a rosette and the α-subunits usually bear the agonist binding sites.
These are fast channels and takes milliseconds to produce action. The subunits are α2, β, γ, δ each with molecular weight of 40–58 kDa. The four subunits show marked sequence homology and analysis of the hydrophobicity profile. The acetylcholine (ACh) binding site lie at the interface between one of the two α-subunits and its neighbor. Both must bind ACh molecules in order to be activated.
 
Nicotinic Receptor
Most excitatory neurotransmitters, such as acetylcholine (ACh) at the neuromuscular (NM) junction or glutamate in the central nervous system (CNS), cause an increase in Na+ and K+ permeability. This results in net inward current carried mainly by Na+, which depolarizes the cell and increases the probability that it will generate action potential (AP).
The action can be indirect involving a G-protein and other intermediaries or direct, where the drug itself binds to the channel protein and alters its function, e.g. local anesthetics (LA) act on voltage gated Na+ channels, drug molecule plugs the channel physically blocking ion permeation.
Example are:
  • Dihydropyridines inhibit L-type calcium channel.
  • Benzodiazepines bind to GABA receptor/chloride channel.
  • Sulfonylureas act on adenosine triphosphate (ATP) sensitive potassium channels of β cells of pancreas.
 
Nonreceptor-mediated Drug Action
Drugs may target enzymes to produce their action. They may affect carriers or reuptake mechanisms for their actions. Cellular proteins like tubulin or immunophilines may also be targets for drug action.
 
Nicotinic Cholinergic Receptors (Fig. 1.6)
These receptors are selectively activated by nicotine and blocked by tubocurarine and hexamethonium. These are rosette-like pentameric structures which enclose a ligand gated cation channel. Activation of the channel causes opening of the channel with rapid flow of cations resulting in depolarization and generation of action potential. On the basis of location and selective agonists and antagonists two subtypes Nm and Nn are recognized.
14
zoom view
Figures 1.6A and B: Nicotinic acetylcholine receptor. (A) Longitudinal view; (B) Cross-sectional view.
 
Sites of Location
  1. Muscle receptors which are confined to the skeletal neuromuscular junction.
  2. Ganglionic receptors—sympathetic and parasympathetic ganglia.
  3. CNS type receptors—brain.
 
Muscle Type (Nm) Receptor
(α1)2 β1Єδ—Adult, (α1)2 β1γδ—Fetal.
  • Site: Skeletal neuromuscular junction.
  • Mechanism: Opening of channel → increase in permeability of Na+ and K+. Excitatory end plate potential → depolarization → skeletal muscle contraction.
  • Agonists: Acetylcholine (ACh), nicotine.
  • Antagonist: Atracurium, vecuronium, d-tubocurarine and pancuronium.
 
Nn Type (α3)24)3
  • Location: Autonomic ganglia and adrenal medulla.
  • MOA: Same—depolarization – secretion of catecholamines.
  • Agonist: ACh and nicotine.
  • Antagonist: Trimethaphan and mecamylamine.
 
CNS Type (α4)2, (β4)3, (α7)5
 
α-toxin Insensitive, α-toxin Sensitive
  • Location: Pre- and postsynaptic.
  • MOA: Same as in α-toxin sensitive channel which increases Ca+2 permeability.15
  • Agonist: Anatoxin A.
  • Antagonist: Dihydro-β-erythrodine, mecamylamine for α-toxin insensitive; α-bungarotoxin, α-lonotoxin for α-toxin sensitive.
 
BIOTRANSFORMATION
Process by which the body brings about chemical changes in drug molecule is called biotransformation. It is needed to render nonpolar, lipid-soluble compounds more polar or lipid-insolubles, so that they are not reabsorbed in the renal tubules and are excreted. Most hydrophilic drugs, e.g. streptomycin, neostigmine, decamethonium, etc. are not biotransformed and are excreted unchanged. So, biotransformation reactions alter the physiochemical properties of a drug so that a drug with high lipid or water partition coefficient will be converted into a polar and water-soluble one for easy disposal from the body.
 
Organs Involved
Liver is the main organ involved. Other sites are intestinal mucosa, nasal epithelium, lungs, skin, (as cortisol, testosterone, betamethasone), kidney, (as insulin, vitamin D), brain (e.g. levodopa), plasma (e.g. succinylcholine, procaine).
 
Enzymes Involved
 
Microsomal
  • These enzymes are present in the smooth endoplasmic reticulum (ER) of liver, kidneys and gastrointestinal tract (GIT). Important microsomal enzymes present in the hepatic cells are mixed function oxidase P450. Other enzymes are hydroxylase, reductase, dehydrogenase, glucuronyl transferase, glutathione S-transferase.
    The micorosomal enzymes are responsible for most of the oxidation reactions, some reduction, hydrolysis, glucuronidation and glutathione conjugation reactions. These enzymes are primarily the substrates of high lipid water partition coefficient. The microsomal enzymes can be inducible by drugs, diet and other factors.
 
Nonmicrosomal
  • They are present in the cytoplasm, mitochondria and extracellular spaces of different organs. High concentration are found in the liver, plasma, kidneys and other tissues.
    Nonmicrosomal enzymes are esterase, amidase, hydrolase, sulfotransferase and glutathione S-transferase.
    These enzymes catalyze all conjugation reactions (except glucuronide and glutathione conjugation), hydrolysis, some oxidation and reduction reactions.
    These enzymes cannot be induced but can be inhibited by drugs.
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Types
The chemical reactions involved in biotransformations are classified as—
 
Phase I Reactions
In which enzymes carry out oxidation, reduction on hydrolysis reactions. Phase I enzymes lead to the introduction of what are called functional groups, resulting in a modification of the drug, such that it now carries an OH, -COOH, -5H, -O, or NH2 group. Reactions in phase I lead to inactivation of an active drug. In certain instances metabolism specially, hydrolysis of ester or amide linkage results in bioactivation of a drug which are called prodrugs. If the phase I metabolite is sufficiently polar, then it will be excreted in the urine. Some metabolites not excreted are further metabolized by phase II reactions. A single drug may undergo several biotransformation steps. Phase I oxygenases are—cytochrome P450 s, flavin containing monooxygenases (FMOs), epoxide hydrolases (MEH, SEH). The CYPs and FMOs are super families of enzymes. Each super family comprises multiple genes.
Cytochrome P450: Cytochrome P450 enzymes are heme proteins, comprising a large family (super family) of related but distinct enzymes (each referred to as CYP followed by a defining set of numbers and letters, number designates family and letter denoting the sub family). The name cytochrome P450 (CYP) is due the spectral properties of the hemoprotein. In its ferous form, it binds to carbon monoxide to produce a complex which absorbs maximum light at the range of 450 nm. These enzymes differ from one another in—
  • Amino acid sequence.
  • In regulation by inhibitors and inducing agents.
  • In the specificity of the reactions they catalyze.
Different members of the family have distinct but often overlapping substrate specificities. This unusual feature of extensive overlapping substrate specificities by the CYPs is one of the underlying reasons for the predominance of drug-drug interactions.
Purification of P450 enzymes and DNA cloning has yielded 74 CYP gene families of which 3 main ones CYP1, CYP2, CYP3 are involved in drug metabolism in human liver. CYPIA2 is one of the main enzymes.
Heme contains one atom of iron in a hydrocarbon cage that functions to bind oxygen in the CYP active site as part of the catalytic cycle of these enzymes. CYPs use O2 plus H+ derived from the cofactor reduced nicotamide adenine dinucleotide phosphate (NADPH) to carry out the oxidation of substrates. The H+ is supplied through the enzyme NADPH cytochrome P450 oxidoreductase. Metabolism of a substrate by a CYP consumes one molecule of molecular oxygen and produces an oxidized substrate and a molecule of water as a by product. The O2 is usually converted to water by the enzyme superoxide dismutase.
The reactions carried out by mammalian CYPs are
N – dealkylation, O – dealkylation aromatic hydroxylation, N – oxidation, S – oxidation deamination dehalogenation.
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Inducers of P450
Inhibitors of P450
Rifampicin
Quinidine
Ethanol
Ketaconazole
Carbamazepine
Cimetidine
Phenobarbitone
Metronidazole
Glucocorticoids
Disulfiram
INH
Omeprazole
Chloral hydrate
Allopurinol
Phenylbutazone
Erythromycin
Griseofulvin
Clarithromycin
DDT
Chloramphenicol
As a family of enzymes CYPs are involved in the metabolism of dietary and xenobiotic agents, as well as synthesis of steroids and metabolism of bile acids. In contrast to the drug metabolizing CYPs, the CYPs that catalyze steroid and bile acid synthesis are substrate specific. The CYPs that carry out xenobiotic metabolism have a tremendous capacity to metabolize a large number of structurally diverse chemicals. The most active CYPs for drug metabolism are those in CYP2C, CYP2D, CYP3A subfamilies. CYP3A4 is the most abundantly expressed and involved in the metabolism of about 50% of clinically used drugs. Some examples—
  • CYP1A1: Theophylline.
  • CYP1A2: Caffeine, paracetamol, tacrine and theophylline.
  • CYP2A6: Methoxyflurane.
  • CYP2C9: Ibuprofen, phenytoxin, warfarin and tolbutamide.
  • CYP2C19: Omeprazole.
  • CYP2D6: Clozapine, codeine and metaprolol.
  • CYP3A4/5: Cyclosporine, losartan, nifedipine and terfenadine.
Within human populations there are major sources of interindividual variation in CYP 450 enzymes. The causes include—genetic polymorphism, environmental factors, enzyme inhibitors and inducers, their presence in diet, e.g. grape fruit juice and St. John's wort (in alternative medicine) inhibit enzymes but Brussels sprout and cigarette smoke induce CYP 450 enzymes.
(Possible uses of enzyme induction—(1) congenital nonhemolytic jaundice—phenobarbitone, (2) Cushing's syndrome—phenytoin decreases manifestations, (3) liver disease and (4) chronic poisoning.)
 
Phase II (Conjugation) Reaction
If a drug molecule has a suitable hydroxyl, thiol or amino group, it is susceptible to conjugation reaction. The resulting conjugate is almost always pharmacologically inactive and less lipid soluble than its precursor and is excreted in urine or bile.
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Conjugation with glucuronic acid, glycine conjugation, methylation, acetylation and sulfate occurs in phase II reactions.
 
SECOND MESSENGERS
As first messenger binds with its specific receptor, the drug receptor complex is formed which subsequently causes the synthesis and release of another intracellular regulatory molecule termed second messenger. These are—cyclic AMP, cyclic GMP, calcium, inositol 1, 4, 5 triphosphate, diacylglycerol, calmodulin.
 
Function
Second messenger molecules are produced in response to neurotransmitter binding to a receptor, translate the extracellular signal into a response that may be further propagated or amplified within the cell.
  • Cyclic AMP—
    • First to be recognized.
    • Synthesized by plasma membrane attached adenylyl cyclase. Adenylyl cyclase converts adenosine triphosphate (ATP) into cyclic adenosine monophosphate (AMP).
    • Mediates responses, such as ionotropy, chronotropy of heart muscles, relaxation of smooth muscles, breakdown of carbohydrates in liver, breakdown of triglycerides (TG) in fat cells, calcium homeostasis, other endocrine and neural processes, acts exclusively through cyclic AMP dependent protein kinase (A kinase), phosphorylates enzymes and proteins involved in cell function-transfer of phosphate from ATP occurs.
  • Calcium—intracellular calcium plays an important role in the function of most of the cells.
    • Intracellular calcium occurs in both bound and free form.
    • Free form of calcium is responsible for action.
    • Intracellular free calcium is about 10,000 times less compared to extracellular.
    • As cells are stimulated by agonist, intracellular Ca+2 concentration increases rapidly.
    • Intracellular free calcium brings about cellular action while bound form is present in the inner surface of cell membrane, ER, mitochondria, and secretory granules.
    • Responsible for neurotransmitter release, muscle contraction and various function.
  • Cyclic GMP—
    • Cyclic GMP is produced from the guanosine triphosphate (GTP) by an enzyme guanylyl cyclase which is present in the inner phase of the plasma membrane.19
    • The enzyme is activated when muscarinic receptors are occupied by an agonist.
    • Cyclic GMP → activates cyclic GMP-dependent protein kinase (G kinase).
    • Subsequent effect is not yet known.
  • Inositol 1, 4, 5 triphosphate—
    • Hydrolytic product of phosphatidyl (PI) inositol, a minor phospholipid of the cell membrane.
    • Activation of enzyme phospholipase which causes hydrolysis of phosphatidylinositol 4, 5 biphosphate (PIP2).
    • Formation of water-soluble IP3 and diacylglycerol.
    • This IP3 stimulates release of Ca from ER, this Ca is responsible for effect.
    • IP3 is then converted to IP2, IP1 inositol and finally PI.
  • Diacylglycerol—
    • It formed from the metabolic product of PIP2.
    • This diacylglycerol activates directly intracellular located protein kinase C (C kinase).
  • Calmodulin—
    • Single peptide chain containing 148 amino acid residues.
    • Considered to be the receptor for intracellular free calcium.
    • It has four binding sites.
    • Three or four of these need to be occupied by Ca+2 before calmodulin will activate the myosin light chain kinase (MLCK)
    • As phosphorylated myosin forms cross bridges with actin and sliding of actin over myosin filaments occur—producing contraction of muscle.
 
ADVERSE DRUG REACTIONS
An adverse drug reaction may be defined as a harmful or significant effect caused by a drug at doses intended for therapeutic effect that warrants reduction of dose or withdrawal of the drug and foretells hazards from future administration. Adverse effect or reaction refer to all unwanted effects attributable to the drug.
All drugs are xenobiotics and there is nothing like a safe drug. Whenever a drug is administered a risk is undertaken. This risk may be due to the properties of the drug, patient factors of the environment.
 
Classification
Adverse drug reactions may be classified as—
  • Type A or predictable reactions—based on the pharmacological properties which are “augmented”. Effect often is reversible.
  • Type B or unpredictable reactions—unrelated to pharmacological actions, e.g. idiosyncratic reactions. These effects are usually irreversible and bizarre. Such indirect toxicity may be direct or immunologic in nature, e.g. agranulocytosis with carbimazole. Other effects are liver or kidney damage, bone marrow suppression, carcinogenesis and disordered fetal development.
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According to cause adverse drug reactions may be classified as—
  • Side effects: Unwanted often unavoidable pharmacodynamic effects that often occur at therapeutic doses.
  • Secondary effects: These are indirect consequences of primary actions of the drug.
  • Toxic effects: These are the result of excessive pharmacological actions of the drug due to either overdosage or due to prolonged or chronic use. The CNS, CVS kidney, liver, lung, skin and blood toxin organs are most commonly affected.
  • Drug-drug interactions: With the use of polypharmacy, response of one drug may be altered due to the administration of another resulting in untoward effects.
  • Allergic drug reactions: These are common form of adverse drug reactions. A drug or its metabolite can act as a hapten and can be immunogenic.
 
Type A Reactions
Over expression of normal pharmacological action, e.g.
  • α1 antagonists—causes hypotension.
  • Anticoagulants—causes bleeding.
  • Glycosides—causes cardiac arrhythmia.
  • Anxiolytic—causes sedation.
  • Insulin—causes hypoglycemia.
 
Type B Reactions
Rare and unpredictable, e.g.
  • Paracetamol—causes hepatotoxicity.
  • Thalidomide—causes teratogenicity.
  • Chloramphenicol—causes aplastic anemia.
  • Practalol—causes mucocutaneous syndrome.
  • Carbimazole—causes agranulocytosis.
 
Side Effects
Unwanted effects due to pharmacodynamic profile of the drug in therapeutic dose regimens, e.g.
  • Promethazine—causes sedation.
  • Codeine—causes constipation.
  • ACEI—causes cough.
 
Secondary Effects
Indirect consequences of primary action of the drug, e.g.
  • Corticosteroids—causes osteoporosis.
  • Tetracycline—causes superinfection.
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Toxic Effects
Due to excessive pharmacological actions or due to direct tissue injury. Drug- induced cell damage occurs due to—
Noncovalent reactions: Lipid peroxidation, generation of toxic oxygen radicals, reactions causing depletion of glutathione, modification of sulfhydryl groups.
Covalent reactions: Targets are DNA and protein or peptide molecules, e.g.
  • Hepatotoxicity
    — Paracetamol
    — INH
    — Iproniazid
    — Halothane
    — Methotrexate.
    It occurs when hepatocytes are exposed to toxic metabolites from oxidation by CYP 450.
  • Nephrotoxicity: Kidney is exposed to high concentration of drugs and drug metabolites. Renal damage occurs due to—interstitial nephritis, papillary or tubular necrosis, decrease in compensatory vasodilator PGs.
    Drug-induced nephrotoxicity occurs due to NSAIDs specially phenacetin
    ACE – I, methicillin, caffeine, captopril, cyclosporine.
  • Mutagenesis: Mutation is a change in the genotype of a cell that is passed on when the cell divides. Chemical agents cause mutation by covalent modification of DNA. Mutation in protooncogenes, tumor suppressor genes result in carcinogenesis and usually involves more than one mutation. Drugs are relatively uncommon causes of birth defects and cancers.
  • Carcinogenesis: Alteration of DNA is the first step in the complex multistage process of carcinogenesis. Carcinogens are chemical substances that cause cancer and can interact directly with DNA or act at a later stage to increase the likelihood that mutation will result in the production of a tumor. Most chemical carcinogens act by modifying bases in DNA particularly guanine, the O6 and N7 positions of which readily combine covalently with reactive metabolites of chemical carcinogens. Some therapeutic agents increase the risk of cancer—estrogen, pyrimethamine and methoxsalen.
  • Teratogenesis: The term teratogenesis signifies production of gross structural malformations during fetal development. The timing of the teratogenic insult in relation to the stage of fetal development is critical in determining the type and extent of damage produced. It is during organogenesis days (17–60) that drugs can cause gross malformations. The structural organization of the embryo occurs in a well defined sequence, i.e. eye and brain, skeleton and limbs, heart and major blood vessels, palate and genitourinary system. The type of malformation produced thus depends on the time of exposure to the teratogen.
Drugs with teratogenic potential are thalidomide, hydantoin, alcohol, nicotine, antithyroid drugs and steroids (stilbestrol).
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Allergic Reaction to Drugs
It is the most common form of adverse responses to drugs. Most drugs being low molecular weight substances are not immunogenic in themselves. A drug or its metabolites act as a hapten by interacting with protein to form a stable conjugate that is immunogenic.
Drug-induced allergic reactions may be Ab-mediated (types I, II, III) or cell-mediated (type IV). Important clinical manifestations include—
  • Anaphylactic shock: It may be life threatening due to respiratory obstruction. Most deaths are caused by penicillin. Drugs causing anaphylaxis are penicillin, streptokinase, asparginase, hormones, like ACTH, heparin, dextran, radiological contrast agents and vaccines.
    Treatment is done with injection of adrenaline which is lifesaving. Penicilloyl polylysine is used as a skin test reagent for penicillin allergy. Other type I reactions are—bronchospasm and urticaria.
  • Drug-induced hematological reactions are produced by type II, type III, type IV hypersensitivity.
    • Type II reactions can affect any or all of the formed elements of the blood. Hemolytic anemia is related with sulfonamides and methyldopa.
    • Agranulocytosis which can be irreversible is caused by sulfonamides, chloramphenicol and carbimazole.
    • Thrombocytopenia is caused by quinine, heparin and thiazide diuretics.
 
Adverse Effects due to Chronic Use
  • Eye—
    • Cataract—may be caused by chloroquine, steroids, phenothiazine and anticancer drugs.
    • Corneal opacity—may be caused by chloroquine, phenothiazine and amiodarone.
    • Retinal injury—may be caused by chloroquine, ethambutol and thioridazine.
  • Kidney: Analgesic nephropathy caused by NSAIDs.
  • Allergic liver damage: Type II, III—hypersensitivity reaction as in halothane hepatitis due to reactive metabolite of halothane which couples to liver protein to form an immunogen. Enflurane (trifluoroacetyl chloride) may also cause Ab—mediated liver damage.
  • Drug-induced SLE: Type III reaction which involves antibody to nuclear material and is a multisystem disorder affecting skin, lung, kidney, CNS. Subsides when offending drug is stopped of hydralazine and procainamide.
 
Adverse Drug Reaction
Adverse drug reaction (ADR) is a major consequence of pharmacotherapy and monitoring is an integral part of good clinical practice. If adverse drug reactions are not noticed, unnecessary morbidity and mortality occurs, hence comes the importance of pharmacovigilance.
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Prevention
  • Easy availability of ‘over the counter’ drugs to be stopped.
  • Genetic screening for status of GL-6-PO4 dehydrogenase, pseudocholinesterase deficiency, acetylator status to be noted.
  • Knowledge of the drug prescribed.
  • Polypharmacy to be restricted to minimize drug-drug interactions.
  • Recognition and reporting system of ADR to be practiced.
  • Good clinical practices with detection of toxicities during preclinical as well as clinical trials.
  • Finally risk–benefit ratio to be weighed before initiation of therapy.