Anti protozoal Drug

http://faculty.ksu.edu.sa/Hanan%20Hagar/Lectures%20232/ANTIAMOEBIC%20DRUGS%20(new).pdf

CNS STIMULENT & SEDATIVE & HYPNOTICS

CNS STIMULANTS

Nervous System:

The Nervous System can be classified into:

The Central Nervous System (CNS): Brain and spinal cord

The Peripheral Nervous System (PNS): The nervous system outside of the brain and spinal cord. Peripheral Nervous System (PNS) can be divided into-

1.    Sensory division (Afferent): Conducts impulses from receptors to the CNS and Informs the CNS of the state of the body

2.       Motor division (Efferent): Conducts impulses from CNS to effectors organs.

Motor Neurons: The motor division is also divided into:

1.      The Somatic Nervous System :  VOLUNTARY (generally) Somatic nerve fibers that conduct impulses from the CNS to skeletal muscles

2. The Autonomic Nervous System:  INVOLUNTARY (generally) conducts impulses from the CNS to smooth muscle, cardiac muscle, and glands 

Neurons:  

They are the basic functional unit of the nervous system. They contain three major parts: 

1.      Cell body

2.      Dendrites

3.      Axon

Neurotransmitters of CNS:

They can be classified into: 

1. Excitatory: Acetylcholine, Glutamate, Aspartate, Serotonin (5-HT) and Nor-Epinephrine 

2. Inhibitory: GABA (Gama Amino Butyric Acid), Glycin

CNS Stimulants:

Stimulants are a substance which tends to increase behavioral activity when administered.

Signs and Symptoms:

Elevate Mood, Increase Motor Activity & Alertness, Decrease need for Sleep, Overdose lead to convulsion and death

Types of CNS Stimulants:

1.       Xanthines and Methyl-xanthines (Theobromide, Theophylline, Caffeine)

2.       Nicotine

3.       Amphetamines (Methamphetamine)

4.       Methylene Dioxy Methamphetamine (MDMA)

5.       Cocaine

6.       Strychnine Nux Vomica

1.   Xanthines and Methyl-xanthines:

Mechanism of Action:  Xanthine and Methylxanthines block enzyme Phospho-diestarase which prevent metabolism of cAMP and cGMP. By this way we get long activity of second massager as well as stimulating effects.

Indications of Theobromide:

Angina pectoris, Diuretics on Edema, Vasodilator

Indications of Theophylline:

Relaxing Bronchial Smooth muscle, Increase heart muscle contractility and efficacy as well as increase heart rate and Blood Pressure, Increase Renal Blood flow, Anti-infammatory effects, CNS stimulating effect

Medical Use: Chronic Obstructive Pulmonary Disease (COPD), Asthma

Adverse Effect: Insomnia

Indications of Caffeine:

Reduction of fatigue, improved concentration, clearer flow of thought, reduces reaction time and speed of calculation, relief headache.

2.   Nicotine:

Nicotine binds with cellular Nicotinic Muscarinic receptor which produces muscarinomimetic action. Ultimately, we get neuronal excitation.

Indications:

Increase learning in stress condition, Relax smooth muscle, Decrease gastrointestinal motility which leads less food intake, ultimately smoker’s has average 4 kg less body weight than non-smoker.

Pharmacokinetics:

Nicotine metabolizes in liver and produces inactive metabolite Continine which has long plasma half life. Measuring Continine concentration in blood, we may assume patient’s smoking habit.

Adverse effects: Tachycardia, Tolerance, Dependency

3.   Amphetamines (Methamphetamine):

Mechanism of Action:

Block the reuptake of norepinephrine and dopamine into the pre-synaptic neuron and increase the release of these monoamines (Norepinephrine and Dopamine) into the extra-neuronal space.  This leads increase motor activity, euphoria and excitement, anorexia and also stimulation followed by depression

Clinical use: Narcolepsy (Fall asleep suddenly), Attention-deficit hyperactivity disorder (ADHD)

Adverse effects: Hypertension, Weight loss, Abdominal pain, Loss of appetite, Headache, Insomnia, Feeling nervous.

4.   Methylene-dioxy-methamphetamine (MDMA):

Mechanism of Action:

It inhibit reuptake of 5-HT (Serotonin) into the pre-synaptic neuron as well as increase release of 5-HT (Serotonin), which produces CNS stimulant effects.

Indication: “Party Drug”

It is called Party Drug because it is euphoretic, facilitates energetic dancing as well as produces high ambient body temperature. By this way, people get pleasure in party.

Adverse effects: Hyperthermia may cause Kidney failure

5.   Cocaine:

Mechanism of Action:

Cocaine inhibit uptake of Nor Epinephrine and Dopamin and increase peripheral effects of sympathetic nerve activity which produces CNS stimulation by producing euphoria, increase motor activity and magnification of pleasure, peripheral vasoconstriction which leads increase blood pressure

Medical Use: Local Anesthetic in ophthalmology, minor nose and throat surgery

Pharmacokinetics:

Cocaine can intake by inhalation or injection. It has less duration of action and metabolites deposits in hair.

Adverse effects: Tachycardia, little hallucination

6.   Strychnine Nux Vomica:

Mechanism of Action:

Strychnine is competitive antagonist of the CNS inhibitory glycin receptors which facilitates CNS stimulating effects by Tonic Convulsion as well as muscle contraction.

SEDATIVE HYPNOTICS

Sedative:  Drugs that clam the patient and reduce anxiety without inducing normal sleep

Hypnotic:  Drugs that initiate and maintain the normal sleep

Classification of Sedative-Hypnotic Drugs:

1. Benzodiazepines (BDZ):

According to Duration of Action:

Short Acting (3-5 Hours): Midazolam, Triazolam

Intermediate acting (6-24 hours): Alprazolam, Lorazepam, Oxazepam, Temazepam

Long acting (24-72 hours): Diazepam, Nitrazepam, Clonazepam, Flurazepam

According to Uses:

Sedative (Anxiolytics): Alprazolam, Chlordiazepoxide, Diazepam, Prazepam

Hypnotics: Triazolam, Lorazepam, Estazolam, Temazepam, Flurazepam, Nitrazepam

Preanesthetics:  Diazepam, Midazolam

2. Barbiturates:

Ultra Short Acting (25 minutes): Thipental Sodium (Anesthetic)

Short Acting (3-8 hours): Pentobarbital, Hexobarbital, Secobarbital

Intermediate Acting (8-24 hours): Amobarbital, Butabsarbital

Long Acting (24-28 hours): Penobarbital (Anticonvulsant)

3. Newer Drugs:

Buspirone, Zolpidem, Zaleplon

Benzodiazepines:

Mechanism of Action:

Benzodiazepines binding to Benzodiazepine receptors (BZ1 or BZ2) to facilitate GABA-induced chloride channels hyper polarization which cause GABA-mediated inhibitory neurotransmission.

Benzodiazepines facilitate GABA action on GABA receptors ® chloride channels opening ®           

Increase chloride influx to the cell ® cell membrane hyperpolarization ® inhibition of propagation of action potential ® inhibitory effect on different sites of the brain especially motor cortex, and limbic system

Pharmacokinetics:

1. Most of them are well absorbed orally,

Rapid absorption e.g. triazolam & Alprazolam, diazepam & chlorazepate 

Slow absorption  e.g. lorazepam & oxazepam, temazepam (LOT)

2. Chlorazepate is a prodrug converted by acid hydrolysis in stomach to form nordiazepam  (desmethyldiazepam).

3. Can be given parenterally, Diazepam-Chlordiazepoxide (IV only), Midazolam – Lorazepam (IV or IM)

4. Benzodiazepines are lipid soluble and widely distributed

5. Redistribution from CNS to skeletal muscles, adipose tissue) (termination of action)

6. Cross placental   barrier during pregnancy and are excreted in milk (Fetal & neonatal depression).

7. Highly bound to plasma protein.

8.  ALL Bzs are metabolized in the liver

     Phase I: (liver microsomal system), Phase II: glucouronide conjugation and excreted in the urine.

9. Many of Phase I metabolites are active® ­ elimination half life of the parent comp. ® cumulative effect with multiple doses, except on active metabolites are formed for (LEO) Lorazepam, Estazolam, Oxazepam

Pharmacological Actions:

1. Anxiolytic action.

2. Depression of cognitive and psychomotor function.

3. Anterograde amnesia.

4. Hypnotic actions at higher dose, BDZs change sleep pattern: Induction of normal sleep (latency of sleep is reduced).  Increase non REM sleep (stage II).  Decrease REM sleep & slow waves sleep (3,4 stages). Usage for more than 2 weeks ® tolerance to their effect on sleep patterns

4. Anticonvulsant effect: especially diazepam, lorazepam, clorazepate, clonazepam, nitrazepam.

5. Central skeletal muscle relaxant effect e.g. Diazepam relaxes muscle spasticity by pre-synaptic inhibition in the spinal cord.

6. CVS and respiratory system: Minimal depressant effects in therapeutic doses & in normal patients.

Therapeutic Uses:

Anxiety disorders:   Alprazolam, General anxiety disorders, Panic attack - major depressive disorders 

Sleep disorders (Insomnia):  Triazolam initiate sleep. Estazolam - Lorazepam - temazepam sustain sleep

Flurazepam - Quazepam Long acting drugs can cause hangover.

To control withdrawal symptoms of alcohols: Diazepam- chlordiazepoxide

Treatment of epilepsy: Diazepam-Lorazepam: Status epilepticus. Clonazepam-Clorazepate: absence, myoclonic seizures.

Muscle relaxation: in spastic states (Diazepam)                

In anesthesia: Preanesthetic medication diazepam, Induction of balanced anesthesia (Midazolam), Adjunct therapy during minor surgery (endoscopy, bronchoscopy, dental surgery).

Adverse Effects:

1. Ataxia (motor incoordination), cognitive impairment.

2. Hangover Sleep tendency, drowsiness, confusion especially in long acting drugs.

3.  Tolerance, Physical and Psychological dependence, Withdrawal symptoms: Rebound Insomnia, anorexia, anxiety, agitation, tremors and convulsion.

6. Drug Interaction: Synergistic effect with other CNS depressants, Enzyme Modulators [Rifampicin (decreases half life), Cimetidine (increases half life)]

7. Skin rash, Teratogenic effect, Dose reduction needed in Liver disease and Old people

Contraindication: To be combined with Alcohol and other CNS depressants, antihistaminics. 

Diazepam’s indications:

Anxiolytic, Sedative-Hypnotics, Muscle relaxation, Anesthetic premedication, Coronary vasodialation

Why diazepam is preferred than other benzodiazepins?

a)      Rapid onset of action

b)     Long acting (Plasma half life 30 hours)

c)      Single daily dose (5-15 mg)

d)     Rapid absorption from GIT

e)      Metabolic products are also active

f)       Less withdrawal syndrome after chronic use

g)      Specific antagonist (Flumazenil) is available

Adverse effects: Tolerance, Dependency, anxiety, weakness, restlessness

Midazolam’s Indications:

Sleep inducing agent (Sedation), Anticonvulsant action, Anxiolytic, Muscle relaxant

As sedative: Rapid onset, shortness of sleep onset, reduce the wake phases, less tolerance, Non-embryolytic and Non-teratogenic

Flumazenil:

Mechanism of Action:

A selective competitive antagonist of Benzodiazepine receptors (Bz1)which blocks action of benzodiazepines, zaleplon and zolpidem but not other sedative/hypnotics as well as blocks psychomotor, cognitive and memory impairment of BZs.

Pharmacokinetics:

It has short duration of action (Half life 1 hour), absorbed orally, undergoes extensive first pass metabolism, no active metabolites, should be used IV in case of toxicity, repeated doses are necessary

Therapeutic Uses:

1.  Acute BZD toxicity (comatose patients).

2. Reversal of BZD sedation after endoscopy, dentistry.

Side Effects:  Nausea, Dizziness, Precipitate withdrawal symptoms

Barbiturates:

Barbiturates are derivatives of barbituric acid and second choice as sedative – hypnotic. Thiobarbiturates are highly lipid soluble.

Mechanism of Action:

1. Facilitation of GABA action on the brain as well as increase the duration of the GABA gated channel   opening but in   large dose, they can directly activating chloride channels. (Not through BZD receptors).

2. Depress excitatory Glutamate neurotransmitter actions (Inhibit AMPA Glutamate receptor)

3. Interfere with Na & K transport across cell membranes (reticular activating system inhibition).

4. Less selective in action than Benzodiazepine

Pharmacokinetics:

All barbiturates are weak acids, lipid soluble, absorbed orally, distribute throughout the body. Thiobarbiturates are very lipid soluble (high rate of entry into CNS- very brief onset of action). Redistribute in the body from the brain to skeletal muscles- adipose tissues. Metabolized in the liver to inactive metabolites and excreted in the urine. Alkalinization increases excretion (NaHCO3). Barbiturates also cross the placenta ( @ pregnancy).

Pharmacological actions:  

1. CNS depression in a dose-dependent fashion: Sedative, Hypnotic, Anesthesia in large dose, Anticonvulsant action, Coma and death

2. Respiratory depression is dose related: Suppress hypoxic and chemoreceptor response to CO₂, Large doses respiratory depression & death.

3. CVS depressions: Healthy patient: at low doses, they have insignificant effects. Hypovolemic  states,  CHF, normal doses may cause cardiovascular collapse. Large dose ® circulatory collapse due to medullary vasomotor depression ® direct vasodilatation

4. Enzyme induction: CYT P-450 microsomal enzymes inducers (Tolerance - drug interaction). Increase activity of hepatic gamma amino levulinic acid synthetase ALA ® synthesis of porphyrin (# porphyria). 

Clinical Uses:

Anticonvulsants:  (Phenobarbitone), Tonic-Clonic seizures, status epilepticus and febrile convulsion. Induction of anesthesia (thiopental, methohexital), Hypnotic (pentobarbital), Hyperbilirubinemia and kernicterus in the neonates (increase glucouronyl transferase activity).    

Adverse effects:

Respiratory depression, Hangover: residual sedation after awakening, Tolerance, Withdrawal symptoms, Precipitation of acute attack of porphyria, Many drug interactions, Allergic reaction: urticaria and skin rash,

Toxicity (Respiratory depression, Cardiovascular collapse, coma and death)

Drug Automatism:

Barbiturates cause drowsiness, confusion and amnesia (inability to remember). So patient confuse and forget that he took drug or not. For that reason, there is a chance of taking drug repeatedly which ultimately cause drug poisoning

Barbiturate Poisoning:  

CNS: Drowsiness, Coma.

CVS: Cardiovascular Collapse, Hypotension, Dehydration.

Lung: Pulmonary Edema, Bronchopneumonia

Kidney: Renal failure

Body Temperature: Hypothermia

Eye: Miosis

Treatment:

1. Oxygen inhalation, Artifical respiration, Stomach wash by Activated Charcoal, Provide fluid (0.9% NaCl solution), Antibiotic for preventing infection on Lung, Inject cardiotonic injection Dopamine. Forced alkaline diuresis (Barbiturates are acidic drug). Use specific antidote Bemigride

Contraindications:  

Acute intermittent porphria, Respiratory obstruction, Liver & kidney diseases, Shock, Old people ( mental confusion), Pregnancy, Hypersensitivity to barbiturates.

Drug interactions:

 Other CNS depressants: Ethanol, MAOI: potentiate CNS depression, Phenytoin, warfarin, and dicumarol (their metabolism is increased)  

Advantages of Benzodiazepine over Barbiturates:

1. Minimal respiratory and cardiovascular depression by BZD than Barbiturates

2. Better anxiety disorder management by BZD than Barbiturates

3. Barbiturates lack CNS specificity

4. Barbiturates has more drug-drug interactions

5. Benzodiazepine has high therapeutic index whereas Barbiturates has low therapeutic index

6. Benzodiazepine has less hangover

7. No enzyme induction by BZD but Barbiturates induce glucouronyl transferase activity

8. Less tolerance and dependence with minimal withdrawal symptoms by BZD

9. Specific antagonist (Flumazenil) available for BZD

10. Less overdose toxicity showed by BZD

Newer Drugs:

Buspirone:

Mechanism of Action: Buspirone inhibit brain’s excitatory neurotransmitter 5-HT (Serotonin) specifically, which ultimately produces anxiolytic action on brain. It does not bind with GABA receptor.

Pharmacokinetics: Rapidly absorbed from GIT and go for high First Pass Metabolism

Clinical Uses and advantages: Eradicate Mild Anxiety. It has no tolerance, hypnotic, anticonvulsant and muscle relaxant effects

Zolpidem:

Mechanism of Action: It is an imidazopyridine derivative which acts on benzodiazepine receptors (BZ 1) & facilitate GABA mediated neuronal inhibition.  Its action is antagonized by flumazenil. 

Pharmacokinetics: It is rapidly absorbed from GIT and metabolized to inactive metabolites via liver CYT P450 and has short duration of action (2- 4 h). 

Pharmacological Actions and Advantages: It has only hypnotic effect and its efficacy is similar to benzodiazepines which has minor effect on sleep pattern, but high doses suppress REM. Respiratory depression occur at high doses in combination with  other CNS depressant as ethanol. It has no muscle relaxant, anticonvulsant effect. Zolpidem has minimal psychomotor dysfunction, tolerance & dependence and rebound insomnia.

Uses: A hypnotic drug for short term treatment of insomnia and dose should be reduced in hepatic or old patients.

Adverse Effects: GIT upset, Drowsiness, Dizziness

Drug interactions: Rifampicin (decreases half life), Cimetidine (increases half life)

Zaleplon:

Mechanism of Action: Zaleplon binds to Benzodiazepine receptors and facilitate GABA actions.

Pharmacokinetics: Rapid absorption, rapid onset of action, short duration of action (1 hr), metabolized by liver microsomal enzymes, metabolism is inhibited by cimetidine.

Uses and Advantages: Only hypnotic effect, decreases sleep latency, Little effect on sleep pattern, Potentiates action of other CNS depressants (alcohol). Used as hypnotic drug

Advantages: Less impairment of pyschomotor performance than Benzodiazepines or zolpidem.