Main chemical transmitters in CNC G3FR_35

Excitatory Inhibitory
- monoamines e.g. NE, 5-HT - A.Ch
- Amino acid e.g. glutamate & aspartate Amino acid e.g. GABA & glycine

Analgesics
definition Drugs that relieve pain
classification Narcotic analgesics Antipyretic analgesics
example Morphine Aspirin
potency Potent Less potent.
Relieve all types of pain (deep visceral) but not itching Relieve mild pain especially superficial
Mechanism Mainly central (spinal& supraspinal) central on thalamus & peripheral
Other action Drowsiness (narcosis) Anti-inflammatory & Antipyretic
Prolonged use Tolerance then dependence No Tolerance & No dependence

Opiate receptor
Present in Brain stem thalamus, spinal cord, limbic system, sensory nerve and peripheral tissue including vascular, cardiac, lung & gut & circulating inflammatory cell
Receptor subtype μ(mu) κ (kappa) δ (delta)
• Supra-spinal and spinal analgesia
Effect of • Sedation • Psychotomimetic (hallucinogenic) effects
stimulation • Inhibition of respiration \
• Constipation • Constipation
• Modulation of hormone & • Modulation of hormone &
neurotransmitter release neurotransmitter release
Endogenous Endorphins dynorphins for (κ) enkephalins for (δ)
opiates peptides have highest affinity for (μ)

Narcotic analgesics
Definition Drug that relief pain centrally but in large dose produce drowsiness & prolonged use produce tolerance and dependence
Classification
According to source & nature According to action
Natural Opium alkaloids Semi-synthetic Synthetic Pure agonist Mixed agonist-antagonist Pure antagonists
morphine derivatives morphine substitutes
Phenanthrenes Benzyl isoquinolines - Heroin - Meperidine - Morphine (strong) -Nalbuphine - Naloxone
- Morphine -Papaverine (spasmolytic & vasodilator) - Apomorphine - Fentanyl - codeine (mild) -Buprenorphine(partial μ agonist) - Naltrexone
- codeine - narcotine (antitussive) - Methadone -Butorphanol - Nalmephene
- narcetine (convulsant) -Dextropropoxyphene -Pentazocine
 Opium Alkaloids G3FR_36
Phenanthrene Benzyl isoquinolines
Morphine Codeine Papaverine
- Well orally, S.C & I.M (but low oral bioavailability 30%) Therapeutic uses of morphine methyl morphine • Spasmolytic used as anti-spasmodic
Absorption

- Lozenges (from oral mucosa to avoid 1st pass met.) • Smooth muscle relaxation: biliary,
- In shock ! diluted I.V (not S.C or I.M due to impairment of peripheral circulation)
1- Pain: analgesic in severe visceral pain e.g. • l 0% of codeine ! morphine in the body.
bronchial, GIT: used in colic
a. Cardiac pain e.g. myocardial infarction. • Similar to morphine but:
- By transdermal patch & epidural in anesthesia. -Better oral bioavailability (50%). • VD of cerebral, coronary,
- by nasal insufflations ! escape hepatic 1st pass effect (in addiction) b. Cancer pain in terminal stages. peripheral & pulmonary vessels.
- Short duration (2-4 h).
- distributed all-over the body c. Colic: renal or biliary colic but add atropine. - weaker, (1\5 morphine) as analgesic, constipation & Noscapine (narcotine)
Distribution

- It cross placental harrier: d. Postoperative: except in cholecystectomy & after eye addiction.
a. During pregnancy ! congenital malformations & fetal addiction. operations As potent as morphine as anti-tussive.
Non-narcotic central
b. During labor ! depresses fetal R.C neonatal asphyxia (treated by naloxone I.M to the
e. Fracture: but not in head injuries as it depresses R.C. • Large doses: excitation, depresses R.C & V.M.C. anti-tussive.
mother before labor or intra-umbilical to the baby after labor)
- Morphine is lipophilic compared to heroin & fentanyl which rapidly penetrate brain causing 2- Preanesthetic medication: Therapeutic uses of codeine
intense rush (highly addictive). • Morphine used to provide analgesia, amnesia & 1- Anti-tussive: in dry dangerous cough as, post-operative
- hepatic conjugation with glucuronic acid into: sedation but has disadvantages: cough.
2- Analgesic: in mild or moderate pain + aspirin or
Metabolis

a. morphine 3-glucuronide (neuro-excitatory metabolite). a- Delay awakening from anesthesia paracetamol.

b. morphine 6-glucuronide (more active). b- Depresses R.C &VMC. c- Bronchospasm
m

- These metabolites are polar, so CNS penetration is limited & easily excreted in kidney d- Miosis (PPP). e- Vomiting.
Toxicity of morphine
- in LD or in renal failure ! exaggerated response of these metabolite may occur
f- Post operative urine retention & constipation. Acute morphine toxicity (overdose)
- Metabolism is deficient in elderly & children so produce supersensitivity - Symptoms: coma, P.P.P, hypotension, hypothermia, hypoxia & hypoventilation.
Exc - In ALL body secretions e.g. urine, saliva, milk 3-Pulmonary edema (acute left ventricular failure):
- re-excreted in stomach (gastric lavage in toxicity even if not oral) a- Reduce anxiety !decreases after load. - Cause of death: respiratory failure.
MOA Direct stimulation of opiate receptors in CNS & periphery ! b- Reduce preload by venodilatation. - Treatment of Acute morphine toxicity:
- Gi !"adenyl cyclase !"cAMP. c- Suppresses over stimulated R.C & cough center. 1) stomach wash (permanganate & saline): even if not oral.
- Block presynaptic voltage gated Ca++ channels !"release of excitatory mediators e.g. 4- Primary neurogenic shock: slow IV (not S.C or I.M). 2) specific antidote: naloxone or nalmefene (long t1/2= 8-10)
glutamate, substance P & PG 3) artificial respiration & respiratory stimulant: (95% O2 + 5% CO2)
- Open Postsynaptic K+ channels !hyperpolarization (IPSP).
• In shock not given by S.C as there is delay absorption
due to V.C so repeated S.C doses is dangerous as after
Pharmacological actions correction of shock with increasing of blood flow !
Chronic morphine toxicity (addiction)
CNS Depressant actions Stimulant actions increase absorption from the injected sites toxicity. Tolerance then psychic dependence & physical dependence
- Analgesic: • Very effective in deep visceral pain - Euphoria & excitation in some female &
5- Anesthesia: IV, intrathecal or epidural injections. • chronic constipation & PPP, drug seeking habit (psychological dependence) & slow
not in itching (#histamine release) some animal species. reaction to stimuli.
• "pain perception ("substance P & glutamate) Side effect • Sudden stop of morphine + withdrawal symptoms (abstinence syndrome) (reverse of
- Narcosis: Stupor & drowsiness. 1- CNS: morphine actions):
- "R.C, cough center - (+) EWN ! Miosis (PPP). • Suppresses RC & VMC, while (+) CTZ ! vomiting. a. CNS: pain. muscle spam, anxiety. insomnia, yawing & mydriasis.
- "V.M.C - (+) CIC ! bradycardia. • Increases intra-cranial pressure (ICP).
- "H.R.C (through κ receptors) - (+) CTZ ! vomiting b. Secretions: increase Sweating. lacrimation & rhinorrhea.
2- Respiratory system: bronchoconstriction. c. Skin: itching.
-"polysynaptic spinal reflex “withdrawal reflex” - #monosynaptic reflex e.g. stretch reflex. 3- GIT: constipation. 4- Urinary: urine retention.
- Decreases release ACTH, FSH & LH. - #ADH release. d. GIT Vomiting & diarrhea.
5- Allergy. 6- Hypotension 7- Dependence.
ANS depresses sympathetic !hypotension Enhances parasympathetic !bradycardia treatment of morphine addiction (dependence)
Eye • Miosis, accommodation to near vision & " I.O.P Contraindications 1- hospitalization & psychotherapy.
• The action is antagonized by: Naloxone, ganglion blockers & atropine. 2- gradual withdrawal of morphine
1- very young or very old !defective metabolism.
CVS - Therapeutic dose ! no effect. 2- Head injuries as morphine produces: 3- gradual replacement by methadone or buprenorphine (long acting opioid)
- Large dose: a) (+) CIC ! bradycardia a. (-) R.C ! CO2 accumulation cerebral VD !#ICP 3- gradual withdrawal of methadone.
b) Direct venodilatation (if IV) & Histamine release ! Hypotension b. Miosis ! mask sign of lateralization (diagnosis) . 4- clonidine: α2 agonist.
Resp • Depresses RC: decrease sensitivity of R.C to CO2 ! hypoventilation & hypoxia. 3- Increased intra-cranial pressure & epilepsy. 5- oral naltrexone: maintenance therapy to prevent desired effect of morphine.
• Depresses cough center ! anti-tussive.
• Histamine release ! bronchospasm in asthmatics. 4- Impaired pulmonary functions e.g. bronchial asthma Tolerance to morphine
1 - Decreases all secretion except salivary secretion. & COPD & emphysema. • Tolerance to some CNS effect e.g. analgesia & depression of R.C occurs after10-14
5- Impaired liver functions.
(spasmogenic constipation)

2- Saprogenic: stimulates segmental (non-propulsive) contraction & days of continuous use.

inhibits propulsive movement + spasm of sphincter ! constipation. 6- Alone in biliary or renal colic. • No tolerance for P.P.P, constipation & excitation.
3- Inhibition of defecation reflex. 7- Acute abdomen e.g. appendicitis (relieve pain but this
4- The addicts neglect the act of defecation. • Cross tolerance may occur with other C.N.S depressants
GIT

will mask the diagnosis).

5- Biliary tract: • Spasm of sphincter of Oddi & bile duct !increases intra-biliary pressure.
8- During pregnancy & lactation: neonatal addiction then
Drug interactions of morphine
• Also, it may aggravate pain in biliary colic (so add atropine). 1- with sedative & hypnotics more C.N.S. depression.
• It. also stimulates pancreatic amylase. withdrawal syndrome (crying. irritability, diarrhea &
convulsions). 2- with anti-depressants sedation & C.V.S side effects.
• The spasmogenic effect of morphine on G.I.T is due to stimulation of (μ & δ) receptors in GIT
So, naloxone completely antagonizes spasmogenic effect of morphine on intestine. 9- During labor: suppress RC ! neonatal asphyxia. 3- with MAOls hyperpyrexia & coma.
Renal a. Urine retention: • (+) wall, (+) sphincter (not used alone in ureteric colic) 10- Endocrinal disease: - myxedema (decreases BMR)
• (-) micturition reflex b. Oliguria: due to hypotension " GFR & # A.D.H. - Addison (decreases ACTH)
Other 1- Spasmogenic effect on smooth muscle. 11- history of allergy & history of addiction.
action 2- "BMR in myxedema & adrenal insufficiency.
2- Neonatal asphyxia if taken during labor.
3. Skin: histamine release + VD. itching & wheal formation (diagnosis of addiction)
G3FR_37 Synthetic Morphine substitutes Semi-synthetic
(Non-Phenanthrenes) morphine derivatives
Meperidine (Pethidine) Fentanyl Methadone Dextropropoxyphene Heroin
Chemistry Synthetic phynylpipeidine (Alfentanyl, Sufentanil Remifentanil) - Narcotic analgesic as potent as morphine • Related to methadone. Di-Acetyl Morphine
• 50% oral bioavailability. - Synthetic narcotic analgesic related to - Inhibit RC, cough center, constipation, miosis • As analgesic as codeine • Highly lipid soluble concentrated in
• Quick onset & short duration (2-4h). meperidine - strong local anesthetic action. • Less (inhibition of R.C. the brain deacetylated to morphine.
• Metabolized in liver into: - Strong μ agonist 80 times more potent than - longer duration (t1/2 =24hrs) addiction & antitussive) • Short t1/2 = ½ h, less emetic but
P/K

a. Meperidenic acid: inactive conjugation with morphine. - longer then morphine (more tissue binding) & slow highly addictive
glucuronic acid urine. - Highly lipophilic so quick onset & short release less withdrawal symptoms so less dependence
b. Nor-meperidine: active excitation duration especially remifentanil
& convulsions
1- Analgesic: in sever visceral pain e.g. MI (can alone or with droperidol as analgesic ± nitrous 1-analgesic in severe pain e.g. terminal cancer analgesic with not used
be used alone in colic) oxide as anesthetic 2- ttt of morphine & Heroin dependence aspirin & caffeine.
Uses

2-Pre-anesthetic medication:better than morphine

3- Labour: obstetric analgesia.

(Morphine like + Atropine like) Thalamonal Diphenoxylate (Lomotil) Dextromethorphan Apomorphine

• Less Analgesic (l\10 morphine)
- Fentanyl + Droperidol: analgesic & tranquilizer It has morphine like action on (GIT) - Synthetic antitussive. • Direct dopamine agonist !
• Less Addiction
(Neuroleptic analgesia) • Some lipid solubility some cross BBB ! C.N.S effect. - No (analgesia. addiction & stimulates CTZ central emetic.
• Less emetic.
- Fentanyl + Droperidol + nitrous oxide • Used to treat diarrhea. inhibition of R.C) • Anti-parkinsonism.
• Less inhibition of R.C.
(Neuroleptic anesthesia) • Combined with atropine (not used in children).
P/D

• No Anti-tussive effect • No PPP (mydriasis).

- The emetic effect of fentanyl is blocked by Loperamide (Imodium)
• No constipation • No Drowsiness.
Droperidol
• Local anesthetic. • Increases ADH release. - Stimulates opiate receptors present in GIT but not pass
Uses: neurosurgery & endoscopy
• Antagonized by naloxone. BBB.
Side effects: vomiting, marked, RC, tone &
• LD: excitation (atropine like + nor-meperidine). 2- inhibits intestinal motility (as morphine).
rigidity (need muscle relaxant)
Uses: in diarrhea of various etiologies
Mixed Agonist-Antagonists Narcotic Analgesics Narcotic antagonists Tramadol
Buprenorphine Butorphanol Pentazocine Nalbuphin Nallorphine Levalorphan Naloxone Nalmefene Naltrexone Mechanism
partial μ agonist agonists at κ receptors & antagonists at μ receptors. • pure opiate antagonists (Mainly μ receptors) but also block (κ, δ, sigma) • Centrally acting analgesic by
• They are agonists in absence of morphine (no morphine addiction) κ agonists • block all actions of opiates - blocks serotonin uptake
analgesic Injection Oral - inhibits NE transporter
• In presence of morphine (addiction) μ antagonist ! withdrawal symptoms. - weak μ agonist
Short duration (1-2 hrs) Long duration (10 hrs)
(except buprenorphine: μ partial agonist)
Characters

Metabolized by hydroxylation & derivative from

• Mild dependence ! mild withdrawal symptoms.
glucuronic acid conjugation. naloxone
• Partial agonist at R.C (low ceiling effect): With increasing dose increasing the
analgesic effect but no increase in R.C depression
but if respiratory depression occurred it will be resistant to naloxone reversal
• slow dissociation from
receptor ! long duration.
• orally or better sublingual
to bypass 1st pass effect.
analgesic & can be used in diagnosis of opiate addiction. - acute morphine poisoning. opioid Addiction chronic neuropathic pain.
ttt of opioid & heroin - neonatal asphyxia overdose (after detoxification)
dependence (IM to the mother before labour)
USES

(Intra-umbilical after labour).

- diagnosis opiate addiction
(S.C. naloxone ! mydriasis &
withdrawal symptom)
- long duration - vomiting histamine In LD ! respiratory depression tachycardia, arrhythmia. hepatotoxicity Toxicity
SE

- sedation - nightmares release nausea, sedation seizures

- anxiety (contraindicated in epilepsy)
 Antipyretic analgesics “NSAIDs” G3FR_38
Relieve pain centrally without narcosis, lower elevated body temperature to normal
Most of them (except Paracetamol) have anti-inflammatory and anti-rheumatic effects = Non-Steroidal Anti-Inflammatory Drugs (NSAIDs).
Mechanism of action of NSAIDs
NSAIDs inhibit Cyclo-oxigenase (C.O.X) enzyme !decrease synthesis of prostaglandins (PGs), Prostacyclin (PGI2) & Thrmboxane-A2 (TXA2).
Types of Cyclooxygenase Enzymes (COX)
COX-1 COX-2 COX-3
Constitutive ! Physiological Inducible by inflammation !Pathological present only in C.N.S
- Stomach !"HCI !Prevent peptic ulcer - Infection ! toxins ! IL-1 & TNF ! stimulates COX-2 !#PG ! pain & fever
- Kidney !Renal VD 1) CNS: a- Hypothalamus ! HRC ! Fever.
b- Thalamus ! pain.
2) Periphery ! Inflammation.
Classification of Anti-Cox (Anti-PGs)
Non-selective COX-Inhibitors Selective COX-II Inhibitors
Salicylates Anilines Pyrazolones lndols Aryl Acetic Acid Nabumetone Propinic acid Fenamates Oxicams Celecoxib Meloxicam Nimesulide Nabumeton
Aspirin Paracetamol Phenylbutazone Indomethacin Diclofenac Naproxen Mefenamic Piroxicam Effective anti-inflammatory & anti-Rheumatic with
Phenacetin Dipyrone Sulindac Ibuprofen acid less gastric toxicity
Aminopyrine Ketoprofen
Acetylation Selective Long t1/2 =
Irreversible inhibits CNS 36-100 h
inhibition COX (COX-3)

Selective inhibition of COX enzymes

Relative selectivity to COX-I Less selective for COX-I Equipotent on COX- I & COX-2
aspirin, indomethacin, Sulindac & Piroxicam Ibuprofen naproxen, diclofenac & Flubiprofen

Chemical mediators of inflammation

l- Amines: histamine & serotonin
2- Lipid: PG, LT & PAF
3- Small peptides: bradykinin
4- Large peptides: interleukin & substance P.
5- Tissue destructive enzymes: protease, fibrinolysin & hyaluronidase
6- Toxic O2 products: from killing organisms by eosinophil & neutrophil.
N.B. Toxic O2 product + protease ! damage of host tissue
 I-Salicylates G3FR_39
Pharmacokinetic Preparations Therapeutic uses
Absorption well from upper GIT ! acid pH enhances absorption 1- Acetyl salicylic acid (Aspirin): simple or with antacid ! (Alexoprin: Aspirin A) Local use
Distribution bound to plasma albumin ! displaces other drugs + ALOH3) 1- Salicylic acid: Keratolytic, fungistatic, antiseptic & remove hair scales
Metabolism •Mostly conjugation with Glucuronic acid !Inactive metabolites 2- Sodium salicylate: enteric-coated tablets (1/2 potency of aspirin). 2- Methyl salicylate: counterirritant for arthritis & myositis.
• 25% is oxidized to gentisic acid. 3- Diflunisal: - Potent anti-inflammatory -Not antipyretic. B) Systemic Uses
Excretion • Mainly renal. Some excretion in saliva & milk. -No auditory effect. - Less effect on gut & platelet. 1- Analgesic: in superficial pain: headache, arthralgia & dysmenorrhea.
• Alkalinization of urine !enhance renal excretion 4- Sulphasalazine: (5-aminosalicylic acid linked to sulphapyridine): 2- Antipyretic: in fever: non-specific & non-causal.
(t1/2) • SD (< 4g) ! First order kinetics ! Constant t1/2: 3-5h Used in ulcerative colitis. 3- Common cold: to treat fever, headache & pain.
• LD (>4g) ! Zero-order kinetics !#t1/2 with increasing dose 4- Gout: only by large dose (5-6 g/d).
MOA Acetylation ! Irreversible inhibition of both COX-I & COX-2 both in CNS & periphery 5- Rheumatoid arthritis: large dose 5-6g/.
Actions of salicylates 6- Rheumatic fever (50mg/kg/day in divided doses after meals).
• Used in rheumatic arthritis but not in carditis, chorea or nodules.
Local actions “Salicylic acid” • Not used in heart failure (Na+ retention).
1- Keratolytic ! used in corns removal. 2- Local antifungal. 3- Counter-irritant but methyl salicylate 7- Prophylaxis of thromboembolic disease (small dose = 75-100mg)
Systemic actions Toxicity of salicylates
C.N.S Anti-inflammatory action (large dose=5gm\d) A. Acute Toxicity
1- Analgesic: Inhibits COX enzyme ! decreases PGE1,2 • Inhibition of PG production either directly (inhibits COX) or indirectly (increase - Manifestations:
(centrally: increase pain threshold & peripherally: anti-inflammatory). cortisone production which inhibits phospholipase A2 ! inhibits PG synthesis). 1- Hyper-reflexia, excitation, convulsions then coma & depression of RC.
• Mainly relieve somatic pain, e.g. headache not visceral pain. CVS & Blood 2- Hyperpyrexia, hyperventilation & hyperhidrosis ! dehydration.
2- Anti-pyretic: (decrease PGE1,2) - In large dose: decreases blood pressure due to suppression of VMC ! VD 3- Hyperacidity & irritation: nausea, vomiting, pain, ulcer & bleeding.
• Lower high body temperature (fever) to normal through (HRC) - Hypoprothrombinemia:(by L.D) ! coumarine like ! compete with Vit-K in 4- Hyperglycemia. 6- Hypotension.
increase heat loss through: liver ! decrease synthesis of activated factor II, VII, IX and X. 5- Hypoprothrombinemia. 7- Acid\Base imbalance.
a. Mobilization of fluids from tissue to blood. - Inhibits Platelets aggregation: (S.D = 75-150mg) selective inhibition of TXA2 - Management:
b. Dilatation of cutaneous blood vessels. synthetase enzyme ! decreases TXA2 1- Gastric lavage with NaHCO3 to neutralize hyperacidity.
c. Increase Sweating (diaphoretic) - Reduction of ESR to normal. 2- Alkalinization of urine with NaHCO3 to help excretion of salicylate.
N.B. Toxic dose ! hyperthermia due to uncoupling of oxidative - Idiosyncrasy in G6PD deficiency !hemolytic anemia. 3-Symptomatic: • Cooling fomentation (cold water or alcohol) for
phosphorylation ! increases oxidative metabolites hyperpyrexia. • Correction of dehydration & acid base by fluids.
Respiration & Acid\base balance GIT • Correction of hyperglycemia
- SD ! no effect. - Gastric irritation due to decrease PG leads to: • Vit. K or blood transfusion for hemorrhage
- LD in adult: stimulates R.C (directly or through CO2 production) due to • Increase HCL (Hyper-acidity) ! ulceration & bleeding 4- Hemodialysis in severe cases.
uncoupling of oxidative phosphorylation !hyperventilation! loss of CO2 ! • Decrease mucous secretion ! decrease GIT protection. B. Chronic toxicity (Salicylism):
respiratory alkalosis which could be compensated by renal excretion of alkali ! • Also due to aspirin trapping in mucosa cells (acidic media enhances aspirin Large dose for long time (RF) ! headache, blurred vision, ringing car.
compensated respiratory alkalosis absorption into mucosal cells to be trapped inside them). nausea. vomiting. hyperventilation & tinnitus (reversible)
- Toxic dose in children ! metabolic acidosis due to: - Nausea & vomiting: central (stimulation CTZ) & peripheral (local irritation). Side effects
a. Metabolites of salicylate metabolism (gentesic acid). - To antagonize gastric irritant effect: 1- Reye’s syndrome: salicylates in infant & children (< 10 yearn) with
b.Accumulation of pyruvic & lactic acid due to suppression of CHO metabolism • Aspirin is uses after meals in divided doses. chickenpox or influenza ! fatal hepatotoxicity & encephalopathy.
c. Renal insufficiency due to vascular collapse. • Used in buffer form = aspirin+ NaHCO3 2- Hypoprothrombinemia ! bleeding tendency.
- Precipitate attack of bronchial asthma in susceptible patients as ! it • Used of enteric coated tablets (Alexoprin). 3- GIT irritation: nausea. vomiting, pain, ulceration & bleeding.
inhibits COX enzyme shifting arachidonic acid metabolism to LOX pathway ! • Give prostaglandin analogue (misoprostol). 4- Allergy (hypersensitivity): rash, urticaria. angio-edema.
increasing LT (SRS-A) then main mediator in bronchial asthma • Addition of antacids or proton pump inhibitors. 5- Teratogenicity: cardiac septal defect.
Kidney Metabolic actions 6- idiosyncrasy: hemolysis in patient with favism.
• SD: (1-2g\d) !increase uric acid level by decrease uric acid excretion. a. CHO metabolism: 7- Nephropathy. 8- Bronchial asthma in susceptible patient.
• LD: (5g\d) ! decrease uric acid level through: • Small dose ! hypoglycemia (insulin like). Drug interactions
a. Increase Uric acid excretion (uricosuric). • Large dose ! hyperglycemia due to Glycogenolysis. 1- Displace drugs from ppb e.g. oral anticoagulants & oral hypoglycemic
b. Prevent uric acid reabsorption from PCT. b. Nitrogen metabolism: 2- Compete with other uricosuric e.g. probencid & Phenylbutazone.
• N.B. Salicylates antagonize other uricosuric drugs. • S.D: increase nitrogen excretion due to increase protein breakdown. 3- Barbiturates potentiate analgesic effect of salicylates.
• In large dose: aspirin causes nephropathy due to decrease PG E & I so • L.D: accumulation of glutamine !#glutamate/GABA ratio !convulsion 4- #incidence of peptic ulcer with other anti-rheumatic & corticosteroids
unopposing effect of noradrenalin & angiotensine-II. c. Uncoupling of oxidative phosphorylation ! elevate basal metabolic rate
• N.B. Chronic toxicity leads to nephritis or renal papillary necrosis. (BMR) ! increase O2 consumption & CO2 production.
Immunological action Endocrinal actions Contraindications
cortisone release ! decreases antigen antibody reaction. • Increase adrenaline. • ACTH ! increase cortisone. • # plasma thyroxin level I- Allergy. 2- Idiosyncrasy. 3- Bleeding tendency.
Uterus (Tocolytic) Liver 4- Bronchial asthma. 5- Peptic ulcer. 6- Pregnancy.
• Decreases uterine contraction ! delay onset of labor (decrease PGE2&F2). • Hydrocholeratic: increases bile volume (increase water content). 7- Gout (if used in small dose). 8- Children (Reye's syndrome).
• Glycogenolysis: increases adrenaline release from adrenal medulla. 9- Should be stopped one week before operations.
G3FR_40 II-Aniline Derivatives III- Pyrazolone Derivatives IV- Indole derivatives VI- Nabumetone X-Selective COX2
Phenacetin Acetaminophen (paracetamol) Phenylbutazone 1- Sulindac • Prodrug ! converted to acetic acid.
• Less GIT irritation.
inhibitors
Absorption • Prodrug ! active metabolite less Celecoxib
- Prom GIT (oral & rectal) • Well orally, rectally & parenterally. toxic & long duration.
Side effect • Analgesic, antipyretic & anti-
- Acetaminophen metabolized through 1st pass in intestine & liver • 98% bind to plasma protein. • Inhibits both COX & LOX enzymes + inflammatory.
1- Photosensitivity
anti-oxidant effect (O2 scavenger) • Selective inhibition of COX-2 so
Metabolism 2- Pseudoporphoria.
• Enterohepatic recycling. less side effects specially in GIT.
• Phenacetin (active) through hepatic metabolism to paracetamol
(active metabolite).
• Metabolized to 2 active metabolites:
a. Oxyphenbutazone: potent, long-acting
• Less effect on renal PG. VII- Tolmetin • COX-2 is essential (constitutive)
• Short duration. • Rapid excretion. in kidney so its inhibition ! renal
Then paracetamol is conjugated with glucuronic & sulphuric acid. anti-inflammatory. toxicity.
• 5% of paracetamol is hydroxylated to N-acetyl Benzoquinoneimine b. γ hydroxyl phenbutazone: short-acting • Not used due to High side effect
• Celecoxib is sulphonamide so !
(NABQI) which then conjugated with glutathione (SH-containing). uricosuric (renal excretion) VIII- Oxicams skin rash.
• In toxic dose: #NABQI production leads to depletion of
glutathione ! accumulation of NABQl which will react with SH
Piroxicam • Selective COX-2 inhibitors,
2- Indomethacin Hepatic metabolism with inhibit COX-2 mediated
constituent in renal & hepatic cells ! liver & kidney damage.
enterohepatic circulation so long T1\2, prostacyclin synthesis so not
Action so given once daily cardio protective as other NSAIDs.
I-Inhibition of COX-3 (C.N.S mainly) : analgesic & antipyretic only • inhibits COX ! decrease PG ! 1- Potent inhibitor of COX enzymes.
2- No anti-inflammatory (no decrease in PG synthesis peripherally), Anti-inflammatory, analgesic & antipyretic. 2- Potent inhibitor of PLA2& PLC. Side effect Meloxicam
no GIT irritation & no uricosuric activity • Uricosuric 3- Reduce neutrophil migration. 1- Skin rash
4- Decrease T & B- cells proliferation. Nimesulide
2- peptic ulcer & bleeding (20mg\d ).
Nabumeton
Uses Meloxicam
Analgesic antipyretic in patients cannot tolerate aspirin e.g. 1- Rheumatoid arthritis & ankylosing 1 - Anti-inflammatory in ankylosing • Inhibit COX-2 >C OX-I
- Peptic ulcer. - gout -Bleeding tendency (hemophilia). spondylitis. spondylitis, R.A & gout. • weak inhibition in synthesis of TXA2
- Bronchial asthma. - Children with viral infection. 2- Gout: during attack (analgesic & anti- 2- Dysmenorrhea & preterm labor. • Used in rheumatic disease &
- During oral anticoagulant therapy inflammatory) & in between (uricosuric ). 3- Close PDA in neonates osteoarthritis with few GIT troubles.
Side effect IX- Propionic Acid
1- Methaemoglobinaemia (phenacetin) ! treated by Methylene blue 1- Allergy: skin rash. 1- Allergy 1- Naproxen
2- Acute hemolytic anemia & nephrotoxicity (with phenacetin). 2- Agranulocytosis. 2- Agranulocytosis. Stronger 20 times > aspirin as
3- LD of paracetamol ! depletion of SH of glutathione ! 3- GIT irritation. 3- GIT: increase HCL ! nausea. ulcer anti-inflammatory
hepatotoxicity& nephrotoxicity. 4- Liver & kidney damage. & bleeding.
N.B. N-acetylcysteine is the available antidote used in overdose 5- Na+ & H2O retention ! edema & 4- Eye: blurred vision & corneal opacity. 2- Ibuprofen
toxicity of paracetamol. 4- Allergy. hypertension. 5- CNS: dizziness, headache & vertigo. Used as analgesic in small doses

Advantages of acetaminophen Drug interaction V- Aryl Acetic Acid 3- Flubiprofen

1- can he used when salicylates are contraindicated. Displace oral anticoagulant, oral
2- Not affects platelets function & blood clotting. hypoglycemic & sulfonamide
3- could be used as antipyretic analgesic in viral infections. increase level of free drug ! toxicity.
4- Not antagonize uricosuric drugs so as antipyretic analgesic of Contraindication
choice in gout. 1- HTN & Cardiac disease. 2- peptic ulcer
3- Liver & kidney disease
Benotrylate Sulphinpyrazone
• Ester of paracetamol + aspirin (broken in GIT but less irritation). - Metabolite of Phenylbutazone.
• Antipyretic, analgesic & anti-inflammatory effects. - Uricosuric in gout. - Uses: anti-platelet.
Diclofenac (Voltaren)
• Orally, rectally & IM ! distributed
all over the body (concentrated mainly
in synovial fluid).
• Rapid metabolism short t1/2
Side effect
1- renal troubles in risky patients
2- # Liver transaminases.
CI in: angioedema & bronchospasm.
4- Ketoprofen
• Inhibits both COX & LOX.
• Probenecid !#level of Ketoprofen.
• Few side effects so could be used
with oral hypoglycemic &
anticoagulant.
 Anti-Rheumatic Drugs G3FR_41
I-Slow-Acting Anti-Rheumatic Drugs (SAARDS) II-Anti-cytokine therapy III-Steroidal
Gold salt Chloroquine D-Penicillamine Methotrexate Etanercept Infliximab anti-inflammatory
(Gold Na+ thiomalate & Auranofin) Hydroxychloroquine
Taken up by macrophages ! - stabilization of Lysosomal membrane - decrease blood level of - immunosuppressant so - Recombinant fusion Monoclonal
- Inhibit phagocytosis - trap free radicals Rheumatoid factor effective in rheumatoid protein binds to TNF-α antibody against IV-NSAIDs
- Suppress lysosomal enzymes - slow progression of bone destruction - slow progression of bone arthritis (autoimmune disease) & inhibit lymphotoxin TNF-α all NSAIDs except paracetamol
MOA

& induce remission destruction - rapid onset (3 - 4 weeks).

- anti-malarial drug - Analogue for A.A. cysteine - anticancer in L.D
V-Colchicine
VI-Counter irritant
Slow the course of the disease. induce remission & prevent further destruction of the joints & tissue but have slow onset (3-4 months). methyl salicylate
rheumatoid arthritis (RA) (when NSAIDs are ineffective). - Juvenile arthritis Oil of winter green
USES

in rapidly progressive type of rheumatoid - cystinuria - severe cases not responding (alone or with
arthritis in early cases - heavy metal poisoning (Copper) to NSAIDs & others methotrexate)
- dermatitis of skin & mucus membrane LD !Eye affection (Optic neuritis) dermatitis, nephritis & aplastic - Agranulocytosis, - Blood dyscrasis,
- damage of the kidney ! proteinuria, anemia neutropenia & pancytopenia - Demyelinated CNS
SE

- BMD ! aplastic anemia. - Nausea, mucosal ulceration disorders.

- liver cirrhosis

GOUT
Metabolic disorder due to disturbance purine metabolism characterized by: • Hyperuricemia >7mg\dl • Deposition of urate crystals in joint (arthritis), kidney (nephropathy) & under the skin (tophi).
A) Drugs used in acute attack B) Drugs used in prophylaxis Uricolytics
I-Uricosurics II- Inhibition of uric acid synthesis Rasburicase &
I- Colchicine & Demeclocine II-Steroids III-NSAIDs Probenicid Sulphinpyrazone Allopurinol Febuxostat pegylated-uricase
A) Anti-Gout effect: ACTH naproxen - S.D:" uric acid secretion - Uricosuric inhibits xanthine oxidase enzyme • More selective & - rDNA form of urate
• It binds to microtubular protein (tubulin) of PMNL ! inhibits - L.D: (>1gm/d)"uric acid -"platelets aggregation (responsible for formation of uric acid potent inhibitor of oxidase (uricase) that
migration of PMNL to the joints ! no phagocytosis of mono- prednisone Phenylbutazone reabsorption from xanthine & hypoxanthine) !"uric xanthine oxidase than
converts uric acid to
Actions

Na urate crystal ! no rupture of leukocytes ! no release of Indomethacin - Probencid !"tubular acid synthesis allopurinol.
allantoin !more soluble
lactic acid ! no inflammatory acidity! no release of Piroxicam secretion of penicillin, para- Drug-drug interaction • Dose: X0- 120 mg
chemotactic factors e .g. glycoprotein , IL-I , LTB4 ! no amino salicylic acid, once\day orally. & readily excreted
Sulindac 1- "metabolism of 6-mercaptopurine &
further precipitation of urate crystals. naproxen, Ketoprofen &
probencid (inhibition of XO).
B) Anti-Mitotic effect: inhibits cell division. indomethacin !prolong 2- "metabolism of oral anticoagulant
• Colchicine not affects synthesis of uric acid nor its excretion their duration. (microsomal enzyme inhibitor).
• Colchicine used only in acute gouty arthritis not used in other chronic gout in LD - gout. In hyperuricemia or chronic gout in: Second line agent if I.V. in hyperuricemia
types of arthritis. (2 weeks after acute attack) - thromboembolic diseases a- Gouty nephropathy. allopurinol cannot be associated with tumor lysis
1-Acute attack of gout (drug of choice): c- Urate stones. tolerated.
syndrome
USES

• 1mg followed by 0.5 mg every 2h till pain is relived or b- Impaired renal function.
toxicity appears(diarrhea) or I.V: 0.5 mg every 2 hours. d- If Uricosurics are ineffective or CI.
2- prophylaxis gout: in early treatment with allopurinol to
decrease uric acid mobilization to joint.
3- prophylaxis of Familial Mediterranean Fever (FMF).
4- Sarcoidosis & Liver cirrhosis.
1- GIT irritation: nausea. vomiting, diarrhea & abdominal - GIT irritation & skin rash a- Headache drowsiness.
pain~ dehydration & CVS collapse. - urate stones b- Cataract & allergy.
SE

2- Kidney damage. 3- Bone marrow suppression. c- Nausea, vomiting & diarrhea.

4- Hair loss. 5- Allergy 6. Myopathy d- #liver enzymes & hepatomegaly.
e- Isolated cases of exfoliative dermatitis.
Precaution for patients with gout Drugs contraindicated in gout
1- Administration of huge amount of fluid (3-5\d) & Alkalinization of urine to minimize deposition of uric acid in kidney. 1- Thiazide & Diazoxide. 2- Acetazolamide. 3- Salicylate in SD
2- Avoid aspirin in small dose. 3- Coffee & tea not contraindicated 4- Probenicid in small dose 5- Pyrazinamide (ttt of TB ).
 Sedative hypnotics & Anxiolytics G3FR_42
Sedative: Drug that calm behavior but produces drowsiness. hypnotics: Drugs that induce state like sleep. Anxiolytics: drugs that relieve anxiety & nervous tension
Sedative hypnotic drugs
I-Barbiturates II- Benzodiazepines (BZd) III- Other hypnotics
Classification Zolpidem
Type Long-acting Intermediate- Short-acting Ultrashort acting Long acting Short acting • Not BZd but acts as BZd receptor agonist.
Examples Phenobarbitone Amobarbitone Pentobarbitone Thiopental Diazepam Clonazepam Flurazepam Nitrazepam Triazolam Midazolam • No anticonvulsant. no muscle relaxation,
• No tolerance
Secobarbitone Methohexital Oxazepam Lorazepam Temazepam • Uses: hypnotic, rapid onset & short duration 3h
solubility Low Moderate High Very high Clorazepate Chlordiazopoxide Alprazolam • Side effects: nightmares. confusion. drowsiness
BBB Slow Moderate High Very high Classification According to their activation & inactivation & P/K & GIT upset.
GIT abs Slow Moderate Rapid Irregular A) Absorption: • Flumazenil antagonizes zolpidem action
Onset Slow Moderate ½ h Rapid ¼ h Immediate • Well absorbed orally:
Duration 6-8 h 4-6 h 2-4 h ½h Clorazepate (inactive & prodrug) converted by gastric HCL into active metabolite (nordiazepam)
P.P.B 30% 40 % 50% 70 % B) Metabolism: Mainly by HME:
Zaleplon
Fate 25% hepatic Moderate Rapid Redistribution ! escaped from 1-Activation (drug to active metabolite) e.g. diazepam, Flurazepam Alprazolam, Triazolam & Very similar to zolpidem in its hypnotic action
75% renal So, hepatic metabolism hepatic metabolism circulation & uptaken by adipose tissue Chlordiazopoxide but Zaleplon causes fewer residual effects on
Alkalinization of & muscle then hepatic metabolism 2- Inactivation by oxidation & conjugation: most of BZd. psychomotor and cognitive functions compared
urine !#excretion - Repeated administration prolongs its C) Excretion: renal excretion of inactive hydrophilic metabolites. to zolpidem or the benzodiazepines, this may be
duration due to tissue saturation N.B. Duration of actions of BZd: duration of parent drug + active metabolite. due to its rapid elimination (t1/2 = l hour ).
MOA a. Binds to & stimulates specific binding site on GABA receptor ! facilitates binding of GABA to its • BZd binds to specific binding site (BZ receptor = ω receptor; ω1 & ω2) on GABA receptors ! facilitate Eszopiclone
binding site ! opening of Cl- channels !Cl- influx ! postsynaptic hyperpolarization & inhibition. binding of GABA to its site on GABA receptor ! open Cl- channels ! hyperpolarization & inhibition
- BZ1 receptor agonist,
b. Inhibits release of excitatory neurotransmitters. • BZd & zolpidem bind to site between α & γ subunit of the GABA receptor ! opening of Cl- channel
• GABA binds to 2 specific sites between α & β subunits of GABA receptor (GABA binding sites). - similar to zolpidem and Zaleplon,
uses: insomnia
Pharmacological action Classification According to their uses, Pharmacological action & Uses SE: anxiety, dry mouth & peripheral edema
C.N.S Non-selective C.N.S depressant from sedation to anesthesia & coma: 1- Anxiolytic = antianxiety = minor tranquilizer = taming effect on animals: Ramelteon
1- Sedative: but produces drowsiness (The dose of barbiturates as sedative is 1/3 of the hypnotic dose) • Due to inhibition of neurons in limbic system.
2- Hypnotic: but abnormal sleep due to "REM sleep leads to: • e.g. diazepam, Chlordiazopoxide, Clorazepate, Oxazepam, lorazepam & alprazolam. • selective agonist at the MT1 and MT2
a. Hang over. b. Rebound paradoxical sleep (night mare) after tolerance or stoppage of drug. 2- Hypnotic: • Long acting: Flurazepam & Nitrazepam & Temazepam. • Short acting: Triazolam. subtypes of melatonin receptors in
3- Amnesia. 4- Potentiate analgesics e.g. morphine but not used alone. 3- Antiepileptic: e.g. diazepam & clonazepam in status epilepticus & grand mal epilepsy. supra-chiasmatic nucleus.
5- Anticonvulsant: all barbiturates treat all types of convulsions but as antiepileptic only Phenobarbitone 4- Antispasticity = skeletal muscle relaxant: • e.g. diazepam in multiple sclerosis & cerebral palsy. • no dependence or withdrawal effects.
treats grand mal & status epilepticus. 5-Induction of anesthesia: I.V administration of: • Long acting: diazepam. • Short acting: midazolam
• SE: dizziness, fatigue and somnolence.
6- Anesthesia (thiopental): but ! hang-over & large dose ! depresses RC.
7- LD: • (-) RC ! hypoventilation & hypoxia. • (-) VMC ! hypotension. • (-) HRC ! hypothermia. Advantages of BZd over barbiturates as hypnotics Chloral hydrate
CVS LD & IV !hypotension due to • (-)VMC •"cardiac contraction & •"sympathetic tone ! VD) Barbiturates Benzodiazepines • Prodrug converted by hepatic
Hormone increase ADH release. 1- Sleep Marked inhibition of REM: Less inhibition of REM: metabolism into active trichlorethanol.
Liver hepatic microsomal enzyme inducer: tolerance, cross tolerance & drug interactions. pattern a. Hang over b.Rebound paradoxical sleep a. Less hang over b.Less paradoxical sleep Trichlorethanol is then converted to
USES 1- Anticonvulsant & Antiepileptic: • Phenobarbitone is anticonvulsant even in subhypnotic dose also used 2- HME Induction of HME: No HME induction: inactive metabolites (tricholoacetic acid
in status epilepticus, grand mal epilepsy & febrile convulsions. a. Tolerance & cross tolerance a. Less tolerance & less cross tolerance
2- Anesthesia & Preanaethetic medication: b. Dependence c. DI b. Less dependence c. Less DI
& urochloralic acid) !excreted in urine.
a- IV thiopentone. b- Hexobarbital rectally ! basal anesthesia 3- TI Low (depress R.C)!narrow safety margin Higher (safe on R.C) !wide safety margin • uses:
3- Hyperbilirubinemia & kernicterus in neonates as it is HME inducer !#bilirubin metabolism 4- antidote None Flumazenil - orally diluted with milk or fruit juice.
SE & 1- Allergy: skin rash. 2- Idiosyncrasy: excitation especially in elderly. 1- Daytime sedation (long acting) or Daytime anxiety (short acting). 1- Sedative hypnotic in old age & patient
Toxicity 3- Idiosyncrasy: precipitate attack of porphyria in patient with intermittent porphyria due to # of
2- Dependence ! addiction !sudden withdrawal! anxiety, confusion, agitation, insomnia with bronchial asthma.
γ aminolaevulinic acid synthetase !# porphyrin so aggravates disease i.e. demyelination & haemolysis.
3- Affect mental. psycho-motor & sexual functions. 2- Preanaethetic medication in old safer
4- Induction of HME: a. !#metabolism of the drug itself ! tolerance than barbiturates.
b. #metabolism of other drugs of same group (hypnotics)! cross tolerance. 4- Amnesia especially short acting Triazolam.
5- Aged patients ! mental confusion & hypotension. • Toxicity:
c. #metabolism of other drugs: dicumarol, digitalis, Vit.D & folic acid (megaloblastic anemia)
5- Interactions with other drugs: 6- Additive to alcohol (alcohol intolerance) ! severe C.N.S inhibition. 1- Acute: coma. P.P.P, (-)V.MC & R.C.
a. Phenobarbitone is cytochrome P450 inducer !#metabolism of drugs. 7- Ataxia. 8- Allergy. 2- Chronic: dependence.
b. They potentiate CNS depressants e.g. alcohol. analgesic. & anesthetics. 9- Amenorrhea, inhibit ovulation & ejaculation even teratogenic. 3- With alcohol marked C.N.S inhibition
6- Amnesia & Automatism, drowsiness & impaired coordination.
l0- Stimulates appetite ! increase body weight. • CI: peptic ulcer, Liver & kidney
7- Abnormal sleep pattern:"REM ! hangover & rebound paradoxical sleep. disease, Proctities “rectum”
8- Extravasation of thiopental: sloughing & gangrene. 11-Acute toxicity: rare unless if used with alcohol.
9- Acute Barbiturates toxicity: Treatment of acute toxicity: flumazenil + supportive treatment. Paraldehyde
• Manifestations: coma, hypoxia. hypotension, hypothermia. Death from respiratory failure. • Liquid of bad odor or taste.
• Managements: a. Endotracheal intubation & artificial respiration. Flumazenil • Action & uses:
b. Stomach wash, hemodialysis, Alkalinization of urine. 1- Orally: hypnotic in respiratory distress
c. Fluid (dextran, albumin) or blood in case of hypotension ± NA. Selective & competitive Bzd receptor blocker ! antagonizes all Bzd actions.
d. Analeptics e.g. bemegride or caffeine retention enema. • Given by repeated I.V injections or by I.V infusion (0.3- l mg). by diluting in milk.
10-Addiction = dependence = chronic toxicity:Sudden stop!(excitation, tremor, seizure & cardiac arrest) • Uses: 1- Acute Bzd toxicity. 2- Awake patients from anesthesia. 2-IM: anticonvulsant in status epilepticus
CI 1- Allergy to barbiturates. 2- Idiosyncrasy (porphyria). 3- Head injury. 4- Hypotension (shock). 3- hepatic coma to block endozepine present in high concentrations in patients with & eclampsia 3-rectally: basal anesthesia
5- Liver & kidney diseases. 6- Depressed RC. 7- Respiratory: emphysema, bronchial asthma. hepatic coma. • CI: liver & kidney disease.
 G3FR_43
Selective anxiolytic
I-Buspirone
Acts as partial agonist on presynaptic (5-HT1A) in brain.
Advantages “anxioselective”
- No anticonvulsant. - No muscle relaxation.
- No hypnosis. - No rebound anxiety if stopped.
- No cross tolerance or cross dependence with other sedative & hypnotics.
- Little dependence & least additive to alcohol.
- Its anxiolytic effect appears after 1-2 weeks so effective in generalized
anxiety syndrome not in acute panic attacks.
Side effects
1- Tachycardia, palpitation & nervousness.
2- If taken with MAO inhibitor ! hypertension.
II-Propranolol
• Non-selective β -blocker.
• Blocks both psychic & somatic symptoms of anxiety.
Uses
• situational panic or phobic disorders.
• in sports need calm skill e.g. bowling or shooting
• in examination sittings.
 Antidepressant drugs G3FR_44
Depression is a serious disorder characterized by intense feeling of sadness, hopelessness, inability to experience pleasure in usual activities, change in sleep pattern and appetite, loss of energy and suicidal thoughts.
Pathogenesis Deficiency of central norepinephrine, serotonin & dopamine.
MOA OF a. Reduction of the uptake of biogenic amines, facilitating neurotransmission, enhancing serotonin transmission ! improves mood while enhancing norepinephrine transmission !increases motor activity.
ANTIDEPRESSANT b. Chronic use ! increases the sensitivity of postsynaptic α receptors, decreases the activity of presynaptic receptors (downregulation of inhibitory auto receptors), this leads to greater synthesis and release of
neurotransmitters into the synaptic clefts and enhancing signaling in postsynaptic neurons.
• Clinical effects are related to chronic rather than acute changes, explaining the Delayed onset of action (2-3weeks) of antidepressants.
I-Monoamine oxidase II- Tricyclic antidepressants III-Selective 5-HT & NE IV-Selective serotonin reuptake V-Atypical antidepressants
inhibitors (MAOIs) (TCAs) reuptake inhibitors inhibitors (SSRI)
Members Phenelzine Imipramine, Clomipramine, Desipramine, Venlafaxine Fluoxetine, Fluvoxamine, Paroxetine 1-Bupropion
Tranylcypromine Amitriptyline, Nortriptyline, doxepin Duloxetine Citalopram, Sertraline
P/K • Well absorbed orally. • Well orally. • t½ ranges from 10 to 80 hours. • Well orally. • t½ ranges from 16 to 36 h • MOA: still unidentified.
• Onset is slow (2-4 weeks). • Significant 1st pass effect. • Metabolized in liver & excreted via kidney • Uses: decrease craving for nicotine
• Termination of action depends on • Metabolized in liver then excreted via kidney. • paroxetine & sertraline !fecal excretion. in tobacco abusers.
enzyme regeneration
MOA irreversible inactivation of MAO. • block both, NE and 5-HT reuptake into the • They selectively inhibit the reuptake • inhibitor of 5-HT reuptake having 300-1000
• SE: dry mouth. sweating, tremors,
!#stores of NE, 5-HT and Dopamine neurons ! increases concentrations of of both 5-HT and NE. fold greater selectivity for 5-HT transporter as seizures at high doses.
monoamines in the synaptic cleft. • effective in treating patients in than NE transporter, 2- Nefozodone, Trazodone
• They also block M, H and α receptors. which SSRI are ineffective. • little ability to block dopamine transporter.
Action - mild amphetamine like stimulant 1- Elevation of mood. improve mental • little blocking muscarinic, alpha & histamine • MOA:
effect. alertness, increase physical activity. receptors !less SE than TCA - #5-HT1 presynaptic autoreceptors,
2- Antimuscarinic ! blurred vision, dry mouth, • Because fewer side effects and being safe in - inhibits 5-HT reuptake
retention of urine, constipation. overdose, SSRI have largely replaced TCAs and
3- α-blocking ! orthostatic hypotension. MAO-ls. • SE: sedation, priapism (trazodone)
4- Antihistaminic ! sedation.
Uses 1-Depression (to people not respond 1- Depression.
2- Nocturnal enuresis (imipramine).
1- Depression.
2-Obsessive compulsive disorder (fluvoxamine)
3-Mirtazepine
or show allergy to other treatment).
2- Phobias. 3- Neuropathic pain (amitriptyline ). 3- Panic disorder. • MOA: #5-HT2 & α2 receptors.
4- Generalized anxiety. • SE: sedation, sexual dysfunction,
SE 1- Excessive central stimulation:1- Blurred vision, dry mouth, retention of urine, - dizziness I - Sleep disturbances. weight gain
tremors. irritability, hyperthermia.
constipation. - insomnia 2- Sexual dysfunction.
2- Postural hypotension. 2- Orthostatic hypotension. - venlafaxine in high doses ! 3- Nausea, vomiting & diarrhea.
3- Constipation, dry mouth. 3- Sedation. increased blood pressure.
4- weight gain 4- Sexual dysfunction.
5- #catecholamines ! cardiac overstimulation
(life-threatening in overdose).
DI 1- With tyramine containing food 1- Imipramine is enzyme inducer. • SSRI with MAOI ! serotonin syndrome
(cheese, beer, red wines) ! 2- Potentiate the effect of directly acting which is characterized by: hyperthermia, muscle
hypertensive crisis sympathomimetic rigidity, myoclonus, change in mental status
2- With SSRI !serotonin syndrome 3- Block the action of indirectly acting
sympathomimetic.
4- With MAOI ! hypertension.
CI 1- Glaucoma.
3- Myocardial infarction.
2- Senile prostatic enlargement.
4- With MAOI.
 Mania & bipolar disorder G3FR_45
Mania: Mental disorder characterized by extreme self-confidence, elevated mood & impaired judgment.
Mood stabilizing drugs “Anti-manic drug”
Lithium - Carbamazepine - Valproate - Lamotrigine
Lithium carbonate
P/K • Monovalent cation that have some characteristics of sodium.
• Well-absorbed orally,
• Not bound to plasma protein & not metabolized in liver.
• Excreted in urine and (tears. saliva, sweat & milk).
MOA decreasing release of NE, dopamine and serotonin
Uses 1- Acute mania.
2- Prophylactic against recurrence of bipolar disorder.
3- Aggressive behavioral disorder.
4- Inappropriate ADH secretion.
SE 1- Hypothyroidism.
2- Nephrogenic diabetes insipidus.
3- Cardiac arrhythmias.
4- Weight gain.
Toxicity Plasma levels of 1.5-3 mmol/L: tremors, ataxia, drowsiness, thirst & diarrhea.
Plasma levels of 3-5 mmol/L: confusion convulsion, dehydration & coma.
ttt of 1- Gastric lavage
toxicity 2- Osmotic diuretic “mannitol” !#increase lithium excretion
3- Hemodialysis in severe cases
 Anti-psychotic drugs = Anti-schizophrenic = neuroleptics = Major tranquilizers G3FR_46
Drugs used primarily to treat schizophrenia they are also effective in other psychotic states such as mania & delirium.
Schizophrenia: A mental disorder characterized by !
Positive symptoms Negative symptoms
Delusions, hallucinations (often auditory), thought disorders Loss of social interaction, diminished response to emotions
• It has a strong genetic component. • It probably reflects some biochemical abnormalities mainly an over activity of the mesolimbic dopaminergic neurons
• However other transmitters are involved in the pathogenesis (increase in serotonin & decrease in glutamate levels ).
The major pathways containing dopamine in C.N.S.
Mesolimbic, mesocortical pathway Nigrostriatal pathway Tubero-infundibular pathway Medullary periventricular pathway
important for control behavior important for coordination of movements dopamine inhibits prolactin secretion concerned with eating behavior.
Classification of Anti-psychotic drugs
1-Typical 2-Atypical
affect dopamine receptors and Positive symptoms mainly affect serotonin receptors and negative symptoms mainly.
A) Phenothiazine B) Butyrophenones C) Thioxanthenes Clozapine, Olanzepine, Loxapine, Qutiapine
Chloropromazine, Promazine Droperidol, Haloperidol, Thiothixene, Flupentixol Risperidone, Ziprasidone,
Thioridazine, Mesoridazine Siroperidol. Sertindole, Molindole & Pimozide
P/K • Oral absorption is slow and irregular. I.M. injection increases bioavailability by 4 to 10 times. • Metabolized in liver and excreted in urine & bile. • PPb more than 90 %. • t½ is from 10 to 24 hours.
MOA • Typical drugs ! blockade of D2 receptors in mesolimbic system. • atypical drugs ! inhibition of 5-HT receptor & block pre-synaptic D1 receptors.
• Blockade of dopamine receptors in:
- Nigrostriatal pathway ! extrapyramidal adverse effects - Tubero-infundibular pathway !#prolactin secretion.
- C.T.Z ! antiemetic action. - Medullary periventricular pathway !change in eating behavior
• block cholinergic, adrenergic and histaminergic receptors.
ACTION 1- Anti-psychotic action: • cause emotional quietening, psychomotor slowing without serious Impairment of consciousness. • delayed onset of action (2-3 weeks)
2- extrapyramidal effects: • Dystonia. • Parkinson’s symptom: bradykinesia, tremors, ms rigidity. • Tardive dyskinesia: irreversible movement occurs months or years of ttt.
- thioridazine ! strong anticholinergic effects ! few extrapyramidal effects.
- Atypical agents !low extrapyramidal symptoms.
- haloperidol ! Highest incidence with low anticholinergic
3-Antiemetic: • Effective against drug or disease-induced vomiting • ineffective against motion sickness.
4-Hyperprolactinemia less with atypical agents
5- Antimuscarinic effects: - blurring of vision, - dry mouth, - urine retention & constipation Especially: - Chloropromazine, Thioridazine - Clozapine, Olanzepine
6- α1 blocking effect Especially: chloropromazine ! orthostatic hypotension.
uses 1- Schizophrenia. organic psychosis, manic phase of manic-depressive illness. 2- Antiemetic. 3- Persistent pruritis. 4- Hiccough.
5- Neuroleptic analgesia (droperidol + fentanyl): for minor procedure as endoscopy. 6- Tics (haloperidol is used). 7- Hypothermic anesthetic medication (lytic cocktail)
SE 1- Extrapyramidal manifestation. 2- Anticholinergic side effects. 3- Galactorrhea, gynecomastia, amenorrhea. 4- Orthostatic hypotension. 5- increased appetite weight gain.
6- Cholestasis jaundice (especially chloropromazine) 7- Phenothiazine ! urticaria, dermatitis & photosensitivity. 8- Clozapine ! agranulocytosis.
DI 1- Phenothiazine, Thioxanthenes ! potentiate C.N.S. depressants as alcohol & sedative-hypnotics. 2- Chloropromazine ! potentiates the effects of antihypertensive.
3- Neuroleptics antagonize dopamine agonists: levodopa. amphetamine
CI 1- Epilepsy as antipsychotics lower seizure threshold. 2- Agranulocytosis (avoid clozapine). 3- Infertility. 4- Liver impairment (chlorpromazine ).
 Neurodegenerative Diseases G3FR_47
1-Parkinsonism 2- Alzheimer's Disease
Parkinsonism is a progressive neurologic disorder of muscle movement characterized by tremors, muscle rigidity, bradykinesia and postural & gait abnormalities. loss of short-term memory & cognitive dysfunction
• The basal ganglia controls movement by 2 balanced systems: 1-One excitatory (cholinergic). 2- The other is inhibitory (dopaminergic). • loss of cholinergic neurons in the basal forebrain.
• Parkinsonism is associated with lesions in nigrostriatal dopaminergic system. • Current therapies are aimed at:
Etiology

• Dopamine levels are reduced, so cholinergic system becomes dominant. - improve cholinergic transmission in CNS
Causes: 1- Idiopathic. 2- Disease-induced ! viral encephalitis. - preventing the excitotoxicity actions of NMDA
3- Drug-induced ! a. Block dopamine receptors: phenothiazine & Butyrophenones. b. Deplete dopamine stores: reserpine. c. Inhibit dopamine synthesis: α-methyl dopa. glutamate receptors.
Drug therapy
A- Dopaminergic B-Antimuscarinic 1-cholinesterase Inhibitor
I-Levodopa (L-dopa) II-Bromocriptine III- Selegiline IV-Tolcapone V-Amantadine Benztropine, Biperiden Competitive Uncompetitive
Pergolide (Deprenyl) Entacapone Trihexyphenidyl Galantamine Donepezil, Tacrine
• Dopamine itself does not cross BBB. • Older ergot derivatives • MAO-B inhibitor ! • COMT inhibitors ! • #dopamine releases, • Block cholinergic transmission, so Rivastigmine
• Its immediate precursor (levodopa) can cross • Agonist on D2 receptors "metabolism of "Synthesis of methyldopa • "dopamine uptake restore balance between • Reversible cholinesterase inhibitors for
MOA

BBB where it is decarboxylated to dopamine • Dopamine agonists have longer dopamine, !# (which compete with L-dopa • slight anticholinergic dopaminergic/cholinergic systems. mild to moderate cases.
which replenishes stores. duration of action than levodopa. dopamine levels in brain. for active uptake in CNS) • "bradykinesia & muscle • Improve tremors and rigidity
•#action of levodopa. rigidity but short-acting • little effect on bradykinesia • More selective for cholinesterase in CNS
• less efficacious than levodopa than the periphery.
P/K • absorbed rapidly from intestine ("by food) USES SE
• decarboxylated to dopamine in peripherally 1- Alternative to L-dopa in case off • With Levodopa to • With Levodopa to Anti-viral drug against Effective against drug-induced 1. Nausea. anorexia, vomiting.
• Only 1-3 % of the oral dose reach the brain. wearing off & on-off phenomena.
• Transported to the brain via active transport.
reduces the required increase CNS influenza A2. parkinsonism. 2. Muscle cramp.
2- Inhibit lactation.
• Coadministration of a peripheral dose of levodopa. concentration 3. Tacrine ! hepatotoxicity.
3- Blocks prolactin secretion:
decarboxylase inhibitor reduces daily treatment of amenorrhea-galactorrhea • Improves on-off • reduce wearing off 2-NMDA Receptor Antagonists
requirements of levodopa by 75%. This also (induce ovulation). phenomena phenomena.
reduces nausea, vomiting, risk of cardiac Memantine
4- pituitary tumors with
arrhythmias and postural hypotension. hyperprolactinemia Overstimulation of NMDA receptors show
1. Anorexia, nausea, vomiting (reduced by 1. Anorexia, nausea, vomiting, • related to increased 1. Nausea, vomiting & 1. CNS: insomnia. - Blurred vision excitotoxic effect on neurons and is
domperidone). dyspepsia, constipation, bleeding dopamine activity. diarrhea. hallucinations. rarely fits - Dry mouth suggested as a mechanism for
2. Postural hypotension & cardiac arrhythmias. peptic ulcer. • Unlike non-selective 2. Postural hypotension. 3. Ankle edema.
- Constipation neurodegenerative process.
3. Visual & auditory hallucinations and 2. Postural hypotension: First dose MAOI. Selegiline at 3. Hallucinations & Dyskinesia 2. Skin: livedo-reticularis. MOA
involuntary movements (dyskinesia). phenomenon (sudden collapse). recommended doses has 4. Fulminant hepatic necrosis 4. Postural hypotension. - Urine retention.
4. Mood changes & depression. 3. Arrhythmia, digital vasospasm. little potential for (Tolcapone) 5. Used with caution in It is uncompetitive inhibitor of NMDA
5. Mydriasis 4. Dyskinesia, mental disturbances. causing hypertension. patients with seizures and receptors, slowing the rate of memory loss.
6. Brownish discoloration of urine. 5. Erythromyalgia: swollen, red, hot • In LD ! selectivity is MOA congestive heart failure. Side effects
7. Fluctuation of the response: & tender feet. lost !sever hypertension • Normally, the methylation of 6. Dry mouth and urine 1.Confusion 2.Agitation. 3.Restlessness
• Wearing off effect: progressive reduction in levodopa by COMT to 3-O- retention.
SE

duration of benefit.
• On-off effect: unpredictable swings from
relative mobility to hypotonia and bradykinesia.
• Management:
a. Increase the frequency of intake of L-dopa.
h. Use of slow release preparations.
c. Add long-acting direct dopamine agonists
e.g. bromocriptine.
d. Drug holiday for 3- 21 days.
1. Closed angle glaucoma.
2. Melanoma.
CI
Advantages of methyl dopa is the minor pathway 3- Huntington's Disease
bromocriptine over L-dopa for levodopa metabolism.
Inherited disorder characterized by
• when peripheral dopa
1. Does not need synthesizing decarboxylase activity is inhibited progressive chorea and dementia.
enzymes, more specific on D2 receptor by carbidopa, !#3-O-methyl
dopa that competes with levodopa Etiology
2.No active transport system, no
competition with amino add.
for active transport into CNS. • Loss of GABA-mediated inhibition
• Inhibition of COMT !"
3. Longer t½ so its use is associated plasma concentration of 3-O- in basal ganglia produces
with less fluctuation in response. methyl dopa !#central uptake hyperactivity in dopaminergic neurons
of L-dopa, and its concentration
1. Peptic ulcer. Treatment
2. History of myocardial infarction.
1-Reserpine

3. History of coronary artery disease. 3. Peripheral vascular diseases.

4. Severe psychosis.
1. Carbidopa + Benserazide ! potentiate its
action and reduce side effects.
DI
4. Psychiatric illness. depletes central dopamine by
Ropinirole, Pramipexole preventing intra-neuronal storage.
• Newer non-ergot derivatives 2-Haloperidol, chloropromazine

2. Vitamin B6 !#peripheral decarboxylation.

3. Non-selective MAOI ! hypertensive crisis.
• Madopar (levodopa + benserazide)
• Sinemet (levodopa + carbidopa).
Preparation
• Actions as bromocriptine. but Dopamine receptor antagonists
unlike ergot derivatives, they
3-Baclofen
don't exacerbate peripheral
vasospasm. fibrosis, nausea & GARA agonist

• Start with a small dose then gradually

increased until full therapeutic effect or side hallucinations.
effects occur.
 Migraine G3FR_48
• Severe recurrent throbbing headache affecting only one side of the head. • females are 3-fold more affected than males.
Types of migraine headache
Migraine without aura (85% of patients) Migraine with aura (15% of patients)
severe, unilateral, pulsating headache that typically lasts from 2 to 72 hours. These are aggravated the headache is preceded by neurologic symptoms which can be visual, sensory and/or
by physical activity and are accompanied by nausea, vomiting, photophobia and phono-phobia. cause speech or motor disturbances.
The biological basis of migraine headache
• Aura is caused by reduced blood flow (hypo-perfusion) in the posterior part of the cerebral hemisphere then gradually spreads forward.
• In the headache phase hyper-perfusion occurs.
• Pain may be due to extracranial and intracranial arterial dilatation with subsequent release of neuroactive substances such as substance P.
Drug therapy of acute migraine Drug used for Prophylaxis of Migraine
I-Triptans II-Ergotamine III-Analgesics I-Methysergide II-Pizotifen III-β-Blockers IV-Flunarizine V-Clonidine
Sumatriptan, Naratriptan, Rizatriptan, Dihydroergotamine is a derivative from NSAIDs Propranolol
Eletriptan & Zolmitriptan Ergotamine ! IV administration e.g. aspirin Nadolol
MOA • HT1D receptor agonist • Ergotamine is α-blocker with vasoconstrictor 5-HT2 antagonist Calcium channel
• This subtype of serotonin receptors is found effect. 5-HT1 partial agonist blocker
on small peripheral nerves that innervate the • It has similar actions to Triptans but with less
intracranial vasculature. selectivity at 5HT receptors.
• Their activation !"substance P.
USES • Acute attack of migraine headache • acute attacks of migraine (1 mg oral to 4 mg). Mild to moderate Indications
• Sumatriptan ! orally, S.C. or intranasal. • administered with caffeine as cafergot migraine • If the attack occurs two times or more per month.
(to enhances ergotamine absorption) • If the headache is complicated by serious neurologic signs.
(1 mg ergotamine + 100 mg caffeine).
SE 1. Nausea & vomiting. 1. Nausea & vomiting. • uses for long periods !
2. Paresthesia. 2. Hypertension. fibroblastic changes in the
3. Chest pain. 3. Peripheral ischemia. pleural cavity &endocardium
4. Anginal pain. • hallucinations.
CI - patients with hypertension 1. Peripheral vascular diseases.
- ischemic heart diseases. 2. Hypertension.
3 Angina.
4. Pregnancy.
5. Not given with Triptans or beta-blockers.
 Antiepileptic drugs G3FR_49
Epilepsy chronic disorder characterized by recurrent seizures due to abnormal discharge of cerebral neurons. Due to Abnormal electrical discharge from cerebral neurons due to imbalance between excitatory (Ach, glutamate, aspartate) and inhibitory (GABA) influences.
Types of epilepsy
A) Generalized seizures B) Partial (focal) seizures
1- Generalized tonic-clonic (grand mal) 2- Petit mal (Absence) 3-Epileptic myoclonus 4- Febrile convulsions 5- Status epilepticus 1- Simple partial 2- Complex partial seizures
• Begins with aura followed by loss of consciousness and tonic in children, there is brief loss of muscle contraction for short occur in young children (3 months -5 continuous fits without localized to a single Simple +Attacks of confused behavior,
spasm of all muscles followed by a clonic phase in which there is consciousness accompanied with period, myoclonus seizures occurs year) caused by high fever any period of recovery limb or muscle group with disturbance in consciousness,
powerful jerky movements of the face, body and limbs, and then mild clonic jerking of the eye lids or secondary to hypoxia, uremia or and consist of generalized tonic-clonic hallucinations of smell, taste & hearing
the patient lies in a flaccid comatose state extremities encephalitis. convulsions. with disturbance in memory.
Mechanism of action of antiepileptic drugs
1. Reduction of cell membrane permeability to Na+ e.g. phenytoin, carbamazepine, valproate & lamotrigine. 2. Block of voltage-dependent T-Calcium channels e.g. ethosuximide, valproate.
3. Modifying neurotransmitters: a. Enhancement of GABA mediated synaptic inhibition e.g. barbiturates, benzodiazepines, vigabatrin & valproate. b. Decreased excitatory amino acid function e.g. felbamate.
I- Phenytoin II- Carbamazepine III-Valproic acid IV- Ethosuximide V-Phenobarbitone VI-Acetazolamide
P/K • Oral absorption is complete. • after oral absorption !enters the brain rapidly • Well absorbed orally. • Well absorbed orally. has selective anticonvulsant activity
• About 90% bound to plasma protein. • t½ = 12-36 hours. • HME inducer ! • 90% bound to plasma proteins. • Not PPB
• hydroxylated in the liver and needs folic acid as cofactor - half-life decreases with chronic administration. • Metabolized in the liver. • 75% are metabolized
• Elimination follows saturabe kinetics. - #metabolism of other antiepileptic drugs • 25% excreted unchanged
• Fosphenytoin: prodrug of phenytoin, available for • Related to tricyclic antidepressants.
parenteral use in status epilepticus.
• # Na+ channels !"reduces the propagation of abnormal impulses in the brain potentiating the inhibitory pathway Inhibit carbonic anhydrase enzyme in
MOA • At higher concentrations, it can block voltage-dependent • # Ca++ channels !"release of neurotransmitters. (GABA) central neurons with local
++
Ca channels !"release of neurotransmitters accumulation of chloride !
• #GABA conc in synapse through: hyperpolarization & stabilization cell
- "GABA transaminase membranes.
- "GABA reuptake
uses 1.Antiepileptic: selective antiepileptic action without l. Grand mal and focal seizures. 1. broad spectrum antiepileptic: effective in 1st DOC in absence seizures - grand mal & partial epilepsy absence seizures
causing CNS depression. 2. Trigeminal neuralgia. grand mal epilepsy & partial seizures - febrile convulsion.
ST
a. 1 DOC IN grand mal and focal seizures. 3. Cerebral or nephrogenic D.I. -not 1ST DOC (sedation & hepatotoxicity)
b. Status epilepticus IV 4. Mood stabilizer. 2. Petit mal epilepsy.
2.Ventricular arrhythmia ("automaticity, excitability & 3. Febrile convulsion 4. Myoclonus.
#conduction) 5. Prophylaxis of migraine.
SE 1. anorexia nausea & vomiting. 2- nystagrmus, ataxia, diplopia & vertigo. 1. anorexia nausea & vomiting 1. anorexia nausea & vomiting 1. Sedation. nystagmus, ataxia - allergy - drowsiness. - paresthesia
3. Hypersensitivity as rash, fever, lymphadenopathy 2. Hepatotoxicity. 1. drowsiness, dizziness & 2. Megaloblastic anemia.
2. Gingival hyperplasia. 6. Liver dysfunction. 3. Hair loss. headache 3. Osteomalacia.
4. Osteomalacia with hypocalcemia occurs with chronic use 4. Hyponatremia, water toxicity. 4. Teratogenic: spina bifida 3.skin rash & urticaria. 4. Addiction.
("vit D hydroxylation & "absorption of calcium) 5. Aplastic anemia, agranulocytosis. Primidone VII-Benzodiazepines
5.Megaloblastic anemia "folate absorption & metabolism Oxacarbazepine • metabolized to Phenobarbitone 1.Diazepam
7. Hirsutism and acne due to increased androgen secretion. (active metabolite of carbamazepine) and Phenyl-ethyl-malonamide DOC for status epilepticus
8. Teratogenicity: - if taken in 1ST trimester ! • It is anticonvulsant. C.N.S. toxicities are which have longer half-lives than (rapid onset).
cleft palate and hare lip (fetal hydantoin syndrome) similar to that of carbamazepine. the parent drugs.
-if taken before labor ! Hypoprothrombinemia of the baby • No hepatic failure or BMD • Its SE as Phenobarbitone
2. Clonazepam& Lorazepam.

DI 1. Displacement of phenytoin from plasma proteins: • "metabolism of Phenobarbitone,

Phenylbutazone, oral anticoagulants & sulfonamides. phenytoin and carbamazepine.
2.#Phenytoin metabolism by: carbamazepine & • It displaces phenytoin from PPB
Phenobarbitone
4."phenytoin metabolism by chloramphenicol & valproate
3. Phenytoin increase metabolism of warfarin, steroids.
Precautions Choice of antiepileptic drugs Treatment of status epilepticus
1. Serum level monitoring is essential. Grand mal & partial seizures Petit mal epilepsy Myoclonus febrile convulsion 1. Diazepam: slow IV (1st choice). 2. phenytoin IV.
2. Oral hygiene (frequent brushing, gum massage). First choice carbamazepine & phenytoin. ethosuximide. valproate Phenobarbitone & 3. General anesthesia in highly resistant cases
3. Vit D and folate supplements Alternative valproate & Phenobarbitone. valproate, clonazepam & lamotrigine clonazepam diazepam (thiopent.al IV, intubation. muscle relaxant & artificial respiration).
VIII- Adjunct antiepileptic drugs
Vigabatrin Tiagabine Gabapentin & Pregabalin Lamotrigine Zonisamide Felbamate Topiramate Levetiracetam
+
MOA irreversible inhibition of GABA block GABA uptake - #release of GABA. - blocks Na channels Modifies the release of glutamate
transaminase - block Ca++ channels and GABA.
- enhances GABA receptor - competes with glycine Bind to GABA receptors !#opening
function at NMDA receptors. of chloride channel.
Uses Grand mal and focal seizure - generalized tonic-clonic convulsion refractory partial refractory epilepsy refractory partial seizures.
&partial seizures
- migraine and neuropathic pain
SE sedation, dizziness & behavioral change dizziness & GIT upset dizziness, headache & ataxia. kidney stones & oligohidrosis liver & B.M. toxicities diplopia, weight loss & kidney stones dizziness & sleep disturbances
 C.N.S. Stimulants G3FR_50
I- Cerebral stimulants II- Brain stem stimulants III- Spinal cord
stimulants
Nicotine Cocaine Amphetamine Methylphenidate Analeptics Strychnine
Active ingredient in tobacco Highly addictive drug, sympathomimetic Non- Potent dopamine transport • Stimulate the depressed medullary centers (RC & VMC). MOA & ACTION
catecholamine that shows inhibitor. • In toxic doses: clonic convulsions occur
P/K • highly lipid soluble. • given by chewing, intranasal neurological effects quite • Well absorbed orally. (1) Direct (2) Indirect (3) Dual • Blocks postsynaptic
• More than 90 % of nicotine inhaled in snorting, smoking or I.V. • Concentrated in brain glycine receptors
smoke is absorbed. • It is rapidly de-esterified and similar to more than plasma. A) Bemegride B) Lobeline A) Nikethamide
• Metabolized in liver and lung demethylated with urinary cocaine. • De-estrified then
leading to spinal cord
• safe & strong antidote Reflex stimulates • converted to stimulation.
• Urinary excretion. excretion. excreted in urine. in: RC nicotinamide in liver.
MOA • blocks reuptake of monoamines • increases release of stored • In toxic doses: !
(5-HT, NE, DA) ! potentiates - barbiturate toxicity USES: • rapid onset & short t1/2. - Tetanic convulsion
catecholamines - neonatal asphyxia neonatal asphyxia • USES: mild respiratory - (+) RC & VMC.
C.N.S. and peripheral actions
• It also inhibits MAO.
• It also inhibits MAO. (intra umbilical). (intra umbilical). depression
Action 1. C.N.S: 1. C.N.S: l. C.N.S: it increases alertness, B) Picrotoxin B) Carbogen Toxicity
• In low doses !#alertness, improves • Powerful stimulant of the cortex decreases fatigue, decreases
attention. and brain stem. Increasing
• Blocks action of GABA (5% CO2 + 95% O2) ! 1. Hypertonia and
• In high doses ! central respiratory awareness, feeling of well-being,
appetite & causes • Induce experimental stimulates RC direct and hyperreflexia.
paralysis, hypotension caused by euphoria, it increases motor insomnia. convulsions reflex. 2. Tetanic convulsion
medullary paralysis. activity. (obsolete now)
2. Peripheral effect: • In high concentrations: it causes C) Pentylenetetrazole C) Doxapram Treatment of
• (+) sympathetic ganglia ! adrenal tremors, convulsion followed by
medulla ! hypertension and respiratory and vasomotor toxicity
tachycardia. depression. • Used in ttt of: l. Stomach wash by
• (+) parasympathetic ganglia ! 2. Sympathetic nervous system depressed RC following tannic acid-K+
#activity of the bowel. ! tachycardia & hypertension. Used to induce anesthesia. permanganate.
• In high concentrations !block of 3. Hyperthermia: as it impairs 2. Symptoms of increased
experimental • SE: hypertension, 2. Dark quiet room.
parasympathetic ganglia ! sweating and cutaneous VD. sympathetic stimulation.
- blood pressure falls, convulsions. arrhythmia & vomiting. 3. Specific antidote:
- activity in both G.I.T. & bladder ceases Mephenesin IV.
Uses Local anesthetic during eye, • Not used due to psychological 1. ADHD.
ear and throat surgery. and physiologic dependence. 2. Narcolepsy.
• It was used in ADHD, narcolepsy
and obesity.
SE l. Irritability & tremors. 1. Hypertension & tachycardia 1. Addiction.
2. Diarrhea & intestinal cramps. 2. Convulsions. 2. C.N.S: insomnia, irritability, 1. C.N.S: insomnia &
3. Increased blood pressure & heat rate. 3. Drug dependence. dizziness, delirium, panic states & nervousness
4. Withdrawal symptoms: irritability, 4. Chronic inhalation: perforation suicidal tendencies. 2. G.I.T: nausea &
anxiety, difficulty in concentration, of nasal septum 3. C.V.S: tachycardia, arrhythmias, abdominal pain.
headache & insomnia hypertension & anginal pain.
IV- Hallucinogenic Drugs (Psycho-mimetics)
Produce profound changes in thought patterns and mood
A) Lysergic acid diethylamide (LSD) B) Tetrahydrocannabinol C) Phencyclidine
• Psychoactive alkaloid contained in marijuana Angel’s dust
which is available as dronabinol.
MOA • 5-HT agonist at presynaptic receptors at midbrain and activates • Acts on CB1 receptors as neuromodulators. • inhibits reuptake of dopamine, serotonin and
sympathetic System norepinephrine.
• In low doses produces hallucinations with brilliant colors. Mood • Blocks NMDA receptors.
alteration also occurs.
• Tolerance and physical dependence occur
Pharmacological actions & Uses Pharmacological actions
• Dronabinol is administered orally. l. Dissociative anesthesia (insensitivity to pain
• It is used as appetite stimulant in AIDS patients without loss of consciousness).
who are losing weight. 2. Analgesia.
• Also used in severe emesis caused by some cancer 3. Numbness of extremities.
chemotherapeutic agents. 4. Slurred speech.
SE 1. Hyperreflexia. 2. Nausea. 1. #heart rate & "blood pressure. 5. Hostile and bizzar behavior
3. Muscle weakness. 2. Reddening of the conjunctiva. 6. In high doses: anesthesia, stupor & coma
4. High doses: long -lasting psychotic changes in susceptible persons. 3. Toxic psychosis at high doses.