Sedative Hypnotics

These include 3 types of drugs;

• Benzodiazepines
• Barbiturates
• Miscellaneous agents

Benzodiazepines (BZ)

• These were introduced in 1960.
• These are most commonly used.

Mechanism of Action

• It is based on GABA receptors stimulation.
• GABA (amino acid) binds with receptors and chloride channels open and there is influx of chloride ions which leads to hyper-polarization of membrane and sedation occurs. This is normal phenomenon.
• Benzodiazepines facilitate this mechanism by facilitating the binding of GABA receptors to their receptors which lead to sustained hyper-polarization.
• It is dose dependent effect;
• Low dose…. Sedation
• High dose… Hypnosis
• If GABA concentration is low, BZ are not able to perform their action because these only facilitate binding not the release of GABA.

Classification of BZ

Their classification is based on duration of activity;

Short Acting BZ

• Drugs with half life less than 5 hours and include;
• Midazolam
• Triazolam

Medium Acting BZ

• Drugs with half life b/w 5-24 hours and include
• Alprazolam
• Lorazepam

Long Acting BZ

• Drugs with half life greater than 24 hours and include
• Diazepam
• Chlorodiazep

Flumazenil

• This drug is used to treat the toxicity of BZ b/c it is antagonist of BZ.

Effects of BZ

• These act as anti-convulsants and also reduce the anxiety.
• These are poor analgesic but good muscle relaxant.
• Effects on CVS and respiratory systems are negligible.

Therapeutic Uses

• Sedative and hypnotic
• Anti-convulsants
• Used for sleep disorders
• Pre-anesthetic
• Midazolam can be used as anesthetic agent.

Problem

• If used for longer duration, problem of dependency occurs and abrupt withdrawal leads to anxiety, convulsions and other withdrawal symptoms.

Barbiturates

• These are synthesized from urea and malonic acid.
• Urea and malonic acid combine to form Barbituric acid.
• Barbituric acid is not having hypnotic property.
• When hydrogen at 5^th carbon in Barbituric acid is replaced by other substitutes, then these have hypnotic property.
• If thiaurea is used instead of Urea, Thiobarbiturates are formed which are good lipid soluble. Sodium salts of Thio-barbiturates are used as injectable anesthetics.
• These are having dose dependent effect;
• Low dose…Sedation
• High dose…Hypnosis
• Higher dose…..Anesthesia
• In BZ, higher dose do not lead to anesthesia.
• So Barbiturates are used as general anesthetics.

Classification of Barbiturates

Their classification is also based on duration of activity;

Ultra-short acting

• Drugs with half life b/w 10-30 minutes and include;
• Thiopental
• Thiobarbitone
• hexobarbitone

Short acting

• Drugs with half life b/w 30min-3hours and include;
• Pentobarbitone
• Secobarbitone

Medium acting

• Drugs with half life b/w 3-6 hours and include;
• Butobarbitone
• Amylobarbitone

Long acting

• Drugs with half life more than 6 hours and include;
• Phenobarbitone
• Mephobarbitone

Effects of Barbiturates

• Sedation, hypnosis and anesthesia
• Anti-convulsants
• Poor analgesics
• Higher doses can lead to respiratory failure and death. To treat this, respiratory center stimulants (Doxapram) are used.

Therapeutic Uses

• Sedative, hypnotic and anesthetic
• Anti-convulsants (Phenobarbitone, Primidone)

Miscellaneous Drugs

• Chloral Hydrate through oral route can be given.
• Chlorobutanol
• Bromides
• Ethyl Alcohol
• Cannabis (Bhang)

Classification of Anesthetics

There are two bases for classification of general anesthetics;

• Physical
• Route of Administration

Inhalant Anesthetics

Anesthetics which are inhaled, reach the alveoli, exchanged with arterial blood and distributed to different body parts especially Brain are called as inhalant anesthetics.

There are 3 important phases of anesthesia;

• Induction
• Maintenance
• Recovery

Factors Affecting Anesthesia

• Blood Gas Solubility
• Potency
• Gas Lipid Solubility

Blood Gas Solubility

• More the solubility of the inhalant anesthetic, it will take more time to saturate and more time to depress the Brain and vice versa.
• So, more the solubility of an inhalant anesthetic, it will take more time for induction and recovery of Anesthesia.

Low solubility inhalant anesthetic

• Low the solubility of inhalant anesthetic, minor change in concentration will lead to greater change in depth of anesthesia.
• Low solubility inhalant anesthetics include Nitrous oxide, Ether, Halothene, Fluorine.

Potency

• It is the ability of the drug to depress the CNS. It is measured by MAC value.
• MAC (Minimum Alveolar Concentration)
• Minimum concentration in alveoli which can induce anesthesia in 50% of the patients
• Lower the MAC value, more potent is the anesthetic agent.
• MAC value of drugs is in following order;
• Methoxy Fluorine < Halothene < Isofluorine < Ether < Nitrous Oxide

Gas Lipid Solubility

• If a drug is more lipids soluble, it will take more time for induction and recovery. Its value is in the following order;
• Nitrous Oxide > Isofluorine > Halothene > Ether > Methoxy Fluorine

Examples of Inhalant Anesthetics

Volatile

Chloroform, Ether mixture, Halothene, Isofluorine, N-fluorine, Methoxy fluorine, vinyl ether

Gaseous

Cyclopropaine, Nitrous Oxide

Chloroform

• In 1847, it was used as general anesthetic. It is still in use.
• In 1846, ether was used as general anesthetic.
• If it is used externally, it is rubifacient.
• If it is used by oral route, it has anti-spasmatic (Muscle relaxant), anti-zymatic (stop production of gas) and carminative (removal of gases) effects.
• If inhaled, it induces anesthesia. It induces rapid induction. It gives good analgesia and muscle relaxation.
• It can also cause irritation in alveoli. So, Bronchial and salivary secretions are increased and there is possibility of pneumonia. So, along with this drug, Head should be down and atropine can also be used.
• It also induces hepato-toxicity, myocardial sensitization to epinephrine. So, there are chances of Cardiac Arrhythmia.
• It is non-explosive and non-inflammable.

Ether

• It increases bronchial and salivary secretions when inhaled due to irritation.
• Good analgesic and relaxant
• Induction is slow.
• It is inflammable and explosive.
• Low toxicity problem. So, mixture of chloroform and ether is best combination as an anesthetic.
• ACE (alcohol, chloroform and ether mixture) in the ratio of 1:2:3 is also available.

CycloPropaine

• Inflammable, explosive
• Good analgesic and relaxant
• Can cause myocardial sensitization

Nitrous Oxide (Laughing Gas)

• It induces light anesthesia (pleasant induction).
• Used in humans
• Low toxicity
• Rapid induction and recovery

Injectable Anesthetics

These are of two types;

Depressants

• Barbiturates (thiopental, pentobarbitone, secobarbitone, hexobarbitone)
• Chloral-hydrate
• Etomidate
• Midazolam

Dissociative

• Phencyclodine
• Ketamine
• Tiletamine
• These induce superficial sleep. There is good analgesia, poor relaxation and poor hyporeflexia.
• Myotonia, reflexes and amnesia is also present.
• Eyelids remain open and there are chances of corneal ulceration. So, use some ointment to close eyes.
• Use some tranquilizers or sedatives
• Ketamine and Xylazine combination is best.
• Ketamine is used in veterinary practice.

Examples of Injectable Anesthetics

Thiobarbitone

• It induces rapid and smooth induction and recovery.
• Its termination of effect is due to Re-distribution (It is lipid soluble. So, highly perfused organs like brain receive more concentration and then drug moves to periphery).
• Give less dose of this drug.

Pentobarbitone

• It is metabolized

Propofol

• It induces smooth & rapid induction and recovery.
• Its termination of effect is due to metabolism because drug moves to all body parts.

Chloral-Hydrate

• It induces slow induction but prolonged recovery.
• Termination is due to metabolism.
• Hypnotic in nature due to metabolite called Trichloro Ethanol.
• Perivascular leakage also leads to necrosis.
• Still used in equines.
• Pre-anesthetic agents are used with these drugs.

Anesthetic Agents & Anesthesia

• Anesthesia is the loss of sensation by giving anesthetic agents.
• Agents which cause the loss of sensation are called as anesthetic agents.

These are of two types;

Local

• These cause loss of sensation but animal is conscious.

General

• These cause loss of sensation due to unconsciousness.

Objectives of Anesthesia

• Sensory block to have analgesia. In this, sensory stimuli from the periphery are blocked.
• Mental block to have hypnosis or Amnesia (animal know nothing, what is happening around). Activity of CNS is blocked.
• Motor block to have muscle relaxation
• Reflex block to have hyporeflexia
• In case of local anesthetics, only one purpose is not the case of interest which is the mental block.

Stages of Anesthesia

• Based on ether anesthesia, there are following stages of anesthesia;
• Excitement stage (voluntary movements occur)
• Delirium stage (involuntary movements occur)
• Surgical Stage
• Medullary paralysis

There are 3 stages of anesthesia;

• Induction
• Maintenance
• Recovery

Ideal Properties of Anesthetic Agent

• It should cause rapid & smooth induction and recovery.
• It should be easy to maintain anesthesia (light or deep).
• It should be non-toxic and safe to internal organs.
• It should be non-irritant.
• It should be non-inflammable and non-explosive.
• Myocardial sensitization to epinephrine should be least.
• It should be compatible with other drugs.
• It should be easily available, cheap and easy to administer.

Pre-anesthetic Agents

These are the drugs given before anesthesia.

Why to give?

• To reduce anxiety of patient
• To reduce the amount of anesthetic agent
• To reduce the adverse effects of anesthetic agent
• To reduce the toxicity problems
• To reduce secretions especially Bronchial & Salivary
• To increase analgesia

Examples

• Opiods (Morphine, Mepridine) which induce analgesia
• Tranquilizers (Xylazine, Acepromazine) which reduce anxiety
• Anticholinergic drugs (Atropine sulphate, scopolamine) which reduce secretions
• Muscle relaxants (Gallamine, Pancuronium, d-tubocurarine, succinylcholine)

Medication during Anesthesia

• To reduce Blood pressure
• To induce muscle relaxation
• To stop bleeding

Post-Anesthetic Medication

• Analgesics
• Anti-inflammatory
• Anti-microbial
• Cholinergic drugs to relieve retention of urine E.g. Bethanicol

Introduction to Pharmacology of CNS

CNS consists of two main organs;

• Brain
• Spinal Cord
• This is the information superhighway of the body. It carries information up to the brain and instructions back down.

Brain

It consists of following parts;

Cerebellum

• Mostly deals with movement. It regulates and coordinates movement, posture and balance. Also involved in learning movement

Cerebrum

• The cerebrum or cortex is the largest part of the human brain, associated with higher brain function such as thought and action.

Midbrain

• Midbrain/ Mesencephalon- the rostral part of the brain stem, which includes the tectum and tegmentum
• It is involved in functions such as vision, hearing, eyemovement, and body movement.

Types of Drugs in CNS

• In CNS, synapses are the main junctions at the neuronal terminals.
• Drugs are based on the type of neurotransmitters which are of 2 types;
• Excitatory
• Inhibitory

Stimulants

• Drugs stimulating the excitatory neurotransmitters are called stimulants. E.g. Ach, Dopamine, epinephrine and nor-epinephrine.

Depressants

• Drugs stimulating inhibitory neurotransmitters are called depressants. E.g. GABA (gamma amino butyric acid)(Brain), Glycine (spinal cord).
• Depressants are mainly used in human practice.

Stages of Stimulation

Stages of Depression

Terminology

Sedation

There is slight depression but animal is awake.

Hypnosis

Animal is greatly depressed and seems to be asleep but can be awakened.

Tranquilizers

Slight Depression but animal behaves abnormally to external stimuli.

Narcosis

There is greater depression and animal is asleep and can be awakened but will again sleep. There is good analgesia.

Anesthesia

Animal is under greater depression and asleep but cannot be awakened. There is hyporeflexia.

Dissociative Anesthetics

Animal is superficially anesthetized and there is myotonia (movement in muscles).

There is analgesia but reflexes are present.

Basal Anesthetics

This anesthesia is maintained by other agents.

Adrenergic Blocking Agents...Pharmacology

• Adrenergic blocking agents are drugs that selectively inhibit specific receptor sites from sympathetic stimulation.
• Blocking agents may interact with specific alpha and beta receptors. The release of nor-epinephrine from storage sites may be blocked.

Types of Adrenergic Blocking Agents

Adrenergic blocking agents are of two types;

• α-Blockers
• β-Blockers

α-Blockers

• Phenoxybenzamine is the prototype drug which blocks α-1 and α-2 receptors.
• Phentolamine, Tolezoline…… blocks α-1 and α-2 receptors
• Przosine, Doxazosine, Terazosine….. Blocks α-1 receptors
• Atipamazole…. blocks α-2 receptors

β-Blockers

• Propranalol is the prototype drug which blocks both types of beta receptors.
• Timolol, Ndolol, Pindolol also block the both types of beta receptors.
• Atinilol, Esmalol blocks beta-1 receptors.
• Butamoxine blocks beta-2 receptors.
• Labetalol, Carvedalol block both alpha & beta receptors.

Therapeutic Uses

α-Blockers

• Phenoxybenzamine blocks α-1 and α-2 receptors by making covalent bond, It is irreversible inhibition.
• Other alpha blockers are reversible inhibitors.
• For hypertension, these drugs are used.
• Orthostatic Hypotension…In standing condition, hypotension occurs due to these drugs. So, initial dose should be given before bed.
• Pheochromocytoma….Tumor of chromafin cells in adrenal glands, so, adrenaline quantity increased and Blood pressure remains constantly high. To diagnose it, phenoxybenze is used which will lower the blood pressure.
• To remove the toxicity of α-2 agonists, alpha-2 antagonists are used.

β-Blockers

• These are used as anti-hypertensive drugs. E.g. propranalol
• Timolol is used to treat glaucoma by decreasing the intraocular pressure.

Adrenergic Drugs..Pharmacology

• Sympathomimetic drugs are substances that mimic the effects of the sympathetic nervous system, such as catecholamines, epinephrine (adrenaline), norepinephrine (noradrenaline), dopamine, etc. Such drugs are used to treat cardiac arrest and low blood pressure, or even delay premature labor, among other things.
• These drugs act at the postganglionic sympathetic terminal, by directly activating postsynaptic receptors, blocking breakdown and reuptake, or stimulating production and release of catecholamines.

There are two types of adrenergic drugs.

• Direct Acting Drugs
• Indirect Acting Drugs

Direct Acting Drugs

These are of two types

Natural compounds (catecholamines)

These include;

• Epinephrine
• Nor-epinephrine
• Dopamine
• If these catecholamines are released from nerve fibers, these are called neurotransmitters.
• If released from glands, these are called as hormones.
• If released from the outside, these are called as drugs.

Synthetic Compounds

These are of further two types;

α-agonists

These stimulate α receptors. These include;

• Phenylephrine, Methoxyline (stimulate α-1 receptors)
• Clonidine, Detomedine, Xylezene (stimulate α-2 receptors)

β-agonists

• Isoprotalenol (stimulate β-1 & β-2 receptors)
• Dobutamine (stimulate β-1 receptors)
• Terbutalin, Sulbutamol, Clenbutarol (stimulate β-2 receptors)

Indirect Acting Drugs

• These increase level of nor-epinephrine on receptors. These stop removal of nor-Epinephrine by stopping re uptake or by increasing the release of nor-epinephrine from the storage vesicles. These are divided into 3 categories;

Releasers

• These enhance release of Nor-epinephrine from the endings. These include Tyramine, Amphetamine and Ephedrine (mixed).

Uptake Inhibitors

• These drugs block and reverse the activity of nor-epinephrine transporter (NET). NET is a transport protein present on surface of some cells that clears adrenaline and nor-adrenaline from the extracellular space and into the cells, thus terminating the signaling effect.
• These drugs include cocaine, Triphenylamine.

MAO Inhibitors (MAOI)

• Adrenaline and nor-adrenaline are metabolized by the enzyme monoamine oxidase. These drugs inhibit the activity of this enzyme, thus producing sympathomimetic effects.
• These drugs include Isocarboxazid, Phenelzine, Iproclozide, Procarbazine, Hydralazine and Phenoxypropazine.

Prototype Drug

Prototype drug in adrenergic drugs is;

• Adrenaline b/c it stimulates all four types of receptors.
• Nor-adrenaline cannot stimulate β-2 receptors.
• Others stimulate only 1 or 2 receptors.

Therapeutic Uses

• Asthma can be treated by β-2 agonists.
• Cardiac arrest can be treated by β-1 agonists.
• Retention of Urine
• To decrease the intestinal motility
• Vasoconstriction to increase blood flow and treat nasal congestion
• Spray of α-1 agonist during surgery to decrease bleeding from small blood vessels
• To enhance the duration of action of local anesthetics, adrenaline is used which decrease the absorption of anesthetic by causing vasoconstriction.
• Cocaine is used as local anesthetic but vasoconstrictor is not used along with it b/c it is itself a vasoconstrictor.
• Stimulate CNS E.g. Cocaine
• Some used in allergic reactions
• Some used to delay the labor condition of uterus near parturition to manage the delivery at proper time.
• Glycogenolysis and gluconeogenesis are increased by stimulation of β-receptors in liver, muscles and adipose tissue.

Adrenergic Receptors..Pharmacology

Two types of receptor sites are theorized to explain adrenergic effects.

Alpha-Receptors

• Alpha-receptors are associated mainly with increased contractibility of vascular smooth muscle and intestinal relaxation.

Alpha1

• The alpha1 is located at postsynaptic effector sites to stimulate transmitter release in smooth muscle. For example, the smooth muscle of peripheral blood vessels is contracted in alpha1 stimulation.

Alpha2

• The alpha2 receptor site is located presynaptic on axon terminals to inhibit the release of nor-epinephrine (the transmitter). The effects of alpha2 stimulation results in relaxation of the intestinal tract--motility and tone are decreased.

Beta-Receptors

• Beta-receptors are associated with vasodilation and relaxation of nonintestinal smooth muscle and cardiac stimulation.
• Beta1 Stimulation of beta1 receptor sites results in cardiac stimulation and lipolysis.
• Beta2 Stimulation of beta2 receptor sites causes bronchodilation, relaxation of blood vessels (usually in skeletal muscles), and muscle glycogenolysis.

Alpha Receptor Site: Important features of the site include in order of importance: An anionic site - which binds the positive ammonium group. One hydrogen bonding area A flat area non-polar area for the aromatic ring. Beta Receptor Site: Important features of the site include in order of importance - also see the graphic on the left: An anionic site - shown as Asp anionic negative acid group which binds the positive ammonium group. Two hydrogen bonding areas - shown as two Serine with alcohol (OH) groups hydrogen bonding to the phenol OH groups of the NE. A flat area non-polar area for the aromatic ring.  Tissue   Receptor Subtype  Agonists  Antagonists  Heart   beta1 NE, EP, dobutamine, xamoterol atenolol, metoprolol.  Adipose tissue   beta1, beta 3? Vascular Smooth Muscle  beta 2  EP, salbutamol, terbutaline, salmeterol butoxamine Airway Smooth Muscle   beta 2  terbutaline, salbutamol, salmeterol and zinterol, butoxamine  Smooth muscle contraction  alpha 1  NE, EP, phenylephrine, oxymetazoline) prazosin, doxazocin  Inhibition of transmitter release Hypotension, anaesthesia, Vasoconstriction  alpha 2 clenbuterol, alpha-methylnoradrenaline, dexmedetomidine, and mivazerol, clonidine, clenbuterol yohimbine, idazoxan, atipamezole, efaroxan, and rauwolscine Receptor Sites  alpha-receptor  beta-receptor  Vasoconstriction  vasodilation (b2)  iris dilation  cardioacceleration (b1)  intestinal relaxation  intestinal relaxation (b2)  intestinal sphincter contraction  uterus relaxation(b2)  bladder sphincter contraction  bronchodilation (b2)

Family Oestridae..Genus Oestrus (Nasal Bot Flies)

• Larvae of these flies spend most of their time in the nasal passage of sheep & Goat. So called nasal bots
• Adult flies are having short life span (1 week) whereas larvae having 1 year or more of life span.

Morphology

• Adult flies are 1cm in size and of grey color.
• Small dark spots are present on the abdomen with a covering of short brown hair.
• Size of Larvae is 3cm and color is yellowish white. Larva is tapering anteriorly with prominent step posteriorly.
• Body is segmented having dark transverse bands dorsally (each segment).

Nasal Bot fly injecting larvae

Life Cycle

• Adult female is viviparous and produce larvae.
• Sheep become infected by squirting of jet of liquid containing larvae.
• During the flight, fly deliver 25 larvae.
• Newly emerged larva is 1mm in length.
• Larva migrates from nasal passage to frontal sinuses.
• Larva feed on mucous secreted by movement of larva.
• In the nasal passage, larva mould to L2.
• In the frontal sinuses, larva completes their development and then migrates to nostrils where they are active throughout the year.
• Become dormant in winter season if temperature is below 18.
• From the nostrils, L3 larvae fall on the ground and from larva, pupa develops.
• From the pupa, adult emerges. Adult having very short life span
• Survive for only 1 week and during this period, produce about 500 larvae.

Pathogenic effects

• Itching and Irritation
• Rubbing the nostrils against hard objects
• Nasal discharge which later on becomes mucopurulent
• In coordination, convulsions
• Also called false gid (signs resembling coenurus cerebralis)
• Cause swelling of eyes in human called as keratoconjunctivitis and inflammation of lips called stomatitis
• Loss of weight

Treatment

• Refoxanide, Ranide…. 1ml/25kg BW subcutaneously
• Nitroxynil, Trodex….1ml/20kg BW subcutaneously
• Ivermectin………….1ml/50kg BW subcutaneously

Control

Regular use of insecticidal drugs should be followed.