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UNIT -1 Sources of drugs
Drugs are obtained from different sources Most of the drugs that are currently used are manufactured synthetically Recently drugs are synthesized by genetic technologies like human recombinant gene technology Ex Erythropoietin
Specific source and drugs
Ant cholinergic Cardio tonic Narcotic analgesics Anti-diabetic Ant tetanus Anti- coagulant Antidote Purgative Antacid Antibiotic Antibiotic Anti-cancer Analgesics Antacid Anti-pyretic Anti-epileptic Hypnotic
Digitalis- Digitoxin Opium - Morphine Pork, Beef – Insulin
Horse – Tetanus anti toxin Various animals - Heparin Charcoal
Magnesium sulfate Aluminum hydroxide Penicillium Notatum – Penicillin
Actinomycetes – Streptomycin E. Coli - L- asparaginase Aspirin Cimetidine
Paracetamol Phenitoin Phenobarbitone
Pharmaceutical companies dispense a drug in a variety of formulations suitable for a single or multiple routes of administration Some antibiotics are available in tablet, capsules or suspension form for oral administration So doctor can choose the formulation suitable for the patient It is important because it influences the bioavailability of drug For ex Digoxin when injected intravenously, the bioavailability of that drug is 1.00 But when the same amount of the drug is administered into the body by oral route in tablet form, the bioavailability is about is 0.62 On the other hand, the bioavailability of digoxin elixir administered orally is 0.80 When a tablet form of drug is swallowed, it is necessary to disintegrate as well as to dissolve before absorption But in case of capsule, there is no question of disintegration , only dissolution is necessary In case of suspension, there is no disintegration or dissolution So, the rate of absorption is greater in suspension than capsule or tablet
Route of administration
To produce a pharmacological effect it is very important for the drug to reach the site of action This depends on the transfer of drugs across one or more membrane barriers Drugs after reaching the blood circulation builds up a therapeutic concentration The concentration depends on the volume of distribution, biotransformation and excretion There are some drugs which are not absorbable from one site but get into the circulation from another Benzyl penicillin is inactivated in the stomach at gastric PH and is not administered orally Some drugs absorbed from the gastrointestinal tract pass the intestinal mucosa and the small intestine but metabolized by the gut wall (such as chlorpromazine , dopamine) or by the liver ( such as lignocaine, pethidine, propranolol) In order to select the route for administration this first-pass biotransformation is considered and on occasions is avoided Slowly absorbed drug may have delayed onset of effect and may even fail to achieve effective concentration
4 Mechanism of drug action Many drugs produce their effects by binding to specific target proteins like receptors. Through enzymes and pumps 3. inside or outside the cell to produce their effect Drugs may act by one or more complex mechanisms of action The fundamental mechanism of drug action may be 1. Through ion channels 4. By chemical interaction 6.Through receptor 2. By altering metabolic process 1. enzymes and ion channels . Through the receptors Drugs may act by interacting with specific receptors in the body Receptor It is a macromolecular site on the cell with which an agonist binds to bring about a change Affinity Its the ability of a drug to bind to a receptor Efficacy Its the ability of a dung to elicit a response after binding to the receptor Agonist An agonist is a substance that binds to the receptor and produces a response It has affinity and intrinsic activity . Drugs may act on the cell membrane. By physical action 5.
anxiety. while beta – carbolines bind to the same receptors to cause arousal . after binding to the receptors produce opposite to those produced by a pure agonist Eg Diazepam acting on benzodiazepine receptors produces sedation. muscle relaxation and controls convulsions. isolated and extensively studied Site The receptors may be present in the cell membrane. in the cytoplasm or on the nucleus Nature receptors Receptor are proteins Synthesis and life – span Receptor proteins are synthesized by the cells They have a definite life span after which the receptors are degraded by the cell and new receptors are synthesized Function of Receptors Recognition and binding o the ligand Propagation of the message For the above e function . the receptor has two functional domains (areas) A ligand binding domain .The site to bind the drug molecule . anxiolyses. increased muscle tone and convulsions Ligand is a molecule which binds selectively to a specific receptor Various receptor are have been identified.5 Antagonist An antagonist is a substance that binds to the receptor and prevents the Action of agonist on the receptor It has affinity but no intrinsic activity Partial agonist It binds to the receptor but has low intrinsic activity Inverse agonist Some drugs .
6 An effecter domain – which undergoes a change to propagate the message The drug – receptor interaction has been considered to be similar to lock and key relationship where the drug specifically fits into the particular receptor ( lock) like a key. digoxin 3. Through enzymes and pumps Drugs may act by inhibition of various enzymes. The agonist itself is the first messenger The entire process involves a chain of events triggered by drug receptor interaction 2.mediated reactions Ex Allopurinol inhibits the enzyme xanthene oxidizes .Acetazolamide inhibits carbonic anhydrase Membrane pumps like H-K ATPase may be inhibited by drugs Ex Omeprazole. thus altering the enzyme. Interaction of the agonist with the receptor brings about changes in the receptor which in turn conveys the signal to the effectors system The final response is brought about by the effecter system through second messengers. Through ion channels Drugs may interfere with the movement of ions across specific channels Ex Calcium channel blockers and potassium channel blockers .
bran Osmotic property . Chemical interaction Drugs may act by chemical reaction Antacids .I 131 Radio.Osmotic diuretics.Barium sulphate contrast media 5.Like potassium permanganate – germicidal Chelating agents . Altering metabolic processes Drugs like antimicrobials alter the metabolic pathway in the micro.opacity . Physical action. Osmotic purgatives – Magnesium sulphate Radioactivity .organisms resulting in destruction of the micro-organisms Ex Sulfonamides interfere with bacterial folic acid synthesis .7 4.Bind heavy metals making them nontoxic 6.Neutralize Gastric Acids Oxidizing agents . The action of a drug could result from its physical properties like Adsorption Activated charcoal in poisoning Mass of the drug .Bulk laxatives like psyllium.Mannitol .
9 Cholinergic receptor .
10 GABA Receptor .
11 Opium receptor .
12 Receptor effectors coupling .
13 Neurotransmitter .
14 Secondary messengers .
15 Ligand gated ion channels .
16 G protein coupled receptor .
17 TRK RECEPTOR .
18 Nuclear receptor .
19 Regulation of receptor .
20 Def The chemi from one .
Expiatory neurotransmitter It is responsible for the conduction of impulse from the presynaptic neuron to the postNeurotransmitter + Receptor--. Glycine. nor-adrenaline.21 CLASSIFICATION 1. glutamate (glutamic acid) and aspirate(aspartic acid) B. Inhibitory neurotransmitter A . adrenaline B. Depending on chemical nature A. Expiatory neurotransmitter B. Amino acids The neurotransmitters of this group are involved in fast synaptic transmission & are inhibitory and excitatory in action Ex GABA. Inhibitory neurotransmitters The inhibitory neurotransmitter inhibits the conduction of impulse from the presynaptic neuron to the post-synaptic neuron Inhibitory neurotransmitter is released from the presynaptic axon terminal due to the .Opening of Na channels – influx of sodium Ex Acetyl choline. Others Some neurotransmitters do not fit into any of there categories 2. dopamine. Depending on function A. Amines These are modified amino acids These have slow synaptic transmission These have inhibitory or excitatory in action Ex Adrenaline . serotonin and histamine C.
Glycine and Dopamine Important neurotransmitter are Acetyl choline Nor-adrenaline Dopamine Serotonin GABA Histamine Glycine Glutamate Substance P Nitric acid 1 . the action potential is not generated in the post-synaptic neuron Ex GABA . ACETYLE CHOLINE It is a cholinergic transmitter Site of secretion .22 arrival of action potential It causes opening of K channels in post-synaptic membrane and efflux of potassium ions This leads to hyper-polarization which is called inhibitory post-synaptic potential ( IPSP) When IPSP is developed.
M4 and M5 of which the first three are well defined The muscarinic receptors are located on smooth h muscle.--------------------------------. M2.23 Preganglionic parasympathetic nerve endings Postganglionic parasympathetic nerve endings Preganglionic sympathetic nerve ending Neuromuscular junction Cerebral cortex Basal ganglia Thalamus Amacrine cells of retina Synthesis Acetate + Co-Enzyme-A + ATP Acetate activating reaction ------------------------------------Acetyl CoEn-A Choline acetylase Acetyl CoEn-A + CHOLINE -. Nicotinic receptor These are of two subtypes N1 & N2 also referred to as Nm and Nn receptors The nicotinic receptors are located on postganglionic cell bodies in the autonomic ganglia at neuromuscular junctions of skeletal muscle and on neurons of CNS 2. cardiac muscle. M3.ACETYLCHOLINE Receptor Nicotinic receptor and Muscarinic receptor 1. gland cell and some neurons of CNS . Muscarinic receptors These are of five types M1.
24 Function Excitatory function It is synthesized in axon terminals and stored inside the vesicles Excitatory function Opening of legand gated Na channels Ach has very quick and potent action It also destroyed immediately after executing the action It is destroyed by the enzyme acetyl-cholinesterase This enzyme is present in basal lamina of the synaptic cleft 2. Nor-adrenaline It is the neurotransmitter in adrenergic nerve fibers Site of secretion .
Beta – adrenergic receptor . it is the excitatory chemical mediator and in very few places.25 Post gang ionic sympathetic nerve endings Cerebral cortex Hypothalamus Basal ganglia Brainstem Spinal cord In many places. but phenylalanine has to be converted into tyrosine Formation of tyrosine from phenylalanine in the presence of enzyme phenylalanine Hydroxylase Uptake of tyrosine from blood into the chromaffin cells of adrenal medulla by active Transport Conversion of tyrosine into dihydroxyphenylalanine (DOPA) by hydroxylation in the presence of tyrosine hydroxylase Decarboxylation of DOPA into dopamine by DOPA decarboxylase Entry of dopamine into granules of chromaffin cells Hydroxylation of dopamine into nor-adrenaline by the enzyme dopamine beta Hydroxylase Release of nor-adrenaline from granules into the cytoplasm RECEPTOR The action of nor-adrenaline are executed by binding with receptors called adrenergic Receptors They are two types of receptors A.adrenergic receptor B. Alpha. arousal and elevation of moods Synthesis It is synthesized from the amino acid tyrosine in the chromaffin cells of adrenal medulla These hormones are formed from phenylalanine. it causes Inhibition It is believed to be involved in dreams.
Alpha.adrenergic receptor It is subdivided into Alpha1 and Alpha2 Alpha-adrenergic receptors mediate more of nor-adrenaline action than the adrenaline Action 1.26 A. Alpha1 receptor Mode of action .
Beta1. SEROTONINE It also known as 5.receptor These mediate the actions of both adrenaline and nor-adrenaline almost equally 2. Beta2 receptor These receptors are larger than B2 These receptors mediate more of adrenaline actions than nor-adrenaline actions Both B1 and B2 receptors produced their actions by activating adenyl cyclase through G protein and increasing intracellular cyclic AMP 3.adrenergic receptor 1.Alpha 2 receptor It exert their effects by inhibiting adenyl cyclase and reducing intracellular CAMP B. Beta.hydroxyl-tryptamine It is synthesized from tryptophan by hydroxylation and decarboxylation Large amount of serotonin (90%) is found in intero-chromatin cells of GIT Small amount is found in platelets and nervous system It is also called Enteramine as GIT contains 80-90% of all the 5 HT in the body Platelets contain 5HT while passing through the GIT It is secreted in the following areas Hypothalamus Cerebellum Limbic system Midbrain .27 It exert their actions by activating the secondary messenger IP3 through phospholipase C 2.
28 Spinal cord GIT Lungs Platelets Retina Synthesis It is produced from tryptophan .tryptamine (5 HT) --------------------------5HT MAO 5-HT -------------------------------------------5.indole acetic acid (5HIAA) Serotonin receptor There are 4 families of 5 HT receptors—5HT1 – 5HT4 It comprising of 14 receptors subtypes It is contained mainly in the brainstem neurons that innervate practically all other areas of the CNS In general 5 HT has An excitatory effect on motor pathways An inhibitory effect on the sensory pathways It plays important role in the neural pathways controlling moods The presence of descending serotonergic neurons in the brainstem and spinal cord is essential for the analgesic action of morphine 4.Hydroxy.essential amino acid and is metabolized by mono-amine 0xidase Tryptophan hydroxylase Tryptophan --------------------------------------------.5-Hydroxy-tryptophan (5 HTP) O2 decarboxylase 5.Hydroxy. GABA It is an inhibitory neurotransmitter in synapses particularly in CNS It is responsible for presynaptic inhibition It is secreted by nerve endings in the following structures Cerebral cortex Cerebellum Basal ganglia Spinal cord Retina Mechanism of action .
29 Presynaptic inhibition It is also known as indirect inhibition and it occurs because of the failure of presynaptic axon terminal to release the excitatory neurotransmitter substance Post synaptic inhibition It also called direct inhibition It occurs due to the release of an inhibitory neurotransmitter from presynaptic terminal instead of excitatory neurotransmitter substance The most important inhibitory neurotransmitter is gamma amino butyric acid (GABA) and Glycine The GABA acts on post-synaptic membrane by binding with receptor The transmitter receptor complex opens the ligand gated potassium channels instead of sodium channels The K channels which are more in the cell body of post-synaptic neurons more to ECF Simultaneously Cl channels also open and Cl ions which are more in ECF move inside the cell body of post-synaptic neurons The exit of K ions and influx of Cl ions cause more negativity inside. leading to hyper polarization .
GABA B ( G.protein coupled receptor) Hyper polarization K conduction Altering of Ca influx 3. GABA C 5.30 Receptors 1. GABA A ( Intrinsic ion channel receptor) Opening of ion channels known as chloride channels and conduction of chlorine influx of Cl ions 2. DOPAMINE It is secreted by nerve endings in the following areas Basal ganglia Hypothalamus .
HISTAMINE It is formed by decarboxylation of the amino acid known as Histidine It is exciter neurotransmitter It is secreted by nerve endings of . basal ganglia In brain this acts as a neurotransmitter The other physiological functions of circulating dopamine are not understood clearly Functions Vaso-constriction by releasing nor-adrenaline Vasodilatation in mesentery Increases in heart rate via beta receptor Increasing in systolic blood pressure Dopamine dies not affect diastolic blood pressure Deficiency of dopamine in basal ganglia produces nervous dies-order called Parkinsonism 6.G proteins mediated The brain contains more of D2 receptors Synthesis Dopamine is secreted by adrenal cortex Dopamine also secreted by dopaminergic neurons in some areas of brain particularly .31 Limbic system Retina Sympathetic ganglia Receptor Dopamine acts on 5 types of dopamine receptors (D1-D5) .
32 Hypothalamus Limbic cortex Other parts of cerebral cortex Gastric mucosa Mast cells Spinal cord Mechanism of action It is believed to play an important role in arousal mechanism Functions Intra-cerebroventricular administration produces Rise in BP Cardiac stimulation Behavioral arousal Hypothermia Vomiting ADH release Sensation of itching 7. Metabotropic receptor Protein coupled receptor . GLUTAMATE (ASPARATE) It is the most abundant amino acid in the brain and is concentrated in dorsal sensory nerve terminals It is an important excitatory neurotransmitter in dorsal root afferent and at other sits in CNS It depolarizes spinal motor neurons and cortical neurons by increasing Na permeability of the membrane Receptor 1.
Inotropic receptor Legend gated ion channels There are 3 subtypes of receptors In this NMDA ( N.methyl-d-aspirate) are important This receptors play important role in memory and learning 3. stress. neurotexicity. SUBSTANCE – P It is a neuropeptide that acts as a neurotransmitter It is a polypeptide with 11 amino acid residues It belongs to a family called neurokinins The substance p is secreted by the nerve endings of pain pathway in spinal cord It also found in hypothalamus retina and intestine It mediates pain sensation It is a potent vasodilator in CNS It is also responsible for regulations of anxiety. mood disorders. GLYCINE It is inhibitory neurotransmitter It is formed and released by inhibitory inter-neurons which act on motor neurons in the brain and spinal cord In the spinal cord it is responsible for direct inhibition It acts by increasing Cl permeability Site of secretion Fore brain. spinal cord and retina Gyycine concentration in the ventral grey matter of the spinal cord is higher than any other amino acids 9. nausea and vomiting . m – GLU 8. brain stem.33 Mainly involved in production of synaptic plasticity 2.
Psychic dependence 1.34 10. that is withdrawal produce specific symptoms characteristic for each drug type .neuronal cells like the endothelial cells of blood vessels From the site of production it diffuses into the neuronal and non-neuronal cells where it exerts its action It also produced in the brain and is responsible for long term protestation LTP and long term depression (opposite of LTP) NO is synthesized from arginine by action of enzyme NO synthetics It activates guanyl cyclase in cells. A person may be dependent on one or more drugs Drug dependence is of two types namely 1. producing c GMP which brings about relaxation of vascular smooth muscle NO acts as a mediator for the dilator effect Ach on small arteries It indirectly causes dilatation of arterioles NO is inactivated by haemoglobulin NO is released by variety of agents such as Ach. characterized by a compulsion to take the drug continuously or periodically in order to experience the psychic effects of well being or to avoid the discomfort of its absence. Physical dependence 2. atherosclerosis and impotency Drug dependence Drug dependence means a state of physical or psychic or some times both . Physical dependence It is an adoptive state which causes intense physical disturbance when the administration of the drug is stopped These disturbances . sudden increase in tissue blood flow and products of platelet aggregation NO deficiency produces hypertension . NO It is a neurotransmitter in the CNS It is produced by non.
tobacco. methaqualone and meprobamide 6. barbiturates. chlorolhydrates. betel leaves and nutmegs Problems of drug dependence Mere dependence on drugs itself is a problem as it necessitates the use of drugs continuously even though they are not required therapeutically Dependence on caffeine is condonable. Psychic dependence Here there is a feeling of satisfaction and a psychic drive that requires periodic or continuous use of the drug to produce a sense of well being or to avoid discomfort Psychic dependence is specific and it varies with the individuals and with the drug The following drugs are produce drug dependence 1. acetone and carbon tetrachloride 7. Heroin . Socio-cultural problems are that the drug dependence may cause loss of earning capacity of the drug user . The individual problems are that the drugs may adversely affect the physical and mental health of the addict 2. Volatile solvents like toluene. Alcohols . synthetic drugs like pethidine and methadone 3. Opium drugs 2. Caffeine. codeine. Coca leaves and cocaine 4. Dependence on tobacco is avoidable dependence Where as dependence on alcohol has to be condemned and legally prevented The problems associated with drug dependence are of three types 1.35 It may produce tolerance 2. Cannabis—Ganja. chars and hashish 5. diazepam. chlor. Morphine .diazapoxide.
This is development tolerance for alcohol Drugs also follow the same rules Some times tolerance is observed even when drug is administered for the first time Tolerance can be classified into 1. Socio-legal problem is prohibiting and controlling the traffic in such dangerous drugs. Acquired tolerance It is the development of tolerance after a prolonged or rapid or excessive use of drugs . Natural tolerance It is the presence of tolerance without prior exposure to the drug The effect of drug in a few individuals or few species are less in magnitude from the very first exposure to drug Ex Some individuals require more amount of anticoagulants as compared to normal therapeutic doses. this effect is reduced To get the same effect. The reasons are usually genetic 2. one has to consume more amount of alcohol.36 3. Further the smuggling of dangerous drugs is to be considered as criminal activity Tolerance Def Tolerance is the requirement of more amount of drug to produce specific response Concept of can be explained in easiest possible way with the example of effect of alcohol Specific quantity of alcohol produces a certain effect in CNS After periodic consumption of alcohol the same quantity of alcohol the same can not produce the same effect. Natural tolerance 2. Acquired tolerance 1.
Enzyme induction Alcohol induces hepatic microsomal enzymes that are required for its own metabolism So long term use of alcohol results in faster metabolism and elimination and reduced action of alcohol . it is cross tolerance for another drug Such two drugs are usually similar in either structure or in function Ex . Internalization of receptor After prolonged exposure to agonists some receptors are taken inside the cell and they remain unavailable for action 3.Down regulation of receptors It is the decrease in number and sensitivity of receptors for an agonist after prolonged exposure to it 2. the store of nor adrenaline is exhausted and effect of ephedrine is reduced Clinical implications of tolerance Previous prolonged exposure to drug can produce clinical effects that are less than what are expected Development of tolerance when demands increase in doses. decision is not very easy. Because tolerance for effect may not be associated with tolerance for side effects Cross tolerance If prolonged use of one drug results in development of tolerance for another drug. Tachyphylaxis It is the development of tolerance after repeated administrations of a drug Ex Ephedrine stimulates release of stored nor adrenaline from the nerve endings After repeated administrations of ephedrine.37 Mechanism for development of acquired tolerance 1.
poisons are consumed regularly and in small quantities to develop tolerance against them . This type of logic is not scientifically proved DISTRIBUTION .38 Prolonged exposure to barbiturates results in development of tolerance for hypnotic agents Pseudo tolerance From the prehistoric period.
40 METABOLISM .
43 UNIT – 2 .
44 NEURO-HUMARAL TRANSMISSION .
the plasma membrane of the postsynaptic cell In presynaptic neurons Ex Neurotransmitter synthesis and storage in vesicles Synaptic cleft physical space between the cells is known as synaptic cleft Postsynaptic cells can be neurons or other cells( effecter cell in the muscle) At synapse. decrease or inhibition or modulation of neuron activity or biochemistry On postsynaptic membranes Ex Binding to receptors.45 Synaptic transmission involves many steps Synapse It is a region including the axon terminal of a presynaptic neuron. change in ion channel function In postsynaptic neurons Ex Effect on second messenger transduction Stimulations of enzymes Physiological action Communication (transmission of information) across synapses occurs via chemical messengers – neurotransmitters. increases or excitation . electrical transmissions –action potentials along presynaptic neurons are translated into chemical signals which lead to postsynaptic cell responses.stored in vesicles in presynaptic neurons .
and active reuptake into presynaptic neurons Major peripheral neurotransmitters are acetylcholine .46 Action potentials at presynaptic axon terminals initiate steps that release neurotransmitter molecules into a synapse which cross the synaptic cleft and bind reversibly to postsynaptic receptors Receptor activators (ex drugs) are agonists and antagonists are drugs that combine with but do but activate receptors Transmitters are removed form synapses by enzymatic destruction m diffusion. or serotonin and neuropeptides are other neurotransmitters Neurohumoral transmission implies that nerves transmit their message across synapses and neuroeffector junctions by the release of humeral messengers Neurohumoral transmitters substance must fulfill the following criteria 1. major excitatory neurotransmitters are glutamate and aspirate Major inhibitory neurotransmitters are GABA and glycine 5 –HT. It should be released in the medium following nerve stimulation 3. It should be present in the presynaptic neurons ( usually along with enzymes synthesizing it) 2. Its application should produce response identical to those produced by nerve stimulation .catecholamine(ephedrine and dopamine) In brain and spinal cord .
Postjuctional activity 5.47 4. Transmitter release 3. Transmitter action on postjunctional membrane 4. Its effects should be antagonized or potentated by other substances which similarly alter effects of nerve stimulation Steps in Neurohumoral transmission 1. Impulse conduction The resting Tran membrane potential (70 mV negative inside) is established by high K permeability of axonal membrane and high axoplasmic concentration of this ion coupled with low Na permeability and its active extrusion Stimulation or arrival of an electrical impulse causes a sudden increase in Na conductance—depolarization and overshoot ( reverse polarization – 20 mV positive) K ions then move ort in the direction of their concentration gradient and repolarization occurs Ionic distribution is normalized during the refractory period by the activation of Na-K pump The action potential generated sets up local circuit currents which activate ionic channel at the next excitable part of the membrane ( next node of Ranvier in myelinated fiber ) and the AP is propagated without decrement . Impulse conduction 2. Termination of transmitter act ion 1.
Postjunctional activity . enzymes and other proteins)are extruded in the functional cleft 3. so that K moves out and CL moves in (in the direction of their concentration gradients ) resulting in hyper polarization 4. through Ca entry which fluidizes membranes All contents of the vesicle ( transmitter.48 Transmitter release The transmitter (excitatory or inhibitory) is stored in prejunctional nerve endings within synaptic vesicles Nerve impulse promotes fusion of vesicular and axonal membranes. Transmitter action on postjunctional membrane The released transmitter combines with specific receptors on the postjunctional membrane and depending on its mature induces an excitatory postsynaptic potential (EPSP) or (IPSP) an inhibitory postsynaptic potential EPSP It increase in permeability to all cations –Na or Ca influx ( through fast or slow channels) causes depolarization followed by K efflux These ionic movements are passive as the flow is down the concentration gradients IPSP It increase in permeability to smaller ions That is K and Cl ( hydrated K ion is smaller than hydrated Na ion) only.
49 A suprathreshold EPSP generates a propagated postjunctional AP which results in nerve impulse ( in neuron), contraction ( in muscle ) or secretion ( in gland) IPSP stabilizes the postjunctional membrane and resists depolarizing stimuli
5. Termination of transmitter action
Following its combination with the receptor ,the transmitter is either locally degraded (ex Ach) or is taken back into the prejunctional neuron by active uptake or diffuses away (ex NA, GABA) Rate of termination of transmitter action governs the rate at which responded can bet transmitted across a junction (1 to1000 /sec)
1. Choline esters
Acetyl choline Methacholine - 10-30 mg , s/c Carbachol- 0.2 – 0.5mg s/c , or 1-4mg , orally Bethanechol- 2.5 mg s/c, 5 -30 mg orally
2. Naturally occurring alkaloids
Polocarpine Muscarine Arecholine
3. A . Cholinesterase inhibitors
Physostigmine Neostigmine Pyrodostigmine Benzpyrinium Ambenonium Edrophonium Demecarium
3. B Cholinesterase inhibitors (irreversible ) or organ phosphorus compounds
DFP –(Di-iso-propyl fluorophosphate) HETP- (Hexa ethyl tetra phosphate) TEPP – (Tetra ethyl pyrophosphate) OMPA – Octa methyl pyrophosphoramide)
both the sympathetic and parasympathetic ganglia 2. glands .All the preganglionce fibers of ANS I.Brain and spinal core . Skeletal muscles – Somatic nerve endings supplying skeletal muscles 5. is an important neurotransmitter of the ANS The nerves that synthesize. smooth muscles. The postganglionic nerve fibers of parasympathetic nerve endings 3.e. CNS . eyes and CNS Five subtypes of muscarinic receptors – M1 to M5 are recognized Nicotinic receptors are present in the neuromuscular junction. Ganglia . Sweet glands – The sympathetic postganglionic nerve endings supplying the sweet Glands 4.53 Cholinergic system Acetyl choline (Ach) an ester of choline. Adrenal medulla 6. autonomic ganglia and adrenal medulla Two subtypes of nicotinic receptors are identified Nm receptors are present at the skeletal muscle end plate and Nn receptors at the autonomic ganglia and adrenal medulla 1. store and release Ach are called cholinergic The site of release of Ach is Cholinergic receptors There are two classes of cholinergic receptors They are nicotinic and muscarinic receptors Muscarinic receptors are present in the heart.
ganglia and neuromuscular junction Pseudo cholinesterase . smooth muscles CNS CNS Muscarini c Receptor Nicotinic Subtypes Location Nm Nn Neuromuscular junction Autonomic ganglia Adrenal medulla.54 Synthesis of Ach Acetyl choline synthesized from acetyl coA and choline . smooth muscles Glands . CNS Heart.In plasma. catalyzed by the enzyme choline acetyltransferase This Ach is stored in small oval vesicles known as synaptic vesicles in the cholinergic nerve terminals Transmission of an impulse When as action potential reaches the presymaptic membrane. gastric glands. liver and other organs Receptor Subtyp e M1 M2 M3 M4 M5 Location Autonomic ganglia . Ach is released into the synaptic cleft This Ach binds to and activates the cholinergic receptor on the postsynaptic membrane leading to the depolarization of this membrane Thus the impulse is transmitted across the synapse The Ach released into the synaptic cleft is rapidly destroyed by the acetyl cholinesterase enzyme Then the postsynaptic membrane is repolarised Cholinesterase Acetylcholine is hydrolyzed to choline and acetic acid by the enzymes cholinesterase Two types of Ach enzymes are present True cholinesterase .at neurons. nerves. CNS .
55 Cholinergic receptor .
Semi-synthetic substitutes of belladonna alkaloids Homatropine Atropine methyl nitrate Scopolamine methyl bromide Homatropine methyl bromide 3. Belladonna alkaloids Atropine Scopolamine 2. Synthetic substitutes of belladonna alkaloids Methamtheline Propantheline Oxyphenonium Dibutoline Cyclopentolate .56 Parasympatholytic drugs 1.
Alpha receptors Noradrenalin Mephentermine Metarminol Methoxamine Phenylephrine 2. Beta receptor Isoprenaline Isoxsuprine Nylidrine 3.57 Sympathomimetic drugs Classification as per their site and mode of action 1. Acting on both alpha and beta receptor Adrenaline Ephedrine Amphetamine .
58 ANERGIC RECEPTOR .
61 Sympathetic blocking agents 1. Alpha -1 blockers Prazosine B. Alpha – 2 blockers Yohimbine C. Both alpha1 and alpha-2 blockers Phenoxybenzamine Dibenamine Tolazoline Phentolamine Ergot alkaloids 11. Beta adrenergic blocking agents A. Alpha adrenergic blocking agents A. Both beta-1 and beta-2 blockers Propranolol Sotolol Nodolol Timolol . Beta -1 blockers Atenolol Acebutolol Metaprolol B. Beta-2 blockers Butoxamine C.
3 Adrenergic neuron blocking agents Guanethidine Guanoxon Guanachlor Bethanidine Debrisoquine sulphate .62 UNIT .
63 Ganglionic stimulating agents Drugs can act on sympathetic and parasympathetic ganglia producing either stimulation or blockade Ganglionic stimulants have extremely limited therapeutic application But ganglion blocking agents are effective in the treatment of hypertension Though the ganglionic stimulating agents have no therapeutic use. they find use as experimental tools Classification 1.ammonium (TMA) Di-methyl-phenyl. Natural alkaloids Nicotine Lobeline 2. Synthetic compounds Tetra-methyl.piperasinium (DMPP) .
64 Ganglionic blocking agents 1. Non selective muscarinic agonists Acetylcholine Carbachol Pilocarpine Anticholinesterases . Selective blocking agents Nicotine Lobeline Dim ethyl phenyl piperazinium iodide (DMPP) Tetra methyl ammonium (TMA) 2.
Tunocurarine Gallamine Pancuronium Alcuronium Atracurium Vecuronium 2. Depolarizing agents Succinylcholine .65 Neuromuscular blocking agents 1. Competitive agents D.
Surface anesthetics A. Insoluble Benzocaine Butamben Oxethazaine . Injectable A. Short Duration Of Action Procaine Chlo-procaine B. long duration Tetracaine (Amethocaine) Cinchocaine Bupivacaine Ropivacaine 11. Soluble Cocaine Lignocaine Tetracaine B. High potency.66 Local anesthetics Def Local anesthetics are drugs that block nerve conduction when applied locally nerve tissue in appropriate concentrations 1. Intermediate potency and duration Lignocaine (Lidocaine) Prilocaine C. Low Potency.
joined by an intermediate chain through an ester or amide linkage Local anesthetics are weak bases and the infected tissues have a low extra cellular PH Local anesthetics ionize in such medium bases and the infected tissues have a low extra cellular PH Local anesthetics ionize in such medium and a very low fraction of non-ionized LAs available for diffusion into the cell So LA are much less effective in infected tissues Action potential If enough Na channels are opened. dendrites. then the rate of Na entry into the axon exceeds the rate of K exit .67 The action is completely reversible They act on every type of nerve fiber and can cause both sensory and motor paralysis in the innervated area They act on axons. cell body . Lignocaine was synthesized and it continues to dominate the field till today Chemistry Local anesthetics are bases and consist of a hydrophilic amino groups on one side and a lopophilic aromatic residue on the other side . synapse and other excitable membranes that utilize sodium channels as the primary means of action potential generation Cocaine was the first agent to be isolated by Niemann in 1860 and used for 30 years Procaine was synthesized in 1905 and it rules the field for the next 50 years In 1943 .
temperature sense. impulse conduction slows. pressure and vibration sensations in the same order Sensory and motor fibers are equally sensitive Non – myelinated fibers are blocked more readily than the myelinated Pharmacological actions . AP amplitude decreases and finally the ability to generate an AP is abolished These result from binding of LA to more and more Na channels So it prevents the generation of an AP and its conduction The small fibers are blocked first That is autonomic fibers are blocked first followed by sensory fibers conducting pain. then touch. the Na channels regain their normal excitable state and the Na pump restores the lost K and removes the gained Na ions Mechanism of action Local anesthetics prevent the generation and the conduction of nerve impulses The primary mechanism of action is blockade of voltage – gated sodium channels Local anesthetics directly interact with specific site or receptor on voltage – sensitive Na channels and gradually raise the threshold for excitation With increasing concentration.68 Threshold potential At the point where the rate of Na entry into the axon exceeds the rate of K exit that point is called threshold point or threshold point At the this point. resulting in further depolarization that opens more Na channels and so on. Inactivation of the Na channels and the continuing efflux of K ion cause the repolarization of the membrane Finally. rate of rise of AP declines. the entry of Na ions further depolarizes the membrane This opens more Na channels. The fast inward Na current quickly depolarizes the membrane towards the Na equilibrium potential around + 70 m V Then.
unconsciousness . bitter taste is lost firs followed by sweet and sour and salty taste If it is given with adrenaline through injection route. Other effects They produce relaxant effect on smooth muscles and neuromuscular blockade They relax the vascular and brachial smooth muscles Pharmacokinetics These are rapidly absorbed from the mucous membranes and abraded skin Rate of absorption is dependent on the vascularity of the area .tremor and twitching of muscles . they increase the effective refractory periods similar effect of the quinidine so used in the arrhythmias 4.death in a dose dependent manner Procaine and lignocaine are synthetic compounds and much less potent in this regard 3.respiratory depression . the adrenaline reduces the systemic toxicity of local anesthetics because it reduces the rate of absorption and metabolism keeps the plasma concentration lower and increase the activity when exactly the action is required 2.69 1.restlessness . CVS All local anesthetic except cocaine produce vasodilatation and hypotension But cocaine produces vasoconstriction and so a hypertensive effect All LA produces depressant effect on the myocardium.touch They produce blockade of smaller nerve fibers initially followed by large nerve fibers Recovery occurs in the reverse order Applied to the tongue.convulsions . Effect on sensation They cause the reversible loss of sensory perception The order of blockade is pain. CNS They produce sequence of stimulation followed by depression cocaine is a powerful CNS stimulant causing in sequence Euphoria – excitement .temperature.mental confusion .
fissures and ulcers Infiltration anesthesia to anaesthetize nerve endings by subcutaneous infiltration Nerve block anesthesia where I t is injected close to specific nerve Spinal anesthesia where it is injected close to specific nerve Systemic use for anti. hypotension. tremors. mental confusion. twitching. dermatitis . benzocaine and amethocaine Cocaine It is an alkaloid obtained from the leaves of coca plant .arrhythmic affect Some of the important drugs which possess this action are cocaine. shivering. angioedema. dizziness. asthma and rarely anaphylaxis CVS Effects Like light headedness. procaine. auditory and visual disturbances .lignocaine.70 The vasoconstriction decreases the absorption Toxicity depends on the balance between absorption and metabolism That is if it gets metabolized as it gets absorbed. cardiac arrhythmias and vascular collapse Rarely cardiac arrest is seen USES Surface anesthesia or pain due to burns. disorientation. then toxicity is less They are usually administered through the subcutaneous route They are metabolized in the liver and excreted in the kidney Adverse effects Hypersensitive reactions like skin rashes. finally convulsions and reparatory arrest CVS Effects The effects like bradycardia.
71 It is insoluble in water but its salts are soluble in water It is poorly absorbed in the intestines but well absorbed by the mucous membrane and it can be given as surface anesthetic Actions Local anesthetic action CNS stimulants Dilates pupil Raise the body temperature Rise the BP Produces euphoria Toxic effects Mental excitement Confusion Tremors Convulsions Respiratory paralysis Dose 8 – 16 mg by injection Adrenaline has to be given along with cocaine which produces local vasoconstriction and prolong the local anesthetic effect Procaine It is synthetic product having local anesthetic effect .
72 Administration – It I snot absorbed by mucous membrane and hence has to be given by injection It rapidly diffuses from the site of injection and vasoconstrictors like adrenaline as to given , to prolong the effect of procaine
0.25 - 2% solution is injected subcutaneously For spinal anesthesia it is still popular It is injected into the spinal theca to block spinal nerves and to produce spinal anesthesia
Lignocaine ( Lidocaine or xylocaine)
It is an active surface anesthetic and also efficient on injection This is more powerful and more stable and longer acting than procaine
Toxicity is very low It is injected as a 0.5% to 2% solution Duration of action is about 15- 45 min I fit is combined with adrenaline the effect will last for about two hours It can also be used in the treatment of status epilepticus and acute ventricular arrhythmia
This is a local apathetic employed as an application to various mucous surfaces It is incorporated in throat lozenges to relieve the local soreness and is used in rectal suppositories
This is a more powerful anesthetic than procaine It is well absorbed form mucous membrane and is often used in t he form of spray or lozenges to anaesthetize the throat before various manipulations But toxic effects are same as procaine
UNIT - 4
General anesthetics are drugs which produce reversible loss of all sensation and consciousness
Conditional feature of General anesthetics are
Loss of all sensation. Specially pain Sleep ( unconsciousness) and amnesia Immobility and muscle relaxation Abolition of reflexes
1. Inhalation anesthetics A. Gas
Nitrous oxide Cyclopropane Ethylene
Ether Chloroform Halothane Ethyl chloride Vinyl ether
11. Intravenous anesthetics
Thiopentone Methohexitone Ketamine Paraldehyde
Ether ( Di-ethyl ether )
It is one of the oldest anesthetic agents in use It is a colorless and volatile liquid with a pungent odor It is highly inflammable and explosive
74 It is quickly absorbed and eliminated through lungs
5-10% of ether is required in the inspired air to induce anesthetic and at least 3-5% to maintain it It irritates respiratory tract leading to efflux secretion of saliva and mucous from the mouth and respiratory tract So atropine should be given at least half an hour before to paralyses secretion The initial stages are more prolonged with ether in the absence of premeditation
Ether does little damage to the heart It increases cardiac output and coronary blood flow The rate and depth of respiration may be increased It does not cause any damage to liver
It is safest agent . It can be used even by a nurse It produces analgesia It produces skeletal muscle relaxation It produces less inhibition of respiratory centre than other unaesthetic agents It does not effect the blood pressure It dies not interfere with liver or kidney functions It can be given by all techniques
It catches fire Induction of anesthesia as well as Recovery are slow Vomiting is likely to occur postoperatively Generalized convulsions are produced specially in children
It is a volatile liquid having a powerful anesthetic property It is a colorless non-inflammable volatile liquid with a sweetish smell It produces server toxic effects on the liver and heart It is not used at present
75 Actions Anesthesia is induced by the open drop method or by closed circuit method 2% of chloroform is required in the inspired air to induce anesthesia and about 0. colorless liquid.5% for maintenance of anesthesia Other action In addition to general an aesthesia. externally it is used as a rubefacint Internally it is used as a carminative It is used as a vehicle in mixtures Advantages It does not irritate respiratory tract Muscular relaxation is good Recovery is accompanied by less nausea and vomiting than with ether It is non inflammable Induction is rapid and pleasant Disadvantages Chloroform depresses myocardium resulting in slowing down of the heart and even cardiac arrest It depresses the respiratory centre Liver function is affected leading to necrosis and hepatic failure and death Intestinal motility is diminished Margin of safety is very less Blood concentration of about 15 mg% is required to maintain anesthesia but about 20-25 mg% is fatal Halothane Physical properties It is heavy. anesthetic agent It is non inflammable. non toxic fluorinated hydrocarbon .
. fruity odor Recovery is also fast .copper. rubber Advantages Induction is very smooth as it has sweet . and can be used in patients with bronchial asthma Dis advantages Muscular relaxation is inadequate It causes respiratory.76 It has sweet . fruity odor and boils It affects most of metals including stainless steel . cardiovascular depression Mental recovery is delayed Shivering during recovery is very common It is poor analgesic It is expensive. smooth with low incidences of nausea and vomiting It is not inflammable and hence does not irritate respiratory passage inhibits salivary secretion hence endotracheal intunotion is much easier It does not produce bronchospasm. needs special apparatus for administration Nitrous oxide Properties It is also called as laughing gas It induces laughing in the patient under the anesthesia .
non toxic fluorinated hydrocarbon It has sweet. means it requires 90% concentration to produce complete anesthesia Causes cyanosis It produces excitation and euphoria Uses It is used for short duration operations such as tooth extraction or setting right a fracture It is used along with the oxygen for producing partial anesthesia following basal anesthetics Halothane Physical properties I t is heavy . anesthetic agent It is non inflammable . brass. fruity odor and boils at 50 C It effects most of metals including stainless steel. colorless liquid.77 It is colorless gas with sweet odor and taste It is non inflammable Advantages Induction and recovery are quick Irritation is less Does not produce vomiting and cardiovascular collapse It is not toxic to liver and kidney Disadvantages It dies not produce muscular relaxation It is not potent. cupper and rubber .
cardiovascular depression Mental recovery is delayed Shivering during recovery is very common It is poor analgesic It is expensive .78 Advantages Induction is very smooth as it has sweet . special apparatus for administration Intravenous anesthetics Barbiturates are generally used as intravenous general anesthetics for short term operations Of these Thiopentone and hex baritone are the drugs of choice being given by the slow route to avoid respiratory arrest Advantages Easy to administer Induction is rapid and smooth Past anesthetic complications are rare Recovery is very fast Respiratory and myocardial functions remains unaffected No irritation of respiratory passage Less excitement and vomiting . smooth with low incidences of nausea . hence can be used in patients with bronchial asthma Disadvantage Muscular relaxation is inadequate It causes respiratory. larygospasm.needs. vomiting It is not inflammable and hence does irritate respiratory passage inhibits salivary secretion hence end tracheal intubations is much easier It does not produce branch spasm.fruity odor Recovery is also fast.
79 Non-expensive Pre-medication is not needed Disadvantages Usual stages of anesthesia are not clear Muscular relaxation is very poor Poor analgesia Short duration of action Coughing apnea is common during induction Preparations Thiopental sodium Methohexitone Propanidid Ketamine --------2.2mg/Kg General anesthetics General anesthetics are the drugs which are used to produce complete loss of sensation to allow the surgical operations to be performed without the sensation of pain to the patient General anesthetics depress the sensory as well as motor nerves and produce loss of sensation which is reversible The common method of inducing anesthesia is by inhalation. intravenous .5% solution 1% solution 4mg/Kg 1. smoothly and easily controllable BP should remain normal When discontinued the anesthetic should be eliminated quickly without harming the tissues . spinal and rectal anesthesia are also used Requirement of an ideal anesthetic Administration should be easy without requiring complicated apparatus Anesthesia must be induced rapidly.
pupils are dialate and pulse rate is quick 2. Stage of modularly depression or respiratory paralysis 1.80 It should produce adequate muscular relaxation with complete motor and sensory paralysis Stages of anesthesia Induction of general anesthesia is divided into four stages according to the deapth of CNS depression All these stages are continuous but described separately for the sake of clarity Four stage of anesthesia are 1. Stage of surgical anesthesia 4. reflex secretion of mucous and saliva with coughing and sneezing are noticed Muscle are stiff. Stages of induction There is a sensation of warmth and suffocation . Stages of surgical anesthesia . Stage of excitement 3. Stage of induction 2. Stage of excitement Blunting of consciousness occurs There will be loss of self control and motor excitement Pulse rate is rapid Respiration becomes irregular and fast Pupils are dilated and active Sensory nerves cells are paralyzed first but motor reflexes are still present There is a gradual unconsciousness 3.
there will be a fall in body temperature This stage is suitable for surgical operations to be performed as all the motor reflexes are abolished and the muscles are relaxed fully 4.81 Here complete paralysis of the enters of cerebral cortex and Spinal reflexes commences This is reversible Muscles are relaxed . coughing. pulse becomes weak and blood pressure falls. pulse is slow and regular. respiration becomes slow Pupils are contracted Eye balls are fixed. it is thought to be their primary site of action . Stage of modularly depression The modularly centers are gradually depressed There is deep unconsciousness Respiration becomes slower and slower Pupil are dilated and inactive . acute vomiting may occur just before returning to consciousness This is commonly succeed by natural sleep lasting for several hours Mechanism of action Reticular activating system This is a complex polysynaptic pathway in the brainstem reticular formation that projects diffusely to the cortex Activity in the RAS is concerned with maintaining consciousness and because it is sensitive to the depressant action of anesthetics. Finally respiration stops leading to the arrest of the heart and death Recovery from the anesthesia Soon after the removal of the anesthetic the respiration becomes quieter and less strenuous The eye lid and deglutition movements reappear Pupils dilate.
the phenomenon is termed as preanaesthetic medication Aim To induce sedation To decrease gastric secretion To minimize pre and post operative complications To facilitate smooth and rapid induction To overcome secretary effects of general anesthetics To decrease vagal stimulation and secretions Supplement analgesic actions to potentate anesthetics so less anesthetic is needed Drugs used in preanaesthetic medication are 1. at clinically effective concentration of the drug This causes a prolongation of the inhibitory chloride ion current after a pulse of GABA release.amonobutyric acid (GABA A) receptors to the neurotransmitter. Postsynaptic neuronal excitability is thus diminished Others receptors are also affected by volatile anesthetics Ex The activity of the inhibitory glycine receptors in the spinal motor neurons is increased The inhalation anesthetics block the excitatory postsynaptic current of the nicotinic receptors Pre-unaesthetic medication The pharmacological agent when administered externally with an important objective to make anesthetic more smooth and agreeable for patient . GABA.82 The general anesthetics increase the sensitivity of the gamma.Opiods Ex .
Sedatives Ex Diazepam or lorazepam Ant anxiety drugs –for smooth induction 3. Neuroleptics Ex Chlorpromazine To smooth induction and anti-emetic action 5.83 Morphine To produce analgesia 2. pethidine Phenobarbitone. Anti-cholinergic Ex Atropine To reduce salivary and bronchial secretions 4. Anti-emetics Ex Metaclopramide To reduce post operative vomiting S No 1 2 3 Type Opoid analgesic Barbiturates Anxiolytic Drug Morphine. H2 Blockers Ex Ranitidine To prevent the ulcer formation 6.30 mg 30mg 5mg . secobarbitone Diazepam Dose 15.
propylene glycol 3. sorbitol Ethyl alcohol Ethyl alcohol is commonly used alcohol It is the main constituent of all kinds of alcoholic beverages It is generally obtained by fermentation of sugars by yeast The alcohol is separated by simple distillation It is a colorless. ethyl and propyl alcohols 2. volatile and inflammable liquid .6mg 10mg Alcohols Alcohols are aliphatic hydrocarbons They contain one or more hydroxyl groups Classification 1. Poly-hydroxy alcohols Mannitol. Dihydroxy alcohols Ethylene glycols. Mono-hydroxy alcohols Methyl. Tri-hydroxy alcohols Glycerol or glycerine 4.emetic Anti-secretary Skeletal muscle relaxants Promethazine Atropine D-tuocurarine 30mg 0.84 4 5 6 Anti.
a germicidal and an irritant 2. it acts as antiseptic . if injected .85 The alcohol content of various beverages varies between 4-55% by volume Wines containing more than 16% of alcohol Beer contains 4-6 % (v/v) of alcohol Stronger preparation are called Spirit Mechanism of action Alcohol produce CNS depression by a generalized membrane action by altering the state of membrane lipids Alcohol promotes GABAA receptor mediated synaptic inhibition (through chloride channel opening ) as well as inhibits NMDA and type of excitatory amino acid receptors (operating thorough captions channels) Alcohol can indirectly reduce neurotransmitter release by inhibiting voltage sensitive neuronal calcium channels Blockade of adenosine uptake by alcohol could also contribute to synaptic depression The activity of membrane bound enzymes like Na – K ATPase and adenyl cyclase is also altered The activity and translocation of channel or enzyme proteins in the membrane could be affected by alcohol through protein kinase C and protein kinase A mediated alteration in the state of their phosphorlation Pharmacological actions 1. the action is seen only against vegetative forms of organism and spores are resistant Concentrated alcohol . it act as rubifacient and mild irritant action In concentration of 70% . produces tissue destruction Higher concentration denature proteins by partial precipitation and dehydration In such concentration . it acts as an astringent. it increases salivary secretion by reflex action . GIT If taken orally . Externally It evaporates quickly and producing cooling effect and is used for reducing the temperature in fevers It is used in shaving lotion for producing cooling effect on the skin In concentration of 40.50.
vomiting and other symptoms Many alcoholics suffer from gastritis and chronic achlorhydria Many alcoholics suffer from chronic diarrhea as a result of malabsorption from chronic mucosal damage 3. nausea. On respiration Moderate doses produce slight stimulation whereas large doses produce respiratory depression which may be fatal .P is not affected Moderate doses cause tachycardia and a mild rise in BP due to increased muscular activity and sympathetic stimulation Large doses cause direct myocardial as well as vasomotor centre depression and there is fall in BP Chronic alcoholism may contribute to hypertension and lead to cardiomyopathy Atrial fibrillation and other cardiac arrhythmias may occur due to conduction defects and Q-T prolongation 5.by releasing histamine and gasstrin from the antrum of the stomach Concentration above 15% inhibit both motility and secretion and effect may persist for many hours Concentration above 20% reduce the enzymatic activity of the gastric and the intestinal juices Concentration above 40% and over have a direct toxic effect on gastric mucosa and may precipitate gastritis. giving rise to pain. CNS It is primarily a CNS depressant and acts by enhancing the inhibitory GABA receptor activity or inhibiting NMDA receptors Proteins are the primary site of its actions It produces initial excitation due to depression of higher inhibitory centers This is followed by progressive depression. CVS Small dose produce only cutaneous and gastric vasodilatation B. sleep and unconsciousness as the dose is increased Sudden withdrawal of alcohol causes excitation and hyperactivity of the CNS 4.86 It has an irritant action on the gastric mucous membrane and act as appetizer 50 ml of 7-10% alcohol increases the gastric secretion . drowsiness.
87 6. Skeletal muscle . Aggressive sexual behavior is due to loss of inhibitory control It also provokes the sensation but takes away the performance Chronic alcoholism can produce impotence. but heat loss is increased in cold surroundings High intake of alcohol produces depress temperature regulating centre 9. Body temperature Alcohol produces a sense of warmth due to cutaneous and gastric vasodilatation . Kidney Diuresis is often notified after alcohol intake It is due to depression of ADH production It does not impair renal function 7. Liver It produces fatty liver on chronic administration It mobilize peripheral fat and increases fat synthesis in liver Proteins may also accumulate in liver because their secretion is decreased Acetaldehyde produced during metabolism of alcohol appears to damage the hepatocytes on chronic ingestion of large amounts Increased lipid peroxidation and glutathione depletion occurs Regular alcohol intake induces microtonal enzymes 10. gynaecomastia and infertility 8. Sax Alcohol is reputed as an aphrodisiac.
but muscle work is increases or decreased Weakness and myopathy occurs in chronic alcoholism 11. Fatigue is produced by small doses.88 Alcohol produces little direct effect. fate and excretion Alcohol is absorbed in the stomach (25%) and 75% in small intestine It is metabolized in the liver as follows Alcohol dehydrogenase Ethyl alcohol -------------------------------------------------------Acetaldehyde Aldehyde dehydrogenase Acetaldehyde-------------------------------------------------------------Acetyl CoA Acetyl CoA is further metabolized to carbon dioxide and water Alcohol is eliminated mostly through kidneys and lungs Toxicity Side effects of moderate drinking Nausea. hangover. flushing. respiratory depression Coma and death Treatment . traffic accidents Acute alcoholic intoxication Fall in body temperature Hypotension gastritis hypoglycemia Collapse. Blood Regular intake of small to moderate amounts has been found to raise HDL levels and decrease LDL oxidation Megaloblastic anemia has been seen in chronic alcoholism due to interference with folate metabolism Absorption . vomiting .
diazepam are the preferred drugs now These have a long duration of action and can be gradually withdrawn later Disulfiram It is a drug for the treatment of chronic alcoholism It is a inhibits the enzyme aldehyde dehydrogenaase So acetaldehyde is not converted into Acetyl CoA This leads to accumulation of acetaldehyde which produces nausea and vomiting . because food is neglected and malabsorption may occur Alcoholic cirrhosis of liver. stroke and skeletal myopathy are complications Treatment Psychological and medical supportive measures are needed during withdrawal Many CNS depressants like barbiturates .89 Gastric lavage maintain patent airway and take steps to prevent aspiration of vomit us Positive pressure respiration may be needed if it is markedly depressed Most patients will recover with supportive treatment. phenothiazines. chloral hydrate have been used as substitution therapy in the past to suppress withdrawal syndrome but benzodiazepines like chordiazepoxide. tolerance develops to subjective and behavioral effects of alcohol It is both pharmacokinetic and cellular tolerance Psychic dependence often occurs even with moderate drinking Physical dependence occurs only on heavy and round the clock drinking Heavy drinking is often associated with nutritional deficiencies. arrhythmias. maintenance of fluid and electrolyte balance and correction of hypoglycemia by glucose infusion till alcohol is metabolized Recovery can be hastened by haemodialysis Insulin + fructose drip has been found to accelerate alcohol metabolism Chronic alcoholism On chronic intake. CHF. hypertension. cardiomyopathy .
It is administered at a dose of 500 mg once daily for a week and alter 250 mg daily as maintenance dose When alcohol is ingested after taking disulfiram, the concentration of acetaldehyde in tissues and blood rises and a number of distressing symptoms (aldehyde syndrome ) are produced These are Flushing Burning sensation Throbbing headache Perspiration Uneasiness Tightness in chest Dizziness Vomiting Visual disturbances Mental confusion and circulatory collapse Duration of the syndrome (1-4 hours ) depends on the amount of alcohol consumed Disulfiram is used in chronic alcoholics who are motivated and sincerely desire to leave the habit Sensitization to alcohol develops after 2-3 hours of first dose and lasts for 7-14 days after stopping it ,because inhibition of aldehyde dehydrogenase with disulfiram is irreversible Synthesis of fresh enzyme is required for return of activity It should not be used in patients who are physically dependent on alcohol Side effect of disulfiram are Drowsiness Headache Cramps Rashes Metallic taste Nervousness Abdominal upset
Unit - 5
Hypnotics and sedatives
Hypnotics are drugs which produce sleep resembling natural sleep Sedatives are drugs which reduce excitement without producing sleep Qualitatively hypnotics and sedatives produce depression of CNS and the difference between them is mainly quantitative 1. Barbiturate derivatives 2. Non – barbiturate derivatives
1 .Barbiturate derivatives
A. Long acting barbiturates (8 -12 hours )
Phenobarbitone Mephobarbitone Methylphenobarbitone Barbitone
B. Intermediate acting barbiturates
Amylobarbitone Butobarbitone Allobarbitone Vinbarbitone
C. Short acting barbiturates
Pentobarbitone Secobarbitone Cyclobarbitone Hepatobarbitone
D. Ultra short acting barbiturates
Thiobarbitone Hexabarbitone Methobarbitone
11. Non –barbiturate derivatives
Chloral hydrate Chloral formamide Paraldehyde
Potassium bromide Sodium bromide Ammonium bromide
Ethyl alcohol Tribromo-ehamol Amylene hydrate
E. Piperidine derivatives
primarily because barbiturates induce tolerance. also there is hangover effect after awakening Analgesic effect . hypnosis and general anesthesia Sleep Barbiturate induced sleep resembles natural sleep But it decreases the time spent on rapid-eye movement sleep. physical dependence and severe withdrawal symptoms The barbiturates in severe doses produces coma Mechanism action of barbiturates The sedative – hypnotic action of the barbiturates is due to their interaction with GABA A receptors which enhances GABA nergic transmission The binding site of distinct from that of the benzodiazepines Barbiturates potentate GABA Acton on chloride entry into the neuron by prolonging the duration of the chloride channel openings In addition .93 Barbiturates o derivatives of barbituric acid which is obtained by condensation of urea and malonic acid Barbituric acid itself does not possess hypnotic activity but hypnotic activity is produced. they have been largely replaced by the benzodiazepines. if the hydrogen atoms at position 5 are replaced by alkyl or aryl groups The barbiturates were formerly the mainstay of treatment used to sedate the patient or to induce and maintain sleep Today . barbiturates can block excitatory glutamate receptors Anesthetic concentration of pentobarbital also block high frequency sodium channels All of these molecular action lead to decreased neuronal activity Pharmacological actions On CNS Barbiturates produce all degrees of CNS depression like mild sedation. drug metabolizing enzymes.
consultant effect Barbiturates like phenobarbitone which have a phenyl group at the 5 th carbon atom have anticonvulsant effect Respiration Respiration is not affected at sedative or hypnotic dose Large dose administered intravenously may produce death due to central respiratory paralysis GIT Intestinal motility is not affected at a normal dose. but gastric secretion may be depressed Uterus Force and frequency of uterine contractions are depressed at toxic dose Kidney No effect at normal dose but anesthetic dose decreases urinary output due to decrease in glomerular filtration and release of Ach Liver No effect at normal dose but anesthetic dose may produce hepatic dysfunction Enzyme induction Barbiturates induce P450 microsomal enzymes in the liver Chronic barbiturate administration diminishes the action of many drugs that a re dependent on P450 metabolism to reduce their concentration ADME .94 Barbiturates do not relieve pain without producing unconsciousness They enhance the analgesic effect of salicylates and para-amino phenol derivatives Anesthetic effect Thionarbiturates and some ultra short acting oxybarbriturates produce anesthesia on intravenous administration Anti.
95 Barbiturates can be administered by oral and parenteral routes They are distributed in all tissues and body fluids They cross placental barrier and also are excreted in milk They are chiefly metabolized in the liver and to a small extent in kidney and brain Excretion is through urine both in free form and as glucuronic acid conjugate Adverse reaction Intolerance like nausea. headache and diarrhea Fetal respiratory depression if administered during labor Drug automatism due to repeatedly taking the drug owing to forgetfulness Tolerance because of increased inactivation in the liver Dependence and withdrawal symptoms Therapeutic uses Sedation in case of anxiety or tension Hypnosis to relieve insomnia Anticonvulsant effect in case of tetanus or status epilepticus Pre anesthetic medication and to produce basal anesthesia Potentiation of analgesics like salicylates In psychiatric practice and in neonatal jaundice Benzodiazepines .
tolerance and dependence to the less extent and reparatory depression Chloral hydrate . leading to increase in the GABA activity GABA activating the chloride channels leading to increase in the Cl conductance and hence decrease firing of the regions Benzodiazepines produce increase in pre-synaptic inhibition .96 These are very important class of hypnotics and sedatives because of their high therapeutic index The important Benzodiazepines are Diazepam Flurazepam Nitrazepam Lorazepam Oxazepam Mechanism of action The GABA (Gamma amino butyric acid ) is acts as an inhibitory neurotransmitter in the body It acts on GABA receptors But the benzodiazepine receptor are associated with GABA receptors These benzodiazepines acts on GABA and stimulate the GABA receptors .hypnotic withdrawal symptoms As diagnostic aid for treatment in psychiatry Adverse effects Drowsiness. nor adrenaline and dopamine These also posses GABA agonistic activity Therapeutic uses In anxiety and insomnia As a pre-anesthetic medication Treatment of epilepsy and seizure states or muscular relaxation in spastic conditions In control of ethanol and sedative. impaired motor in co-ordination. decrease in turnover of 5HT. confusion.
trichloroethanol. gastric irritation.97 Chloral hydrate is a trichlorinated derivative of acetaldehyde . myocardial depression and arrhythmia Paraldehyde It is nauseating and volatile. It is converted to the active metabolite . respiratory and vasomotor depression . liquid hypnotic which is harmless and quick in Acton It is more potent than the chloral hydrate and polymer of acetaldehyde During labor it causes analgesic effect but it can cross placenta and may delay respiration in new born Higher doses may cause hypotension. respiratory depression and coma It can be used as anticonvulsant . hypnotic and basal anesthetic It is absorbed thorough the oral and parental administration It is excreted through the lungs with offensive smell It reacts with plastic materials so cannot administer with the plastic syringes Rectal administration cause irritation to mucosa of rectum an may cause ulceration Ethyl alcohol . in the body The drug is an effective sedative and hypnotic that induces sleep in about thirty minutes and lasts about six hours Chloral hydrate is irritating to the gastrointestinal tract and causes epigastric distress It also produces an unusual. unpleasant taste sensation It synergizes with ethanol It does not have the analgesic activity but may produce excitement and delirium in presence of pain Adverse effects Nausea. vomiting.
98 It has antianxiety and sedative effects . but its toxic potential outweighs its benfits Alcoholism is a serious medical and social problem Ethanol is a CNS depressant producing sedation and ultimately hypnosis with increasing dosage It is readily absorbed orally and has a volume of distrinution close to that of total body water It is metabolized primarily in the liver. gastritis and nutritional deficiencies Cardiomyopathy is also a consequence of heavy drinking The treatment of choice for alcohol withdrawal are the benzodiazepines Carbamzepine is effective in treating convulsive episodes during withdrawal Antianxiety drugs . but a fraction is excreted through the lungs Ethanol synergizes wit h many other sedative agents and can produce severe CNS depression with antihistamines or barbiturates Chronic consumption can lead to severe liver disease. first to acetaldehyde by alcohol dehydrogenate and then to acetate by aldehyde dehydrogenate Elimination is mostly through the kidney.
99 Def Antianxiety drugs (anxiolytics) are CNS depressants which control symptom of anxiety They produce a calming effect in anxiety states 1. muscle relaxant and anticonvulsant actions They are less toxic and addiction liability is very low Mechanism of action It is believed that these agents facilitate the effects of GABA receptor activation in the CNS It potentates GABA ergic inhibition Side effects Sedation Lethargy Ataxia Weight gain Confusion Tolerance Dependence Diazepam . Benzodiazepines Diazepam Oxazepam Lorazepam Alprazolam 2. hypnotic. Azapirones Buspirone Gipirone Benzodiazepines These are the commonly used antianxiety drugs They have anxiolytic.
muscle relaxant and anticonvulsant actions It is quickly absorbed on oral administration Uses Acute panic states Anxiety associated with organic disease Status epileptic us Dose 2. anxiolytic. it has a hypnotic.100 It is an important benzodiazepine compound L Like all other benzodiazepines.5 mg twice a day Oxazepam It is active metabolites of diazepam This benzodiazepine is slowly absorbed on oral administration also It also penetration slow It has a short duration of action So it is used mainly in short lasting anxiety states Dis-advantages It is short acting It is not well absorbed Dose 10 mg Lorazepam This benzodiazepine is slowly absorbed on oral administration It also penetration in brain is slow .
101 It has a short duration of action So it is used mainly in short lasting anxiety states Dose 1-4mg Alprazolam It is a recently introduce antianxiety drug In addition to anxiolytic effect It has a mood elevating action It also produces less drowsiness USE Anxiety states associated with depression Dose 0.25-1 mg three times daily Meprobamate The drug produces calmness In as individual It reduces tension and hostility Reactions of the patient to his environment become – congenial Unlike phenothiazines it dies not abolish conditioned reflexes Adverse reaction Drowsiness Angioneurotic edema and other r allergic manifestations Blood dyscrasias Disadvantages .
its actions resemble barbiturates It produces calmness It also produces sedation It produces skeletal muscle relaxation It stimulates appetite Adverse reaction Drowsiness. hypnotic.102 Tolerance develops IT produces drug Dependence USES Anxiety Neurosis Chlordiazapoxide Though it is a benzodiazepine. lethargy and ataxia Hypotension is produce in few Disadvantages Tolerance develops It induces physical dependence . withdrawal symptoms are produced on its stoppage Use Anxiety and neurosis It is used to suppress withdrawal symptoms of alcohol As preanaesthestic medication Buspirones It is new antianxiety drug It does not have sedative. muscle relaxant and anticonvulsant effects as .
Mephenesin group Mephenesin Carisoprodol Chlorzoxazone .103 produced by benzodiazepines It has a slow action and the effect is delayed for even two weeks Mechanism of action It acts by stimulating presynaptic 5-HT 1A auto receptors USE Mild to moderate anxiety Dose 10-30 mg daily is divided doses Flumazinil It is a benzodiazepine antagonist It binds competitively with benzodiazepine receptors and blocks many of the pharmacological actions of benzodiazepines USE To reverse benzodiazepine anesthesia In Benzodiazepine overdose Hepatic coma and alcohol intoxication Centrally acting muscle relaxants Skeletal muscle relaxation without altering consciousness or normal voluntary movement is necessary during unwanted muscular spasms and rigidity and during operative procedures The classes of drugs which can be used fro skeletal muscle relaxation are centrally acting drugs and drugs acting peripherally at neuromuscular junction 1.
respiratory paralyses and death The drug is will absorbed orally and parent rally .but duration of action is short It is used to treat acute spasm of skeletal muscle in tetanus and status epileptic us It is used to produce muscular relaxation during operative procedures Use to reduce agitation in chronic alcoholism an to relieve muscular rigidity and tremors in parkinsonism Dose orally 1 gram to 3 grams Parentally 100mg to 1 gram Mephenesin carbamate an ester of mephanesin has a longer duration of action and hence is preferred Dose – 1 to 1. Central alpha 2 agonists Tizanidine Mepaenesin It is the first centrally acting muscle relaxant which was introduced in 1946 still being widely used today It relaxes normal and spastic skeletal muscles without interfering within neuro-muscular transmission In moderate dose it reduces muscle tone and motor activities But large doses produce hypotension.Benzodiazepines Diazepam and others 3.2 gram per day orally Methocarbamol This chemically elated to mephenesin carbamate . GABA derivative Baclofen 4.104 Chlormezamone Methocarbamol 2 .
2 rams per day in divided doses Serious side effects are leucopenia and jaundice Muscle relaxants are contra-indicated in pregnant women .105 It acts both as muscle relaxant and sedative It is orally active with a longer duration of action and milder side effects Uses . vertigo.M or I.0 3.Same as mephenesin Dose – 0. weakness and allergic reactions on skin Dose . in the presence of renal damage and myasthenia gravis Muscle relaxants acting at neuromuscular junction The contraction of skeletal muscle is initiated by acetyl choline at the neuromuscular junction Acetyl choline acts on the receptor of the muscle producing contraction But there are drugs which block the action f acetyl choline on skeletal muscle receptors thereby producing muscle relaxation They are of two types namely 1.V route Carisoprodol It is chemically related to meprobamate It produces muscle relaxation and sedative effects It is used in cerebral palsy to produce muscular relaxation Unwanted side effects are drowsiness. Competitive blockers 2. Depolarization blockers .5 grams per day orally It can also be given by I.350 mg oral Metaxalone Dose .
It is that it causes release of histamines from the tissues Gallamine It is a synthetics quaternary ammonium compound with curare like action It also acts as a skeletal muscle relaxant by competitive blockade of acetylcholine But is less potent than d – tubocurarine It does not release histamine It is not active orally Hence given parent rally It is also used to produce muscular relaxation during operative procedures Dose .V injection Depolarization blockers Here the drugs act by depolarizing the receptor motor end plate of the muscle which becomes resistance to further stimulation The drug which stimulation The drug which acts by this process and relaxing skeletal muscles is succinyl chloride It has very short duration of action .106 1.100 mg by I. Competitive Blockers The drugs which act by this mechanism are d-tubocurarine and gallamine They compete with the acetylcholine to reach the muscle receptors D-Tubocurarine This is the dextro rotatory alkaloid obtained from the strychnos species Curare was mainly used as an arrow poison in South America It competes with acetyl choline to reach the receptors and thus blocks the action of acetylcholine at the neuromuscular junction and produces muscle relaxation It is inactive orally.6 to 10 mg given with general anesthetic Disadvantage . but is active parent rally The drug is given intravenously for muscle relaxation during operative procedures Dose -.
107 Its action can be enhanced by anti-choline esterasis like neostigmine It does not release histamine It is used in anesthesiology to produce muscle relaxation by continuous I. V infusion Other drugs which act this process is decamethonoum .
Miscellaneous Oxypertine Tetrabenazine Pimozide . Phenothiazines Chlorpromazine Triflupromazine Fluphenazine Thioridazine 2. Rauwolfia alkaloids Reserpine 4. Butyrophenones Haloperidol Trifluperidol 3. since they reduce agitation and disturbed behavior seen in schizophrenia 1. Indolic derivatives Molindine 6. Thioxanthines Chlorprothixene Thiothixene 5.108 Unit .6 Anti-psychotic drugs These are the drugs which used in treatment of major psychosis They are also called a major tranquilizers.
ant cholinergic or antihistaminic Mechanism of action Phenothiazines and other antipsychotic drugs produce beneficial effects probably by affecting three of the major integrating systems in the brain Mesolimbic system Mesocortical system Hypothalamus Cause blockage mainly of postsynaptic dopaminergic (D2) receptors and to smaller extent 5-HT receptors Modify the function of the mesolimbic system Reduce the incoming sensory stimuli by acting on the brainstem reticular formation Pharmacological actions On CNS When chlorpromazine is given to patients with psychosis .109 CHLOPROMAZINE (CPZ) These are the most widely used compounds in the treatment of major psychoses Phenothiazines are three ringed structures In which two benzene rings are linked by a sulphur and a nitrogen atom Chlorpromazine is the important phenothiazine and was synthesized in 1950 According to the chemical structure . phenothiazines could be predominantly antipsychotic c. it produces Psychomotor slowing Emotional quietening Decreased initiative Decreased anxiety Phenothiazines do not have as analgesic effect But they potentate the analgesic effect of morphine They dontot have anticonvulsant effect .
initiative and motor activity. relieves anxiety and brings about emotional quietening and drowsiness It normalizes the sleep disturbances characteristic of psychoses Other CNS actions Cortex CPZ lowers seizure threshold and can precipitate convulsions in untreated epileptics Hypothalamus CPZ decreases gonadotrophin secretion and may result in amenorrhea in women It increases the secretion of prolactin resulting ins galactorrhiea and gynaecomastia Basal ganglia CPZ acts as a dopamine antagonist and therefore results in extra-pyramidal motor symptoms ( drug induced parkinsonism) Brainstem Vasomotor reflexes are depressed leading to a fall in BP Anti-emetic action CPZ has a powerful anti emetic effect These block the dopamine (DA) receptors in the CTZ This effect is produced by depress the chemoreceptor trigger zone On ANS The actions on the ANS are complex CPZ is an alpha adrenergic blocker .110 Behavioral effects In normal subjects CPZ reduces motor activity. produces drowsiness and indifference to surroundings In psychotic agitated patients. it reduce aggression .
constipation and urinary retention The degree of anti cholinergic activity also varies with each drug CVS CPZ produce hypotension due to alpha blockade action and reflex tachycardia It also has a direct myocardiac depressant effect like guanidine It also has anti. amamenorrhea and lactation in females In males.111 The alpha blocking potency varies with each neuroleptic CPZ also has ant cholinergic properties which leads to side effects like dryness of mouth.fibrillatory effect Local anesthetic effect These has local anesthetic properties but is not used for the purpose since in is an irritant Kidney CPZ depresses ADH secretion and has weak diuretic effects Tolerance develops to the sedative and hypertensive actions while no tolerance is seen to the anti psychotic actions On endocrine glands These produces inhibition of ovulation. it produces loss of libido These effect are produced by blocking the action of dopamine on hypothalamus and pituitary Other actions Inhibition of hiccough Skeletal muscle relaxant effect Pharmacokinetics It is well absorbed after oral and parenteral administration It is highly protein bound High concentration is found in the lungs. liver and adrenal glands . decreased gastric motility. reduced sweating. blurred vision.
nasal stuffiness and urinary retention These occur due to the ant cholinergic effects CVS effects Hypotension. agranulocytosis and skin rashes Drug interactions CPZ enhance the sedative effects of CNS depressants. psychotic reactions.112 It is subjected to enterohepatic circulation This increases its duration of action The half life period is 20 to 24 hours and is therefore given once a day It is metabolized in the liver and the metabolic products are excreted in urine s Adverse reaction CNS effects Drowsiness. palpitation and tachycardia Hemopoietic effects Agranulocytosis. the effects may be additive These inhibit the actions of dopamine agonists and Levo dopa Dose Chlorpromazine tablets and syrup. constipation. excitement. confusion and parkinsonism ANS effects Blurred vision. thrombocytopenia and aplastic anemia Endocrine effects Gymaecomastia.25 to 1000mg by mouth . lactation and menstrual disturbances Hypersensinitivity reactions Jaundice. alpha blockers and of ant cholinergic drugs When combined with these groups of drugs .
cough It is used in pre.anesthetic medication It used in neuropsychiatry disorders such as Huntington’s disease Drug dependence They are useful in the management of psychosis associated with chronic alcoholism tbu are contraindicated in acute withdrawal syndromes for fear of precipitating seizures Haloperidol This is a very potent drug. in agitated and violent patients Depot injection preparation of haloperidol are also available . there times day It can also be given IM in the dose of 2-10 mg.113 Chlorpromazine injection-25 to 50 mg by intramuscular injection Uses These are given orally ( chlorpromazine 100 – 800mg) In acute psychosis they may be given intramuscularly and response is seen in 24 hrs While in chronic psychosis it takes 2-3 weeks of treatment to demonstrate the beginning of obvious response It is used in the treatment of major psychosis It is used to control aggressiveness in children It is used as ant emetic CPZ can control intractable hic.5mg .5 to 7. belonging go the class of butyrophenones but with similar clinical effects as piperzine phenothiazines It is more effective in highly agitated or manic patients and has less prominent sedative and autonomic effects than chlorpromazine It is given orally in the dose of 1. repeated every hour up to a total of 30 mg.
114 The incidence of EPS with this drug is high and it dies not seem to be superior to phenothiazines in the routine treatment of schizophrenia The irreversible toxic encephalopathy has been reported in patients on lithium if they are given high doses of haloperidol The other drugs of this series are trifluperidol and droperidol which are used in combination with fentamyl for neuroleptanalgesia Rauwolfia alkaloids It is alkaloid obtained from a plant called Rauwolfia serpentine In ancient Ayurvedic medicine. hence it is no more used as an antipsychotic drug CVS . the extract of this plant has been claimed to be useful in cases of insomnia . insanity and snake bite It is called serpentine because of the resemblances of the root to a snake Mechanism of action Reserpine is of great pharmacological interest because it produces depletion of endogenous catecholamine and 5-HTfron the brain and peripheral sites by interfering with amine storage Such depletion can last for day or weeks A single dose of 5 mg / kg body weight is sufficient to cause 90% reduction in brain nor adrenaline and 5-HT over a period of 10 days This depletion of cerebral monoamines is believed to be responsible for its central actions Pharmacological actions of reserpine CNS It has central antipsychotic action resembling those of phenothiazines It differs from the latter compounds in that it has no antihistaminic. it produces a similar calming effect as well as extra pyramidal action as those observed flowing chlorpromazine It does not produce clouding of consciousness Reserpine is less effective than phenothiazines in t he treatment of schizophrenia It may cause mental depression precipitating suicidal tendencies . cholinergic blocking or direct adrenergic blocking effects In man .
vomiting .5 mg once daily and gradually increased to 200. its other actions include antiadrenergic . retardation and social withdrawal It is started in the dose of 12. it produces antipsychotic effects similar to other standard neuroleptics Its major advantage is that the drug improves not only the positive symptoms but also the negative symptoms such as emotional withdrawal. related to heterotricyclic compounds like imipramine . anti5-HT and ant cholinergic actions It differs from phemothiazines in that it causes fewer EPRs and does not cause hyperprolactinemia It given orally. and confusion . bunted affect.450 mg / day in divided doses Adverse reactions These includes nausea. was synthesized in 1960 It was found to cause agranulocytosis and its use was abandoned It has selective effects in the limbic.115 It is used as antihypertensive drug Reserpine is less effective tam phenothiazines in the treatment of schizophrenia But is commonly used as an antihypertensive drug Clozapine This antipsychotic drug. sedation . hypotension . severe tachycardia . dopaminergic systems.
Try cyclic compounds Imipramine Desipramine Amitriptyline Nortriptyline 111. Selective Serotonin reuptake inhibitors Fluoxetine Citalopram Escitalopram Paroxetine Sertaline IV. Monoamine oxidase inhibitors Meclobemide Phenelzine Isocarboxazid Nialamide 11.116 Anti-depressant drugs These are the drugs used for the treatment of mental depression They are also called as psycho analeptics or mood elevators Classification of Anti-depressant drugs 1. Serotonin or nor epinephrine re-uptake inhibitors Phenelzine Tranylcypromine .
epinephrine and serotonin receptors and it may be responsible for the antidepressant action of these drugs Two MAO inhibitors are currently available for treatment of depression. MAO functions is to deaminate and inactivate any excess neurotransmitter molecules (nor epinephrine. permitting neurotransmitter molecules to escape degradation and therefore to both accumulate within the presysaptic neuron and leak into the synaptic space This causes activation of nor. Mono-amine oxidase inhibitors (MAOI) Monoamine oxidase (MAO) is a mitochondrial enzyme found in nerve . liver and gut In the neuron.Phenelzine and tranylcypromine The use of MAO inhibitors is now limited due to the complicated dietary restrictions required of patients taking MAO inhibitors Mechanism of action MAO inhibitors such as phenelzine form stable complex with enzyme. dopamine and serotonin) that may leak out of synaptic vesicles when the neuron is at test The MAO inhibitors may irreversibly or reversibly inactivate the enzyme. On CVS No effect on heart or circulation at normal dose 3. Potentiation of sympathomimetic amines These compounds potentiate the action of symathomimitic amines like amphetamine and tyramine These have a mild. these compounds elevate the mood The patient feels more energetic and fresh 2.Behavior In case o f mental depression. causing irreversible inactivation These results in increased stores of nor epinephrine. serotonin and dopamine within the neuron and subsequent diffusion of excess neurotransmitter into the synaptic space These drugs inhibit the MAO in brain and as well as in t he peripheral Pharmacological actions 1.117 1. amphetamine like stimulant effect Pharmacokinetics .
ataxia and tremors ANS effects Dry mouth. excitement and disturbed sleep CNS effects Twitching. Tricyclic antidepressants These blocks nor epinephrine and serotonin uptake into the neuron . constipation and blurred vision Hypertension Tyramine is met abolished by the enzyme MAO In presence of MAOI . tyramine is not metabolized These leads to accumulation of tyramine Tyramine produces rise in blood pressure by releasing nor adrenaline 11.118 These drugs are will absorbed on oral administration Antidepressant effects require two to four week of treatment MAO inhibitors are metabolized and excreted rapidly in the urine Uses MAO inhibitors are indicated for depressed patients who are un.responsive or allergic to TCA or who experience strong anxiety These drugs are also useful in the treatment of phobic state s MAO inhibitors also used in the treatment of a special subcategory of depression called atypical depression Atypical depression is characterized by labile mood . rejection sensitivity and appetite disorders Adverse effects Behavioral effects Headache.
they are widely distributed and readily penetrate into the CNS This lipid solubility also causes these drugs to have long half lives – 4 – 17 hours for imipramine .increase physical activity The onset of the mood elevation is slow .histamine and muscarinic receptors Pharmacological actions 1. Behavior These elevate mood. palpitation and blurred vision ADME Imipramine is well absorbed on oral administration Because of their lipophilic nature . improve mental alertness .119 These drugs are voluble alternative for patients who do not respond to SSRIs Mechanism of action These are potent inhibitors of the neuronal re-uptake of nor epinephrine and serotonin into presynaptic nerve terminals This produces increase in its concentration at the receptor sites These contributes for the antidepressant action TCAs also block serotonergic. alpha adrenergic . constipation . ANS Imipramine produces anti cholinergic effects like dry mouth. requiring two weeks or longer These drugs do not produce CNS stimulation or mood elevation in normal individuals Physical and psychological dependence have been reported The drugs can be used for prolonged treatment of depression without loss of effectiveness 2. CVS No effect at normal dose But toxic doses may produce cardiac arrhythmias 3.
headache and drowsiness ANS effects Dry mouth. constipation and tachycardia CVS effects Cardiac arrhythmias and hypotension Allergic reactions Skin rashes and photosensitivity Uses These are very effective in treating severe major depression Some panic disorders also respond to TCA Imipramine has been used to control bed. particularly amitriptyline . Selective serotonin re-uptake inhibitors ( SSRIs) Drugs which belongs to these groups are Fluoxetine Citalopram Escitalopram Paroxetine Sertaline These drugs do not produce CNS stimulation or mood elevation in normal individuals They selectively inhibit 5 – HT reuptake .120 These drugs are metabolized by the hepatic microsomal system and conjugated with glucuronic acid The TCA are excreted as inactive metabolites via the kidney It actions are mediated through desmethyl-imipramine which is a metabolite product Adverse reactions CNS effects Lethargy. have been used to treat chronic pain 111.wetting in children by causing contraction of the internal sphincter of the bladder TCAs .
enatiomer of citalopram Fluoxetine and paroxetine are potent inhibitors of a hepatic cytochrome P-450 iso enzymes responsible for elimination of tricyclic antidepressant drugs Excretion of the SSRIs is primarily through the kidneys except for paroxetine and sertraline which also undergo fecal excretion USES The primary indication for SSRIs is depression. panic disorder. leading to increased concentrations of the neurotransmitter in the synaptic clefts and to greater postsynaptic neuronal activity Anti-depressants including SSRIs typically take two weeks to produce improvement in mood and maximum benefit may require twelve weeks or more The patients that do not responds to one antidepressant may respond to another and approximately eithy percent or more will respond to at least one antidepressants drug Pharmacokinetics These are well absorbed on oral administration Peak levels are seen in five hours on average Food has little effect on absorption Only sertraline undergoes significant first –pass metabolism All these agents are well distributed The half life of SSRIs are in-between 16 -36 hours These are metabolized by the P-450 – dependent microsomal enzymes These produced the conjugation of glucuronide or sulfate conjugation Both citlopram and fluoxetin are racemic mixtures Escitalopram is the pure S.121 They have less antimuscarinic effects and also sell sedation They are safer than tricyclic antidepressants These have little ability to block the dopamine transporter Pharmacological actions SSRIs block the re-uptake of serotonin . generalized anxiety . for which they are as effective as the tricyclic antidepressants A number of other psychiatric disorders also respond favorably to SSRIs m including obsessive compulsive disorder.
Sleep disturbances Paroxetine and fluvoxamine are sedating and may useful in patients who have difficulty sleeping 2.manic drugs The following drug are used in the treatment of manic disorder Lithium salts Carbamazepine Valproic acid Lithium carbonates It is a small monovalent cation In 1949 it was found to be sedative in animals and to exert beneficial effects in manic patients . Use in children and teenagers Anti depressants should be used cautiously in children and teenagers .122 Adverse reaction SSRIs have fewer and less severe adverse effects than the tricyclic antidepressant and MAOI 1. delayed ejaculation and anorgasmia are underreported side effects often noted by clinicians but not prominently featured in list of standard side effects 3. clonic muscle twitching and changes in mental status and vital signs when used in the presence of a monoamine oxidase inhibitor Anti. but fluoxetine may cause seizures All SSRIs have the potential to cause a serotonin syndrome characterized by hyperthermia . muscle rigidity . because about one out of fifty children become more suicidal as result of SSRI treatment Pediatric patients should be observed for worsening depression and suicidal thinking whenever one of these drugs is started or their dose is increased or decreased 4. Overdoses Large intakes of SSRIs do not cause cardiac arrhythmias. Sexual dysfunction Loss of libido.
123 Mechanism of action The mechanism of antimanic and mood stabilizing action of LI is not known It has been proposed that Lithium partly replaces body Na and is nearly equally distributed in and outside the cells ( contrast Na and K ) . It acts as a mood stabilser in bipolar disease Given to patients in acute mania. ultimately attaining a rather uniform distribution in total body water . Most of the filtered Lithium is reabsorbed in the proximal convoluted tubule . this may affect ionic fluxes across brain cells or modify the property of cellular membranes Lithium has been found to decrease the release of Na and DA in t he brain of treated animals without affecting 5 –HT release This may correct imbalance in the turnover of brain monoamines Pharmacological actions On CNS Lithium has practically no acute effects in normal individuals as well as in MDI patients It is neither sedative nor euphorient.8 L/kg The lithium is handled by the kidney in much the same way as Na . but on prolonged administration. apparent volume of distribution at steady. it gradually suppresses the episode taking 1-2 weeks The markedly reduced sleep time in manic patients is normalized Other actions Lithium inhibits action of ADH on distal tubules and causes a diabetes like state It has some insulin like action on glucose metabolism Leukocyte count is increased by lithium therapy Lithium reduces thyroxin synthesis by interfering with iodination of tyrosine Pharmacokinetics Lithium is given orally and the ion is excreted by the kidney It is neither protein bound nor metabolized It first distributes in the extra cellular water and then gradually enters cells and slowly penetrates into the CNS .state averages 0.
indomethacin and ACE inhibitors can also cause lithium retention . a larger fraction of filtered Na is reabsorbed . On long term use some patients develop renal diabetes and goiter has been reported in about 4 % Interactions Diuretics ( thiazide.30 hours Renal clearance of lithium is 1/5 of creatinine clearance On repeated medication steady-state plasma concentrations achieved in 5-7 days Levels are higher in older patients and in those with renal insufficiency Peaks in plasma lithium level over and above the steady-state level occur after every dose and produce episodes of toxicity if steady-state level if high or the dose is large Divided daily dosing in 2-4 portions is needed to avoid high peaks Lithium is excreted in sweat and saliva also salivary concentration is proportionate to serum concentration and may be used for noninvasive monitoring Lithium is secreted in breast milk Mothers on lithium should not breastfeed Adverse reaction Side effects are common but are mostly tolerable Toxicity occurs at levels only marginally higher than therapeutic levels Nausea. giddiness.124 When N a is restricted. motor in coordination. so is Li After a single dose of li urinary excretion of rapid for 10. mental confusion. vomiting and mild diarrhea occur initially. ataxia. can be minimized by starting at lower doses Thirst and polyuria are experienced by most. slurred speech. some fluid retention may occur initially but clears later Fine tremors and rarely seizures are seen even at therapeutic concentrations CNS toxicity – coarse tremors. furosemide0 by causing ) Na loss promote proximal tubular reabsorption of Na as well as lithium – plasma levels of lithium rise Tetracycline’s .12 hours followed by a much slower phase is 16.
the combination of haloperidol and lithium produces marked tremor and rigidity Dose Lithium used as its carbonate salt because this is less hygroscopic and less gastric irritant than lithium chloride or other salts It converted into chlorides in the stomach It is generally stared at 600 mg/day and gradually increased to yields therapeutic plasma levels. the leaves (bhang) . impulsive behavior. the resinous exudation (Charas) or the whole drug ( Hashish) In U. sometimes . LSE -25 . bufotenine and harmoline Cannabis It is obtained from cannabis indica or Indian hemp Flowering tops (ganja).S. delirium ( confusion and excitement). mostly 600-1200 mg /day is required Hallucinogens These are drugs which alter mood. broadly illusions and hallucinations There will be alteration of the sense of time and space with personality changes Memory is not affected The drugs which possess their actions are cannabis. auditory perception. space. it is called as marihuana Cannabinal (chemically an alcohol) a red syrapy oil is said to be the active principle It produces hallucinations of time . mescaline. thought and perception in a manner similar to that seen in psychosis In appropriate doses these produce changes in visual. in smell and taste . behavior.A. imagination. euphoria ( sense of well being).125 Lithium reduces presser response to NA Lithium tends to enhance insulin / sulfonylurea induced hypoglycemia Succinyl-choline and pancuronium have produced prolonged paralysis in lithium treated patients Haloperidol have been frequently used along with lithium without problem . psilocybin . mania ( mental disorder) Cannabis is not useful therapeutically . mental exaltation.
126 Mescaline It is an alkaloid obtained from a cactus When given orally the drug produces sympathomimetic effects and visual hallucinations and a sense of floating in space It also produces excitement . change of mood and intelligence It is used only for experimental purposes to produce psychotic states LSD – 25 ( Lysergic acid diethylamide) This is a derivative of ergot alkaloid. now being used in psychiatric research It induces psychotic states in which repressed memories form the subconscious mind are brought of light It stimulates emotional activity producing the sense of lightness and withdrawal from reality It brings about personality change It may be used in obsessional thoughts and anxiety conditions accompanied by mental tension It is orally active in a dose of 25 micro gram But it is widely misused for its hallucinogenic effects The person become disoriented and his activities disorganized It is noticed that it can induce chromosomal abnormalities and fetal malformation and possibly leukemia and hence it I withdrawn even form research Other minor hallucinogens like bufetinine. restlessness. psilocybin and harmolin produce similar psychic effects but not used therapeutically .
Benzodiazepines Clonazepam Clobazam Diazepam 7.Epileptic drugs It is a collective term applied for a group of convulsive disorders The common features of epilepsy are Loss or disturbance of consciousnesses Characteristic body movements (usually. Barbiturates Phenobarbitone Primidone 3. Newer antiepileptic Lamotrigine Gbapentine 8. Succinimides Ethosuximided 5.7 Anti. Hydantoins Phenytoin 2. Aliphatic carboxylic acid Sodium valproate 6. but not always) CLASSIFICATION 1.127 Unit . Iminostilbbenes Carbamazepine 4. Miscellaneous Trimethadione Acetazolamide .
but its anticonvulsant property was discovered only in 1938 It is effective in suppressing tonic-clinic and partial seizures and is a drug of choice for initial therapy. particularly in treating adults Mechanism of action Phenytoin blocks voltage-gated sodium channels by selectively binding to the channel in the inactive state and stabilizes the neuronal membrane It inhibits the generation of repetitive action potentials At much higher concentrations . phenytoin can block voltage-dependent calcium channels and interfere with the release of monoaminergic neurotransmitters Pharmacological action Phenytoin exerts antiseizure activity without causing general depression of the CNS It is one of the most effective drugs against generalized tonic-clonic seizures and partial seizures Phenytoin reduces the propagation of abnormal impulses in the brain Pharmacokinetics Phenytoin is poorly water soluble hence absorption is slow It is 90% bound to plasma proteins It is metabolized in liver Phenytoin is enzyme inducer Therapeutic uses Phenytoin is highly effective for all partial seizures ( simple and complex). for tonicchronic seizures and in the treatment of status epileptics Phenytoin is not effective for absence seizures. which often may worsen if treated with this drug .128 Phenytoin Phenytoin was synthesized in 1908.
cleft palate.129 Adverse effects It depend dose . ataxia are common Gingival hyperplasia is more common in children on prolonged use Peripheral neuropathy Phenytoin inhibits insulin release and produces hyperglycemia Decreases the release of ADH Osteomalacia . both increases each other metabolism Phenytoin and carbamazepine enhance each others metabolism Valproate displaces protein bound phenytoin Cimetidine and chloramphenicol inhibit the metabolism of phenytioin resulting in toxicity Antacids decreases the absorption of phenytoin . anorexia Nystagmus. and harelip Drug interactions Phenytoin is an enzyme inducer Phenytoin given with phenobarbitone . vomiting. phenytion produces fetal hydantion syndrome characterized by hypo plastic phalanges. and neutropenia Megaloblastic anemia – Phenytoin decreases absorption and increases excretion of folates Teratogenicity When taken by the pregnant lady. SLE. hepatic necrosis . epigasric pain.Rashes . duration and route Nausea. hypocalcaemia due to altered metabolism of vitamin D and inhibition of intestinal absorption of Ca Hypersensitivity . diplopia.
nausea and vomiting Agitation and confusion occur at high doses Rebound seizures can occur on discontinuance of Phenobarbital . whereas the examining drug is excreted unchanged by the kidney It is a potent inducer of the cytochrome P450 system and when given chronically. especially in patients who donot respond to diazepam plus phenytoin It also used as a mild sedative to relieve anxiety.130 Phenobarbitone Phenobartitone was the first effective antiepileptic drug to be introduced in 1912. including febrile seizures It also used to treat recurrent tonic-clonic seizures. but it is not very effective for complex partial seizures The drug had been regarded as the first choice in treating recurrent seizures in children. vertigo . nervous tension and insomnia Adverse effects Sedation. ataxia. It still remains one of the widely used drugs It has antiepileptic activity and raises the seizure threshold Mechanism of action Barbiturates enhances the inhibitory neurotransmission in the CNS by enhancing the activation of GABA receptors and facilitating the GABA mediated opening of chloride ion channels Pharmacokinetics It is well absorbed orally The drug freely penetrates the brain Approximately 75 % of the drug is inactivated by the hepatic mocrosomal system. it enhances the metabolism of their agents Therapeutic uses It provides favorable response for simple partial seizures.
lives than the parent drug It is effective against tonic-clinic and simple partial seizures and phenyl-ethylmalonamide is effective against complex partial seizures Primidone is often used with carbamazepine and phenytoin It is well absorbed orally It exhibits poor protein binding These drug has the same adverse effects as those seen with Phenobarbital .131 Primdone It structurally related to Phenobarbital and it resembles Phenobarbital in its anticonvulsant activity It is an alternative choice in partial seizures and tonic – clonic seizures It has more efficacy due to the its metabolites Phenobarbital and phenyl-ethylmalonamide which have longer half.
Lorazepam has a longer duration of action and is preferred by some clinicians All of the antiepileptics. Dizziness and behavioral changes Respiratory depression and cardiac depression may occur when given intravenously in acute situations . the benzodiazepines are the safest and most free from severe side effects All benzodiazepines have sedative properties Side effects Drowsiness.132 Benzodiazepines Several of the benzodiazepines show antiepileptic activity Diazepam and lorazepam are the drugs of choice in the acute treatment whereas Clonazepam and clorazepate and clorazepate are used for chronic treatment of status epilepticus Clonazepam It suppresses seizure spread from the epileptogenic focus and is effective in absence and myoclonic seizures . Somnolence. but tolerance develops Clonazepate Clorazepate is effective in partitial seizures when used in conjunction with other drugs Diazepam It is effective against Pedestal epilepsy Mylclonic seizures Status epilepsy It is drug of choice for status epilepticus Lorazepam Lorazepam and diazepam are both effective in interrupting the repetitive seizures of status epilepticus. Fatigue. Ataxia.
but because of its hepatotixic potential. including sodium channel blockade and enhancement of GABAergic transmission It is the most effective agent available for treatment of myoclinec seizures It also diminishes absence seizures. the rest is converted into active metabolites by the liver It is metabolized by cytochrome P450 enzymes Metabolites are excreted by kidney It can cause nausea. ataxia and tremor are common It inhibits the metabolism of a number of antiepileptic drugs . it is a second choice It also reduces the incidence and severity of tonic-clonic seizures The drug is effective orally and is rapidly absorbed About 90% is bound to the plasma proteins .133 Ethosuximide It reduces propagation of abnormal electrical activity in the brain. carbamazepine and ethosuximide . including Phenobarbital. most likely by inhibiting t.only 3% of the drug is excreted unchanged. lethargy. vomiting . restlessness . dizziness . agitation . anxiety and the inability to concentrate are often observed Valproic Acid It is a broad spectrum anticonvulsant It has multiple actions .type calcium channels in a manner similar to the action of phenytoin on sodium channels It is the first choice in absence seizures It is well absorbed orally and is not bound to plasma proteins About 25% of the drug is excreted unchanged in the urine and 75% is converted to inactive metabolites in the liver by the microsomal cytochrome P450 system It does not induce P450 enzyme synthesis The drug is irritating to the stomach and nausea and vomiting may occur on chronic administration Drowsiness.sedation.
which decrease the effects of drugs that are metabolized by his enzyme Therapeutic uses It is effective in Temporal lobe epilepsy Trigeminal neuralgia Used in post hepatic pain Adverse effects Chronic administration of carbamazepine can cause stupor. and blurred vision The drug is irritating to the stomach and nausea and vomiting may occur Drug interaction The hepatic metabolism of carbamazepine is inhibited by several drugs Toxic symptoms may arise if the dose is not adjusted .134 Carbamaepines Actions It reduces the propagation of abnormal impulses in the brain by blocking sodium channels. thereby inhibiting the generation of repetitive action potential in the epileptic focus and preventing their spread ADME It is absorbed slowly following oral administration It enters the brain rapidly because of its high lipid solubility It induces the drug metabolizing enzymes in the liver The enhanced hepatic cytochrome p450 system activity also increases the metabolism of many drugs including other antiepileptic drugs It is an inducer of the cytochromep450 isozyme cyp3a4. vertigo. ataxia. coma and respiratory depression It also produces drowsiness.
there is degeneration of nigrostriatal neurons in the basal ganglia resulting in dopamine deficiency The balance between inhibitory dopaminergic neurons and excitatory cholinergic neurons is disturbed Antiparkinsonian drugs It can only help to alleviate the symptoms and improve the quality of life The two strategies in the treatment are 1.activity . progressive.parkinsonism It was described b James Parkinson in 1817 and is therefore named after him Parkinsonism is a chronic .135 Anti . motor disorder Characterized by Akinesia Muscular rigidity Tremors Other symptoms Excessive salivation Abnormalities of posture and gait Seborrhea Mood changes The incidence is about 1% of population above 65 years of age It is usually idiopathic in origin but can also be drug induced In idiopathic parkinsonism. To depress cholinergic over. To enhance dopamine activity 2.
Dopamine precursor Levodo[a B. Drug influencing cholinergic system A. Central anticholinergics Bintropine Benzhexol Biperidine B. Dopaminergic agonists Bromocryptine Lisuride D. Drugs that increase dopamine levels A. Inhibit dopamine metabolism MAO inhibitors .136 Classification of Anti parkinsonism drugs 1. Antihistamines Diphenhydramine Promethazine . Drugs that release the dopamine Amantidine C.Selegiline 11.
Dopamine is a catecholamine Endocrine -.Dopamine stimulates CTZ to induce vomiting CVS .137 Levodopa Acetylcholin and dopamine are excitatory and inhibitory neurotransmitters in the corpus striatum The dopaminergic system is impaired in parkinsonism.Dopamine suppresses prolactin secretion . there is an overall improvement in the patient as all the symptoms subside Other actions CTZ . so the balance is disturbed Levodopa acts by getting converted to dopamine and restoring the balance Parkinsonism is due to dopamine deficiency Levodopa improves all the manifestations of parkinsonism But it is not effective in drug induced parkinsonism Decarboxylase inhibitors like carbidopa are administered with levodopa They decrease the peripheral decarboxylation of levodopa Dopamine is of no therapeutic value because it dies not cross the blood.Large amounts of levodopa converted to dopamine in the pheiphery causes postural hypotension and tachycardia.Brain-Barrier and is taken up by the surviving nigrostriatal neurons Decarboxylase ------------------------------------------- Levodopa Dopamine Actions On administration of levodopa.brain barrier Levodopa is a prodrug which is converted to dopamine in the body It crosses the Blood.
They reverse the effects of levodopa . depression .138 Pharmacokinetics Levodopa is rapidly absorbed from the small intestine The presence o food delays absorption Some amino acids in the food compete with levodopa for the absorption and transport to the brain It undergoes first pass metabolism in the gut and the liver Its half life is 1-2 hours Adverse reactions Large amounts of levodopa is converted to dopamine is the periphery. several adverse effects are expected Nausea. metoclopramide and reserine are DA antagonists. postural hypotension palpitation and occasionally arrhythmia can occur Tolerance develops to these effects after some time Behavioral effects like anxiety. hallucinations and sometimes psychosis can occur Use Levodopa is the most effective drug in idiopathic parkinsonism but is not useful in drug induced parkinsonism Drug interactions Pyridoxine enhances peripheral decarboxylation of levodopa and reduces its availability to the CNS Phenothiazines. vomiting.
they prevent the formation of dopamine in the periphery They do not cross the BBB and hence allow levodopa to reach the CNS The combination is synergistic and therefore levodopa is always given with carbidopa or benserazide Advantages of combination Dose of levodopa can be reduced by 75% Response to levodopa appears earlier Side effects like vomiting and tachycardia are largely reduced Pyridoxine does not interfere with treatment Amantadine It is an antiviral drug It enhances the release of dopamine in the brain and diminishes the re-uptake of DA The response starts early and its adverse effects are minor Large doses produce insomnia. postural hypotension . dizziness. vomiting .sudden cardiovascular collapse . postural hypotension. hallucinations.off phenomenon An alternative inn patients unable to tolerate levodopa Adverse effects It include vomiting . skin eruptions and first dose phenomenon .139 Carbidopa and benserazide These Are Peripheral Dopa Decarboxylase Inhibitors When carbidopa or bensrazide are given with levodopa. hallucinations and ankle edema Amantadine id used in mild cases of parkinsonism It can also be used along wit h levodopa as an adjunct Bromocriptine It is an ergot derivative having dopamine agonistic activity at D2 receptors It is used as An adjunct to levodopa in the management of on.
trihexyphenidyl are used Antihistamines owe their beneficial effects in parkinsonism to their anticholinergic properties Atropine like side effects such as dry mouth . blurred vision may be encountered Uses Anticholinergics are used as Adjunct to levodopa Drugs of choice in drug induced parkinsonism Drug induced parkinsonism Drugs like reserpine.Mild cases of parkinsonism are started on selegiline’It is also used as an adjunct to levodopa Anti.B is present in DA containing regions of the CNS Selegilline prolongs the action of levodopa by preventing its degradation Selegiline may delay the progression of parkinsonism Uses .B inhibitor MAO. seborrhea and sialorrhiea are reduced more than rigidity Atropine derivatives like benzhexol. benztropine.. metoclopramide and phenothiazines are dopamine antagonists Treatment withdrawal of the drug usually reverses the symptoms When drugs are needed. metoclopramide and phenothiazines can induce parkinsonism Resrpine depletes catecholamine stores. constipation. one of the anticholinergics are effective .140 Lisuride and pergolide are similar to bromocriptine Seleglline It is a selective MAO.cholinergic The cholinergic over activity is overcome by anticholinergics Tremors.
opioid Analgesics These drugs have three main function – Analgesics . These drugs do not produce addiction All these drugs produce an anti-inflammatory effect.Salicylates Acetyl-salicylic acid Sodium salicylate Methyl salycilate Salicylic acid 2. Non selective COX inhibitors 1.8 Analgesics and Anti-pyretics Analgesic Antipyretics --These are drugs which produce relief of pain These are drugs which reduces increased body temperature These drugs relieve pain of lesser intensity like tooth-ache and muscle pain But they do not relieve severe pain like visceral pain which is relieved by opioid analgesics. Pyrazolon derivatives Phenyl butazone Oxypehenbutazone Aminopyrine Antipyrine . they are called as non. so these are called as non-steroidal anti-inflammatory drugs ( NSAID ) These are weak analgesics as compared to narcotic analgesics and have primary action on peripheral pain mechanism They act without interacting with opioid receptors.Para.aminophenol derivatives Paracetamol Phenacetin 3.141 Unit . Anti-pyretic and Anti-inflammatory action A.
redness and pain ) These prostaglandins produce hyperalgesia -. Oxicam derivatives Poroxicam.oxygenase ------------------------------------Prostaglandins Arachidonic acid The arachidonic acid is liberated from damaged cells during an inflammatory reaction Prostaglandins and other mediators of inflammation are formed from Arachidonic acid with the help of an enzyme Cyclo-oxygemase The prostaglandin formed are responsible for many of the features of inflammation I. – swelling. Propionic acid derivatives Ibuprofen. Anthranilic acid derivative Mephenamic acid 7. Selective COX – 2 inhibitors Celecoxib.They sensitize the nerve endings to pain and other mediators of inflammation like bradykinin and histamine The NSAID block the action of enzyme cyclo-oxygenase and thus prevent or reduces the production of prostaglandins and other mediators of inflammation .------------------------------------Cyclo. Rpfecpxon Mechanism of action These drugs does not act on Central nervous system Phospholipase A2 Membrane -. Ketoprofen 5. Preferential COX -2 inhibitors Nimesulide. Meloxicam C.142 4.e. Indole derivatives Indomethacin 6. Aryl acetic acid derivative Diclofenac 8. Tenoxicam B.Phospholipids--.
The hypothalamic heat regulating center ( thermostat of the body) is set for a higher temperature in fever This is reset for a lower temperature by salicylates B.143 Asprin It is a acetyl salicylic acid It is one of the oldest analgesic-anti-inflammatory drugs and is still widely used It is rapidly converted in the body to salicylic acid which is responsible for most of the actions Other actions are the result of acetylation of certain macromolecules including COX Mechanism of action It inhibits cycloxygenase which is responsible for the synthesis of prostaglandin and thromboxane It also inhibits platelet aggregation Pharmacological actions 1.aching pain of low intensity They do not relieve severe pain like visceral pain They act by preventing the integration of pain sensation in the thalamus But they do not alter the emotional reaction to pain 2. Analgesic action Asprin is a weaker analgesic than morphine These are effective only in dull.inflammatory action . Anti. The salicylates produce sweating which also lowers body temperature 3. Anti-pyretic effect Salycylates do not lower normal body temperature Only the elevated temperature is lowered Mechanism A.
On respiration Salycylates stimulate respiration The stimulation is depend on the dose Salicylates stimulates respiration directly by stimulating the respiratory centre Stimulate the respiration indirectly by through CO2 At anti –inflammatory respiration is stimulated by peripheral( increased CO2 production) and central ( increased sensitivity of respiratory centre to CO2 ) actions Hyperventilation is prominent in salicylate poisoning Further rise in salicylate level causes respiratory depression Death is due to respiratory failure 5. GI Tract Salicylates produce nausea and vomiting due to Direct stimulation Stimulation of chemoreceptor trigger zone Salicylates can also cause gastric ulceration and hemorrhage 7. it diminishes the formation of prostaglandins and modulates those aspects of inflammation in which prostaglandins act as mediators Asprin inhibits inflammation in arthritis 4. Cardiovascular system No effect at normal dose Large doses increase cardiac output to meet increased peripheral O2 demand and cause direct vasodilatation Toxic doses produce paralysis of vasomotor centre and BP may fall 6. vasodilatation and leukocyte infiltration are suppressed Asprin inhibits cyclo-oxygenase activity.6 grams /day Signs of inflammation like pain.rheumatic effect Salicylates have powerful anti-rheumatic effect . swelling . tenderness.144 Asprin exert the anti-inflammatory action at high doses 3. Anti.
Metabolic effects Salicylates produce uncoupling of oxidative phosphorylation They produce hyperglycemia and glycosuria They inhibit the synthesis but enhance the breakdown of fatty acids 10. muscle. and brain . Hormones Salycylates stimulate the release of adrenaline from adrenal medulla They also stimulate the release of adreno-corticotrophic hormone (ACTH) They interfere with the binding of thyroxin with plasma proteins This free thyroxin depresses the secretion of thyroid stimulating hormone (TSH) 11. especially salicylic acid and methyl salicylate have antiseptic.145 T his effect is produced by reducing pain and inflammation of the joints 8. fungi static and keratolytic effects ADME Salicylates are absorbed from the stomach and small intestine They are bound to plasma proteins They are mainly concentrated in the liver. Blood Salicylates lower the erythrocyte sedimentation rate (ESR) which is high in rheumatic fever They also decrease prothrombin level of plasma Uricosuric effect Slicylates promote the excretion of uric acid This effect is produced by inhibiting the reabsorption of uric acid in the proximal tubule Immunological effect Salicylates inhibit antigen. Local actions Salicylates . heart.antibody reaction and so prevent the release of histamine 9.
vomiting .146 They are metabolized in liver by conjugation with glycine and glucuronic acid The metabolic products are mainly excreted through urine Adverse reactions Gi tracts disturbances like nausea.3 g . a metabolite of phenacetin is found to be safer and effective It has analgesic . lethargy and confusion Preparation and doses Aspirin Tab Acetyl.1 gram oral 0.salicylic acid powder Sodium salicylate as mixture Methyl salicylate Salicylic acid 0. ulceration perforation and hemorrhage Intolerance leading to skin rashes of various types Bone marrow depression leading to agranulocytosis .inflammatory properties . thrombocytopenia and a plastic anemia Fatty infiltration of liver and kidney Salicylism characterized by headache. difficulty in hearing. anti-fungal and keratolytic Pracetamol It is a Para-amino phenol derivative It has analgesic and antipyretic effects like salicylates Parcetamol . good antipyretic and weak anti.6 g .3 g – 1 gram oral 0. diarrhea .2 gram oral Ointment Ointment Uses It is used as analgesic for light and moderate pain Used as anti-pyretic in fever It is used as anti-rheumatic It also used as antiseptic . drowsiness.
147 Due to weak PG inhibitory activity in the periphery.base balance .regulating centre Its weak anti-inflammatory activity is related to inhibition of prostaglandin synthesis in the CNS ADME It well absorbed orally 30% protein binding It is metabolized by the hepatic microtonal enzymes by glucuronide conjugation (60% ) And glutathione conjugation (20% ) Treatment Stomach wash is given Activated charcoal prevents further absorption Antidote is N-acetylcysteine more effective when given early (150 mg/kg IV infusion over 15 min followed by 70 mg/kg every 4 hours -17 doses) N.cetylcysteine partly replenishes the glutathione stores of the liver and prevents binding of toxic metabolites to the cellular constituents Adverse effects In antipyretic doses . it has poor ability too inhibit cyclo-oxygenase It does not stimulate respiration It has no action on acid. cellular metabolism . it has poor anti-inflammatory actions Paracetamol is active on cyclo-oxygenase in the brain which accounts for its antipyretic action In presence of peroxides present at the site of inflammation . cardiovascular system and platelet function It does not produce gastrointestinal irritation and uricosuric effect Mechanism of action Paracetamol exhibits analgesic action by peripheral blockage of pain impulse generation It produces antipyresis by inhibiting the hypothalamic heat. paracetamol is safe and well – tolerated .
inflammatory activity and has both central and peripheral effect Temperature is reduced in febrile patients It is a potent inhibitor of the enzyme cycloxygenase resulting in t he blockage of prostaglandin synthesis It also prevents formation of thromboxane A2 by platelet aggregation .inflammatory.148 Nausea and rashes may occur But when large doses are taken. analgesic and antipyretic activities Analgesic. acute paracetamol poisoning results Children are more susceptible due to their ability to conjugate by glucuronidation to poor 10 – 15 grams in adults cause serious toxicity Symptoms Nausea Vomiting anorexia Abdominal pain Parecetamol is hepatotoxic and causes severe hepatic damage Hepatic lesions are reversible when promptly treated Uses Paracetamol is used as an analgesic in painful conditions like toothache. headache and myalgia As an antipyretic Chronic pulpitis. antipyretic and anti-inflammatory efficacy is slightly lower than aspirin It is 99% bound to plasma proteins Its analgesic activity is independent of anti. periodontal abscess. post.extraction – parcetamol is used with Ibuprofen Ibuprofen It is propionic acid derivatives It is a better tolerated than aspirin It exhibits anti.
Surgical removal of impacted tooth – a combination of ibuprofen with a skeletal muscle relaxant like chlorzoxaxone is recommended 4. GI bleeding .149 Adverse effects Nausea Vomiting Gastric discomfort CNS effects Hypersensitivity reactions Dose 400. 90% bound to plasma proteins & half life is 4 – 6 hours Dose 25 -30 mg BD-TDS Adverse effects Adverse effects are high . vomiting . diarrhea and peptic ulcers can occur . gingival abscess – a combination of ibuprofen with paracetamol is preferred Indomethacin It has anti-inflammatory. antipyretic and antigout actions It is a portent inhibitor of cycloxygenase thus reducing prostaglandin synthesis It relieves pain and reduces temperature in febrile patients reduces pain and joint swelling in rheumatoid arthritis but does not modify progress It is well absorbed. periodontal abscess. It is used in the treatment of gout 3. analgesic.800 mg TDS Uses 1. Gastrointestinal irritation with nausea. Chronic pulpits. It has analgesic and antipyretic activity 2.
confusion. depression and psychosis Hypersensitivity reactions like skin rashes. beta blockers and ACE inhibitors by causing salt and water retention Uses Rheumatoid arthritis Gout Ankylosing sodalities For closure of patent ductus arteriosus Nimesulide It is a sulfonamide compound is a weak inhibitor of prostaglandin synthesis with a higher affinity for COX-2 then COX-1 The action of nimesulide is somewhat different form that of classic NSAD It inhibits leukocyte function. inflammatory It is well absorbed orally. furosemide. prevents the release of mediators and in addition has antihistaminic and ant allergic properties It has analgesic. leucopenia and asthma in aspirin sensitive individuals Drug interactions Indomethacin blunts the diuretic action of furosemide and the anti-hypertensive action of thiazides. dizziness. hallucinations. extensively bound to plasma proteins and has a half life is 3 hours It is excreted by kidney Dose 50 -100 mg BD Adverse reaction . ataxia. antipyretic and anti-inflammatory actions like other ASAID May also inhibit release of tumor necrosis factor alpha and thus reduce the formation of cytokines Relief of mild to moderate pain and fever.150 CNS effects include headache.
inflammatory activity.151 Nausea Diarrhea. toothache. BD Small doses may be given 3-4 times a day to avoid gastric irritation Adverse effects Phenyl butazone is more toxic than aspirin and is poorly tolerated – dyspepsia. post-operative pain and arthritis It is beneficial in patients who develop bronchospasm with other NSAID Phenyl. is more potent but has poorer analgesic and antipyretic effects I is an urocosuric agent It causes retention of Na and water. Peptic ulceration and diarrhea may occur Hypersensitivity reactions like rashes. Thus after 1-2 weeks of use edema results It can also precipitate CHF Pharmacokinetics It is completely absorbed from orally IM injection is not recommended because its absorption is slow as it binds to local tissue proteins and also causes local tissue damage It is 98% bound to plasma proteins . Half life is 60 hrs Dose 100 – 200 mg . dermatitis and jaundice can occur . antipyretic and anti. epigastric distress nausea and vomiting . nephritis.inflammatory agent for short periods as in headache. serum sickness stomatitis hepatitis. myalgia. Vomiting Rash Dizziness Somnolence Headache Long term use can cause hepatotoxicity Uses It is used as an analgesic. dysmenorrheal. sinusitis.butazone It has good anti.
optic neuritis.152 It may inhibit iodine uptake by thyroid resulting in hypothyroidism and goiter on lojg term use CNS effects like insomnia vertigo. antipyretic and anti-inflammatory agent It is tissue penetrability is good and attains good concentration n synovial fluid which is maintained for a long time Mechanism if action Inhibition of the enzyme cycloxygenase in prostaglandin synthesis Prostaglandins are known to be associated with inflammation Diclofenac is available as the sodium or potassium salt The potassium salts are absorbed rapidly and action sets in much earlier Adverse effects are mild Dose 50 mg BD. toxic and drug interaction profile Dose 100 – 200 mg BD Diclofenac sodium Diclofenac is an analgesic. pharmacokinetic.TDS . blurring of vision and convulsions may be encountered Uses Rheumatoid arthritis Ankylosing sodalities Osteoarthritis Gout Other musculoskeletal disorders Oxyphenbutazone It is a major metabolite of phenylbutazone. similar in pharmacodynamic.
operatively for relief of pain and inflammation Severely painful conditions live acute pulpits and acute periapical abscess Mephenamic acid An analgesic.displacement interactions can occur Plasma half life is 2 – 4 hrs Adverse effects Diarrhea is the most important dose related side effect Epigastria distress is complained. antipyretic and anti-inflammatory drug which inhibits COX as will as antagonists certain actions of PGS Mephenamic acid exerts peripheral as will as central analgesic action Pharmacokinetics Oral absorption is slow but almost complete It is highly bound to plasma proteins.153 Gel is available for topical application Ophthalmic preparation is available for use in postoperative pain Uses Treatment of chromic inflammatory conditions like rheumatoid arthritis and osteoarthritis Acute musculo-skeletal pain Post. joint and soft tissue pain where strong anti-inflammatory action is not needed It may be useful in some cases of rheumatoid and osteoarthritis but has mo distinct advantage . dizziness and other CNS manifestations have occurred Hemolytic anemia is rare but serious complication Dose 250 – 500 mg TDS Uses Mephenamic acid is indicated primarily as analgesic in muscle. but bleeding is not significant Skin rashes.
semi-synthetic and synthetic drugs which have morphine like action i.154 Opioid analgesics Analgesics These are drugs which relieve pain without causing loss of consciousness Opioid analgesics These are the natural accruing. Benzo-isoquinoline derivatives Papaverine Noscapine 11. Synthetic opiods Pethidine Methadine Tramadol . Natural opium alkaloids Morphine Codeine B. Phenanthrene derivatives Morphine Codeine Thebaine B . Semi synthetic opium alkaloids Heroine Pholcodeine C. relief of pain and depression of CNS 1. According to ring structure A .e. According to synthesis A.
155 Morphine Morphine is a natural opium alkaloid It is a dried extract obtained from the capsules of the poppy plant known as papaver somniferum Mechanism of action Opioids exert their major effects by interacting with opioid receptors in the CNS Opioids causes hyper polarization of nerve eells . it produces sleep 3. inhibition of nerve firing and presynaptic inhibition of transmitter release Morphine acts at kappa receptors in lamina 1 and 11 of the substantia gelatinosa of the spinal cord and decreases the release of substance p.CNS Morphine produces euphoria in presence of pain But in the absence of pain . which is modulates pain perception in the spinal cord Pharmacological actions 1. it produces dysphoria With an increased dose. Analgesia Morphine causes analgesia Morphine relieves severe pain like visceral pain and pain of trauma Mechanisms Opioids relieve pain both by raising the pain threshold at the spinal cord level and more importantly by altering the brains perception of pain It alters the emotional reaction to pain It produces sleep which also elevates the threshold 2. Respiration At normal doses morphine causes respiratory depression by reduction of the sensitivity of respiratory center neurons to CO2 .
morphine directly stimulates the chemoreceptor trigger zone in the area postrema that causes vomiting Tolerance develops to vomiting on prolonged use But a large dose of morphine inhibits vomiting 6. Anti-tussive property Morphine has anti-tussive property Morphine suppress cough by depressing the cough center 5.156 At higher doses it produces respiratory ceases Respiratory depression is the most common cause of death in acute overdose 4. Billary tract Morphine increase billiary tract pressure due to contraction of the gallbladder and constrictor of the biliary sphincter This produces increase in intrabiliary pressure . results from stimulation of u and k receptors Morphine produces constriction of pupil ( miosis) The effect is blocked by atropine Morphine addicts have constricted pupil 7. Emesis In small doses. Pupil The pinpoint pupil. Gastro-intestinal tract Morphine decreases peristaltic propulsive movements It produces spasm of intestinal smooth muscles and sphincters It also increases absorption of water So the feces get dried All these effects lead t o constipation 8. characteristic of morphine use.
asthmatics should not receive the drug 11. cerebral vessels dilate and increase the cerebrospinal fluid pressure Morphine is usually contraindicated in individuals with severe brain injury 10.157 Atropine antagonizes t his effect 9. causing urticaria. Cardiovascular system Normal dose of morphine produces no effect on heart rate . ACTH It increases prolactin and growth h hormone release by diminishing dopaminergic inhibit ion It increases antidiuretic hormone and leads to urinary retention ADME Absorption of morphine from GI T is slow and incomplete Quick effect is produced on subcutaneous injection It is partly bound to plasma proteins It is metabolized by conjugation with glucuronic acid It is almost completely excreted in urine within 24 hours Dose Morphine sulphate or Morphine hydrochloride . FSH. Hormonal actions Morphine inhibits release of GRH and corticotrophic releasing hormone and it decreases the concentration of luteinizing hormone. Histamine release Morphine releases histamine from mast cells. seating and vasodilatation Morphine can cause the bronco-constriction . blood pressure or circulation But hypo tension and bradycardia may be produced at toxic dose Because of respiratory depression and carbon dioxide retention.
analgesic. motor and psychological responses that incapacitate the individual and cause serious .158 Adverse reactions GIT Symptoms – Nausea. monoamine oxidase inhibitors and tricycle antidepressants Tolerance and dependence Repeated use produces tolerance to the respiratory depressant. reduced body temperature. delirium and skin rashes Depression of fetal respiration Drug interactions The depressant actions of morphine are enhanced by phenothiazines. vomiting and constipation Acute morphine poisoning characterized by respiratory depression.and sedative effects of morphine Physical and psychological dependence readily occur with morphine Withdrawal produce a series of autonomic . euphoric . hypotension . shock and coma Tolerance and drug dependence Central effects like dysphoria and mental clouding Intolerance like tremor. pin point pupil cyanosis.unbearable symptoms Uses It is an analgesic for the relief of severe pain Used as pre-anesthetic medication For producing sleep and sedation Used as anti-tussive For the treatment of diarrhea In the treatment of acute left ventricular failure .
morphine Naturally .a synthetic cough depressant that has mo analgesic action and a low potential for abuse Codeine has good activity by oral route Single oral dose acts for 4 – 6 hours Constipation is a prominent side effect when it is used as analgesic It has been used to control diarrheas The abuse liability of codeine is low Though codeine phosphate is water soluble and can be injected Parental preparation is not available in India and most other countries . miosis and addiction are less with codeine It rarely produces dependence Codeine produces less euphoria then morphine Codeine is often used in combination with aspirin or acetaminophen In most non – prescription cough preparations . codeine has been replaced by drugs such as dextro.159 Codeine It is a phenanthrene alkaloid of opium It is methyl. nausea and vomiting . it appears in opium and is partly converted in the body to morphine It is less potent than morphine and also less efficacious It is more selective cough suppressant Sub-analgesic doses (10 – 30 mg ) suppress cough It has a predominant anti-tussive effect It is a less potent analgesic when compared to morphine Codeine has very low affinity y for opioid receptors The other action like spasmogenic effect.methorphan .
160 Heroin It is a diamorphine.brain barrier more rapidly than morphine Heroin is converted to morphine in the body It enters brain more rapidly but duration of action is similar It is considered to be more euphorient (specially on iv injection) and highly addicting The sedative. emetic and hypertensive actions are said to be less prominent It has mo outstanding therapeutic advantage over morphine and has been banned in most countries except U.K Pethidine It is a synthetic compound It is a opioid structurally unrelated to morphine It is used for acute pain . or diacetylmorphine It does not occur naturally It is produced by di-acetylation of morphine It is a semi-synthetic derivative of morphine It is a about 3 times more potent than morphine It is more lipid soluble Due to its greater lipid solubility allows it to cross the blood.
tussive effects Pharmacokinetics It is well absorbed from the GIT when given orally and parental administration It most often administered IM It crosses the placental barrier.161 Mechanism of action Pethidine binds to opioid receptors. it produces a decrease in peripheral resistance and an increase in peripheral blood flow and it may cause an increase in cardiac rate It does not produces the anti. It also secreted in the milk T he drug has a duration of action of two to four hours which shorter than that of morphine It is converted normeperidin the liver and is excreted in the urine DOSE Pethidine hydrochloride tablets – 25 –100 mg Pethidine hydrochloride injection – 25 – 100 mg by subcutaneous or intramuscular injection and 25 to 50 mg by iv injection Adverse reactions . increases CSF pressure and contracts smooth muscle It does not cause pinpoint pupil but rather causes the pupils to dilate because of an atropine like action It has mo significant cardiovascular action when given orally On IV administration . particularly U receptors It also binds well to k receptors Pharmacological actions Respiratory depression Sedation and euphoria Analgesic effect Spasmogenic effect on smooth muscles and sphincters It dilates cerebral vessels.
nausea and vomiting Local irritation on parenteral administration Respiratory depression. coma and convulsions Addiction and tolerance Uses It provides analgesia for any type of severe apin For producing sedation and sleep As pre-anesthetic medication Methadone it is a synthetic. dysphoria. orally effective opioid it has equal potency to morphine it produce less euphoria and has a somewhat longer duration of action It has somewhat longer duration of action than morphine .162 Euphoria. weakness and palpitation Depression o fetal respiration Dry mouth.
constipating and biliary actions similar to morphine Pharmaco-kinetic actions It is readily absorbed following oral administration It accumulates in tissues. emetic . where it remains bound to proteins. respiratory depressant . anti-tussive . from which it is slowly released The drug is biotransformed in the liver and excreted in the urine Adverse effects It can produce physical dependence like that of morphine Uses It has been used primarily as substitution therapy opioid dependence It can also be used as an analgesic for the same conditions as morphine It is occasionally employed as anti-tussive Tramadol It is a centrally acting analgesic that binds to the u – opioid receptor It weakly inhibits re-uptake of nor-epinephrine and serotonin It is used to manage moderate to moderately severe pain Its respiratory-depressant activity is less than that of morphine .163 Mechanism of action The actions of methadone are mediated by the u receptors Pharmacological actions It is chemically dis-similar but pharmacologically very similar to morphine It has analgesic .
100 mg SR tab 50 mg/ml inj in 1 and 2 ml amps Opioid antagonists Pure opioid antagonists 1. Naltrexone 3.164 Its analgesic action is only partially reversed by opioid antagonist known as naloxone Tramadol causes less respiratory depression. sedation. urinary retention and rise in intrabiliary pressure than morphine It is well tolerated Pharmaco-kinetics Oral bioavailability is good The half life is 3-5 hrs and effects last 4-6 hrs Adverse effects Dizziness Nausea Sleepiness Dry mouth Sweating Drug interaction Tramadol should also be avoided in patients taking mono amine oxidase inhibitors Dose 50 mg cap. constipation. Nalmefene . Naloxone 2.
Naltrexone It is chemically related to naloxone and is anther pure opioid antagonist It is more potent than naloxone It has actions similar to those of naloxone Naltrexone differs from naloxone in being orally active and having a long duration of action (1 – 2 days) .morphone and a competitive antagonist on all types of opioid receptors It blocks u receptors at much lower doses than those needed to block k or delta receptors Naloxone is a competitive antagonist at u.8 mg ) . Naloxone It is N.fold higher affinity for u receptors than for k Naloxone produces no pharmacologic effects in normal individuals .bound opioid molecules and is able to reverse the effect of a heroin overdose Within 30 sec of iv injection of naloxone. the respiratory depression and come characteristic of high doses of heroin are reversed.4 – 0. k and delta receptors with a ten. causing the patient to be revived and alert Naloxone has a half-life o f60 – 100 minutes No physical or psychological dependence has been observed Injected intravenously (0.4 mg iv every 2 -3 min. it acts in 2 – 3 min The primary pathway of metabolism is glucuronidation Plasma half life is 1 hour in adults and 3 hours in new borns USES Naloxine is the drug of choice for morphine poisoning ( 0.165 1. maximum 10 mg) It also partially reverses alcohol intoxication 2. it promptly antagonizes all actions of morphine It is inactive orally because of high first pass metabolism in liver Injected iv . but it precipitates withdrawal symptoms in opioid abusers Naloxone is used to reverse the coma and respiratory depression of opioid overdose It rapidly displaces all receptor.alyl-nor.oxy.
but benzodiazepines and clonidine are preferred Naltrexone is hepatotoxic Dose 50 mg tab Side effects Nausea Headache Higher doses can causes hepatotoxicity 3.166 It has a longer duration of action than naloxone and a single oral dose of naltrexone blocks the effect of injected heroin for up to 48 hours Alcohol craving is also reduced by naltrexone . Chronic hypoventilation with CO2 retention 2. Post anesthetic respiratory depression . Respiratory failure in newborns 3. it is being used to prevent relapse of heavy drinking Naltrexone in combination with clonidine and sometimes with bruprenorphine is employed for rapid opioid detoxification It may also be beneficial in treating chronic alcoholism by an unknown mechanism . Nalmefene This is recently developed pure opioid antagonist lacks No hepatotoxicity It has higher oral bioavailability and long duration of action CNS Stimulants These are brain stimulants which markedly stimulate the respiration and circulation These in large doses acts as convulsants’The. Respiratory failure due to overdose of CNS depressants 4.y are useful in the following conditions 1.
the most widely consumed stimulant in the world. cola drinks . Xanthene alkaloids Caffeine Theophylline Theo-bromine Aminophylline 2.167 1. is found in highest concentration in coffee. but is also present in tea. Direct CNS stimulants A. chocolate candy and cocoa Mechanism of action . Sympathomimetics Amphetamine Methyl phenidate B. Cortical stimulants 1. Spinal stimulants Strychnine 11. Reflex CNS Stimulants Lobeline Nicotine Veratrine Ammonia Xanthene alkaloids Methyl xanthenes includes theophyline found in tea and Theo bromine found in cocoa Caffeine . Medularly stimulants Picrotoxin Pentylene-tetrazol Nikethamide Doxapram C.
168 Several mechanisms have been proposed for the actions of methylxanthine All Xanthene alkaloids inhibit phosphodiesterase and blockade of adenosine receptors Due to above mechanism there is increase in translocation of extra cellular calcium Increase in cyclic adenosine monophosphare Increase in cyclic guanosine monophosphate Which causes various pharmacological actions including increase in force of contraction of heart and relaxation of vascular and non vascular smooth muscles Pharmacological actions On CNS The caffeine contained in one to two cups of coffee (100 – 200mg) causes a decrease fatigue and increased mental alertness as a result of stimulating t he cortex and other areas of the brain Consumption of 1. chloride and potassium . also they produces dilatation of coronary and pulmonary blood vessels due to the stimulation of vagal nerve On bronchioles Caffeine and its derivatives relax the smooth muscles of the bronchioles Decrease in fatigue of smooth muscles Diuretic action Caffeine has a mild diuretic action that increases urinary output of sodium. vasomotor and vagal centers Tolerance can rapidly develop to the stimulating properties of caffeine Withdrawal consists of feelings of fatigue and sedation On CVS A high dose of caffeine has positive inotropic and chronotropic effects on the heart Increased contractivity can be harmful to patients with angina pectoris Xanthenes produce a direct stimulant effect on the myocardium.5 grams of caffeine ( 12 – 15 cups of coffee ) produces anxiety and tremors The spinal cord is stimulated only by very high doses (2 -5 g) of caffeine It also produces stimulation or respiratory .
Methylxanthines stimulates secretion of hydrochloric acid from the gastric mucosa Individuals with peptic ulcers should avoid beverages containing methylxanthines
The methylxanthines are well absorbed orally Caffeine distributes throughout the body , including the brain The drugs cross the placenta to the fetus and are secreted into the mothers milk All the methylxanthines are metabolized in the liver and the metabolites are then excreted in the urine
Moderate doses of caffeine cause insomnia , anxiety and agitation High dosage is produced emesis and convulsions The lethal dose is about 10 grams of caffeine about 100 cups of coffee which induce cardiac arrhythmias Lethargy, irritability and headache occur in users who have routinely consumed more than 600 mg of caffeine per day roughly six cups of coffee per day and then suddenly stop
Caffeine and its derivatives relax the smooth muscles of the bronchioles Antidepressants Coronary vasodilators Diuretics
It is the active ingredient in tobacco The drug is not currently used therapeutically except in smoking It is mostly widely used CNS stimulant
170 Nicotine represents a serious risk factor for lung and cardiovascular disease and various cancers Dependency on the drug is not easily overcome
Mechanism of action
In low doses, nicotine causes gang ionic stimulation by depolarization At high doses, nicotine causes gang ionic blockade Nicotine receptors exist in the CNS, where similar actions occurs
Nicotine is highly soluble in lipid and readily crosses the blood-brain barrier Cigarette smoking or administration of doses of nicotine produces some degree of euphoria and arousal as well as relaxation It improves attention, learning , problem solving and reaction time High doses of nicotine result in central respiratory paralysis and severe hypotension caused by modularly paralysis
The peripheral effects of nicotine are complex Stimulation of sympathetic ganglia as well as the adrenal medulla increases blood pressure and heart rate The use of tobacco is particularly harmful in hypertensive patients Stimulation of parasympathetic ganglia also increases motor activity of the bowel At higher doses , blood pressure falls and activity ceases in both the GIT and bladder musculature
Nicotine is highly lipid-soluble Absorption readily occurs via the oral mucosa, lungs, gastrointestinal mucosa and skin Nicotine crosses the placental membrane and is secreted in the milk if lactating women
Most cigarettes contain 6-8 mg of nicotine The acute lethal dose is 60 mg More than 90% of nicotine inhaled in smoke is absorbed Clearance if nicotine involves metabolism in the lung and the liver and urinary excretion Tolerance to the toxic effects of nicotine develops rapidly
The CNS effects of nicotine include irritability and tremors Nicotine may also cause intestinal cramps, diarrhea and increased heart rate and blood pressure Cigarette smoking increases the rate of metabolism for a number of drugs
Nicotine is an addictive substance and physical dependence on nicotine develops rapidly and is severe Withdrawal is characterized by irritability, anxiety, restlessness, difficulty concentrating , headaches and insomnia Appetite is affected and gastrointestinal pain often occurs
Cocaine is an inexpensive , widely available and highly addictive drug that is currently abused daily by more than three million people in the USA It is an alkaloid obtained from the leaves of coca plant It is insoluble in water but its salts are soluble in water
smoking or intravenous injection The peak effect occurs at fifteen to twenty minutes after intra-nasal intake of cocaine powder . cocaine potentates the action of nor-adrenaline and produces the fight or flight syndrome characteristic of adrenergic stimulation This is associated with tachycardia.172 It is poorly absorbed in the intestines but well absorbed by the mucous membrane and it can be given as surface anesthetic Mechanism of action The primary mechanism of action of cocaine is blockade of re-uptake of the monoamines ( nor epinephrine. papillary dilation and peripheral vasoconstriction Local anesthetic action Dilates pupil Raise the body temperature Rise the BP Produces euphoria Pharmacokinetics Cocaine is often self-administered by chewing intra-nasal snorting. hypertension. followed by respiratory and vasomotor depression Sympathetic nervous system Peripherally. serotonin and dopamine) into t he presymaptic terminals from which these neurotransmitters are released Pharmacological actions On CNS CNS stimulant Cocaine acutely increases mental awareness and produces a feeling of well being and euphoria similar to that caused by amphetamine Cocaine can produces hallucinations and delusions Cocaine increases motor activity and at high doses m it causes tremors and convulsions.
ear .nose and throat surgery The anesthetic action of cocaine is due to a block of voltage – activated sodium channels An interaction with potassium channels may contribute to the ability of cocaine to cause cardiac arrhythmias Drug Abuse The use of drugs for non-therapeutic purposes and mainly the drugs acting on CNS is termed as misuse or drug abuse.173 Rapid but short-lived effects are achieved following iv injection of cocaine Toxic effects Mental excitement Confusion Tremors Convulsions Respiratory paralysis Stimulation followed by depression Cocaine can induce seizures as well as fatal cardiac arrhythmias IV administration of diazepam and propranolol may be required to control cocaine – induced seizures and cardiac arrhythmias Dose 8 – 16 mg by injection Adrenaline has to be given along with cocaine which produces local vasoconstriction and prolong the local anesthetic effect Uses Cocaine has a local anesthetic action Cocaine is applied topically as a local anesthetic during eye. .
cannabis and mescaline.174 They may be misused for the production of dangerous and thrilling effects for escaping from physical discomforts like hunger.frustration and anxiety. Generally the drugs which are abused are – ethanol. LSD-25 . Public must be given drug education on the harmful physical and mental effects of drug dependence and abuse Legal prohibition of possession and transportation in these drugs which may be abused for non-medical purposes . Reduction of interest in and demand for such drugs for non-medical use. fatigue. methaqualon. methadone. Control of drug dependence and abuse First it should be identified whether the dependence on a particular drug is addiction or abuse or socially acceptable. morphine. pethidine. The methods of controlling drug abuse are Limitation of availability of specified drugs for the addicted persons. diazepam. heroin. pain or mental discomforts like boredom .
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