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CHEMICAL TRANSMITTERS IN THE CNS

1- Amino-acids: a- Excitatory � Glutamate & Aspartate

acting on NMDA & AMPA receptors b- Inhibitory � GABA ( in brain) & Glycin ( in spinal cord)

2- Opioids 3- Others: a- Acetyl choline b- Noradrenaline & Dopamine c- Histamine & Serotonin d- Peptides ( eg.: Purines – Melatonin – Nitric oxide)

Drugs acting on CNS

Depressants Stimulants 1. Sedative, Hypnotic & Anxiolytics 2. Analgesics 3. Anticonvulsants 4. Antiparkinsonians 5. Antipsychotics 6. General anaesthesia

1. Cerebral stimulant 2. Brain stem stimulant 3. Spinal cord stimulant 4. Antidepressants 5. Hallucinogens

SEDATIVE, HYPNOTIC & ANXIOLYTICS Classification:

1) Benzodiazepines: The most important

2) Bz1 receptor agonist ( Zolpidem) & Bz2 receptor agonist ( Zopiclone & Eszopiclone) 3) Buspirone (5-HT1A partial agonist):

Anxiolytic but not sedative or hypnotic 4) Barbiturates: obsolete now, used only in anaesthesia & epilepsy 5) B blockers ( Propranolol):

Used to treat some forms of anxiety by blocking peripheral sympathetic responses rather than central effects

6) Ramelteon (Rozerim): a new hypnotic drug acting as a melatonin receptor agonist 7) Others (Older):

Chloralhydrate – Paraldehyde – Ethyl alcohol – Thalidomide – Glutethemide - Meprobamate

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Benzodiazepines

Classification according to t1/2

Ultrashort (<6h) Short (12-18h) Medium (24h) Long (24-48h)

-Triazolam - Midazolam

- Lorazepam*(ativan) - Oxazepam* - Temazepam*

- Alprazolam (xanax) - Nitrazepam*

- Diazepam (valium) - Clonazepam* - Chlorzepate - Chlordiazepoxide - Flurazepam

Pharmacokinetics

1) Absorption: - Oral: - Well absorbed orally - Chlorzepate (prodrug) Nordazepam

(active & rapidly absorbed)

- IV: - Diazepam & Midazolam � as IV anesthesia & Anticonvulsants - IM: - Slow absorption - Midazolam & Lorazepam may be used in status epilepticus when IV is difficult

2) Distribution: 1. All over the body – passes BBB & placental barrier 2. Redistributed & gradually accumulate in body fat 3. Highly bound to plasma protein 3) Metabolism: 1. Most of them � oxidation producing active metabolites followed by

conjugation with glucuronic a. 2. Some of them � conjugation directly with glucuronic a. producing inactive

Metabolites (as: LOT / Nitrazepam / Clonazepam) 4) Excretion: Excreted in urine after conjugation with glucuronic acid N.B: Classification of Bz. according to activation & inactivation in body:

1) Bz. Inactivated in body: LOT / Nitrazepam / Clonazepam 2) Bz. Activated in body: 1. Activated by gastric Ph: Chlorzepate 2. Activated by liver: others

Gastric

HCl

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Mechanism of action Through binding with Bz. Receptors [Bz1, Bz2 & Bz3] which facilitate GABAA transmition �� frequency of Cl- channel opening �� Cl- conductance � hyperpolarization & post-synaptic inhibition

NB: Inverse agonist: �-carbolines bind with Bz. Receptors & act as inverse agonist (� anxiety & convulsions)

Actions & uses 1) Sedation & Taming effect in animals 2) Hypnotic in cases of insomnia: - Short acting is used to initiate sleep & long acting to maintain it - Advantages over Barbiturate: a. less � of REM sleep � less hang over (Headache – Drowsiness – Depression) b. less Tolerance as it is not HME inducer c. wide safety margin d. specific antidote is available (Flumazenil) 3) Anxiolytic 4) Panic disorders 5) Preanaesthetic medication (sedation – hypnosis – amnesia) 6) IV Anaesthesia (Diazepam – Midazolam) 7) Muscle relaxant (Diazepam – Clonazepam) 8) Anticonvulsant (Diazepam – Clonazepam – Lorazepam) 9) Antidepressant ( Alprazolam only) 10) Control ethanol withdrawal symptoms 11) Diagnostic in psychiatry 12) Respiration & CVS: - No effect in healthy persons - Respiratory & cardiovascular depression in patients with respiratory or cardiovascular disease

Side effects

1- Day time sedation after long acting & Anxiety after short acting 2- Depress bone marrow & Depress respiration & heart specially in diseased patient

3- Allergy 4- Appetite increase & GIT disturbances 5- Alcohol intolerance (supersensitivity)

6- Aged patient� Confusion & Hypotension 7- Amenorrhea in females 8- Accumulate in fetus & neonates & Teratogenic

9- Anterograde amnesia (Amnesia during drug intake) 10- Aggravate Schizophrenia & Sexual dysfunction

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11- Chronic use � Dependence, Tolerance & Addiction: - After long use > 1 week

- Cross tolerance with other hypnotics - Withdrawal should be gradual 12- Acute toxicity: � � CNS – CVS – Respiration ttt: IV Flumazenil : - Competitive antagonist at Bz. Receptors

- Extensive hepatic metabolism � use IV - Short t1/2 � use repeatedly or infusion

Zolpidem &Zopiclone

- Zolpidem: 1- Non-benzodiazepine acting as selective Bz1 receptor agonist facilitate GABAA transmition & antagonized also, by Flumazenil 2- Metabolised into inactive metabolite 3- Used as Hypnotic & short term anxiolytic 4- Unlike Benzodiazepines : - Weak anticonvulsant & muscle relaxant - Minimal Dependence & Tolerance

- Zopiclone: selective Bz2 receptor agonist – as Zolpidem but has bitter taste

Buspirone Kinetic:

1- Rapidly absorbed orally 2- Extensively metabolized in the liver into several active metabolites which may have �2-blocking effect

Mechanism of action: Partial agonist at 5-HT1A receptors in brain Actions:

1- Anxiolytic with no sedation, hypnosis, CNS depression or drug dependence 2- The effect appears after 1- 2 weeks

Uses: Chronic generalized anxiety especially in eldery

Side effect: 1. Nervousness 2. Dose dependant pupillary constriction 2. GIT disturbances 3. Tachycardia 4. Hypertension & serotonin syndrome with MOA.I

NB.: Ipsapirone & Gepirone: as Buspirone

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Barbiturates Classification

Ultrashort (20-30 min) Short (2-4h) Medium (4-6h) Long (6-8h)

- Thiopentone - Hexobarbitone

- Pentobarbitone - Secobarbitone

Amobarbitone - Barbitone - Phenobarbitone

Chemical structure

- They are derived from Barbituric acid - Barbituric acid is a condensation of urea + malonic acid (malonyl urea) - Barbituric acid itself is not sedative or hypnotic

Kinetic 1- Absorption: well absorbed orally & from injection sites 2- Distribution:

- All over the body, passes BBB & placental barrier - Ultrashort is rapidly redistributed into fat - Bound to plasma protein (30% long – 50% short – 70% ultrashort)

3- Metabolism: - Metabolised in liver by oxidation then conjugation except Phenobarbitone & Thiopentone - Phenobarbitone depends mainly on renal excretion - Thiopentone depends on tissue & fat redistribution

4- Excretion in urine: - After conjugation, BUT Phenobarbitone is excreted mainly unchanged - Alkalinization of urine �� their excretion

Mechanism of action

As Bz.: they facilitate GABAA transmition �� duration of Cl- channel opening �� Cl- cnductance � hyperpolarization & post-synaptic inhibition

Actions 1- CNS:

a- Sedative – Hypnotic – Anxiolytic b- Amnesia � Automatism c- Anaesthesia d- Analgesia: potentiate analgesics but not analgesic alone even it may cause

hyperalgesia if used alone e- Anticonvulsant f- Large dose� � RC – VMC – HRC

2- CVS: Large dose � Hypotension 3- Respiration: Large dose� � RC 4- GIT: - � tone & motility - HME inducer � � metabolism of other drugs & their own metabolism

Pheno. Thio.

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5- Urinary bladder: Urine retention due to: - � wall - � Bl.pr - � ADH 6- Uterus: � contractility 7- Sk. m.: Curare like 8- Hormones: � ACTH - � ADH

Uses They are obsolete as sedative & hypnotic & they are used for:

1- Thiopentone: IV anesthesia 2- Phenobarbitrone: - Anticonvulsant

- Hyperbilirubinaemia as it � HME

Side effects & Toxicity 1- Allergy 2- Abnormal sleep : � REM� Hang over (Headache – Drowsiness – Depression) 3- Acute porphyria in patients with Acute intermittent porphyria as barbiturate � � ALA

synthase � � level of ALA (which is responsible for the acute attack) Succinyl Co-A + glycine ALA Protoporphyrin Haem

NB.: In Acute intermittent porphyria there is � of the strong enzyme � accumulation of ALA

4- Inducer of HME � tolerance – cross tolerance & drug dependence 5- Idiosyncrasy: excitation instead of sedation especially in eldery 6- Acute poisoning: [narrow safety margin]:

- Manifestation: hypothermia – hypotension – hypoventilation – hypoxia – coma & death [� RC]

- Management: • Promote drug elimination:

- Gastric lavage, but may cause aspiration pneumonia - Promote excretion: - Alkalinization of urine by NaHCO3

- Diuretics - Haemodialysis

• Respiratory care: - Artificial respiration - Analeptics e.g.: Bemegride - Antibiotics to guard against Pneumonia

• CVS care: Correct hypotension by IV fluids 7- Chronic poisoning : [Addiction]

- Sudden stop � withdrawal symptoms & status epilepticus - So, the drug should be gradually withdrawn

Drug interaction

1- ���� HME: - Tolerance & cross tolerance - � metabolism of other drugs as oral anticoagulants – digitalis ……

2- Potentiate other CNS depressants as aspirin – ethyl alcohol – anesthesia 3- Physiological antagonism with caffeine

���� ALA synthase

Strong enz.

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Contraindication 1- Acute intermittent porphyria 2- Allergy 3- Alone in pain 4- Aged patients & neonates 5- Head injury 6- Respiratory or cardiovascular disease 7- Liver or Kidney disease 8- During pregnancy or Labour

Chloral hydrate Kinetics:

1- Well absorbed orally & rectally 2- Distributed all over the body & passes BBB 3- Metabolized in liver & RBCs into more active metabolite "Trichloroethanol" then inactivated by oxidation or conjugation with glucuronic acid 4- Excreted in urine

Dynamics: 1- Hypnotic: - Onset 1/2 h - Duration 6-8 h - Does not � RC or VMC in therapeutic dose - Bad taste 2- HME inducer

Uses: 1- Hypnotic esp in eldery & children 2- Prenaesthetic medication

Contraindication: 1- Liver disease – Kidney disease – Peptic ulcer 2- With ethanol � synergism � RC & coma

Toxicity: 1- Acute: Vomiting – pin point pupil (P.P.P) – respiratory failure – cardiovascular

failure 2- Chronic: Tolerance – Dependence – Addiction

Paraldehyde

Actions & Uses: Route of administration change the action

1- Orally � Hypnotic 2- IM � Anticonvulsant 3- Rectally � Basal anesthesia

Contraindication: 1- Liver disease

2- Lung disease

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ANALGESICS

CNS depressants that relieve pain centrally without loss of consciousness or other sensations

*Classification of analgesics A) Central (Proper analgesics): 1- Narcotic (Opioid) analgesics 2- Antipyretic analgesics B) Peripheral (Non-proper analgesics): 1- Causal: eg.: a- Anticolics eg.: Atropine b- Antianginal drugs eg.: Nitroglycerine 2- Non-causal: eg.: a- Local anesthetics b- Astringents

c- Physical protectives as demulcents d- Counter-irritants

e- Obtundants in tooth cavity

Narcotic (Opioid) Antipyretic 1- Example Morphine Aspirin 2- Potency & type of pain relieved

Potent, effective in all types of pain esp. deep visceral pain but not itching

Less potent, effective in superficial pain

3- Site of action Central on spinal & supraspinal level - Central on thalamus - Peripheral as anti-inflammatory

4- With analgesia Narcosis [Stupor & Drowsiness] � elevated body temp. to normal 5- Long use Tolerance, dependence & addiction No Tolerance, dependence or

addiction

Narcotic (Opioid) analgesics

CNS depressant drugs that relieve pain centrally, but in large dose they produce Narcosis [Stupor & Drowsiness]. On long use they may cause Dependence.

Classification: 1) Opioid agonist: 1- Phenantherene group of opium alkaloids: Morphine & Codeine 2- Semisynthetic Morphine derivatives: a. Diacetylmorphine (Heroin) b. Dihydromorphinone c. Oxymorphone d. Dihydrocodeinone e. Oxycodone 3- Synthetic Morphine substitutes: a. Meperidine b. Methadone c. Fentanyl d. Dextropropoxyphene 2) Mixed agonist-antagonist: a. Pentazocine b. Nalbuphine c. Butorphanol d. Buprenorphine

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Opium Alkaloids

Opium is the dried milky juice of incised unripe fruit of papaver somniferum

Classification of Opium Alkaloids

A) Phenantherene group: B) Benzyl-isoquinoline group: 1- Members

2- Actions: - CNS - Smooth m.

3- Long use

- Morphine (the main) - Codeine - Thebaine (convulsing) Narcotic – analgesic spasmogenic Addiction

- Papaverine - Narcotine - Narceine (convulsing) Not narcotic – Not analgesic spasmolytic No addiction

Morphine

Natural main alkaloid (10%) of phenantherine group of opium.

Pharmacokinetic 1. Absorption: a. Absorbed orally, but low bioavailability (25-30%) b. Better absorbed S.C & I.M c. In case of shock, it is given diluted & slowly I.V 2. Distribution: All over the body. Passes BBB & placental barrier � neonatal asphyxia during

labour (treated by Naloxone IV to mother or IU to neonate) 3. Metabolism: a. Extensively metabolized in the liver by conjugation with glucuronic acid b. Morphine-6-conjugate is more active than morphine but morphine-3-

conjugate is inactive 4. Excretion: a. Saliva: used to test racing horses b. Stomach: stomach wash in every case of poisoning even parentral poisoning c. Bile: enterohepatic circulation. & Some are excreted in stool d. Milk: may affect suckling baby e. Renal: the major excretory route

Mechanism of action

Morphine is a direct opioid receptor agonist:

*Opioid receptors: -Site: CNS & periphery esp. smooth m. & GIT -Structure: G-proteine coupled receptor either:

- � Adenylate cyclase enz. � � c.AMP - Opening of K+ Channels �hyperpolarization - Close Ca++ Channels �� Ca++ influx �� release of mediators

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-Types: mu (�1&2), kappa (�1&2), delta (�1&2), sigma (�), epsilon (�): -Agonists: - Exogenous opioid agonist (e.g: Morphine)

- Endogenous opiopeptides : - Enkephalins[short duration] - Endorphins[long duration] - Dynorphins)

-Relation to other mediators: �� substance P �� Serotonin & Dopamine

Actions

1) C.N.S: mixed �&�

Depressant actions: Stimulant actions:

1. Analgesia: a. All types of pain esp. deep visceral pain b. not effective in itching as it releases histamine c. Mechanism: - Spinal: � release of substance P - Supraspinal: - � pain threshold in sensory cortex - Alter psychological reaction to pain on frontal area - Narcosis is an adding factor 2. Narcosis: stupor & drowsiness 3.� R.C: 4.� Cough center 5.� V.M.C�VD & hypotension 6.� Heat regulating center � Hypothermia 7.� Hormones: ACTH – FSH – LH 8.� Polysynaptic spinal reflexes�� withdrawal reflex

1. Euphoria 2. Excitement & convulsions in some human & animals (eg: horse & mice) esp in I.V large dose due to � of GABA 3.� Edinger Westiphal nucleus (III rd cranial nerve) � pin point pupil (PPP) 4.� CIC � Bradycardia 5.� CTZ � Vomiting esp. in small dose 6.� Hormones: ADH – Growth - Prolactin 7.� Monosynaptic spinal reflexes � �stretch (patellar) reflex in man & Straub reaction in mouse 8. Trunkal rigidity due to� of hippocumbal pyramidal cells

------------------------------------------------------------------------------------------------------- 2) A.N.S: � parasympathetic & � sympathetic ------------------------------------------------------------------------------------------------------- 3) Eye: Miosis & PPP due to � of Edinger Westiphal nucleus ------------------------------------------------------------------------------------------------------- 4) Skin: Histamine release � Itching & triple response

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5) CVS: a. Therapeutic dose � no effect b. Large dose � Hypotension � � V.M.C � Direct veinodilator � Histamine release �Bradycardia � � CIC -------------------------------------------------------------------------------------------------------6) Respiration:

a. Central: - � RC - � Cough center b. Peripheral: Bronchoconstriction due to: histamine release & spasmogenic effect ------------------------------------------------------------------------------------------------------- 7) Spasmogenic on smooth muscle: a- GIT: spasmogenic & constipation 1) Central: � Defecation reflex 2) Peripheral: 1.� All secretion (except salivary) 2. � Propulsive movement 3. � Segmental contraction 4. Spasm of sphincters N.B: Loperamide (no CNS action) & Diphenoxylate (mild CNS) are

selective opiate agonist on GIT � useful in ttt of diarrhea b. Biliary tract: a. Spasm of biliary duct & sphincter of Oddi �

� intrabiliary pressure (Avoid after Cholecystectomy) c. Urinary tract: a. Central: - � ADH � Oliguria - � Micturition reflex

b. Peripheral: Spasm of ureters & sphincters � urine retention d. Uterus: Does not affect contractility but passes placenta � neonatal asphyxia e. Bronchi: Bronchospasm ------------------------------------------------------------------------------------------------------- 8) Metabolism: � BMR N.B.: Tolerance to Morphine: 1. It occurs to the depressant action of morphine after 10-14 days of

continued use due to depletion of endogenous opiopeptides 2. No tolerance to excitatory, miosis or constipation 3. Cross tolerance with other CNS depressants

+ +

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Uses of Morphine

1) Pain: Analgesic in severe visceral pains eg.: a. Cardiac pain: myocardial infarction & cardiogenic shock b. Cancer pain: terminal cancer pain c. Colicy pain: biliary & renal (add atropine) d. Bone fractures (not in head injury) e. Post-operative pains (not after eye or gall bladder operations) 2) Pre-anaesthetic medication: to provide analgesia & sedation *Disadvantage:

a. Miosis – Vomiting – Bronchoconstriction b. Delay awaking from anaesthesia c. Post operative constipation & urine retention

3) Pulmonary edema: due to a. Sedate the patient � � sympathetic � VD � � Afterload b. Venodilator � � venous return � � Preload 4) Neurogenic shock

Contraindication of Morphine

1- Extremities of age 2- History of allergy or addiction 3- Head injury: a. Miosis masks lateralization b.VD � � synthesis of CSF �� ICP �� RC 4- Increased intracranial pressure 5- Epilepsy 6- Myxoedema (� BMR, � liver & CNS actions) 7- Respiratory diseases 8- Acute abdomen eg.: acute appendicitis as morphine mask diagnosis 9- Liver disease & alcoholism 10- Alone in biliary or renal colic 11- Pregnancy & labour: Pregnancy (addict fetus) & labour (neonatal asphyxia)

Side effects & Toxicity of Morphine

1. Dysphoria 2. PPP 3. Itching 4. Vomiting 5. Bronchoconstriction 6. � RC 7. Constipation 8. Urine retention 9. Mask diagnosis of serious infections eg.: acute abdomen 10. Tolerance & cross tolerance with other CNS depressants 11. Acute morphine poisoning: - Coma + Triad (PPP / Respiratory failure / Circulatory failure) � Death - Treatment: a. Artificial respiration b. Stomach wash with K+ permenganate even after injection c. Purgative with MgSO4

d. Specific antagonist: Naloxone 0.4 mg IV or Naltrexone orally

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12. Chronic poisoning (Addiction): a. Occurs after 10-14 days of continued use � Tolerance + Psychic &

Physical dependence b. Due to depletion of endogenous opiopeptides c. Sudden stop � Withdrawal or Abstinance syndrome (reversal of morphine actions� yawning – mydriasis – excitation – diarrhea – urination – sweating – hyperventilation – hypertension – tachycardia - convulsions) d. Management: 1. Hospitalization & Psychotherapy 2. Gradual withdrawal of morphine till stabilizing dose 3. Gradual substitution with long acting opiates as Methadone or Levomethadyl acetate (LAAM) 4. Gradual withdrawal of methadone � less withdrawal symptoms 5. Oral Naltrexone (opioid antagonist) as maintenance to maintain opioid

free state

Codeine ( Methylmorphine)

Like morphine but: - Better oral bioavailability - Shorter duration - Weaker (1/5 morphine) Actions:

a. Narcotic analgesic - Antitussive b. Less constipating - Less addicting - Less � RC

Uses: a. Antitussive b. Analgesic, used alone or with Aspirin & Paracetamol (APC mixture)

Papaverine

Actions: 1. No CNS actions 2. Smooth m.: Direct spasmolytic esp. on GIT, uterus & blood vessels 3. Heart: quinidine like action

Uses: 1. Antispasmodic in colics eg.: intestinal 2. Vasodilator eg.: in pulmonary embolism

Narcotine

Non narcotic, non-addicting, central antitussive

Days

Methadone

Morphine

Dose

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Synthetic Morphine substitutes

1) Meperidine ( Pethedine)

Nature: Synthetic phenylpiperidine Pharmacokinetics:

1. 50% oral bioavailability 2. Rapid onset & short duration 3. Metabolized in liver into

a. Meperidinic acid � conjugation with glucuronic acid � urine b. Normeperidine � active � excitation & convulsions

Pharmacodynamics: Atropine like + 4 less + 4 no + 2L 1. Atropine like 2. Less analgesic 3. Less addictive 4. Less emetic 5. Less � RC 6. No PPP 7. No constipation 8. No narcosis 9. No antitussive 10. Local irritant then local anesthetic 11. Large dose excitation & convulsions (Normeperidine + Atropine like) 12. � ADH secretion

** ttt of toxicity by IV Naloxone Uses:

1- Analgesic as morphine esp. a. Alone in renal or biliary colic ( atropine like) b. Obestatric analgesia (less � RC)

2- Preanaesthetic medication (better than morphine as it is atropine like)

NB.: Meptazinol: as meperidine used mainly in obstetric analgesia

2) Methadone

As potent as morphine but: 1. Better oral bioavailability (50%) 2. Less addiction & withdrawal symptoms

Uses ( orally) a. Analgesic as morphine b. Help withdrawal of morphine

NB.: Levomethadyl acetate (LAAM): as Methadone

3) Fentanyl

1. Derivative of meperidine 2. Strong analgesic (80 times > morphine) & mainly � agonist Uses: as IV anaesthesia:

a. Alone b. Fentanyl + Droperidol "major tranquilizer" = Neurolept analgesia (Thalamonal)

Side effect: Vomiting – Marked � RC – Muscle rigidity

N.B: Alfentanil is more potent & Sulfentanil is short acting

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4) Loperamide ( Imodium) & Diphenoxylate (Lomotil) 1. Derivatives of Meperidine 2. Selective opiate agonist on GIT � constipation � Antidiarrheal 3. Loperamide does not pass BBB � no CNS action, while Diphenoxylate & its active

metabolite Difenoxine has some lipid solubility � narcosis 4. Side effects: - Paralytic ileus

- LD of Lomotil [Diphenoxylate + Atropine] esp. in children � Narcosis & Atropine like toxicity

5) Dextropropoxyphene

1. Derivatives of methadone 2. Analgesic (1/6 morphine). Used in pain resistant to aspirin 3. Large dose � Convulsions & � RC NB.: Tramadol:

- It is a metabolite of antidepressant Trazadone & has an analgesic effect as effective as morphine or meperidine

- Mechanism of analgesia: is a weak � agonist & � uptake of serotonin & noradrenaline

Opioid Antagonists

Pure antagonist

Partial agonist

Naloxone (IV)

Naltrexone & Nalmefene

(Orally)

Nalorphine & Levalorphan

1- Naloxone: Uses: 1. Treatment of: - Acute morphine poisoning: 0.4 mg IV - Neonatal asphyxia: either IM to mother before labor or IU

to neonate 3. Diagnosis of morphine addicts SC Naloxone � withdrawal symptoms

2- Naltrexone & Nalmefene: a. As Naloxone but: effective Orally - Stronger – Longer b. Uses: to maintain the opioid free state in treated addicts

3. Nalorphine & Levalorphan: Actions & uses: 1. In absence of morphine � morphine like � analgesia but cause

Dysphoria & Hallucinations 2- In presence of morphine � antagonist � used to treat acute morphine poisoning 3. In morphine addicts � withdrawal symptoms. Used to diagnose addicts

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Mixed Agonist (�)-Antagonist(�)

- Examples: a. Pentazocine (Talwin) ……. (Parentally & orally) b. Nalbuphine………………. (Parentally)

c. Butorphanol………………(Parentally) d. Buprenorphine ………….(Parentally)

- Actions: 1- In absence of morphine , they act as Agonist � strong analgesic

- Pentazocine &Nalbuphine are less potent while Butorphanol & Buprenorphine as potent as morphine

- Used in ttt of severe pain 2- In presence of morphine they act as antagonist � withdrawal symptoms in addicts 3- Partial agonist on respiratory depression Ceiling effect with low doses (increasing the dose will lead to more analgesia but no more depression of RC) 4- Weak addiction � weak withdrawal symptoms

Morphine Mixed agonist antagonist

Analgesia

� RC � RC

Dose Dose

Analgesia

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Antipyretic Analgesics ( NSAIDs)

1- CNS depressants that relieve pain centrally with decreasing elevated body temperature to normal but without narcosis 2- Most of them (except Acetaminophin [Paracetamol]) have anti-inflammatory effects �Non-steroidal anti-inflammatory drugs (NSAIDs) Mechanism of action:

- They inhibit COX �� synthesis of prostanoids (PGs – PGI2 – ThXA2) - Types of COX enz.: a. COX-1 (Constitutive) esp in � Stomach �� HCl (prevent Peptic Ulcer) �Kidney � Renal VD b. COX-2 (Inducible) by inflammation at inflammatory sites c. COX-3 has been recently identified present mainly in CNS Clasification:

a. Non-selective COX inhibitors: 1. Aspirin (Salicylates) 2. Pyrazolone derivatives eg.: Phenylbutazone 3. Propionic acid derivatives eg.: Ibuprofen 4. Enolic acid derivatives (Oxicams) eg.: Piroxicam 5. Diclofenac 6. Acetic acid derivatives eg.: Indomethacin 7. Fenamates

b. Selective COX-2 inhibitors: Celecoxib – Rofecoxib – Etoricoxib –Valdecoxib They have little side effect on gastric acidity & kidney, but they may cause fatal

arrhytmia c. Selective COX-3 inhibitors:

eg.: Aniline derivatives ( eg.: Paracetamol) They have no anti-inflammatory or peripheral action

I-Salicylates

- They are salicylic acid derivatives. Salicylic a. itself is very irritant - They include:

1. Acetylsalicylic acid (ASA, Aspirin) 2. Sodium salicylate 3. Diflunisal (potent anti-inflammatory – no antipyretic action)

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Pharmacokinetic 1- Absorption: Orally from upper GIT

(better from stomach but more from upper intestine) 2- Distribution: a. All over the body. Passes BBB & placental barrier b. Highly bound to plasma protein 3- Metabolism: a. Mainly conjucated with glucuronic a. & glycine � salcyluric acid (inactive) b. 1% is oxidized � gentesic acid (active) 4- Excretion: Mainly in urine & Alkalinization of urine � � excretion 5- t 1/2: a. At low conc. � 1st order kinetic b. At high conc. � zero order kinetic

Pharmacodynamics Aspirin � irreversibly (by acetylation) COX enzyme (1, 2&3)

1) CNS: A) Analgesic: � PGs : a. Centrally �� pain threshold esp. in thalamus b. Peripherally � anti-inflammatory effect B) Antipyretic:

a. � synthesis of PGs induced by IL1, IL6 & TNF-� that released by bacterial toxins � resetting of HRC � � heat loss by :

- � Mobilization of fluids from tissues to plasma - Peripheral VD � � heat loss by radiation - � Sweating � �heat loss by evaporation

b. Toxic dose � hyperthermia due to uncoupling of oxidative phosphorylation � rate of heat production > heat loss

------------------------------------------------------------------------------------------------------- 2) Anti-inflammatory & anti-rheumatic: 1. � PGs synthesis (directly & indirectly): - Directly: � COX-2 induced by inflammation �� PGs synthesis - Indirectly: large dose of aspirin �� ACTH �� Cortisol �� Phospholipase A2

�� Arachidonic acid synthesis �� PGs synthesis 2. � Kallekrein enz �� synthesis of Bradykinin �� pain &� VD 3. � Hyaluronidaze enz. �� capillary permeability �� swelling & edema 4. � Fibrinolysin & tissue damaging enzymes 5. � Migration of polymorphs & macrophages to inflammatory sites 6. Stabilization of Lysosomes �� release of proteolytic enzymes ------------------------------------------------------------------------------------------------------- 3) CVS: a. Therapeutic dose � no effect.

b. Toxic dose �VD & hypotension

O2

CHO

E

ATP VD

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LD

4) Respiration & Acid/Base balance: a. Small dose: no effect b. Large dose:

1. In adults: � RC (Central direct effect & Peripheral through � CO2 production from uncoupling oxidative phosphorylation) � hyperventilation � CO2 wash � Respiratory alkalosis � excretion of excess alkali by kidney � Compensated respiratory alkalosis

2. In children: Metabolic acidosis due to: a- Dissociation of salicylate ,in blood, into salicylic a. b- Impaired CHO metabolism with accumulation of pyruvic a. & lactic a.

c- Impaired renal function with retention of acids c. Toxic dose: � RC � Respiratory acidosis NB.: Aspirin may precipitate bronchial asthma in susceptible patients?? ------------------------------------------------------------------------------------------------------- 5) GIT & Liver: A- GIT: a. Hyperacidity, Ulceration & Bleeding: due to: - Local irritation due to release of salicylic a. - Systemic due to � synthesis of PGE2 & I b. Nausea & Vomiting: - Local irritation due to release of salicylic a. - Central due to � CTZ.

B- Liver: a. Hydrochloretic (� water in bile � volume) b. Glycogenolysis due to release of adrenaline ------------------------------------------------------------------------------------------------------- 6) Kidney & Uric acid excretion: A- Kidney:

a. � synthesis of PGs �� renal VD � renal VC �� renal blood flow � edema b. LD of aspirin � Nephrotoxic

B- Uric acid excretion: a. Small dose (1-2 gm /day): � uric acid secretion in proximal convoluted tubules� hyperuricemia �worsens the gout (Contraindicated) b. Large dose (5 gm /day):� uric acid reabsorption in proximal convoluted tubules �uricosuric � treat the gout.

------------------------------------------------------------------------------------------------------- 7) Uterus: - Delay onset of labour due to � of PGE2 & PGF2� ------------------------------------------------------------------------------------------------------- 8) Endocrine: a. ���� ACTH due to � of hypothalamus & ant. Pituitary ��cortisol b. ���� Adrenaline due to � of adrenal medulla c. ���� Free form of T3 & T4 due to displacement from plasma proteins �� TSH �� thyroid gland functions eg.: radioactive iodine uptake. ------------------------------------------------------------------------------------------------------- 9) Immunological: �� antigen/antibody reaction trough release of cortisol

SD

HCO3-

H+

H2O

Glycogenolysis

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234

10) Blood: 1.���� Elevated erythrocytic sedimentation rate 2.���� Lecocytosis to normal 3.���� Platelet aggregation in SD (75-100 mg/day)

as in SD it � selectively thromboxane A2 (ThXA2) �� bleeding time 4. Hypoprothrombinemia in LD As it competes with vit K (coumarine like effect) �� synthesis of prothrombin & factors VII, IX & X �� coagulation (prothrombin) time 5. Haemolysis (idiosyncrasy) in patients with G-6-PD deficiency (Favism)

------------------------------------------------------------------------------------------------------- 11) Metabolism: 1. CHO: LD produces hyperglycemia due to � adrenaline & cortisol 2. Protein: LD produces

- - ve nitrogen balance due to � amino acid loss in urine - � Glutamate / GABA ratio � Convulsions

3.���� BMR & hyperpyrexia due to uncoupling oxidative phosphorylation

Uses 1- Local:

a. Salicylic acid as : Keratolytic b. Methylsalicylate as counterirritant

2- Systemic: 1. Analgesic & Antipyretic in:

a- Mild superficial pain eg.: Headache, Toothach, Myalgia, Arthralgia, Neuralgia & Dysmenorrhea

b- Common cold: to treat fever, headache, myalgia & arthralgia c- Rheumatic fever: (10 g/d) d- Rheumatoid arthritis: (8 g/d)

2. Uricosuric: in large dose> 5g/d in ttt of Gout 3. Antiplatelet: (SD = 75-100 mg/d) in Prophylaxis of thromboembolic disease 4. Chronic use of aspirin may decrease Cancer colon & Cataract

Drug & Food interactions

1- Displace other drugs from plasma protein eg.: oral hypoglycemic & anticoagulants � � their effect & toxicity

2- Antagonize : - Other uricosurics eg.: Probenicid - Antihypertensive effect of Thiazide - The anti-inflammatory effect of : Indomethacin – Fenamates – Propionic acid – Pyrazolone derivatives

3- The ulcerogenic effect is ���� by: Alcohol – Cortisone – Phenylbutazone 4- Salicylism is���� by: carbonic anhydrase inhibitors 5- The toxicity is ���� by:

- NH4Cl - Food containing salicylate (Curry powder - Paprika – Prunes

Raisins – Tea – Licorice)

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235

Side effects & Toxicity

1- Acute poisoning: - Manifistation: 1- Hyperpyrexia 2- Hyperhydrosis � dehydration 3- Hyperventillation 4- Hyperacidity, nausea & vomiting 5- Hyperglycemia 6- Hyperreflexia, convulsions & coma 7- Hypotension 8- Hypoprothrombenemia & Bleeding 9- Acid / base disturbances � It is the prominent manifestation (see before..) - Treatment: � no specific antidote 1- Eliminate the drug by: - Stomach wash by NaHCO3 - Alkalinization of urine by IV NaHCO3

- Haemodialysis 2 - Symptomatic ttt: - Cold fomentations for fever

- IV fluids for dehydration - Vit. K for hypoprothrombenemia - Correction of Acid / base disturbances 2- Allergy : urticaria – rash & bronchial asthma

NB.: Bronchial asthma may be due to allergy or � PGs �� LTs 3- Salicylism: long use of LD � headache & irritability

– Vertigo - Tinnitus – Blurring of vision – nausea & vomiting – Hyperventillation

4- Hypoprothrombenaemia & bleeding 5- Gastric irritation: nausea – vomiting – hyperacidity – ulceration & bleeding

Prostaglandins (eg.: Misoprostol) is useful in ttt of NSAID-induced peptic ulcer

6- Reye syndrome: ���� fatal hepatic injury & encephalopathy in children with viral infections (eg.: influenza & chicken pox) 7- Teratogenicity: cardiac septal defect - � bleeding risk at birth – delay labour 8- Idiosyncrasy: haemolysis in patients with G-6-PD deficiency 9- Nephrotoxicity

Contraindications

1- Allergy 2- Idiosyncrasy: patients with G-6-PD deficiency 3- Bronchial asthma 4- Bleeding tendency: eg.: hemophilia 5- Peptic ulcer 6- Pregnancy (but it is the safest anti-inflammatory among NSAIDs if needed) 7- In gout: (a. small dose < 5 g/d b. combination with other uricosurics) 8- Infants & children < 6 years:

(a. Reye syndrome with viral infections b. More susceptible for toxicity)

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236

II- Pyrazolone derivatives 1. Antipyrine 2. Dipyrone (Novalgine): rarely used due to bone marrow depression 3. Phenylbutazone 4. Oxyphenylbutazone

Pharmacokinetic:

1. Well absorbed from GIT (orally& rectally) & parentrally 2. Disributed all over the body 3. Highly bound to plasma protein 4. Metabolized in liver:

a. Phenylbutazone (active) � 2 active metabolites: - Oxyphenbutazone (potent anti-inflammatory & anti-rheumatic) - �-hydroxyphenylbutazone (uricosuric)

b. Conjugation with glucuronic acid 5. Excreted in urine

Pharmacodynamics:

1. Potent anti-inflammatory & antirheumatic 2. Weak analgesic antipyretic 3. Uricosuric

Uses: Anti-inflammatory in: Acute gout – Rheumatoid arthritis Side effects & Toxicity:

1. CNS: Headache, nervousness & vertigo 2. Allergy & skin rash 3. GIT upsets & ulceration 4. Liver & kidney damage 5. Teratogenic 6. Bone marrow depression 7. Salt & water retention : edema & hypertension

Drug interactions:

1. Displaces other drugs from plasma protein �� their activity eg.: oral hypoglycemic, oral anticoagulants

2. HME inducer

NB.: Uricosuric NSAIDs:

1. Salicylates 2. Pyrazolone derivatives

CNS

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237

III- Acetic acid derivatives

1- Indomethacin 2- Sulindac (Prodrug) 3- Etodolac

Indomehacin: *Kinetics:

Absorbed orally – bound to plasma protein – metabolized in liver – excreted in urine & bile (enterohepatic circulation)

*Actions: 1. Potent analgesic, antipyretic & anti-inflammatory 2. Not uricosuric

*Uses: 1. Anti-inflammatory in: Acute gout-

osteoarthritis – pericarditis 2. Patent Ductus Arteriosus

*Side effects: 1. CNS: headache – vertigo – psychosis 2. Corneal opacities 3. Allergy & skin rash 4. GIT upsets & ulceration 5. Liver & kidney damage 6. Teratogenic 7. Bone marrow depression

IV-Propionic acid derivative

1) Naproxen (Naprosyn): long t ½ (14 hours) 2) Tiaprofenic acid (Surgam) 3) Ibuprofen 4) Fenoprofen 5) Ketoprofen 6) Flurbiprofen

Actions: 1. Potent analgesic, antipyretic, anti-inflammatory 2. Not uricosuric

V- Fenamates

Mefenamic acid (Ponstan) & Flufenamic acid � As propionic a. derivatives

VI- Diclofenac (Voltaren & Cataflam)

As propionic acid & concentrated in synovial fluids

VII- Oxicams

Piroxicam – Pivoxicam – Ampiroxicam – Meloxicam As propionic a. & Piroxicam has long t 1/2 (45 h)

VIII- Nabumetone

Prodrug given orally

CNS

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238

IX- Aniline Derivatives

Phenacetin & Paracetamol (Acetaminophen)

Parmacokinetics:

1. Well absorbed orally 2. Distributed all over the body 3. Hepatic metabolism:

Phenacetin (active) � Paracetamol (active)

4. Excreted in urine Pharmacodynamic:

1. They inhibit selectively COX-3 enz. Present mainly central (not peripheral) 2. Antipyretic Analgesic as potent as aspirin 3. No anti-inflammatory – no respiratory – no CVS - no � gastric acidity – no

uricosuric – no � platelet aggregation

Uses:

Antipyretic analgesic in patients who cannot tolerate aspirin as: Children – Bronchial asthma – Peptic ulcer (Paracetamol may be beneficial?) – Gout – Allergy

Side effect & Toxicity:

1. Hepatotoxicity: (Paracetamol) LD [ 10g in adult & 5g in child] � excess toxic metabolite � depletion of S-H of glutathione in liver

ttt: Oral N-acetylcysteine (converted to glutathione in liver ) + Methionine within 8-16 hours

NB.: Alcohol & Phenobarbital are HME inducer

� � hepatotoxicity of paracetamol which may occure at smaller doses

2. Nephrotoxicity (Phenacetin): Fatal chronic interstitial nephritis

3. Met Hb & Haemolytic anaemia in patients with G.6.P.D deficiency with Phenacetin 4. Allergy to Paracetamol & Phenacetin

NB:Propacetamol: is an injectable prodrug of Paracetamol converted to Paracetamol by plasma esterase enzyme NB: Benorylate: Ester of Aspirin + Paracetamol

Toxic metabolite (NAPQI) detoxified by Glutathione

Conjugation with glucuronic acid & sulfuric acid

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Common side effects of NSAIDs

1- Allergy & skin rash 2- Idiosyncrasy: Aspirin & Phenacetin � haemolysis in patients with G-6-PD

deficiency 3- CNS:

a. Phenylbutazone � Nervousness & vertigo b. Indomethacin � Psychosis c. Aspirin LD � Convulsions due to �Glutamate / GABA ratio d. Convulsions when given with Quinolone antibiotics 4- CVS:

a. Aspirin LD � Hypotension b. Phenylbutazone � fluid retention, edema & Hypertension 5- Blood:

a. Aspirin� Hypoprothrombinaemia & bleeding b. Phenylbutazone � bone marrow depression 6- Respiration: Bronchial asthma due to

a. Allergy b. Block of COX pathway & shift to LOX pathway� � LTs

7- GIT: Gastric irritation � Hyperchlorhydria, ulcer & bleeding 8- Hepatotoxicity: with Paracetamol 9- Nephrotoxicity: due to a. � PGs � renal VC � analgesic nephropathy b. Direct toxicity as with Phenacetin

NB.: Selective COX-2 � has little effect on GIT ulceration & kidney 10- Uterus: Teratogenicity (if needed Aspirin is the safest anti-inflammatory &

Paracetamol is the safest analgesic antipyretic) 11- Specific to Aspirin: a. Acute toxicity (see before) b. Salicylism (see before) c. Reye syndrome (see before)

12- Drug interaction: - Most of them are highly bound to plasma protein � displace other drugs �� their activity - Phenylbutazone is HME inducer

Common uses of NSAIDs

1- Analgesic, antipyretic & anti-inflammatory (except Paracetamol has no anti- inflammatory) 2- Dysmenorrhea & as Tocolytic in premature labour 3- Patent Ductus Arteriosus 4- Antagonize hypotension induced by PGs in Systemic mastocytosis 5- Antagonize the flush induced by PGs associated with Niacin

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Treatment of Rheumatoid arthritis (Anti-inflammatory drugs)

1- Steroidal Anti-inflammatory drugs: Cortisol

2- Non-steroidal Anti-inflammatory drugs (NSAIDs): except Paracetamol

3- Disease modifying (Slow acting) anti-rheumatoid drugs (DMARDs):

They alter the course & improve the prognosis of Rheumatoid arthritis. They include:

1. Gold salts: - Preparations: Gold aurothiomalate IM & Auranofin orally - Mechanism: � phagocytosis & lysosomal enz.

- Side effects: Stomatitis – Dermatitis – Nephritis – Bone marrow �

2. Chloroquine & Hydroxychloroquine: anti-malarial drug � T-lymphocytes 3. D-penicillamine: oral chelating for copper

4. Sulphasalazine (Sulphapyridine + 5-Aminosalicylic acid)

5. Methotrexate – Azathioprine: Immunosuppressants 6. Levamizole: Immunostimulants & Anti-helmenthic

7. Leflunomide (Arava): orally - � DNA synthesis in lymphocytes

8. Anticytokines: A- Anti- TNF-� - Etanercept (Enbrel): SC – block TNF-� receptor - Infleximab (Remicade): IV infusion – monocolonal antibody

against TNF-� - Adalimumab (Humira): SC - monocolonal antibody against TNF-� B- Anti-interleukin-1: -Anakinra (Kineret): SC - block interleukin-1 receptor

4- Counter-irritants: used topically as Methylsalicylate & Camphor --------------------------------------------------------------------------------------------------------------- NB.: Colchicine is useful in gouty arthritis only --------------------------------------------------------------------------------------------------------------- NB: Chondroitin & Glucosamine: Are natural products that can be used in ttt of osteoartheritis

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Treatment of Hyperuricemia & Gout Hyperuricemia results from:

• overproduction of uric acid (20%) : from excessive cell destruction (e.g. lymphoproliferative disorders, especially during their treatment, inherited defects that increase purine synthesis & high alcohol intake

• reduced renal excretion of uric acid (80%): renal failure and drugs (e.g. most diuretics, low-dose aspirin and lactate formed from alcohol) can reduce the tubular secretion of uric acid

A) Acute attack: �Anti-inflammatory drugs

1- Colchicine or Demicolcine are the drug of choice 2- NSAIDs: as indomethacin – Phenylbutazone – Naproxen ….. 3- Steroidal anti-inflammatory drugs: as Prednisolone orally & ACTH IM

B) Prophylaxis: � Drugs that � uric a. in blood

1-���� Uric acid excretion (Uricosurics): a. Large doses of: Aspirin (> 5g/d) - Probenicid - Sulphinpyrazone b. Benzbromarone

2-���� Uric acid oxidation: (Rasburicase) 2- ���� Uric acid synthesis: (Allopurinol & Febuxostat)

Uric a.

Nucleoprotein

Purines

Hypoxanthines

XO enz.

Xanthines

XO enz.

Uric a.

Phagocytosis mono Na+ urate Rupture Lactic a. more precipitation Inflammatory acidity

2- Anti-inflammatory

3- Uricosurics #

1- Allopurinol & Febuxostat

1- Colchicine

Macrophages migration

Cell Joint

-

Soluble Allantoin.

Urate oxidase (Not in human)

ttt of Acute attack Prophylaxis

2- Rasburicase

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Colchicine Kinetics:

Well absorbed orally – Excreted in urine & bile

Dynamics: 1) Anti-Gout effect: Drug of 1st choice

a. It binds to microtubular protein (Tubulin) of Granulocytes � � migration of leucocytes (PNLs) to joints � No phagocytosis of urate crystals � No rupture of leucocytes & no release of lactic acid � break the inflammatory cycle

b. � release of Chemotactic factors as Glycoprotein & IL-1that causes pain & inflammation

2) Anti-Mitotic effect: � cell division

Uses: 1- Gout:

a. Acute: it is the drug of choice (orally 1 mg then 0.5 mg /2 h till disappearance of symptoms or appearance of toxicity . May be used IV b. Prophylaxis: 1-2 mg orally / week

2- Prophylaxis of Familial Mediterranean fever (familial paroxysmal serositis) 3- Psoriasis 4- Improve liver functions in liver cirrhosis

Side effects & Toxicity: 1- Alopecia 2- CNS depression 2- GIT: Nausea – Vomiting – Bloody Diarrhea 3- Liver damage 4- Kidney damage: Haematuria 5- Myopathy 6- Bone marrow depression

NB.: Demecolcine: as Colchicin e. Both are Plant alkaloid

Uricosuric Drugs Common side effects:

1- Formation of renal urate stones, prevented by: Alkalinization of urine & plenty of fluids NB.: In patients secreting large amount of uric a. in urine, avoid uricosurics 2- Aspirin antagonize uricosurics 3- Allergy 4- GIT disturbances

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Actions 1- Probenicid:

1- Small dose ( < 1g/d): � uric a. secretion �worsens gout 2- Large dose (> 1g/d): � uric a. reabsorption� uricosuric� ttt gout NB.: Probenicid � tubular secretion of some drugs:

a. Penicillin & PAS � � their duration of action b. Thiazide & Loop diuretics �� their effect

2- Sulphinpyrazone 1. Potent uricosuric used in prophylaxis of gout 2. � Platelet aggregation used in prophylaxis of thrombo-embolic disease 3. It is a derivative of Phenylbutazone but not analgesic , nor antipyretic

3- Benzbromarone: Potent uricosuric 4- Aspirin LD (> 5 g/d) � see before, but not commonly used nowadays

Inhibitors of uric acid synthesis

Allopurinol (Zyloric)

Actions: � Xanthine oxidase (XO)enz.�� uric acid synthesis (It is not uricosuric) Uses:

1- Hyperuricemia in: - Chronic gout esp. in: a. Renal complications b. Patients resistant to uricosurics

- associated with malignancy or not controlled by uricosurics 2- Recurrent renal urate stones

Side effects: 1- Acute gouty attacks during initial stage of treatment (add colchicine) 2- CNS: headache & vertigo 3- Allergy & skin rash 4- GIT disturbances 5- Hepatomegally & peripheral neuritis 6- Bone marrow depression & Leucopenia

Drug interaction: a. � toxicity of Azathioprine & mercaptopurine ( as they are metabolised by XO enz) b. It is HME � � � effect of warfarin

Rasburicase

Mechanism: it is a recombinant urate oxidase enzyme, which oxidize uric a. � allantoin (more soluble metabolite) (NB.: This enzyme is present in mammals other than human) Uses: Prophylaxis of hyperuricaemia associated with malignancies Side effects: anaphylaxis – rash – GIT disturbances N.B: Drugs contraindicated in Gout:

1- Small doses of: Aspirin – Probenicid – Sulphinpyrazone 2- Diuretics: Thiazide – Loop – Acetazolamide 3- Clofibrate: hypocholestremic agent 4- Ethambutol & Pyrazinamide: anti-TB 5- Anticancer drugs

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TREATMENT OF PARKINSONISM

1- Parkinsonism is a disease of basal ganglia characterized by: a- Static tremors b- Muscle rigidity � flexion posture c- Akinesia �mask face & shuffling gait d- Depression 2- It is due to: imbalance between dopamine & A.Ch (� Dopamine & � A.Ch) 3- Aim of ttt is to restore this imbalance, so Antiparkinsonian include:

a. Dopaminergic drugs b. Anticholinergic drugs

A) Dopaminergic drugs

Dopaminergic drugs include: L-Dopa – Seligiline (Deprenyl) – Tolcapone – Amantadine – Bromocriptine - Pramipexole & Ropinerol

1- Levo-dopa (L –Dopa)

Kinetics:

1- Absorbed orally by active process & absorption is � by food esp. proteins 2- 99 % of the ingested L-dopa is metabolized by Peripheral dopa decarboxylase enz.(PDD) & COMT:

- By PDD � Dopamine that cannot pass BBB - By COMT � 3-O-methyl dopa that compete with L-dopa for active uptake in CNS

3- 1 % only of the ingested L-dopa passes BBB where it is metabolized by central dopa decarboxylase (CDD) into dopamine, then dopamine is metabolized by MAO-B enz.

NB.: ���� the brain level of L- dopa by:

1- Add Peripheral decarboxylase inhibitor eg.: Carbidopa & Benserazide a. Carbidopa(25 mg) + L-dopa (250 mg) = "Sinemet" b. Benserazide (25 mg) + L-dopa = "Madopar"

2- Add MAO-B inhibitor eg.: Selegiline (Deprenyl) 3- Add COMT inhibitor eg.: Tolcapone & Entacapone

GIT Blood BBB CNS

L-DOPA 1 % pass

99 % metabolism

COMT

PDD Vit.B6 Dopamine

3-O-methyl dopa

L-DOPA CDD Dopamine MAO-B & COMT Metabolism

-

#

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Side effect: The 2 main Types are: Dyskinesia & On-Off phenomenon 1- Fluctuation in response ("On-Off" phenomenon) due to fluctuations in dopamine level (avoided by using SR preparations) 2- CNS: - Dyskinesia (excessive, abnormal movements) (ttt by decreasing the dose)

- Psychological disturbances (euphoria - hallucinations) – Insomnia – Anxiety – Abnormal sexual activity 3- Eye: Mydriasis - � IOP 4- CVS: Tachycardia – arrhythmia – postural hypotension 5- GIT: Anorexia – nausea – vomiting – peptic ulceration

Contraindications: 1- Psychological disturbances 2- Glaucoma 3- Cardiac disease 4- Peptic ulcer

Drug interactions 1- The effect is antagonized by:

a. D2 receptor blockers as phenothiazine , butyrophenones …. b. Reserpine as it deplete dopamine c. Pyridoxine (vit.B6) as it � PDD enz.

2- The effect is potentiated by: a. Muscarinic antagonist b. PDD inhibitors c. MAO-B inhibitors d. COMT inhibitors

3- With non-selective MAO inhibitors � severe hypertension

2- Selegiline (Deprenyl) Selective MAO-B inhibitor� potentiates the effect of L-dopa NB.: Rasagiline: as selegiline but more potent

3- Tolcapone & Entacapone Mechanism:� COMT� � formation of 3-O- methyl dopa, which compete with L-

dopa for active uptake in CNS Side effect: 1- � L-dopa side effect

2- Diarrhea 3- Hepatic necrosis

NB.: Entacapone: as Tolcapone but no Hepatotoxicity

4- Amantadine (Symmetrel)

Antiviral agent used in prophylaxis of influenza A2 Mechanism: Acts mainly by releasing dopamine & delaying its reuptake Side effect:

1- CNS: Insomnia – irritability – confusion - hallucination 2- CVS: Hypotension – Ankle edema 3- GIT disturbance

L-doopa SE

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5- Bromocriptine (Parlodel) Derivative of ergot alkaloid Kinetics: Absorbed orally – Metabolized in liver – Excreted in urine Mechanism: Direct D2 agonist & D1 partial agonist Uses:

1- Parkinsonism 2- To suppress lactation 3- Hyperprolactinaemia & Galactorrhea-amenorrhea syndrome

Side effects: 1- CNS: Dyskinesia – Psychological disturbance – Visual & auditory hallucination 2- CVS: Arrhythmia – 1st dose hypotension – digital vasospasm – Erythromyalgia (red, tender, hot swollen feet) 3- GIT: Anorexia – nausea – vomiting – peptic ulcer

NB.: Pergolide & Quinagolide: are direct agonist on D1 & D2

6- Pramipexole & Ropinerol Non-ergot dopaminergic agonist

B) Anti-Cholinergic drugs

1-Belladonna alkaloids: a- Natural belladonna: Atropine – Hyoscine b- Synthestic atropine substitutes: Benztropine – Benzhexol (Trihexphenidyl) – Biperiden – Procyclidine - Carmiphen 2- Anti-histaminics: Diphenhydramine – Orphenadrine NB.: Drugs contraindicated in Parkinsonism:

1- Anti-Dopaminergics: - D2-receptor blockers: Phenothiazine – Butyrophenone – Metoclopromide

- Depletion of dopamine: Reserpine - � Dopaminergic synthesis: �-methyldopa 2- Cholinomemitics passing BBB: Pilocarpine – Physostigmine

C.N.S

247

TRETMENT OF EPILEPSY Types of epilepsy:

1- Generalized seizures: loss of consciousness a. Grand-Mal epilepsy (tonic-clonic) b. Petit-Mal (Absence) epilepsy: momentary clouding of consciousness c. Myoclonic: shock like contraction of muscle d. Atonic: sudden loss of muscle tone

2- Partial (Focal) Seizures: a. Simple: no loss of consciousness (sensory, motor, or autonomic symptoms) b. Complex: loss of consciousness (abnormal behavior or sensations + amnesia)

3- Status epilepticus: severe sustained attack lasting more than 30 min. Aim of treatment:

1- � epileptic focus & prevent its spread 2- Treatment should be continued for 2-3 years after the last fit 3- Withdraw anti-epileptic drugs gradually to avoid status epilepticus

Mechanism of action antiepileptic drugs:

1- Potentiation of GABA activity: Barbiturates – Benzodiazepines Vigabatrin – Na Valproate Topiramate – Tiagapine - Gabapentine 2- Inhibition of Glutamate activity: �Block AMPA �Topiramate �Block NMDA � Felbamate 3- Block of Na+ channel: Phenytoin – Carbamazepine – Na Valproate – Lamotrigine – Topiramate - Zonisamide 4- Block of Ca++ channel: Ethosuximide – Na Valproate

A)Grand-Mal & Partial seizures

1- Phenytoin (Diphenylhydantoin) Kinetics:

1- Well absorbed orally, IM & IV 2- Distributed all over the body. Highly bound to plasma albumin 3- Metabolized in liver: a. small dose �1st order kinetic (constant t 1/2)

b. Large dose �zero-order kinetic (longer t1/2) 4- Excreted in urine Mechanism of action: Block of inactivated Na+ channels Uses:

1- Anti-epileptic: � all types except Petit-Mal a. Drug of choice in Grand-Mal & Partial seizures b. Effective in Status epilepticus c. Contraindicated in Petit-Mal epilepsy

2- Anti-arrhythmic: Class I-B anti-arrhythmic. Drug of choice in ventricular arrhythmia with heart block eg.: Digitalis toxicity 3- ttt of Trigeminal neuralgia

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248

Side effects & Toxicity: 1- Allergy & SLE like syndrome 2- Gastric irritation & Gum hyperplasia 3- Hirsutism (due to � androgen) 4- Hepatotoxicity 5- Hormonal: � ADH &� insulin secretion - � androgen 6- Ataxia, nystagmus & vertigo 7- Agranulocytosis & Lymphadenopathy 8- During Pregnancy:

a. In 1st trimester �Teratogenic (Cleft palate & Hare lip) b. Late months�Hypoprothrombenemia in neoborn

& bleeding. Treated by vit. K Drug interactions:

a. Phenytoin is HME inducer: - � its own metabolism � Tolerance - � metabolism of other drugs �� their effect as oral contaceptives,

Theophyllin, Digitalis, other anti-epileptics - � metabolism of Folic a. �Megaloplastic anemia �� Methotrexate

toxicity - � metabolism of vit.K� Hypoprothrmbinemia & bleeding - � metabolism of vit.D� Osteomalecia & hypocalcemia

b. HME inducers (eg.: Phenobarbitone – Carbamazepine – Glutethemide – Alcohol) �� metabolism of phenytoin

c. HME inhibitors (eg.: Cimetidine – Chloramphenicol – Valproate - isoniazide) �� metabolism of phenytoin

d. Phenytoin displaces Oral anticoagulants – Thyroxin – TCA e. Phenytoin is displaced by Aspirin - Na+ valproate

NB.: Mephenytoin & Ethotoin: as phenytoin NB.: Fosphenytoin is a more soluble prodrug of phenytoin used parenterally, IV & IM

2- Carbamazepine (Tegretol)

Kinetics: Given orally Mechanism of action: as Phenytoin Actions & uses:

1- Anti-epileptic: � all types except Petit-Mal a. Drug of choice in Grand-Mal & Partial seizures b. Contraindicated in Petit-Mal epilepsy

2- ttt of Trigeminal neuralgia 3- Antidiuretic, so useful in diabetes insipidus

Side effects: 1- Allergy – Anorexia – Atropine like – Ataxia – Aplastic anemia 2- Fluid retention – Hepatitis like & jaundice 3- HME inducer

NB.: Oxcarbazepine: as Carbamazepine

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249

3- Barbiturates

Include: 1- Phenobarbital 2- Mephobarbital & Metharbital 3- Primidone: Active & metabolized in liver into another active metabolites as Phenobarbitone

Mechanism of action:

Facilitate GABAA transmition �� Cl- channel opening �� Cl- influx � hyperpolarization & post-synaptic inhibition

Antiepileptic effects: � all types except Petit-Mal a. Effective in Grand-Mal & Partial seizures b. Contraindicated in Petit-Mal epilepsy

Side effects: 1- Sedation 2- Ataxia & Nystugmus 3- HME inducer: (as Phenytoin…….)

Petit-Mal epilepsy

1- Ethosuximide (Zarontin)

Mechanism: Blocks Ca++ channels Action & Uses: Drug of choice in Petit-Mal epilepsy Side effects: 1.Sedation 2. Leucopenia 3. Worsens Grand-Mal

2- Acetazolamide (Diamox)

- Carbonic anhydrase enz inhibitor �� CO2 in CNS�� Excitability - Useful in resistant Petit-Mal epilepsy

3- Oxazolidinediones

(Trimethadione & Paramethadione)

- Used in Petit-Mal epilepsy but worsens Grand-Mal Side effects:

1- Alopecia 2- Sedation & worsens Grand-Mal 3- Glare effect (blurred vision in bright) 4- Nephrotic syndrome 5- Hepatotoxicity 6- Bone marrow depression

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Broad spectrum anti-epileptics

1- Benzodiazepines Include: Diazepam (Valium) – Clonazepam - Lorazepam (Ativan) Mechanism of action: As barbiturates facilitate GABAA transmition Antiepileptic effects: � all types & they are drug of choice in Status epilepticus

2- Na+ Valproate (Depakene) Mechanism of action:

1-� GABA transaminase � � GABA level in brain 2- Block Na+ & Ca++ channels

Actions & Uses: � Broad spectrum anti-epileptic effective all types Side effects:

1- Temporary alopecia 2- Sedation 3- GIT irritation 4- Hepatotoxicity 5- Thrombocytopenia 6- Teratogenic (Spina bifida)

Drug- interactions: 1- It is HME inhibitor (the only antiepileptic) �� effect of Phenytoin & Phenobarbitone 2- Displace Phenytoin from plasma protein

3- Vigabatrin:

• Vinyl GABA transaminase inhibitor � � GABA level in brain • Broad spectrum useful in resistant epilepsy esp. Partial seizures • Vigabatrin may cause visual field defect

New anti-epileptics useful in Partial seizures

- Drugs potentiating GABA: 1- Gabapentin & Pregabalin: They are GABA analogs, Potentiate GABA release & replaced carbamazepine in ttt of neuropathic pain due to less side effects 2- Tiagabin: � GABA uptake

- Drugs blocking NMDA receptors Felpamate: Block NMDA receptor of glutamate

- Drugs modifying both GABA & Glutamate: - Levetiracetam: Modifies the release of GABA & Glutamate

- Drugs blocking Na+ channels: 1- Lamotrigine: As phenytoin, blocks Na+ channels but not teratogenic 2- Topiramate: its spectrum like Phenytoin – High incidence of kidney stones

It also, affects both GABA & Glutamate 3- Zonisamide: - A sulfonamide derivative, Block Na+ channels

- Broad spectrum, may cause kidney stones

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PSYCHOTROPIC DRUGS

- Psychotropics are drugs that affect psychology & behavior - Classification:

1- Tranquilizers (Psychotropics): a. Minor tranquilizers (Anxiolytics) b. Major tranquilizer (Anti-psychotics)

2- Antidepressants & Lithium: a. Mood elevating � Antidepressants b. Mood stabilizing � Lithium

3- Psychomotor stimulants: Amphtamine 4- Psychomemitics( Hallucinogenics): eg.: LSD

Major Tranquilizer

(Anti-Psychotic – Anti-Schizophrinc – Neuroleptics)

Psychosis (Schizophrenia): - Characterized by: -ve symptoms (eg: flatting of emotions – society withdrawal) +ve symptoms (eg: hallucinations – delusions) - Cause: may be � Dopamine or � Serotonin

Classification of Anti-Psychotics:

1) Typical: 1- Phenothiazine: Chlorpromazine – Thioridazine – Trifluperazine 2- Thioxanthines: Chlorprothexine – Thiothexine 3- Butyrophenones: Haloperidol – Droperidol

2) Atypical: 1- Clozapine 2- Olanzapine 3- Loxapine 4- Resperidone 5- Pimozide 6- Sulpiride 7- Aripiprazole

NB.: - Most of them block D2 receptors in hypothalamus & limbic system - Reserpine may be used (rarely) as it depletes catecholamines including Dopamine

Chlorpromazine (Largactil)

Kinetics: Well absorbed orally – Metabolized in liver – Excreted in urine --------------------------------------------------------------------------------------------------------------- Dynamics:

1) CNS: 1- Block D2 receptors in:

� Limbic system �Anti-psychotic � Basal ganglia � Worsens �Parkinsonism � Hypothalamus� � Prolactin & � Appetite

� Temperature � Hypothermia � CTZ �Antiemetic in all vomiting except motion sickness

2- Sedation (due to antihistaminic effect) 3- Seizures (as it � seizure threshold)

* Psychotropic (Greek): affecting mind

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2) Receptors: Potent: Antidopamine – Antiserotonine – �-blocker Weak: Antimuscarine (Atropine like) - Antihistamine – Ganglion blocker

3) Endocrine: 1- � Prolactin �Gynecomastia & Galactorrhea 2- � Growth h. – ACTH – FSH & LH � infertility & amenorrhea

4) Curare like on skeletal m. 5) Quinidine like & Local anesthetic effect 6) CVS:

1- Bl.V.: VD – Hypotension – Postural hypotension due to: 1. � VMC 2. Ganglion block 3. �-block 4. Direct VD 5. Direct myocardial depressant

2- Heart: 1. Direct myocardial depressant 2. Tachycardia (Atropine like & Reflex from hypotension)

--------------------------------------------------------------------------------------------------------------- Uses:

1- Psychosis & Schizophrenia 2- Preanesthetic medication 3- Antipruritic 4- Antiemetic in SD in all vomiting except motion sickness 5- Intractable hiccough

--------------------------------------------------------------------------------------------------------------- Side effects:

1) Psychological: 1- Pseudo-depression 2- Toxic confusion 2) Neurological:

1- Extra-pyramidal manifestations: (Acute dystonia – Akathesia [restlessness] – Parkinsonism) 2- Tardive dyskinesia: - Late onset, irreversible, abnormal movement (esp. of the jaw & tongue), after long use & may persist after discontinuation of the drug ) - It is due to upregulation of D2 receptors - It is resistant to ttt & worsens if the drug is stopped 3- Neurolept malignant syndrome (Idiosyncratic reaction similar to malignant hyperthermia due to muscle rigidity & ttt by IV Dantrolene or Bromocriptine) 4- Sedation 5- Seizures

3) Autonomic nervous system: 1- �-block � Postural hypotension – Failure of ejaculation 2- Muscarinic block � Dry mouth – Blurred vision

1

2

3

4 5

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4) Endocrine: 1- Gynecomastia – Galactorrhea 2- Infertility – Amenorrhea 3- Weight Gain

5) Blood: Agranulocytosis 6) Heart: Arrhythmia 7) Liver: Allergic obstructive cholestatic jaundice

8) Hypersensetivity 9) Teratogenicity 10) Photosensitivity & Corneal opacities

--------------------------------------------------------------------------------------------------------------- Drug interactions:

1) Potentiate: 1. Sedatives (eg: Alcohol) 2. Hypotensives (eg: �-blockers) 3. Anticholinergics (eg: Tricyclic antidepressants) 4. Muscle relaxants (eg: Curare) 2) Antagonize: The hypotensive effect of Guanithedine as it � its neuronal uptake 3) Reverse the pressor effect of adrenaline

Other major Tranquilizers

1) Thioridazine: As Chlorpromazine BUT it is Cardiotoxic , causes Ritinopathy & Not antiemetic

------------------------------------------------------------------------------------------------------- 2) Trifluperazine:

More powerful anti-Psychotic & Extrapyramidal manifestation ------------------------------------------------------------------------------------------------------- 3) Thioxanthenes: (Chlorprothixene & Thiothexene) As Chlorpromazine ------------------------------------------------------------------------------------------------------- 4) Butyrophenones: (Haloperidol & Droperidol):

• As Chlorpromazine but stronger • Droperidol + Fentanyl (Thalamonal): ����

a- Neurolept analgesia as IV anesthesia for short operations b- The antiemetic effect of Droperidol antagonize the emetic effect of Fentanyl

------------------------------------------------------------------------------------------------------- 5) Atypical:

• As Clorpromazine BUT less Extrapyramidal manifestation & Not antiemetic • Clozapine � High affinity for D4 & High incidence of Agranulocytosis • Aripiprazole � Partial agonist at D2 & 5-HT1A

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Antidepressant drugs (Psychoanaleptics) - Types: Depression may be Unipolar or Bipolar (depression alternating with mania) - Cause of depression: may be due to deficiency of monoamines (Noradrenaline & 5-HT), so the aim of ttt is to � their level Classification of antidepressant drugs:

1- Tricyclic antidepressants (TCA) 2- Mono-amine oxidase inhibitors (MAOI) 3- Selective Serotonin Reuptake Inhibitors (SSRI) 4- Serotonin /Norepinephrin reuptake inhibitors (SNRI) 5- Atypical antidepressants

(1) TCA

(2) MAO.I

Members: 1- Imipramine 2- Desipramine 3- Clomipramine

4- Amitriptyline 5- Nortriptyline 6- Amineptine 7- Doxipen NB: In liver: - Imipramine (active) � Desipramine (active) - Amitriptyline (active) � Nortriptyline (active)

1) Non-selective MAO-I (A) Hydrazine group: 1- Isocarboxazide 2- Phenelizine 3- Nialamide (B) Non-Hydrazine group: 1- Tranylcypromine 2- Pargyline 2- Selective MAO-B inhibitor: Selegiline (Deprenyl) 3- Selective MAO-A inhibitor - Clorgyline � Irreversible - Moclobemide � Reversible

Mechanism of action: 1- � Neuronal uptake-1 (cocaine like) of monoamines (NA & 5HT) � � intersynaptically 2- Antidepressant effect appears after 2-3 weeks & lasts for 2-3 weeks

1- � MAO enz.� � monoamines (NA & 5HT) intrasynaptically in CNS & body but� VMA & HIAA in urine 2- Antidepressant effect appears after 2-3 weeks & lasts for 2-3 weeks

Actions:

1- Antidepressant 2- Atropine like (strong) 3- Antihistamine (H1) & H2 block 4- Antiserotonin 5- Alpha1 block

1- Antidepressant 2- Atropine like (weak) 3- Pargyline � Antihypertensive & antianginal as it � Sympathetic 4- Selegiline � Antiparkinsonian & in large dose � Antidepressant

MOA

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Uses: 1- Psychic depression 2- Nocturnal enuresis 3- Prophylaxis of migraine

1- Psychic depression 2- Selegiline � in Parkinsonism 3- Pargyline � in Hypertension & prophylaxis of angina

Side effects:

1- Delayed onset (after 2-3 weeks) 2- Appetite stimulation & weight gain 3- Atropine like (Strong) Dry mouth – Blurring vision – Urine retention – Constipation 4- Cardiotoxic � Fatal arrhythmia 5- CNS �Sedation (Excitation & Tremors may occur) 6- Allergic obstructive jaundice

3- Atropine like (Weak) 4- Hypertensive crises - if patients eat food containing tyramine (eg: cheese – broad beans – yoghurt) - ttt by �- blockers 5- CNS� Excitation (Insomnia – Tremors – Convulsions) 6- Hepatotoxic �Hepatocellular jaundice

Drug interactions 1- Potentiate: 1. Sedatives 2. Anticholinergics 2- Antagonize: 1. Hypotensive effect of Guanithidine (� uptake) 2. Hypotensive effect of Clonidine & Methyldopa (down regulation of �2-receptors) 3- With MAO.I �Toxicity (Atropine like)

1- Potentiate: 1. Sympathomimetics 2. Other drugs eg.: Barbiturate & Morphine because MAO.I are HME� 2- Reverse hypotensive effect of Reserpine 3- With TCA �Toxicity (Atropine like) 4- With SSRI � Serotonin syndrome (Hyperthermia – Hypotention – Coma & death) 5- With food containing tyramine � Hypertensive crisis (Cheese reaction)

NB.: 1) In TCA: Amineptine:

1- � mainly uptake of Dopamine with no effect on NA or 5HT 2- Quick onset (7 days) & no anticholinergic effect

2) 2 Types of MAO enzyme:

1. MAO-A 2. MAO-B - metabolizes NA & 5HT in intestine & neural tissues - Inhibited selectively by Clorgyline & Moclobemide

- metabolizes Dopamine in CNS. - Inhibited selectively by Selegiline (Deprenyl)

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3- Selective Serotonin Reuptake Inhibitors (SSRI)

Members: 1- Fluoxetine (Prozac) 2- Fluvoxamine 3- Paroxetine 4- Sertraline 5- Citalopram 6- Escitalopram

Mechanism: SSRI ��5-HT Uses:

1- Depression & obsessive compulsive disorders 2- Prophylaxis of migraine

Advantages: 1- No anticholinergic & Atropine like effect 2- Little drug interaction

Side effects: 1- Anorexia – Nausea –Diarrhea – Weight loss 2- Anxiety – Headache 3- Agitation & jitters 3- Sleep disturbances & insomnia 4- Suicidal attacks especially in children & teenagers 5- Sexual dysfunction: as loss of libido & delayed ejaculation 6- Drug interactions:- Fluoxetine + MAO.I �Serotonin syndrome (Fatal)

- Fluoxetine is HME inhibitor � Potentiate other drugs

4- Selective Serotonin/Norepinephrine Reuptake Inhibitors (SSNRI)

They are effective in ttt of depression associated with neuropathic pain 1- Venlafaxine:

- Potent inhibitor of serotonin & at larger doses it � norepinephrin reuptake - Side effects: GIT disturbances

2- Duloxetine: - Potent inhibitor of both serotonin & norepinephrin at all doses - Side effects: GIT disturbances – Sexual dysfunction

5- Atypical antidepressants

1- Maprotiline: as TCA but - Selectively blocks the uptake of NA - Few Atropine like - Little effect on CNS - Less interaction with Guanithedine

2- Mianserine: - Block presynaptic �2-receptors �� release of NA - Not cardiotoxic but causes sedation

3- Mirtazepine: - Block presynaptic �2-receptors & 5HT2 receptors - No sexual dysfunction & no anticholinergic but may ���� appetite ���� weight gain 4- Bupropion:

- � release of NA - No sedation but may cause seizure at high doses

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Antimanic – Mood stabilizing drugs

Mania characterized by: Excessive exuberance & self confidence – Impulsive actions – Irritability – Aggression – Grandiose delusions

Lithium Lithium is an endogenous monovalent cation with no known physiological role Kinetic:

1- Well absorbed orally 2- No hepatic metabolism 3- Excreted by kidneys

- � excretion by: Osmotic diuretics & Na+ bicarbonate - � excretion by: Loop & Thiazide diuretics

------------------------------------------------------------------------------------------------------- Mechanism of action:

Not clear but may: 1- Affect release of NA, Dopamine, 5HT or, 2- Depletion Phosphatidyl inositol in neuronal membranes of CNS (Inhibit recycling of inositol) or, 3- Affect nerve conduction

--------------------------------------------------------------------------------------------------------------- Uses:

1- Acute Mania (but slow onset) 2- Manic-Depressive disorders (Bipolar depression) (esp. in manic phase)

--------------------------------------------------------------------------------------------------------------- Side effects:

1- CNS: Confusions - Convulsions 2- Thyroid: � Thyroid synthesis � Smooth benign enlargement 3- GIT: Anorexia – Nausea –Vomiting – Diarrhea 4- Kidney: Polyurea (Nephrogenic diabetes insipidus) – Excessive Thirst 5- CVS: Arrhythmia – Hypotension 6- Teratogenic in early pregnancy 7- Acute toxicity: (extremely low safety margin)

� Manifistations: - < 2.5 meq/L � Confusions - Drowsiness -Tremors - > 2.5 meq/L � Convulsions

�ttt: Osmotic diuretics - Na+ bicarbonate – Dialysis in severe cases

NB.: Antiepileptic drugs: Carbamazepine & Valproic acid can be used to alleviate some symptoms of Mania

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C.N.S STIMULANTS

1- Cerebral stimulants: 1. Amphetamine 2. Atropine 3. Metyhlxanthines 4. Methylphenidate: similar to Amphetamine without anorexigenic effect 5. Cocaine

2- Brain stem stimulants: Analeptics 3- Spinal cord stimulants: Strychnine

Methyl-xanthines (Caffeine – Theophylline – Theobromine)

Kinetics: 1- Well absorbed from GIT (orally, rectally) & parenterally 2- Distributed all over the body, passes BBB & Placenta 3- Metabolized in the liver into Methyl uric acid which is soluble & don't precipitate (so not contraindicated in Gout) 4- Excreted in urine

------------------------------------------------------------------------------------------------------- Mechanism of action:

1- � PDE enz. Type IV � � c.AMP 2- Block adenosine receptors

------------------------------------------------------------------------------------------------------- Actions:

NB.: Caffeine is more selective & potent on: CNS, Gastric acidity & Sk..m .

1- CNS: � Caffeine 1. � Cortex: Alertness – Wakefulness – Antifatigue 2. � Medulla: � RC – � VMC – � CIC 3. � Spinal Cord: Hyper-reflexia

2- CVS: � Theophylline

Heart Blood vessel Direct effect: - +ve inotropic & chronotropic

- � Work & Automaticity VD but cerebral VC

Central effect: -ve chronotropic (� CIC) VC Net result: - SD� No effect

- LD� Direct action takes the upper hand � Tachycardia - Arrhythmia

- SD� No effect - LD� Direct action takes the upper hand � Hypotension

3- Respiration:

- Direct: Bronchodilataion & Mast cell stabilization (Theophylline) - Central: � RC (Caffeine)

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4- GIT: Spasmolytic & � Acidity

5- Kidney: �Theophylline 1. Spasmolytic 2. Diuretic: Extrarenal (� CO) & Renal (� NaCl reabsorption)

6- Smooth m.: �Theophylline �Spasmolytic 7- Skeletal m.: �Caffeine ��Capacity for muscle work

--------------------------------------------------------------------------------------------------------------- Uses:

1- Theophylline: a- Aminophylline:

1. Anticolic 2. Bronchial asthma: acute attack – status – prophylaxis 3. Cardiac asthma (Acute pulmonary edema):

+ve inotropic – Diuretic – Bronchodilatation 4. Diuretic

b- Pentoxifylline: used in intermittent claudication (� flexibility of RBCs & � platelet aggregation)

2- Caffeine: 1. Acute Migraine headache (+ Ergotamine) 2. Myasthenia gravis (+ Neostigmine) 3. Mental & physical fatigue 4. Toxicity with CNS depressant

--------------------------------------------------------------------------------------------------------------- Side effects

1- Caffeine: [High therapeutic index] - CNS: Headache – Insomnia – Irritability - Convulsions - GIT: hyperacidity

2- Aminophylline: [Low therapeutic index] 1. Irritant: IV � Thrombophlebitis - Rectal� Proctatitis 2. Rapid IV � Velocity reaction & syncope 3. CNS: Headache – Insomnia – Irritability – Convulsions 4. CVS: Arrhythmia – Arrest – Hypotension 5. GIT: Irritation

3- Long use: Tolerance – Cross tolerance – Psychic dependence --------------------------------------------------------------------------------------------------------------- Contraindications:

1- Arrhythmia 2- Angina 3- Peptic ulcer --------------------------------------------------------------------------------------------------------------- Drug interaction:

1- ���� Metabolism by: 2- ���� Metabolism by: 1. Antimicrobials: Erythromycin & Quinolones 2. Cimitidine 3. Heart & liver disease

1. Anti-epileptics 2. Rifampicin 3. Smoking

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Cocaine Natural from coca leaves Mechanism of action:

1- Local anesthetic: Block Na+ channels 2- � Catecholamines: � Neuronal uptake & MAO inhibitor

Actions: 1- L.A.: as surface anesthesia only 2- CNS: stimulation but less than Caffeine 3- CVS: - Heart: - SD � Bradycardia (�CIC)

- LD � Tachycardia (�catecholamines) - B.V: � VC

4- Eye: Active Mydriasis + Decongestion + Loss of corneal reflex Side effects:

1- Excitation & Convulsions 2- Arrhythmia 3- Death from respiratory failure 4- Dependence (No Tolerance)

Analeptics

Character: 1- Stimulate RC & VMC 2- Awaken deeply anesthetized patient 3- Toxic dose produces Clonic convulsions & with larger dose� Tonic

Classification: 1- Direct:

1. Bemegride: used in acute barbiturate poisoning 2. Phnylenetetrazole (Leptazole – Cardiazole): used in diagnosis of epilepsy 3. Picrotoxin: has narrow safety margin

2- Indirect (Reflex): through stimulation of Chemoreceptors eg: Lobeline 3- Dual:

1. Coramine (Nikethamide) 2. Carbogen (5 % CO2 + 95 % O2) 3. Daptazole (Amiphenazole) 4. Doxapram : the safest – IV infusion 5. Ethamivan

NB.: Analeptics are OBSOLETE nowadays (Except carbogen & doxapram) Other drugs having analeptic effects: 1. Reflex through � of nerve ending eg: Ammonia – Alcohol – Camphor 2. Descending stimulation eg: Aminophylline 3. Ascending stimulation eg: Strychnine 4. Receptor blockers: as Naloxone & Flumazenil only if � RC by opioid or benzodiazepine

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Strychnine Alkaloid from Nux-Vomica seeds Dynamic:

CNS: Stimulation - Compete with Glycine in spinal cord - Ascending: - � Spinal cord � � Polysynaptic

- � Medulla� � RC & VMC - � Cortex �� Sensory area

Toxicity:

1- Tonic convulsions 2- Cause of death: Spasm of respiratory muscles

ttt: 1. Dark room 2. Stomach wash by tannic acid or K+ permanganate 3. Anticonvulsants 4. Specific antidote: Mephenesine IV

Psychomemitic drugs

1- LSD (Lysergic acid diethylamide)

2- Cannabis (Hashish): Tetrahydrocannabinol

- Mechanism: 5-HT1A agonist in CNS &

5-HT2 antagonist in periphery - � Cannabinoid recept �� c.AMP - Block Ca++ channels

- Actions: Eye: Mydriasis – Visual hallucination CNS: - Elation – Mood changes - Bad trip of severe anxiety – Depression & suicide

Eye: Red conjunctiva - � IOP CNS: - Loss of sense of: time – sounds & distance - Euphoria & uncontrolled laughing - Antiemetic (Tried in vomiting due to cancer therapy)

- Long use: - Tolerance but no physical dependence

- Tolerance but no physical dependence

3- Mescaline 4- Adrenochrome