Unit-IV

Pharmacology of drugs acting on central Nervous system

Neurohumoral transmission in the CNS:-

• Four process occur in relation to nerve transmission within the CNS.
• These process are mediated through different transmitters.

These are Follow

i) Neurotransmission occurs through neurotransmitters, which are released in to synaptic cleft, to rapidly stimulate (or) inhibit the post-synaptic neurons.

ii) Neuro-modulation occurs through neuromodulators, which are released by neurons and by astrocytes and act either to slow (or) enhance the pre (or) post synaptic responses.

iii) Neuromediation occurs through neuromediators, which are second messengers like cAMP and $IP_3$.

iv) Neurotropic affects occur through neurotropic factors, which are secreted by neurons, microglia and astrocytes. They act over a longer time to regulate the growth and morphology of neurons.
Some of the major neurotransmitters are

GABA

• GABA (Gamma-Aminobutyric acid) is a major inhibitory neurotransmitter in mammalian CNS.
• It is present fairly uniformly in the brain, very little amount exists in the periphery.
• GABA is synthesized from glutamate by the action of enzyme L-glutamic acid-1-decarboxylase (GAD).
• It is further metabolised by GABA transaminase (GABA-T) to succinic semi-aldehyde and succinic acid.

Synthesis of GABA

Glutamine $\xrightarrow{\text{Glutaminase}}$ Glutamate $\xrightarrow{\text{Glutamate decarboxylase (GAD)}}$ GABA

Metabolism of GABA

GABA $\xrightarrow{\text{GABA-T}}$ Succinic semialdehyde $\xrightarrow{\text{oxidation}}$ Succinate

• There are 2 types of GABA receptors:
  (i) $GABA_A$
  (ii) $GABA_B$

(i) $GABA_A$ receptors

• These are ionotropic receptors.
• They are located post-synaptically and are linked with chloride ion channel.
• Causes hyperpolarisation and reduction in the excitability.
• The major isoform of $GABA_A$ receptor in the brain consists of 5 sub units, namely two $\alpha$, two $\beta$ & one $\gamma$ sub units.

(ii) $GABA_B$ receptors

• It is a G-protein coupled receptor.
• Its activation decreases formation of cAMP.
• These receptors cause pre & post-synaptic inhibition by inhibiting calcium channel opening and increasing $K^+$ conductance.
• The competitive antagonist for $GABA_B$ receptor is saclofen, which has no Clinical use.

Glutamate

• In brain, glutamate is synthesized in the nerve terminals from 2 sources:
  (i) From glucose via Krebs cycle and transamination of $\alpha$-oxaglutarate.
  (ii) From glutamine which is synthesized in glial cells.
• Glutamate is stored in synaptic vesicles & released by calcium dependent exocytosis.
• After action, Glutamate is recaptured by neuronal transporters (GTn) in to the neuron and by glial type transporters (GTg) in to the glial cells.
• Glial glutamate then converted to glutamine by the enzyme glutamine synthetase.
• Later, glutamine enters the adjacent neuron to replenish the glutamine after hydrolysis by mitochondrial glutaminase.
• Five different types of glutamate receptors have been identified.
• Out of these five types, 3 are (NMDA, AMPA, kainate) are ionotropic receptors.
• The other two are metabotropic receptors. Role of metabotropic receptors is being unfolded by new research.

NMDA receptors

• NMDA refers to N-methyl-D-aspartate.
• The receptors are involved in a wide range of diverse functions like memory acquisition, development of synaptic plasticity, epilepsy & neuronal excitotoxicity due to cerebral ischaemia.
• It has atleast 6 binding & modulatory sites.

AMPA & kainate receptors:-

• AMPA refers to $\alpha$-amino-3-hydroxy-5-methylisoxazole-4-propionic acid.
• Both AMPA and kainate receptors mediate fast excitatory synaptic transmission associated with influx of sodium ions through sodium channels.
• AMPA receptors consisting of GLUR 1-4 sub-units.
• Kainate receptors consist of GLUR 5-7 & KA 1-2 sub units.

Glycine

• It is an inhibitory neuro-transmitter, enriched in medulla, spinal cord, the lower brain stem & retina.
• It is structurally & functionally similar to $GABA_A$ receptor and is directly linked to chloride ion channel.

Synthesis : Glutamic acid $\rightarrow$ GABA Serine $\rightarrow$ Glycine

• Release - exocytosis by $Ca^{++}$

Serotonin: (5-hydroxytryptamine, 5-HT)

• It is a neurotransmitter in CNS as well as a regulator of smooth muscle function in CVS and GIT and a regulator of platelet function.

Synthesis : Tryptophan $\xrightarrow{\text{tryptophan hydroxylase}}$ 5-hydroxy tryptophan $\xrightarrow{\text{decarboxylase}}$ 5-hydroxytryptamine (serotonin)

• 5-HT is stored in specialised cells like enterochromaffin cells & in neurons together with various peptide hormones like Somatostatin, Vasoactive intestinal peptide (VIP) as co-transmitter.
• Degradation of 5-HT occurs through oxidative deamination by MAO to 5-hydroxy indole acetaldehyde followed by its oxidation to 5-hydroxy indole acetic acid, which is excreted in urine.

Pharmacological actions :

• CNS : Regulation of mood, behaviour, sleep, thermoregulation.
• CVS : Contraction of vascular smooth muscle except skeletal muscle.
• GIT : Stimulates peristalsis by $\uparrow$ acid & pepsin.

Dopamine (DA)

• It is the most important of the biogenic neurotransmitters in CNS.
• Parkinson's disease is characterised by a marked reduction in the concentration of DA in basal ganglia, while in schizophrenia there is dopaminergic overactivity in the pathway of brain which controls behaviour.
• It is primarily an inhibitory neurotransmitter.
• Five types of DA receptors have been identified among them $D_1$ & $D_5$ belong to one group. $D_2$, $D_3$ & $D_4$ belong to another group.

Synthesis : Tyrosine $\xrightarrow{\text{tyrosine hydroxylase}}$ L-Dopa $\xrightarrow{\text{Dopa decarboxylase}}$ Dopamine

• Dopamine is taken up in to the vesicles by vesicular monoamino transporter (VMAT).
• It is released by exocytosis.
• Reuptake in to presynaptic terminal via VMAT/DAT/PMAT.

General Anaesthetics

• General Anaesthetics (GAs) are drugs which produce reversible loss of all sensation and consciousness.

• The cardinal features of general anaesthesia are
  (i) loss of all sensation, especially pain
  (ii) sleep & amnesia
  (iii) Immobility & muscle relaxation.
  (iv) Alteration of somatic and autonomic reflexes.

Mechanism of General Anaesthesia

• The mechanism of action of GAs is not precisely known.
• Inhalation anaesthetics are non-selective in their actions.
• At molecular level, anaesthetics interact with hydrophobic regions of neuronal membrane proteins which are on interface with membrane lipids.
• Inhaled anaesthetics like barbiturates, benzodiazepines, etomidate and propofol facilitate GABA-mediated inhibition and there by increase chloride ion flux.
• Ketamine blocks the NMDA receptor channel through its action of glutamate.
• Inhalation anaesthetics like enflurane and isoflurane decreases the duration of opening of nicotinic receptor activated sodium ion channels leading to decrease in excitatory effects at cholinergic synapses.
• By influencing neuronal membrane proteins general anaesthetics disrupt neuronal firing and sensory processing in the thalamus, causing loss of consciousness and analgesic effects.
• In addition, motor activity reduce because they decrease neuronal output from the internal pyrimidal layer of cerebral cortex.

Minimal Alveolar Concentration (MAC)

• It is "the lowest concentration of anaesthetic in pulmonary alveoli need to produce immobility in response to a painful stimulus in 50% individuals".
• It is accepted as a fairly valid measure of potency of inhalational GAs, because it remains constant for most young adults.
• The MAC of all inhalational anaesthetics declines progressively as age advances beyond 50 years.

Stages of Anaesthesia

• GAs cause an irregularly descending depression of the CNS, i.e the higher functions are lost first and progressively lower areas of the brain are involved, but in the spinal cord lower segments are affected somewhat earlier than the higher segments.
• Different stages of anaesthesia are:

Stage I: Stage of analgesia

• Starts from begininning of anaesthetic inhalation and lasts upto the loss of consciousness.
• Pain is progressively abolished.
• Patient remains conscious, can hear and see, feels a dream like state, amnesia develops by the end of this stage.
• Reflexes and respiration remain normal.

Stage II: Stage of Delirium

• From loss of consciousness to beginning of regular respiration.
• Apparent excitement is seen, patient may shout, struggle and hold his breath etc.
• Heart rate and BP may rise and pupils dilate due to sympathetic simulation.

Stage III: Surgical Anaesthesia

• Extends from onset of regular respiration to cessation of spontaneous breathing.

• This has been divided in to 4 planes:

  • plane 1:- Roving eyeballs. This plane ends when eyes become fixed.
  • plane 2:- loss of corneal and laryngeal reflexes.
  • plane 3:- pupil starts dilating and light reflex is lost.
  • plane 4:- Intercostal paralysis, shallow abdominal respiration, dilated pupil.

Stage IV: Medullary Paralysis:

• Cessation of breathing and failure of circulation and death.
• Pupil is widely dilated, muscles are totally flabby, pulse is thready (or) imperceptible, BP is very low.

Classification of General Anaesthetics

• They are classified as

(i) Inhalational
(ii) Intravenous

1. Inhalational

• Gas: Nitrous oxide
• Volatile liquids: Ether, isoflurane, Halothane, desflurane, sevoflurane
• Inhalational anaesthetics exist in two forms: (i) gas (ii) liquid.

2. Intravenous

• They are subclassified as:
  • fast acting drugs: Thiopentone sod., Methohexitone sod., propofol, etomidate.
  • slower acting drugs: Benzodiazepines (diazepam, lorazepam, midazolam), dissosciate anaesthesia (Ketamine), opioid analgesia (fentanyl).

Pharmacokinetics of Inhalational Anaesthetics

• Inhalational anaesthetics are gases that diffuse rapidly across pulmonary alveoli and tissue barriers.
• The principles of pharmacokinetics include induction, maintainance, & recovery.

Induction

• It is the time interval between the administration of anaesthetic drug and the development of stage of surgical anaesthesia.
• Lipophilicity is key factor governing pharmacokinetics of inducing drugs.

Maintainance

• It is the period during which the patient remains in a sustained stage of surgical anaesthesia.
• During this stage, the anaesthesiologist monitors the patient's vital signs and response to various stimuli by controlling concentration of anaesthetic to be inhaled (or) infused based on depth of anaesthesia.

Recovery

• The recovery phase starts when the anaesthetic drug is discontinued.
• During this phase, the anaesthesiologist has to ensure that there are no delayed toxic reactions.

Inhalation Anaesthetics

i. Nitrous oxide:

• It has a mild sweetish smell.
• It is used to maintain surgical anaesthesia with 30% oxygen and other volatile anaesthetics like halothane, isoflurane, propofol & a muscle relaxant if required.

ii. Halothane:

• It is a halogenated volatile anaesthetic.
• It is a poor analgesic and poor muscle relaxant. It is used along with nitrous oxide, opioids and skeletal muscle relaxants.

iii. Isoflurane:

• It is a structural derivative of enflurane.
• It is also a potent coronary vasodilator.

iv. Sevoflurane:

• It is a non-pungent anaesthetic.
• It is a good muscle relaxant.

Intravenous Anaesthetics

Thiopental:

• It is a ultra-short acting thiobarbiturate.
• It reduces cerebral blood flow & intracranial pressure.
• It also reduces respiratory rate and tidal volume.

Methohexital:

• Its use has declined due to restlessness, coughing and hiccups during recovery.

Propofol:

• It has no analgesic (or) muscle relaxant effects.
• It possesses anti-convulsant action.
• It causes dose-dependent cortical depression. It is preferred for out-patient surgery.

Complications of general anaesthesia

• During Anaesthesia:

  • Respiratory depression & hypercarbia.
  • Salivation, respiratory secretions.
  • Cardiac arrhythmias, asystole & fall in BP.
  • laryngospasm and asphyxia.

• After Anaesthesia:

  • Nausea & vomiting
  • Persisting sedation
  • Pneumonia
  • Organ toxicities
  • Emergence delirium
  • Cognitive defects.

Pre-anaesthetics

• Pre-anaesthetics refers to the use of drugs before anaesthesia to make it more pleasant and safe.
• The aim of pre-anaesthetic medication is to ensure comfort to the patient and minimise adverse effects of anaesthesia.

• Following drugs are used as preanaesthetics:

  (i) Antianxiety Drugs :

  • Benzodiazepines like diazepam (or) lorazepam are used.

  (ii) Sedative-Hypnotics :

  • In addition to BZDs, promethazine is widely used.
  • It is an antihistamine with sedative, antiemetic & anticholinergic actions.
  • It causes negligible respiratory depression & is useful for children.

  (iii) Opioid Analgesics :

  • Morphine (or) pethidine is used.
  • Fentanil may be used.

  (iv) Anticholinergics :

  • Atropine (or) hyoscine or glycopyrrolate are used to reduce salivary, bronchial secretions, produce bradycardia, and hypotension.

  (v) Antiemetics :

  • Metoclopramide, domperidone or ondansetron are used for gastric emptying prior to emergency surgery.
  • These drugs may be combined with histamine \H_2 receptor blockers.

  (vi) $H_2$ Receptor Blockers :

  • Ranitidine, (or) famotidine are given in night before and in the morning before surgery.

Sedative, Hypnotics

• Sedatives is a drug that subdues excitement and calms the subject without inducing sleep, though drowsiness may be produced. Sedation refers to decreased responsiveness to any level of stimulation.
• Hypnotics are the drugs that induces and/or maintains sleep similar to normal arousable sleep.
• Increasing grades of CNS depression are: Sedation $\rightarrow$ hypnosis $\rightarrow$ general anesthesia $\rightarrow$ coma.

Classification

1. Barbiturates

   • long acting: phenobarbitone
   • short acting: butobarbitone, pentobarbitone
   • ultra-short acting: thiopentone, methohexitone

2. Benzodiazepines

   • antianxiety: diazepam, chlordiazepoxide, lorazepam, alprazolam
   • hypnotic: diazepam, flurazepam, nitrazepam, triazolam
   • anticonvulsant: diazepam, lorazepam, clonazepam, clobazam

3. Newer Non Benzodiazepine Hypnotics

   • zopiclone, zolpidem, zaleplon

i) Barbiturates

• Barbiturates are substituted derivatives of barbituric acid.
• These possess sedative hypnotic properties, & anticonvulsant actions.

Mechanism of Action

• Barbiturates act on the channel modulatory site of $GABA_A$ receptor and potentiate the GABA mediated inhibitory effects by increasing the duration of chloride channel opening.
• At high doses, barbiturates directly increase chloride ion conductance and exhibit GABA-mimetic action and not a GABA facilitatory action.

Pharmacokinetics

• The rate of absorption of barbiturates depends on their lipid solubility.
• They are widely distributed depending on lipid solubility and regional blood flow.
• They are metabolized both by phase I and phase II processes.
• Phase I involves microsomal oxidation while phase II involves glucuronide conjugation.
• They are excreted through urine; but are readily reabsorbed from renal tubules.

Pharmacological Effects

• The ultra-short acting barbiturates exhibit dose-dependent CNS depressant action.
• The long acting barbiturates possess sedative & anticonvulsant actions.
• They may show hyperalgesia action i.e., they may increase reaction to painful stimuli.
• Sedative-hypnotic doses have no effect on cardiovascular system.
• high doses decrease blood pressure, heart rate & depress myocardium.
• Sedative hypnotic doses do not affect respiration. higher doses depress respiration and cause shallow breath.
• Prolonged use increases the size and weight of smooth endoplasmic reticulum leading to enzyme induction.
• higher doses have relaxant affect on GIT, bladder & uterus.

Use

• In anaesthesia: ultra short-acting barbiturates like thiopental are used as intravenous fast inducing anaesthetics.
• As sedative-hypnotics.
• As anticonvulsants: long-acting barbiturates like phenobarbital are used for this purpose & treat hyperbilirubinaemia.

Adverse Effects

• Repeated use of barbiturates causes metabolic tolerance due to enzyme induction.
• They can cause psychic as well as physical dependence on withdrawl after prolonged use.
• They cause hangover, impairment of judgement and drug automatism.
• They cause respiratory depression, laryngeal edema & hypersensitivity reactions causing skin rash & swelling of lips & eyelids.

2) Benzodiazepines (BZDs)

• These were introduced after barbiturates, & they are prefered drugs for hypnotic and sedative activities because:
  1. BZDs produce a lower degree of neuronal depression than barbiturates.
  2. hypnotic doses do not affect respiration (or) cardiovascular functions.
  3. BZDs have practically no action on other body systems. Only on iv injection the BP falls & cardiac contractility decreases.
  4. BZDs cause less distortion of sleep architecture.
  5. BZDs do not alter disposition of other drugs by microsomal enzyme induction.

Mechanism of Action

• Benzodiazepines act preferentially on midbrain & on limbic system.
• BZDs facilitate action on $GABA_A$ receptors.
• BZDs selectively bind with high affinity to the modulatory site on $GABA_A$ receptor in such a way that the binding of GABA to $GABA_A$ receptor is facilitated.
• This modulatory site is distinct from the GABA binding site and is specified for BZDs hence it is also called as benzodiazepine receptor.
• BZDs neither substitute for GABA, nor activate $GABA_A$ receptor but enhance binding of GABA to the binding site of $GABA_A$ receptor to increase the frequency rather than duration of GABA-gated chloride channel opening.

Pharmacokinetics

• Only midazolam is given either by IM (or) IV route. All other BZDs are given orally.
• BZDs like diazepam, oxazepam, chlordiazepoxide are more than 90% bound to plasma protein.
• They cross placental barrier and have high volume of distribution, they are to be used cautiously in pregnancy.
• Active metabolites of present drug are as follows:
  Midazolam : hydroxymethylmidazolam
  diazepam : oxazepam nordiazepam Flurazepam : hydroxymethyl flurazepam
  alprazolam : alpha-hydroxy alprazolam

Uses

• To treat anxiety neuroses.
• To treat insomnia.
• For preanaesthetic medication and induction of anaesthesia.
• As skeletal muscle relaxant.
• As anti-convulsants.
• Treatment of alcohol withdrawl.

Adverse Reactions

• drowsiness, fatigue, disorientation, lethargy & tolerance develops slowly.
• dependance is mild.
• 2 types of BZD receptors have been identified: BZ1 & BZ2.
  • BZ1 receptors are found throughout the brain & in large concentrations in the cerebellum. They are responsible for antianxiety, sedative & hypnotic effects.
  • BZ2 receptors are found mainly in the cerebral cortex, hippocampus & spinal cord and are associated with muscle relaxation, anticonvulsant action & amnesia.

3) Non-benzodiazepine hypnotics

• Non-benzodiazepines like zolpidem, zaleplon, zopiclone, eszopiclone act on BZ1 receptors.
• These drugs have minimal muscle relaxant & anticonvulsant action.

Centrally acting muscle relaxants

• These drugs reduce skeletal muscle tone by a selective action in the cerebrospinal axis without altering consciousness.
• Spasticity is characterised by an increase in tonic stretch reflexes and flexor muscle spasm along with muscle weakness.
• It is associated with disease like cerebral palsy and multiple sclerosis.
• Antispastic drugs control the symptoms of spasticity either by enhancing the activity of inhibitory neurons of the reflex arc (or) by interfering directly with skeletal muscle excitation contraction coupling.
• Their mode of action is non specific & is described as depressants of polysynaptic reflexes at spinal level.

(i) Mephenesin group

• It involves drugs like carisoprodol, chlorzoxazone, chlormezanone & methocarbamol.
• These drugs are blocking agents at the level of brain stem & spinal neuron.
• They are used to treat muscle spasm.

(ii) Benzodiazepine group

• Diazepam, clonazepam have antispastic action.
• They enhance GABA-ergic transmission in brain as well as other GABA synapses.
• They inhibit both monosynaptic & polysynaptic reflexes and produce marked sedation.

(iii) GABA derivative

• Baclofen is an orally active GABA-mimetic drug which acts as an agonist on $GABA_B$ receptors.
• The $GABA_B$ receptors are G-protein coupled receptors which hyperpolarise neurons by increasing potassium ion conductance and reducing calcium ion conductance.
• At spinal level, it inhibits both monosynaptic & polysynaptic responses.
• It is used to relieve painful spasticity & reduces pain associated with spastic conditions.

(iv) Central $\alpha_2$ agonist

• Tizanidine is an $\alpha_2$-agonist with action on CNS and alters neuronal activity in the spinal cord.
• It antagonises spasticity at doses which have minimal effect on blood pressure in comparison to clonidine.

Anti-epileptics

• Epilepsy is a common neurological abnormality characterised by occurence of seizures.
• A seizure means a paroxysmal abnormal discharge at high frequency, from an aggregate of neurons in cerebral cortex.
• Epilepsy involve recurrent seizures.
• Convulsions are involuntary violent & spasmodic (or) prolonged contractions of skeletal muscle.
• A patient may have epilepsy without convulsions.

Classification of seizures

Seizures are classified in to:

(1) Generalised Seizures

• These seizures arise from both cerebral hemispheres and diencephelon simultaneously involving the entire body.
• They are of different types:

a) Grand mal (or) Tonic-clonic Seizures

• These are usually associated with an aura.
• The patient falls to the ground in stiff tonic phase with an epileptic cry, caused by contraction of laryngeal muscles, this is followed by clonic convulsions.
• which may last for 15-30 minutes & then to coma post-ictal state.

b) Petit mal (or) Absence Seizures

• Attack appears without warning.
• There is no loss of consciousness.
• The seizure lasts for few seconds without loss of postural control.
• These are characterised by rapid blinking of eyelids, & clonic jerk of hands.

c) Myoclonic Seizures

• These are bilateral epileptic myoclonus characterised by sudden and brief skeletal muscle contraction which may involve the entire body (or) one part of the body.

d) Atonic Seizures

• These are characterised by sudden loss of postural tone.
• The consciousness may be impaired for a brief period but there is no confusion.

e) Clonic Seizures

• These are characterised by repetitive muscle jerks.

f) Tonic Seizures

• These are characterised by rigid violent muscular contraction with stiff & fixed extended limbs.

(2) Partial Seizures

• also known as localised & focal seizures.
• These are the most common seizures.
• The seizure activity is restricted to a discrete area belonging to one cerebral hemisphere only.
• These are of 3 types:

a) Simple Partial Seizures (Jacksonian Seizures)

• These are characterised by unilateral clonic movements which begin in one group of muscles and spread gradually to adjacent group.
• No loss of consciousness.

b) Complex Partial Seizures (Psychomotor Epilepsy)

• These originate in the temporal lobe and the frontal lobe & are accompanied by partial loss of consciousness.
• patient behaves as partially conscious with automatism.

c) Partial Seizures Evolving to Secondary Generalised Seizures

• These are the type when partial seizures progress to generalised / tonic / clonic / tonic clonic seizures.
• Patients usually report aura before the seizures.

(3) Unclassified Seizures

• It covers undetermined epilepsies and epileptic syndromes like febrile seizures (or) infantile spasm.
• These are generalized tonic-clonic convulsions of short duration but are usually benign which may appear frightening.

Mechanism of Action of Anti-Epileptic Drugs

• Anticonvulsant drugs act by different mechanisms to suppress repetitive firing, action potentials by an epileptic focus in the brain.
• They are classified in two types:

(i) Mechanism in Grand mal and Partial Seizures

• Mechanisms is further sub-classified in to following sub-types:

a) Inhibition of use-dependent sodium ion channels * drugs like phenytoin, carbamazepine etc block voltage-gated sodium channels.

b) Enhancement of GABA ergic action * drugs like phenobarbital & benzodiazepines activate $GABA_A$ receptors to facilitate opening of chloride channels.

c) Blockade of NMDA (or) AMPA receptors * drugs like felbamate block NMDA receptors. * drugs like phenobarbital block AMPA receptors.

d) Blockade of voltage-gated N-type calcium channels * Selective blocking of synaptic vascular protein. f) By blocking effects of neurotropic factors

(ii) Mechanism in Petit Mal (absence seizures)

• It involves inhibition of T-type calcium channels.
• drugs like ethosuximide inhibit calcium channels.

Drugs

Types of seizures & drugs used to treat epilepsy are:

• Absence: ethosuximide, Valproate, lamotrigine, clonazepam
• Myoclonic: Clonazepam, Clobazam, Vigabatrin, topiramate, zonisamide
• Generalised Atonic, clonic, tonic, grand mal: felbamate, topiramate
• Partial Seizures:
  • $\rightarrow$ Simple partial: levetiracetam, tiagabine, carbamazepine, phenytoin
  • $\rightarrow$ Complex partial: oxcarbazepine, phenobarbitone, gabapentin, primidone
  • $\rightarrow$ Secondary generalised
• Unclassified:
  • Infantile spasm $\rightarrow$ ACTH, Vigabatrin
  • febrile $\rightarrow$ Midazolam, ganaxolone, rectal diazepam, diazepam

Alcohols and Disulfiram

• Alcohols (ethanol) are hydroxy derivatives (-OH) of aliphatic hydrocarbons.

Preparation

• Sugar $\xrightarrow{\text{zymase}}$ alcohol
• Starch $\xrightarrow{\text{maltase}}$ Maltose $\xrightarrow{\text{Yeast}}$ ...

Types of Alcohol

• (i) Malted liquors: eg Beer, stout - alcoholic % (3-10%)
• (ii) Wines: eg light wines (9-12%), fortified wines (16-22%), effervescent wines (12-16%)
• (iii) Spirits: eg Rum, Gin, whisky, brandy, vodka (40-55%)

Pharmacokinetics

• Ethanol is rapidly absorbed from GIT.
• It crosses BBB as well as placental barrier, but the concentration in brain is very close to that in blood.
• About 95% of absorbed alcohol is metabolised and remaining 5% is excreted through breath, urine & sweat.
• A sizable fraction of ethanol is cleared by first-pass hepatic metabolism, which follows zero-order kinetics.
• Ethanol is first metabolized to acetaldehyde and then to acetic acid.

Metabolism of Alcohol in Liver

Ethanol $\xrightarrow{\text{Alcohol dehydrogenase}}$ Acetaldehyde $\xrightarrow{\text{Aldehyde dehydrogenase}}$ Acetic acid $\rightarrow$ fatty acids / $CO_2$ + water

• The enzyme alcohol dehydrogenase, found in liver, stomach and intestine oxidises about 75% ethanol to acetaldehyde. Metabolism follows zero order kinetics.
• Another enzyme, mixed function oxidase (CYP450) mainly responsible for remaining 25% of ethanol metabolism.
• About 75-80% of acetaldehyde is converted to acetate in the liver by enzyme aldehyde dehydrogenase (ALDH).
• Only 20-25% of acetaldehyde is converted to acetic acid outside liver by an enzyme aldehyde oxidase.
• This leads to formation of acetate which is further metabolised to $CO_2$ & water.

Effects on Organs

CNS

• The acute effects of alcohol on CNS are sedation, relief from anxiety, loss of inhibitions and impaired judgement as well as driving skills, these effects occur at blood level 50-100 mg/dl.
• Blood levels of 120-160 mg/dl lead to effects like ataxia, slurred speech, mental clouding etc.
• levels b/w 200-300 mg/dl produce emesis, stupor.
• levels above 300 mg/dl lead to coma, respiratory & cardiovascular depression.
• levels above 500 mg/dl are lethal.

Heart

• At blood concentrations of 100 mg/dl ethanol decreases myocardial contractility. In large doses depress vasomotor centre leading to fall in BP.

Smooth Muscles & Other Effects

• Ethanol causes cutaneous vasodilation.
• It produces relaxation of uterus only at high conc.
• diuresis.

Pharmacological Effects (Chronic)

• Chronic ethanol intake adversely effect functions of several vital organs.

  Nervous System

  • Tolerance & dependance are major effects on CNS.
  • Chronic alcohol drinkers, if forced to abstain, experience distressing withdrawl symptoms with physical dependance.

  Neurotoxicity

  • Chronic heavy drinkers show ataxia, dementia, peripheral neuropathies.
  • Alcohol also impairs visual acuity with painless blurring of vision on chronic consumption.

  Liver and GIT

  • Chronic excessive ethanol consumption causes fatty liver with inflammation.
  • leads to irreversible hepatic necrosis, fibrosis...

  Cardiovascular System

  • Chronic alcohol consumption leads to dilated cardiomyopathy, ventricular hypertrophy & fibrosis.

  Endocrine Effects

  • Chronic alcoholism can produce testicular atrophy, gynaecomastia and impotence.
  • Pseudo-Cushing's syndrome is observed in chronic alcoholics.

  Effects on Foetal Development

  • Consumption of about 6-10 units of alcohol per day during pregnancy causes foetal alcohol syndrome.

  Clinical uses of Ethanol

• As a skin antiseptics.

• It has astringent action.

• Used to treat methanol poisoning.

Disulfiram

• The enzyme aldehyde dehydrogenase is inhibited by disulfiram and by other drugs including metronidazole, oral hypoglycemics, some cephalosporins like cefotetan, urinary antiseptics like nitrofurantoin.
• When alcohol is consumed in presence of disulfiram, conversion of acetaldehyde to acetic acid is significantly reduced hence acetaldehyde accumulates to cause effects like facial flushing, nausea, vomiting, dizziness & head ache.
• Hence, disulfiram can be used as an aversion therapy to discourage people from consuming alcohol.
• Adverse reactions of disulfiram include skin rashes, metallic taste & abdominal upset.