Analgesics and Anti-pyretic drugs, Opioid analgesics ,CNS Stimulants & Opioid antagonists

Sunday, October 10, 2010

Analgesic         --    These are drugs which produce relief of pain

Antipyretics     --    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. These drugs do not produce addiction

All these drugs produce an anti-inflammatory effect, 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, they are called as non- opioid
Analgesics

These drugs have three main function – Analgesics , Anti-pyretic and Anti-inflammatory action

A. Non selective COX inhibitors

1.Salicylates

Acetyl-salicylic acid

Sodium salicylate

Methyl salycilate

Salicylic acid
  
2.Para- aminophenol derivatives

Paracetamol

Phenacetin

 3. Pyrazolon derivatives

    Phenyl butazone

    Oxyphenbutazone

   Aminopyrine

   Antipyrine

4. Propionic acid derivatives

     Ibuprofen,
   
     Ketoprofen

 5. Indole derivatives
 
    Indomethacin

6. Anthranilic acid derivative
  
      Mephenamic acid

7. Aryl acetic acid derivative
   
     Diclofenac

8. Oxicam derivatives
   
     Poroxicam,
     Tenoxicam

B. Preferential COX -2 inhibitors

      Nimesulide,
      Meloxicam

 C. Selective COX – 2 inhibitors
       Celecoxib,
      Rpfecpxon
 
Mechanism of action

Inflammation  is usually regarded as a pathological state however, it is a physiological response of the living tissue to injury

Injury may be due to mechanical , physical, chemical  and living agents are also known as bacteria, protozoa’s or fungi 

Inflammation may be acute or chronic .

The clinical signs of inflammation are redness, swelling , heat  and pain.



                                                                   Phospholipase  A2
Membrane    --      Phospholipids   --- -------------------------------------     Arachidonic  acid


         Cyclo- oxygenase
-------------------------------------         Prostaglandins    ---   Inflammation


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-oxygenase

The prostaglandin formed are responsible for many of  the features of inflammation
 I.e. – swelling, redness and pain

The NSAID block the action of enzyme cyclo-oxygenase and thus prevent or reduces the production of prostaglandins and other mediators of inflammation




Salicylates

It includes

Acetyl-salicylic acid  or Aspirin

Sodium salicylate

Methyl salycilate

Salicylic acid

Aspirin

It is a acetyl salicylic acid

These are the salts or esters of salicylic acid

Salicylic acid itself is a strong irritant

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

Mechanism of action

It inhibits cycloxygenase which is responsible for the synthesis of prostaglandin and thromboxane

It also inhibits platelet aggregation

Pharmacological actions

1. Analgesic action

Asprin is a weaker analgesic than morphine

These are effective only in dull- 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. Anti-pyretic effect

Salycylates do not lower normal body temperature

Only the elevated temperature is lowered

Mechanism

  1. 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. The salicylates produce sweating which also lowers body temperature


3. Anti- inflammatory action

Asprin exert the  anti-inflammatory action at high doses 3- 6 grams /day

Signs of inflammation like pain, tenderness, swelling , vasodilatation and leukocyte infiltration are suppressed

Asprin inhibits cyclo-oxygenase activity, it diminishes the formation of prostaglandins and modulates those aspects of inflammation in which prostaglandins act as mediators

Asprin inhibits inflammation in arthritis

4. 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. 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. 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. Anti- rheumatic effect

Salicylates have powerful anti-rheumatic effect

T his effect is produced by reducing pain and inflammation of the joints


8. Blood

Salicylates lower the erythrocyte sedimentation rate  (ESR) which is high in rheumatic fever

They also decrease prothrombin level of plasma

9. Uricosuric effect

Low doses ( 1 or 2/ g day ) may decrease the urate excretion and increase plasma urea concentration

Intermediate doses ( 2 or 3 g / day ) do not alter urate excretion

Large doses ( over 5 g / day ) induce urocosuric effect and lower plasma urate levels 






10. Metabolic effects

Salicylates produce uncoupling of oxidative phosphorylation

They produce hyperglycemia and glycosuria

They inhibit the synthesis but enhance the breakdown of fatty acids


11. Hormones

Salicylates 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)

12. Local actions

Salicylates  , especially salicylic acid and methyl salicylate have antiseptic, fungi static
and keratolytic effects

13. Immunological effects

Salicylates suppress a variety of antigen- antibody reactions, which may be harmful to the body

Pharmaco- kinetics

Salicylates are absorbed from the stomach and small intestine

Sodium salicylate is absorbed more quickly than aspirin

Methyl salicylate is absorbed  from the intact skin

50 – 80 % of salicylate binds to plasma proteins

It can displace other drugs – waffarin from the binding sites leading to severe bleeding   

They are mainly concentrated in the liver, heart, muscle, and brain

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, vomiting , diarrhea , ulceration perforation and hemorrhage

Intolerance leading to skin rashes of various types

Bone marrow depression leading to agranulocytosis, thrombocytopenia and a plastic anemia

Fatty infiltration of liver and kidney

Salicylism characterized by headache, difficulty in hearing, drowsiness, lethargy and confusion


Contra- indications

Hypersensivity , peptic ulcer, liver diseases, bleeding tendencies and hemophilia

Contraindicated in children below 12 years , pregnancy  and avoided in diabetes

Children suffering from the viral fever

Treatment with NSAID s should be stopped one week before any surgery

Special precautions

Aspirin may precipitate bronchospasm and induce asthmatic attack in susceptible  subjects

It may induce gastrointestinal hemorrhage , occasionally major

Use with caution in subjects with gout

 During  lactation

Preparations

Aspirin  Tab                                              

Acetyl- salicylic acid powder                   

Sodium salicylate as mixture                         

Methyl salicylate  ointment                                       

Salicylic acid   ointment                                         


Uses

1. It is used as analgesic for light and moderate pain  ---  0.3  -  0.6 g  -  3 times

2. Used as anti-pyretic in fever  ---   0.3  -  0.6 g  -  3 times

3. Used as anti – inflammatory   &  anti-rheumatic  &  ---4 – 6 g  or  75 – 100mg – 100

     mg/kg/day in divided doses

4. Anti- platelet effect  -  75 – 300 mg / day

5. Used in the treatment of the gout

6. Local action


Salicylism

Prolonged administration of salicylates in the treatment of rheumatic fever or arthritis may produce mild salicylate intoxication called salicylism

The poisoning may be accidental or suicidal

It is more common in children, 15 – 30 g is the fetal dose of aspirin

Symptoms and signs

Dehydration, fever, gastric irritation, vomiting , acid- base imbalance, restlessness , delirium, hallucinations, metabolic acidosis, tremors, convulsions , coma and death due to respiratory failure and cardiovascular collapse

Treatment

1. Gastric lavage to eliminate unabsorbed drugs

2. IV fluids to correct acid- base imbalance and dehydration

3. Temperature is brought down by external cooling with alcohol or cold water sponges

4. If hemorrhagic complications are seen, blood transfusion and vitamin K are needed

5. The IV fluids should contain sodium, potassium, bicarbonates and glucose .
    Blood PH should be monitored

6. In severe cases, forced alkaline dieresis with sodium bicarbonate and a diuretic like   
    frusemide is given along with IV fluids. Sodium bicarbonate ionizes salicylates making
    them water soluble and enhances their excretion through kidneys
 


Pracetamol

It is a Para-amino phenol derivative

It has analgesic and antipyretic effects like salicylates

Parcetamol , a metabolite of phenacetin is found to be safer and effective

It has analgesic , good antipyretic and weak anti- inflammatory properties

Due to weak PG  inhibitory activity in the periphery, 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 , it has poor ability too inhibit cyclo-oxygenase

It does not stimulate respiration

It has no action on  acid- base balance , cellular metabolism , cardiovascular system and platelet function

It does not produce gastrointestinal irritation  and uricosuric effect

It is analgesic and antipyretic of choice especially in patients in whom salicylates or other NSAID are contraindicated


Mechanism of action

Paracetamol exhibits analgesic action by peripheral blockage of pain impulse generation

It produces  analgesic and antipyretic  action by inhibiting  the action of endogenous pyrogen on the hypothalamic heat regulating centers

Its weak anti-inflammatory activity is related to inhibition of prostaglandin synthesis in the CNS



ADME

Rapid absorption on oral administration .  30% protein binding

It is metabolized by the hepatic microtonal enzymes in liver

Plasma half life is 2-3 hrs 

Effects after an oral dose last 3-5 hrs

It is mainly excreted I urine as conjugation products of glucuronic and sulphuric acids

The ability of the infant liver for glucuronidation of paracetamol is poor and this results in enhanced toxicity of the drug in neonates


Adverse effects

In antipyretic doses , paracetamol is safe and well – tolerated

Nausea and rashes may occur

Dose

0.5    - 1 g every 4-6 hrs

Chile 6 – 12 yrs – 250 – 500 mg every 4-6 hrs

1– 5 years  - 120 – 250 mg every 4 – 6 hrs

Less than 3 months  10 mg / kg body weight  every 4 – 6 hrs

Maximum dose for adult – 4 g daily 

Maximum dose for child  4 doses in 24 hrs


 Acute paracetamol poisoning

when large doses are taken, acute paracetamol poisoning results

Children’s are more susceptible because the ability of  their liver to metabolite paracetamol is poor

10 – 15 grams in adults cause serious toxicity


Symptoms

Nausea

Vomiting

Parecetamol is hepatotoxic and causes severe hepatic damage

Hepatic lesions are reversible when promptly treated

Mechanism

Small portion of paracetamol is metabolized to toxic compound – N-acetyl – benzoquinone- imine which is inactivated generally by binding with glutathione in the liver

But when large doses of paracetamol are taken, larger amounts of the toxic compound are fumed and glutathione in the liver is not sufficient to inactivate it

As a result the toxic metabolite now binds to hepatic proteins resulting in hepatic necrosis

Chronic alcoholics and infants are more likely to develop hepatotoxicity

Parecetamol can also cause nephrotoxicity which may result in acute renal failure in some


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- acetylcysteine partly replenishes the glutathione stores of the liver and prevents binding of toxic metabolites to the cellular constituents

Uses

Paracetamol is used as an analgesic in painful conditions like toothache, headache and myalgia

As an antipyretic



Ibuprofen
It is was introduced in 1969

It is propionic acid derivatives

It is a better tolerated than aspirin

Its analgesic activity is independent of anti- 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

It exhibits anti- inflammatory, analgesic and antipyretic activities

All have similar phamacodymamic properties but differ considerably in potency and to some extent in duration of action

Analgesic, antipyretic and anti-inflammatory efficacy is slightly lower than aspirin
It is 99% bound to plasma proteins

Plasma half is 2-3 hours

Adverse effects
Nausea

Vomiting

Gastric discomfort

CNS effects

Hypersensitivity reactions

Dose
400- 800 mg

Uses
1. It has analgesic and antipyretic activity

2. It is used in the treatment of gout

3. Surgical removal of impacted tooth – a combination of ibuprofen with a skeletal   
    muscle relaxant like chlorzoxaxone is recommended

4. It is a drug of choice in rheumatoid arthritis because of lesser adverse effects

Phenyl- butazone

It inhibits COX and somewhat comparable to corticosteroids

The anti-inflammatory activity of phenylbutazone is better than that of salicylates, antipyrine and aminopyrine

The analgesic and antipyretic activity of phenylbutazone is however much les than that of salicylates

It diminishes the reabsorption of urate by proximal renal tubules and exerts uricosuric effect  

Mechanism of action

Like salicylates, it inhibits the biosynthesis of prostaglandins

Pharmacokinetics

The absorption of phebylbutazone on oral administration is rapid and complete, but on intramuscular administration, the drug remains localized at the site of injection for longer time

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

It is completely metabolized in the liver by hydroxylation and glucuronidation

Chronic phenylbutazone administration results in the stimulation of the liver microsomal enzyme systems producing a faster detoxification of pheylbutazone itself and other compounds like barbiturates

Preparation and Dose

Phenylbutozone tablet contains 100 mg of the drugs in an enteric coated tablet

Dose – 200 – 400 mg daily in divided doses

Small doses may be given  3-4 times a day to avoid gastric irritation

Injection phebylbutazone sodium is available in ampoules containing 200 mg of sodium salt/ml

Dose - 200 – 600 mg by deep intra muscular injection


Adverse effects

Phenyl butazone is more toxic than aspirin and is poorly tolerated

Nausea and vomiting

Peptic ulceration and diarrhea may occur

Hypersensitivity reactions like rashes,  hepatitis, nephritis, dermatitis and jaundice can occur

Goiter and hypothyroidism have occurred on long term use

CNS effects like insomnia , optic neuritis, blurring of vision and convulsions may be encountered

Odema as a result of sodium and retention which may precipitate CCF in cardiac patients


Uses

Rheumatoid arthritis

Ankylosing spondylities

Osteoarthritis

Gout

Other musculoskeletal disorders

Oxyphenbutazone

It is a major metabolite of phenylbutazone, similar in pharmacodynamic, pharmacokinetic, toxic and drug interaction profile

Dose 

100 – 200 mg

Diclofenac sodium

Diclofenac is an analgesic, antipyretic and anti-inflammatory agent

Its 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  for oral

25 mg /ml inj

2-3 ml 1-2 times a day by deep IM inj

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  and  sprains and joints pain

Post- operatively for relief of pain and inflammation

Severely painful conditions like acute pulpits



Indomethacin

It has anti-inflammatory, analgesic, antipyretic and antigout actions

It relieves pain and reduces temperature in febrile patients

Reduces pain and joint swelling in rheumatoid arthritis but does not modify progress


Mechanism of action

It is a portent inhibitor of cycloxygenase thus reducing prostaglandin synthesis

Pharmacokinetics

It is well absorbed, 90% bound to plasma proteins & half life is 4 – 6 hours

Adverse effects

Adverse effects are high .

Gastrointestinal irritation with nausea, GI bleeding , vomiting , diarrhea and peptic ulcers can occur

CNS effects include headache, dizziness,  confusion, hallucinations, depression and psychosis

Hypersensitivity reactions like skin rashes, leucopenia and asthma in aspirin sensitive individuals

Drug interactions

Indomethacin blunts the diuretic action of furosemide and the anti-hypertensive action of thiazides,  beta blockers and ACE inhibitors by causing salt and water retention


Dose

25 -30 mg

Uses

Rheumatoid arthritis

Gout

Nimesulide

It is a sulfonamide compound

The action of nimesulide is somewhat different from that of classic NSAID

Mechanism of action
compound is a weak inhibitor of prostaglandin synthesis with a higher affinity for COX-2 then COX-1
Anti-inflammatory action may be exerted by other mechanisms as well

Ex – Reduced generation of superoxide by neutrophils, inhibition of PAF synthesis and
TNF  alpha release and inhibition of metalloproteinase activity in cartilage

Pharmacokinetics
It is completely absorbed orally
99% plasma binding ‘Extensively metabolized and excreted mainly in urine
Half life is 2-5 hours

Pharmacological actions
It has analgesic, antipyretic and anti-inflammatory actions like other ASAID

It inhibits leukocyte function, prevents the release of mediators and in addition has antihistaminic and anti- allergic properties

May also inhibit release of tumor necrosis factor alpha and thus reduce the formation of cytokines

Relief of  mild to moderate pain and fever, inflammatory

Dose 
50 -100 mg BD

Adverse reaction
Nausea

Diarrhea, Vomiting , Rash , Dizziness  and  headache

Long term use  can cause  hepatotoxicity & neprhortoxicity

Uses
It is used as an analgesic, antipyretic and anti- inflammatory agent for short periods as in headache, toothache, ,  sinusitis, post-operative pain and arthritis

It is beneficial in patients who develop bronchospasm with other NSAID
It has been used primarily for short lasting painful inflammatory conditions like like sports injuries and other ear-nose –throat disorders

 Mephenamic acid

 An analgesic, 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- 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, but bleeding is not significant

Skin rashes, dizziness and other CNS manifestations have occurred

Hemolytic anemia is rare but serious complication


Dose

250 – 500 mg

Uses

Mephenamic acid is indicated primarily as analgesic in muscle, 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

Opioid analgesics

Analgesics
These are drugs which relieve pain without causing loss of consciousness

Opioid analgesics
These are the natural accruing, semi-synthetic and synthetic drugs which have morphine like action
i.e. relief of pain and depression of CNS

1. According to ring structure

A . Phenanthrene derivatives

Morphine
Codeine
Thebaine

B . Benzo-isoquinoline derivatives

Papaverine
Noscapine

11. According to synthesis

A. Natural opium alkaloids

Morphine
Codeine

B. Semi synthetic opium alkaloids

Heroine
Pholcodeine

C. Synthetic opiods

Pethidine
Methadine
Tramadol

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 activate 7- transmembrane GPCRs located presymaptically and postsymaptically along pain transmission pathways

High densities of opioid receptors known as mu, delta and kappa are found in the dorsal horn of the spinal cord and higher CNS centers

Most currently used opioid analgesics act mainly at mu- opioid receptors

Morphine acts at kappa receptors in lamina 1 and 11 of the substantia Granulose  of the spinal cord and decreases the release of substance p, which is modulates pain perception in the spinal cord

Opioids have an onset of action that depends on the route of administration

Opioids causes hyper polarization of nerve cells , inhibition of nerve firing and presynaptic inhibition of transmitter release

Cellular effects of these drugs involve enhancement of neuronal potassium efflux
( hyperpolarizes neurons and makes them less likely to respond to a pain stimulus ) and inhibition of calcium influx ( decreases neuro- transmitter release from neurons located along the pain transmission pathway )

Brainstem opioid receptors mediate respiratory depression produced by opioid analgesics

Constipation results from activation of opoioid receptors in the CNS and in the GIT 

Pharmacokinetics

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

Bioavailability is 20 to 40 per cent

Given sc , onset of action is in 15 – 20 min, beak effect in 1 hrs

Duration of action is 3 – 5 hrs
Pharmacological actions

1. 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

The analgesic action morphine is primarily due to its effect on endogenous opioid receptors in midbrain and brain stem areas

Inhibitory impulses from these areas to the dorsal horn constitute the gating system

The morphine also acts directly on the dorsal horn where it inhibits the release of substance P

2.CNS

Morphine produces euphoria in presence of pain

But in the absence of pain , it produces dysphoria  &  restlessness

With an increased dose, it produces sleep

Tolerance is noted  to both  euphoria  (mu receptor ) and dysphoria (kappa receptors)

3. Sedation

Morphine induces sedation in analgesic doses and is useful when pain is accompanied by insomnia

4. Anti-tussive property

Morphine has anti-tussive property

Morphine depress the modularly cough centre , an effect not blocked by naloxone

It is not used clinically and related drugs like codeine,  with less respiratory depressant and addictive liability are used

5. Nausea & vomiting

Nausea and vomiting are common features with analgesic doses and induced by stimulation of the chemoreceptor tiger zone (CTZ)

Tolerance develops to vomiting on prolonged use

Higher doses of morphine inhibit the vomiting centre

6. Papillary constriction

Morphine produces constriction of pupil ( miosis)

Miosis is induced by mu and kappa mediated stimulation of the oculomotor nucleus

The effect is blocked by atropine

Morphine addicts have constricted pupil

Tolerance to papillary constriction is not seen in addicts and pinpoint pupils are indicative of morphine abuse and diagnostic in morphine poisoning ( other respiratory depressants induce papillary dilatation)

7. Respiration

The action of morphine on the respiration is dose dependent
Analgesic doses of morphine induce depression of the respiratory centre resulting in increase in plasma carbon dioxide concentrations
Respiratory center depression is mediated by mu receptors and is the cause of death in morphine poisoning

At higher doses it produces respiratory ceases

Respiratory depression is the most common cause of death in acute overdose

8 .Heat regulation

Opioids shift the equilibrium point of heat – regulating centre so that body temperature falls slightly

9 . Gastro-intestinal tract

Morphine decreases peristaltic propulsive movements

It produces spasm of intestinal smooth muscles and sphincters

Gastric emptying   is delayed

It also  increases absorption of water , So the feces get dried

All these effects leads t o constipation

10 . 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

Atropine antagonizes this effect

11. Cardiovascular system

Normal dose of morphine produces no effect  on heart  rate , blood pressure or circulation

But  hypo tension  and  bradycardia may be produced at toxic dose

Hypotension is due to dilation of peripheral veins and arterioles, histamine release and reduced sympathetic activity and in large doses due to depression of modularly vasomotor center’

Brdycardia is due to stimulation of the vagal nucleus

Because of respiratory depression and carbon dioxide retention, cerebral vessels dilate and increase the cerebrospinal fluid pressure

Morphine is usually contraindicated in individuals with severe brain injury

12. Histamine release

Morphine releases histamine from mast cells, causing urticaria, sweating and vasodilatation

Morphine can cause the bronco-constriction , asthmatics should not receive the drug

13. Hormonal actions

Morphine inhibits release of GRH and corticotrophic releasing hormone  and it decreases  the concentration of luteinizing hormone, FSH  & ACTH

It increases prolactin and growth  hormone release by diminishing dopaminergic
inhibition

It increases antidiuretic hormone and leads  to urinary retention

14. Uterus

No significant effect .  May prolog labor in high doses

15. on excretion

Tone and amplitude of contractions of the urters is increased , tone of external sphincter and volume of the bladder are increased

Opioids inhibit urinary voiding reflex

All these result in urinary retention especially in orderly male with prostate hypertrophy


16. Excitory effect

In high doses it produce convulsions. T hey may increases t he excitability of the spinal cord


Adverse reactions

GIT Symptoms – Nausea, vomiting and constipation

Acute morphine poisoning characterized by respiratory depression, pin point pupil cyanosis, reduced body temperature, hypotension , shock and coma

Tolerance and drug dependence

Central effects like dysphoria and mental clouding

Intolerance like tremor, delirium and skin rashes

Depression of fetal respiration

Drug interactions

The depressant actions of morphine are enhanced by  phenothiazines, monoamine oxidase inhibitors and tricycle antidepressants

Tolerance and dependence

Repeated use of drug produces tolerance to the respiratory depressant, analgesic, euphoric and sedative effects of morphine

Physical and psychological dependence readily occur with morphine

Withdrawal produce a series of  autonomic , motor and psychological responses that incapacitate the individual and cause serious  - unbearable symptoms


Preparation & Dose

Tincture opium  -  0.3 to 2 ml by mouth

Morphine sulphate         -  8 – 20 mg by mouth or by injection

Morphine hydrochloride   -   8 – 20 mg by mouth or by injection


Uses

1. It is an analgesic for  the relief of severe pain

2. Used as pre-anesthetic medication

3. For producing sleep and sedation

4. Used as anti-tussive

5. For the treatment of diarrhea

6. In the treatment of acute left ventricular failure 

Codeine

It is a phenanthrene alkaloid of opium

It is methyl- morphine

Naturally , 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, nausea and vomiting , 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- methorphan  - a synthetic cough depressant that has mo analgesic action and a low potential for abuse
Dose
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

Heroin

It is a diamorphine, 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- 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

 Mechanism of action

Pethidine binds to opioid receptors, 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, 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 , 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- 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.  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

Euphoria, dysphoria, weakness and palpitation

Depression o fetal respiration

Dry mouth, 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 pain

For producing sedation and sleep

As pre-anesthetic medication

Methadone

it is a synthetic, 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

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 , respiratory depressant , emetic , anti-tussive , constipating and biliary actions similar to morphine

Pharmaco-kinetic actions

It is readily absorbed following oral administration

It accumulates in  tissues, where it remains bound to proteins, 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
Preparation and dose
Methadone Hcl tablets I.P mg tab – dose – 5 – 10 mg
Methadone Hcl inj – 5 mg /ml of salt – dose – 5-10 mg s.c injection
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

Its analgesic action is only partially reversed by opioid antagonist known as naloxone

Tramadol causes less respiratory depression, sedation, constipation, 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, 100 mg SR tab

50 mg/ml inj in 1 and 2 ml amps


Opioid antagonists


Pure opioid  antagonists

1. Naloxone
2. Naltrexone
3. Nalmefene

1. Naloxone

It is N- alyl-nor- oxy- morphine 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, k and delta receptors with a ten- fold higher affinity for u receptors than for k

Naloxone produces no pharmacologic effects in normal individuals , 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- 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, 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 – 0.8 mg ) , it promptly antagonizes all actions of morphine

It is inactive orally because of high first pass metabolism in liver

Injected iv , 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 ( 0.4 mg iv every 2 -3 min, maximum 10 mg)

It also partially reverses alcohol intoxication

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)

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 , 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 , but benzodiazepines and clonidine are preferred

Naltrexone is hepatotoxic

Dose

50 mg tab

Side effects

Nausea

Headache

Higher doses can causes hepatotoxicity

3. 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 convulsions’.
They are useful in the following conditions

1. Chronic hypoventilation with CO2 retention
2. Respiratory failure in newborns
3. Respiratory failure due to overdose of CNS depressants
4. Post anesthetic respiratory depression

1. Direct CNS stimulants

A. Cortical stimulants
   
 1. Xanthene alkaloids
           
            Caffeine
            Theophylline
            Theo-bromine
            Aminophylline

   2. Sympathomimetics
           
            Amphetamine
            Methyl phenidate

B. Modularly stimulants

Picrotoxin
Pentylene-tetrazol
Nikethamide
Doxapram


C. 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 , the most widely consumed stimulant in the  world, is found in highest concentration in coffee, but is also present in tea, cola drinks , chocolate candy and cocoa 

Mechanism of action

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 monophosphate

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 the cortex and other areas of the brain

Consumption of 1.5 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 , 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  heart rate and contraction effects on the heart

Increased contractility  can be harmful to patients with angina pectoris

Xanthenes produce a direct stimulant effect  on the myocardium, 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, chloride and potassium

GIT

Methylxanthines stimulates secretion of hydrochloric acid from the gastric mucosa
Individuals with peptic ulcers should avoid beverages containing methylxanthines

Pharmacokinetics

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

Adverse effects

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

Therapeutic uses

Caffeine and its derivatives relax the smooth muscles of the bronchioles

Antidepressants

Coronary vasodilators

Diuretics

Nicotine

It is the active ingredient in tobacco

The drug is not currently used therapeutically except in smoking

It is mostly widely used  CNS stimulant

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

Pharmacological actions

On CNS

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

Peripheral effects

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

Pharmacokinetics

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

Adverse effects

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  

Withdrawal syndrome
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
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

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, 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, followed by respiratory and vasomotor depression

Sympathetic nervous system

Peripherally, cocaine potentates the action of nor-adrenaline  and produces the fight or flight syndrome characteristic of adrenergic  stimulation

This is associated with tachycardia, hypertension, 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, smoking or intravenous injection

The peak effect occurs at fifteen to twenty minutes after intra-nasal intake of cocaine powder

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, 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

Anti- Epileptic drugs & Anti - parkinsonism drugs


Def-  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, but not always)

CLASSIFICATION

1. Hydantoins
Phenytoin

2. Barbiturates
Phenobarbitone
Primidone

3. Iminostilbbenes
Carbamazepine

4. Succinimides
Ethosuximide

5. Aliphatic carboxylic acid
Sodium valproate

6. Benzodiazepines
Clonazepam
Clobazam
Diazepam

7. Newer antiepileptic
Lamotrigine
Gbapentine

8. Miscellaneous
Trimethadione
Acetazolamide

1. Phenytoin

Phenytoin was synthesized in 1908, 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
Antiepileptic drugs are believed to suppress the formation or spread of abnormal electrical discharges in the brain
 There are different mechanisms
  1. Inhibition of t he sodium or calcium influx responsible for neuronal depolarization
  2. Augmentation of inhibitory GABA neurotransmission
  3. Inhibition of excitatory glutamate neurotransmission

1. Effect on ion channels
Under normal circumstances, voltage- sensitive ( voltage gated) sodium channels are rapidly opened when t he neuronal membrane potential (voltage) reaches its threshold

This causes rapid depolarization of the membrane and the conduction of an action potential along the neuronal axon

When action potential reaches the nerve terminal . it evokes the release of a neurotransmitter

After the neuronal membrane is depolarized, the sodium channels is inactivated by closure of the channels inactivation gate

The inactivation gate must be opened before the next action potential can occur

Many antiepileptic drugs , including carbamazepine, lamotrigine, phenytoin and topiramate  prologs the time that the sodium channels inactivation gate remains closed and this delays the formation of the next action  potential

These drugs bind to the channel when it is opened a greater percentage of the time than are slowly firing neurons, the drugs exhibit use dependent blockade

For this reason , the drugs suppress abnormal repetitive depolarization in a seizure focus more than they suppress normal  activity

By these action, carbamazepine and other drugs prevent the spread of abnormal discharges in a seizure focus to other neurons

A few drugs ( Ex – ethosuximide and valproate) block T- type ( low- threshold ) calcium channels that are located in thalamic neurons and participate in the initiation of generalized absence seizures
 2. GABA ergic systems

Antiepileptic drugs facilitate GABA neurotransmission by various means

Benzodiazepines (eg- clonazepam ) and barbiturates ( eg – Phenobarbital ) enhance GABA activation of the GABA A , receptor- chloride ion channel

Topiramate is believed to enhance activation of the GANA A receptor, Ganapentin increases GABA release , whereas valproate inhibits GABA degradation

Drugs that augment GANA may serve to counteract the excessive excitatory neurotransmission responsible for initiation and spreading abnormal electrical discharges

3. Effects on glutaminergic systems

A few antiepileptic drugs, including felbamate, topiramate and valproate , inhibit glutamate neurotransmission and other drugs that work via this mechanism are under development

This is an attractive mechanism of action because it may affect the formation of a seizure focus and thereby terminate a seizure at an early stage of its development

Seizure is caused by the synchronous discharge of a group of neurons in the cortex

Activation of N- methyl-D- aspartate (NMDA) receptors increases calcium influx and nitric oxides synthesis

NO then diffuses to presynpatic neuron and increases the release of glutamate via formation of cyclic guanosine monophosphate

Increased excitatory glutamate neurotransmission leads to long term potentiation

Long term potentiation is believed to facilitate a depolarization shift , characterized by prolonged depolarization s with spikelets

The depolarization shift can cause adjacent neurons to discharge synchronously and thereby precipitate a seizure

 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

Phenytoin prevents the spread of seizures more than that of barbiturates
The drug has membrane stabilizing effects on all neuronal membranes including the peripheral nerve membrane as well as on all non- excitable and excitable membranes

The conversant action produced by drugs like strychnine , picrotixin and pentylenetetrazole are not blocked by phenytoin and the maximal electro shock seizures are effectively controlled by phebytoin

Besides , antiepileptic effects, phenytoin also produces antiarrhythmic effects and is useful in digitalis induced arrhythmias

Pharmacokinetics

Phenytoin is slowly and variably absorbed from the GIT and the peak plasma concentration occurs 3- 12 hrs after ingestion

In plasma it is 70- 95% bound to protein, mainly Albumin

It is metabolized in liver

Phenytoin is enzyme inducer

The inactive metabolite is excreted from the bile, subsequently in urine as a glucronide

Preparation and dose

Phenytoin Sodium I.P

Available as 50 mg and 100 mg Tablets I,V

Preparation containing 50 mg /ml is also available

Normal dose   - 3- 4 mg/kg/day


Adverse effects
Toxicity depends upon  dose , duration and route of administration

Phenytoin inhibits insulin release and produces hyperglycemia

Decreases the release of ADH

Osteomalacia , hypocalcaemia due to altered metabolism of vitamin D and inhibition of intestinal absorption of Ca

Chronic  oral medical effects is dose related and causes change in behavioral effects , increased frequency of seizure , gastric irritation accompanied by nausea and vomiting 

If large amounts are administered intravenously for cardiac arrhythmia or status epileptics  the most important toxic symptoms are cardiovascular collapse or central nervous system depression

Gingival Hyperplasia  -  Hyperpalasia and hypertrophy of the gums with edema and bleeding occur.. It is common in children’s

Hypersensitivity  - Rashes , hepatic necrosis , and neutropenia

Megaloblastic anemia – Phenytoin decreases absorption and increases excretion of folates

Teratogenicity

When taken by the pregnant lady, phenytion produces fetal hydantion syndrome characterized by hypo plastic phalanges, cleft palate,  and harelip

Hirsutism -  Coarsening of facial features ( troublesome in young girls ) , acne


Drug interactions
Phenytoin is an enzyme inducer
Ethanol inactivates phebytoin
Phenytoin given with phenobarbitone , 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
Sucralfate binds phebytoin in GIT and decreases its  absorption


Therapeutic uses

It is used in all types of epilepsy except petit mal

Phenytoin is highly effective for all partial seizures ( simple and complex), for tonic-chronic seizures and in the treatment of status epileptics
It is specifically useful in grand mal, psychomotor and focal cortical epilepsies

It is also used in cardiac arrhythmias - Dose  - 300 – 400 mg/day

Phenytoin is not effective for absence seizures, which often may worsen if treated with this drug


11. Phenobarbitone

Phenobartitone was the first effective antiepileptic drug to be introduced in 1912. 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, whereas the examining drug is excreted unchanged by the kidney
It is a potent inducer of the cytochrome P450 system and when given chronically, it enhances the metabolism of their agents

Dose
60 – 180 mg in divided doses

Adverse effects
Sedation, ataxia, vertigo , nausea and vomiting

Agitation and confusion occur  at high doses
 
Rebound seizures can occur on discontinuance of Phenobarbital

Therapeutic uses
It provides favorable response for simple partial 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, including febrile seizures

It also used to treat recurrent tonic-clonic seizures, especially in patients who donot respond to diazepam plus phenytoin

It also used as  a mild sedative to relieve anxiety, nervous tension and insomnia

111. 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-ethyl-malonamide which have longer half- lives than the parent drug

It is effective against tonic-clinic and simple partial seizures and phenyl-ethy-lmalonamide 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
Dose
500 mg – 5000 mg /day

1V. 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, which decrease                                                      the effects of drugs that are metabolized by his enzyme

Adverse effects
Chronic administration of carbamazepine can cause stupor, coma and respiratory depression

It also produces drowsiness, vertigo, ataxia, 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

Therapeutic uses
It is effective in Temporal lobe epilepsy

Trigeminal neuralgia

Used in post hepatic pain
Dose
It available as 200 mg tab Initial dose 100 mg thrice daily gradually increased to 600 mg – 1200 mg /day

V. Ethosuximide

It reduces propagation of abnormal electrical activity in the brain, most likely by inhibiting t- 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

Adverse effects

Drowsiness, lethargy, dizziness , restlessness , agitation , anxiety and the inability to concentrate are often observed

Dose

It is available as 250 mg capsules and as a syrup (250 mg / 5 ml) , initial dose 250 mg, Maximum dose – 750 – 1000 mg


V1. Valproic Acid

It is a broad spectrum anticonvulsant

It has multiple actions , including sodium channel blockade and enhancement of GABAnergic transmission

It is the most effective agent available for treatment of myoclinec seizures

It also diminishes absence seizures, but because of its hepatotixic potential, 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 ,only 3%  of the drug is excreted unchanged, the rest is converted into active metabolites by the liver

It is metabolized by cytochrome P450 enzymes.   Metabolites are excreted by kidney

Adverse effects

It can cause nausea, vomiting ,sedation, ataxia and tremor are common
It inhibits the metabolism of a number of antiepileptic drugs , including Phenobarbital, carbamazepine and ethosuximide

Dose

It is available as capsules containing the equivalent of if 250 mg of valproic acid.

Normally dose 15 mg / kg to be given in divided doses , maximum dose is 60 mg / kg /day


V11. 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 , 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.

Lorazepam has a longer duration of action and is preferred by some clinicians

All of the antiepileptics, the benzodiazepines are the safest and most free from severe side effects

All benzodiazepines have sedative properties

Side effects

Drowsiness, Somnolence, Fatigue, Ataxia, Dizziness and behavioral changes Respiratory depression and cardiac depression may occur when given intravenously in acute situations

Anti -   parkinsonism

It was  described b James Parkinson in 1817 and is therefore named after him

Parkinsonism is a chronic , progressive, 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, 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. To enhance dopamine activity

2. To depress cholinergic over- activity



Classification of Anti parkinsonism drugs

1. Drugs that increase dopamine levels

A. Dopamine precursor

Levodo[a

B. Drugs that release the dopamine

Amantidine

C. Dopaminergic agonists

Bromocryptine

Lisuride

D. Inhibit dopamine metabolism

MAO inhibitors  -  Selegiline


11. Drug influencing cholinergic system

A. Central anticholinergics

Bintropine

Benzhexol

Biperidine

B. Antihistamines

Diphenhydramine

Promethazine


Etiology and pathogenesis

The causes of neuron degeneration in parkinsonism diseases remain largely unknown

According to oxidative stress theory oxidation of dopamine in the basal ganglia yields highly reactive free radicals that are toxic to dopaminergic neuron and lead to their degeneration

The basal ganglia are a group of interconnected sub cortical nuclei the it include the striatum (caudate and putamen), substantial nigra, globus pallidus and sub thalamus

In healthy individuals, the basal ganglia receive input from the entire cerebral cortex, process this information and send feedback to the motor area of the cortex in a way that leads to the smooth coordination of body movements

Even simple movements such as walking ,involve a complex sequence of motor acts whose smooth execution requires the continuous interplay of the cortex and basal ganglia

In patients with parkinsonism disease , neuron degeneration interrupts this interplay

The basal ganglia function via a series of reciprocal innervations among themselves and the cortex

The striatum receives input from the cerebral cortex and substantial nigra and then sends output to the thalamus via the globus pallidus

The thalamus then feeds information aback to the motor area of the cortex

Two pathways connect the striatum and the thalamus , a direct pathway , which is excitatory and an indirect pathway, which is inhibitory

In patients with parkinsonism disease, t eh degeneration of dopaminergic neuron results in decreased activity in the direct pathway and increased activity in the indirect pathway

As a result, feedback to the cortex is reduced and patients exhibit bradykinesia and rigidity

Excitory cholinergic neurons also participate in the interconnections between structures in the basal ganglia

In parkinsonism disease the degeneration of inhibitory dopaminergic neurons leads to a relative excess of cholinergic activity in these pathways

For this reason, patients with parkinsonism disease can be treated effectively with drugs the inhibit cholinergic activity in the basal ganglia or with drugs that increase dopamine levels and doaminergic activity in the basal ganglia
Levodopa

Acetylcholine and dopamine are excitatory and inhibitory neurotransmitters in the corpus striatum

The dopaminergic system is impaired in parkinsonism, 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- brain barrier

Levodopa is a prodrug which is converted to dopamine in the body

It crosses the Blood- Brain-Barrier and is taken up by the surviving nigrostriatal neurons


                                  Decarboxylase
Levodopa    -------------------------------------------     Dopamine


Actions

On administration of levodopa, there is an overall improvement in the patient as all the symptoms subside

Other actions

CTZ  -  Dopamine stimulates CTZ to induce vomiting

CVS  -  Large amounts of levodopa converted to dopamine in the periphery causes
             postural hypotension and tachycardia. Dopamine is a catecholamine


Endocrine --  Dopamine suppresses prolactin secretion

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, vomiting, postural hypotension ,palpitation and occasionally arrhythmia can occur

Tolerance develops to these effects after some time

Behavioral effects like anxiety, depression , 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, metoclopramide and reserine are DA antagonists.

They reverse the effects of levodopa



Carbidopa and benserazide

These Are Peripheral Dopa Decarboxylase Inhibitors

When carbidopa or bensrazide are given with levodopa, 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, dizziness, vomiting , postural hypotension , 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- off phenomenon

An alternative inn patients unable to tolerate levodopa
Adverse effects

It include vomiting , postural hypotension, hallucinations,  skin eruptions and first dose phenomenon   -   sudden cardiovascular collapse
Lisuride and pergolide are similar to bromocriptine

Seleglline

It is a selective MAO- B inhibitor

MAO- 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  - Mild cases of parkinsonism are started on selegiline. ’It is also used as an adjunct to levodopa

Anti- cholinergic

The cholinergic over activity is overcome by anticholinergics

Tremors, seborrhea and sialorrhiea are reduced more than rigidity

Atropine derivatives like benzhexol,  benztropine, trihexyphenidyl are used

Antihistamines owe their beneficial effects in parkinsonism to their anticholinergic properties

Atropine like side effects such as dry mouth , constipation, 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., metoclopramide and phenothiazines can induce parkinsonism
Reserpine depletes catecholamine stores, metoclopramide and phenothiazines are dopamine antagonists

Treatment withdrawal of the drug usually reverses the symptoms

When drugs are needed, one of the anticholinergics are effective