Pharmacology Lectures Summary

• Anxiolytic agent: A medication that reduces anxiety.
• Hypnotic drugs: Intended to induce sedation and promote sleep.
• Severe, chronic, debilitating anxiety may be treated with anti-anxiety drugs. Many also cause sedation, so they can be used as both anxiolytic and hypnotic.

• Benzodiazepines
• Barbiturates
• Zaleplon, Zolpidem, Eszopiclone (Z-drugs)
• Melatonin receptor agonists
• Antihistamines
• Antidepressants (used off-label for sleep)
• Suvorexant

• Widely used anxiolytic drugs, generally safer and more effective than barbiturates.
• Mechanism of Action: Modulate GABA (gamma-aminobutyric acid, major inhibitory NT in CNS) effects by binding to a specific site on the GABA-A receptor. This increases the frequency of chloride channel openings produced by GABA, leading to hyperpolarization and decreased neurotransmission.
• Relatively safe: Lethal dose is over 1000-fold greater than therapeutic dose.

Comparison of Durations of Action:

• Long-acting (1-3 days): Clorazepate, Chlordiazepoxide, Diazepam, Flurazepam.
• Intermediate-acting (10-20 hours): Alprazolam, Estazolam, Lorazepam, Temazepam.
• Short-acting (3-8 hours): Oxazepam, Triazolam.

• Derivatives of barbituric acid.
• Mechanism of Action:
  • Direct stimulation of GABA receptors (GABA-like action).
  • Enhance the effect of GABA by decreasing GABA uptake or increasing GABA release.
  • Non-selective, leading to generalized CNS depression at large doses.

Classification by Duration:

• Ultra-short acting (15-30 min): Thiobarbitone, Hexobarbitone (used for anesthesia).
• Short acting (2-4 hrs): Pentobarbitone, Secobarbitone.
• Intermediate acting (4-6 hrs): Amobarbitone.
• Long acting (6-8 hrs): Barbitone, Phenobarbitone (used for epilepsy).

Effects:

• CNS effects: More CNS depressant than benzodiazepines. Sedation (small dose), Hypnosis (large dose), more decrease in REM sleep (leading to hangover). Inhibit VMC & RC (decrease sensitivity to CO2). Generalized CNS depression in toxic doses.
• CVS effects: Large doses cause hypotension due to direct myocardial depression, inhibition of VMC, and direct vasodilation.
• Respiratory effects: Respiratory depression by effect on respiratory center.
• Hepatic effect: Microsomal enzyme induction, leading to increased metabolism of other drugs and barbiturates themselves (tolerance).
• Hematological effects: Porphyria in susceptible individuals.

Uses:

• Anxiety and stress (less safe than benzodiazepines).
• Insomnia (short-acting).
• Convulsions & epilepsy (grand mal): Phenobarbitone.
• Anesthesia and pre-anesthetic medication (IV thiobarbitone).
• Treatment of neonatal hyperbilirubinemia and kernicterus (Phenobarbitone stimulates hepatic glucuronyl transferase enzyme).

Side Effects:

• Hypersensitivity.
• Hangover: Drowsiness, dysphoria, depression (with long-acting).
• Physical dependence (treated by gradual withdrawal).
• Paradoxical excitement (idiosyncrasy).
• Drug interactions due to liver enzyme induction.

Acute Barbiturate Toxicity:

• Manifestations: Hypothermia, hypotension, circulatory failure, absence of reflexes, respiratory depression, coma.
• Treatment: Stomach wash, alkalinization of urine, dialysis, ensure patent airway, respiratory support, cardiac stimulants.

• A CNS disorder due to hyper-excitable neurons (epileptic focus) leading to abnormal behavior, loss of consciousness, and/or convulsions.

• Generalized tonic-clonic seizures (grand mal epilepsy)
• Absence seizures (petit mal epilepsy)
• Myoclonic seizures
• Partial seizures
• Status epilepticus: Severe sustained seizures which may be fatal.

• Use minimal number of anti-epileptic drugs to avoid drug interactions.
• Treatment should be continued for 2-3 years after the last seizure.
• Anti-epileptic drugs should be gradually withdrawn to avoid status epilepticus.

• Block of Na+-channels: Phenytoin, Carbamazepine, Valproic acid.
• Block of voltage-gated Ca2+-channels (T-type): Ethosuximide, Valproic acid.
• Blocking receptors of excitatory transmitters (glutamate and aspartate): Felbamate.
• Potentiation of inhibitory action of GABA: Benzodiazepines, Barbiturates, Valproic acid, Vigabatrin.

• Mechanism of action: Na+-channel blocker (membrane stabilization).
• Uses: Grand mal epilepsy, partial seizures, status epilepticus (may be used). Not effective in petit mal epilepsy and may worsen it. Also used for ventricular arrhythmias and trigeminal neuralgia.
• Adverse effects: Gingival hyperplasia (especially in children, irreversible), teratogenic (fetal hydantoin syndrome: cleft lip/palate, cardiac septal defect), cerebello-vestibular dysfunction (vertigo, ataxia, nystagmus, diplopia), hirsutism, inhibits ADH and insulin release.
• Drug interactions: HME inducer (induces its own metabolism and other drugs), displaces thyroxine and TCAs from plasma proteins.

• Mechanism of action: Na+-channel blocker.
• Uses: Grand mal and partial seizures. Not in petit mal epilepsy. Also used for trigeminal neuralgia and central diabetes insipidus.
• Adverse effects: Hypersensitivity, cerebello-vestibular dysfunction, fluid retention and dilutional hyponatremia, teratogenic.
• Drug interactions: HME induction.

• Mechanism of action: Inhibits GABA transaminase (increases GABA levels), blocks Na+-channels, blocks voltage-gated Ca2+-channels (T-type).
• Uses: Treatment of all types of epilepsy (broad-spectrum anti-epileptic).
• Adverse effects: Teratogenicity (spina bifida), cholestatic jaundice (hepatotoxicity), bone marrow depression.
• Drug interactions: HME inhibitor (decreases metabolism of phenytoin), displaces phenytoin from plasma proteins.

• Mechanism of action: Blocks voltage-gated Ca2+-channels (T-type).
• Uses: Drug of choice in absence seizures (petit mal epilepsy).
• Adverse effects: GIT upset, allergy, drowsiness, mood changes, blood dyscrasias.

• Drugs affecting mood, psychology (behavior, thoughts, emotional state), and CNS activity.
• Tranquillizers (Psycholeptics):
  • Minor tranquillizers = Anxiolytics = Antianxiety drugs (e.g., Benzodiazepines, Zolpidem, Buspirone).
  • Major tranquillizers = Neuroleptics = Antipsychotics (used for psychotic disorders like schizophrenia).
• Antidepressants (Psychanaleptics): Elevate mood in depression (e.g., TCAs, MAO-Inhibitors, SSRIs).
• Psychotomimetics = Hallucinogenics = Psychedelics: (e.g., LSD).
• Psychomotor stimulants = Psychostimulants: Induce euphoria, wakefulness, alertness (e.g., Caffeine, Cocaine, Amphetamine).

• Used in treatment of psychotic disorders like schizophrenia.
• Psychosis: Disorder in thoughts, behavior, and emotions. Characterized by:
  • Positive signs: Hallucinations (auditory), delusions (fixed false belief).
  • Negative signs: Emotional dullness, dementia, social withdrawal.
• May be due to increased activity of dopamine-stimulating D2-receptors and/or serotonin-stimulating 5-HT2-receptors in the limbic system.

• 5 subtypes:
  • D1 and D5: Coupled to Gs, increase cAMP synthesis.
  • D2, D3, D4: Coupled to Gi, inhibit adenyl cyclase, decrease cAMP, increase K+ efflux, decrease Ca2+ influx.

Site and Effects of Dopamine Agonists vs. Antagonists:

• Limbic system: Agonists cause euphoria, anxiety, psychosis. Antagonists cause anti-psychotic action.
• CTZ (Chemoreceptor Trigger Zone): Agonists cause nausea/vomiting. Antagonists cause anti-emetic action (except motion sickness).
• Basal ganglia: Agonists cause anti-Parkinsonism. Antagonists induce iatrogenic Parkinsonism/extrapyramidal manifestations.
• Hypothalamus: Agonists inhibit prolactin, increase heat, reduce appetite. Antagonists cause hyperprolactinemia, hypothermia, increased appetite/weight gain.

• Typical Antipsychotics:
  • Non-selective D2-antagonists.
  • Used as anti-psychotic and anti-emetic (except motion sickness).
  • May lead to Parkinsonism (extrapyramidal manifestations) and hyperprolactinemia.
  • Examples:
    • Phenothiazines (Chlorpromazine, Thioridazine, Trifluperazine).
    • Butyrophenones (Haloperidol, Droperidol).
    • Thioxanthenes (Thiothixene).
• Atypical Antipsychotics:
  • Cause less extrapyramidal manifestations.
  • More effective in refractory cases of schizophrenia.
  • Improve negative signs of schizophrenia.
  • Examples:
    • Pimozide and Sulpiride: Block D2 selectively in the limbic system.
    • Clozapine: Blocks D4 and 5-HT2. High incidence of agranulocytosis (1-2% of patients).
    • Risperidone: Blocks equally D2 and 5-HT2.
    • Olanzepine: Blocks 5-HT2 more than D2.

• Pharmacokinetics: Absorbed orally, passes BBB and placental barrier (may cause teratogenicity), metabolized by liver, excreted in urine.
• Mechanism of action: Mainly blocks D2-receptors in the limbic system (anti-psychotic action).
• Pharmacological actions (due to blocking various receptors):
  • CNS: Anti-psychotic, anti-emetic (except motion sickness), Parkinsonism, hyperprolactinemia, hypothermia, increased appetite/weight gain, may cause seizures in epileptics, potentiates CNS depressants.
  • CVS: Tachycardia (reflex, atropine-like, ganglion blocking), negative inotropic action, vasodilation (alpha1-blocking, ganglion blocking, VMC inhibition), postural hypotension.
  • Receptor blocking: Potent D2, alpha1, 5-HT2 blocker; weak M, H1, N blocker.
  • Endocrine: Increases prolactin, decreases ACTH, FSH, LH.
  • Other: Na+-channel blocker (membrane stabilization, local anesthetic, quinidine-like), inhibits neuronal uptake of noradrenaline.
• Therapeutic uses: Schizophrenia (improves positive signs), anti-emetic (not for motion sickness or pregnancy), intractable hiccough, pre-anesthetic medication, hypothermic agent, anti-pruritic.
• Adverse effects: Allergic reactions (dermatitis, photosensitivity, blood dyscrasias, cholestatic jaundice), Parkinsonism/extrapyramidal manifestations (akathisia, acute dystonia, tremors - prevented by antimuscarinics), Tardive dyskinesia (abnormal involuntary movements on prolonged use, no specific treatment but lithium may prevent), seizures, teratogenicity, hyperprolactinemia, increased appetite/weight gain, atropine-like effects, postural hypotension, Neuroleptic Malignant Syndrome (idiosyncratic, similar to malignant hyperthermia, treated by cooling and IV dantrolene), delayed ejaculation.
• Contraindications: Allergy, liver diseases, Parkinsonism, epilepsy, pregnancy, glaucoma, enlarged prostate, hypotension, idiosyncrasy.
• Drug interactions: Potentiates sedatives, analgesics, anticholinergics, vasodilators, muscle relaxants. Hypotensive action not treated by adrenaline (adrenaline reversal). Antagonizes guanethidine.

• Drugs that relieve pain without loss of consciousness.
• Classification: Opioid analgesics, Non-opioid analgesics (NSAIDs), Drugs for specific pain (e.g., Carbamazepine for trigeminal pain, Ergotamine for migraine).

• Bind to CNS opioid receptors whose natural ligands are endorphins and encephalins.

Receptor Stimulation:

• Mu (μ) receptor: Physical dependence, euphoria, analgesia (supraspinal), respiratory depression.
• Kappa (κ) receptor: Sedation, analgesia (spinal), miosis.
• Delta (δ) receptor: Analgesia (spinal & supraspinal), release of growth hormone.
• Sigma (σ) receptor: Dysphoria (opposite of euphoria), hallucination (visual & auditory), respiratory and vasomotor stimulation, mydriasis.

• Natural:
  • Phenanthrene group (Spasmogenic, Potent CNS action, Analgesics): Morphine, Codeine, Thebaine.
  • Benzylisoquinoline group (Spasmolytics, Negligible CNS action, Non-analgesics): Papaverine, Noscapine, Narceine.
• Semisynthetic: Heroin, Hydromorphone.
• Synthetic:
  • Agonists: Meperidine family, Methadone family, Tramadol.
  • Mixed agonist-antagonists: Nalorphine, Nalbuphine, Pentazocine, Butorphanol, Buprenorphine.
  • Antagonists: Naloxone, Naltrexone.

• Source: Natural plant alkaloid from poppy seeds.
• Pharmacokinetics:
  • Absorption: Well absorbed orally but low oral bioavailability (25%) due to extensive first-pass hepatic metabolism. Commonly given by injection (SC, IM, slow IV).
  • Distribution: Passes BBB, passes placental barrier (leads to fetal addiction if given during pregnancy, neonatal asphyxia if given during labor).
  • Metabolism: By conjugation (mainly).
  • Excretion: Mainly in urine.
• Pharmacodynamics (Actions):
  • CNS effects: Analgesia (all types of pain except itching), euphoria, sedation, respiratory depression (dose-dependent, main cause of death in acute toxicity), cough center suppression, miosis (pin-point pupil is diagnostic sign of acute toxicity), nausea/vomiting (due to CTZ stimulation, initial effect), increased intracranial tension (due to CO2 retention from respiratory depression causing cerebral vasodilation).
  • CVS effects: Orthostatic hypotension (due to vagal stimulation, histamine release, VMC depression), bradycardia.
  • GIT effects: Spasm of Oddi's sphincter (increased biliary pressure), decreased GIT motility (constipation).
  • Urinary: Detrusor muscle tone (urinary retention).
  • Uterus: Prolongs labor (inhibits uterine contractions).
  • Allergic reactions: Due to histamine release (itching).
• Tolerance & Dependence:
  • Tolerance: Develops after 10-14 days of continuous administration. Due to inhibition of endogenous opioid peptides or down-regulation of opiate receptors.
  • Physical and psychic dependence (addiction).
• Therapeutic Uses:
  • Analgesia (severe pain, not itching).
  • Acute pulmonary edema (venodilation, decreased preload).
  • Anesthesia (pre-anesthetic medication).
• Adverse Effects: Nausea/vomiting, constipation, urinary retention, bronchospasm, fetal addiction/neonatal asphyxia, bradycardia/hypotension, drowsiness/dysphoria, itching, tolerance/addiction.
• Acute Morphine Toxicity:
  • Manifestations: Respiratory failure (central), hypotension/bradycardia, pin-point pupil (diagnostic).
  • Treatment: Gastric lavage, artificial respiration, specific antidote (Naloxone IV).
• Contraindications: Head injury (increased intracranial pressure), hypothyroidism, respiratory disease (asthma, COPD), pregnancy/labor, liver/kidney impairment, extremes of age, acute abdominal pain.
• Treatment of Morphine Addiction: Gradual withdrawal, substitution (Methadone), Clonidine (for withdrawal symptoms), Naltrexone (for detoxification).

Codeine:

• Methyl ether of morphine (natural, semisynthetic).
• Similar to morphine but less potent (1/12 from morphine).
• More effective cough suppressant.
• Uses: Central antitussive, mild pain.
• Side effects: Less than morphine, constipation, dryness of mucosa, depression of RC (high doses).

Meperidine (Pethidine):

• Synthetic opioid.
• Higher bioavailability than morphine (50%).
• Less respiratory depression than morphine.
• Not antitussive.
• May cause excitation and convulsions (especially with MAO inhibitors).
• Uses: Analgesia (deep visceral pain, MI, cancer, post-operative), obstetric analgesia (less RC depression), pre-anesthetic.
• Preferred to morphine in obstetric analgesia (less RC depression and less constipation).

Methadone:

• Synthetic opioid.
• Similar to morphine but more effective orally and has longer duration of action (t1/2 = 24 hr).
• Less severe withdrawal symptoms.
• Uses: Analgesia, suppress withdrawal manifestations of opioids (e.g., heroin).

Tramadol:

• Weak agonist on mu-opioid receptor + weak inhibition of NA reuptake.
• Uses: Analgesic in postoperative pain.
• Side effects: Less than most opioids, no significant RC depression.

• Naloxone:
  • Competitively blocks all opioid receptors.
  • Effect: Reverses all opioid effects dramatically within 1-2 min and lasts for 1-4 hrs.
  • Uses: Antidote for acute opioid toxicity, given during labor to mothers who received opioids (to minimize neonatal respiratory depression).
• Naltrexone:
  • Similar action to Naloxone but more potent and longer duration of action.
  • Drug of choice in treatment of heroin toxicity & other opioid addicts.

• Nalorphine:
  • Agonist on kappa-receptors and antagonist on mu-receptors.
  • Agonist effect causes analgesia and respiratory depression, but less than morphine.
  • Does not cause cardiac adverse effects.
  • Used as analgesic in severe pain (alternative to morphine).
  • Antagonist effect is used in acute morphine toxicity (reverses respiratory depressant effect).
• Nalbuphine & Buprenorphine: Similar to Nalorphine except analgesic and respiratory depression properties are equal to morphine.
• Pentazocine: Less analgesic effect than morphine, higher doses do not cause proportional increase in respiratory depression, has spasmogenic effect but less than morphine.
• Butorphanol: Similar to Pentazocine, no withdrawal symptoms if given to addict patients.

• NSAIDs (e.g., Aspirin).
• Para-aminophenol derivatives (e.g., Acetaminophen/Paracetamol).
• Glafenine, Nefopam, Dipyrone (Novalgin).

• Source: Active metabolite of phenacetin.
• Kinetics: Well absorbed orally, rapid distribution, passes BBB and placental barrier (not teratogenic), metabolized by liver (mainly conjugation), excreted in urine.
• Action and effects: Weak inhibitor of COX, COX2 & COX3. Has analgesic and antipyretic actions without anti-inflammatory action. No CVS, GIT, respiratory, or platelet effects (Aspirin affects them).
• Uses: Analgesic & antipyretic alternative to aspirin if aspirin is contraindicated or no need for anti-inflammatory effect.
• Side effects & toxicity: Hypersensitivity, CNS (dizziness), GIT (less than NSAIDs). Hepatotoxicity (severe, centrilobular hepatic necrosis) in toxic doses (15 gm in adults, 4 gm in children). Treated by stomach wash, activated charcoal, N-acetyl cysteine (replenishes hepatic glutathione).

• Reduce inflammation and relieve pain, especially related to arthritis, tendinitis, nerve injury, mild to moderate cancer pain.
• Mechanism of Action: Inhibit prostaglandin synthesis by inhibiting COX enzymes (COX-1, COX-2).

Classification:

• Non-selective COX inhibitors: Salicylic acid derivatives (Aspirin), Acetic acid derivatives (Indomethacin), Propionic acid derivatives (Ibuprofen), Fenamic acid derivatives, Oxicams, Pyrazolon derivatives, Diclofenac.
• Selective COX-2 inhibitors: Celecoxib, Rofecoxib, Valdecoxib. Less GIT side effects but higher risk of cardiovascular stroke and cardiotoxicity.
• Selective COX-3 inhibitors: Paracetamol.

Aspirin (Acetylsalicylic Acid - ASA)

• Source: Salicylic acid derivative.
• Kinetics: Well absorbed orally, passes BBB and placental barrier (teratogenic), highly bound to plasma proteins, metabolized by liver, excreted in urine. Elimination follows "zero order kinetics" with large doses.
• Mechanism of action: Irreversible inhibition of COX enzymes (both COX-1 and COX-2).
• Pharmacological actions:
  • Local: Antiseptic-fungistatic, counter-irritant.
  • Systemic: Analgesic, antipyretic (by inhibiting heat regulating center), anti-inflammatory (by inhibiting PG synthesis), action on respiration and acid-base balance (respiratory alkalosis, metabolic acidosis in large doses), CVS (no effect on normal doses, large doses cause VD and hypotension), Blood (antiplatelet by COX-1 inhibition), Uric acid (uricosuric action at large doses), GIT (irritation, ulcers), Kidney (decreased RBF), Metabolic (hyperglycemia, increased AAs catabolism), Endocrine (increased ACTH, cortisone), Liver (hepatotoxicity, Reye's syndrome in children).
• Therapeutic uses: Analgesic (headache, toothache, arthralgia), antipyretic (in fever), anti-inflammatory (RA, OA), prophylaxis of thromboembolism (pediatric aspirin), chronic gout (uricosuric), pre-eclampsia. Contraindicated in children with fever due to Reye's syndrome risk.
• Adverse effects: Hypersensitivity, bronchospasm, GIT disturbances (nausea, vomiting, bleeding, ulcers), bleeding disorders, teratogenicity, Reye's syndrome, salicylism (tinnitus, dizziness, blurred vision).
• Acute Salicylate Toxicity:
  • Manifestations: Convulsions, hypotension, hemorrhage, hyperglycemia, hyperventilation, respiratory alkalosis then metabolic acidosis.
  • Treatment: Gastric lavage, artificial respiration, sodium bicarbonate (correct acidosis), Vitamin K (for hypoprothrombinemia), IV fluids, urinary excretion (alkalinization), hemodialysis.
• Drug interactions: Antacids decrease absorption, NaHCO3 increases renal excretion. Displaces digitoxin, warfarin, TCAs from plasma proteins. HME inducers increase metabolism. Antagonizes sulphonamides, beta-blockers, ACE inhibitors.

• Reversible short-term loss of sensations in a certain part of the body without loss of consciousness or alteration of patient awareness.

• Effective (reversible and rapid action)
• Non-irritant
• Non-allergic
• Non-toxic
• Sterile (Pyrogen free)
• Not expensive

• According to Chemistry (weak base):
  • PABA Esters: Cocaine, Procaine, Tetracaine.
  • Amides: Lidocaine, Mepivacaine.
• According to Nature (Source):
  • Natural: Cocaine.
  • Synthetic: All other drugs.
• According to Method of Use:
  • Topical Only: Cocaine.
  • Injection Only: Procaine.
  • Topical & Injection: All other drugs.

• Routes of Administration:
  • Topical: Applied to mucous membrane (e.g., 10% lidocaine spray - fast onset/short duration; 5% lidocaine gel - slower onset/longer duration).
  • Infiltration anesthesia: Drug deposited near terminal nerve fibers.
  • Regional (Nerve block) anesthesia: Drug deposited near a nerve trunk.
• Distribution: Pass BBB & Placental barrier (may cause fetal bradycardia - all are contraindicated in pregnancy except Lidocaine).
• Metabolism:
  • Esters: Metabolized by plasma Pseudo-Choline esterase.
  • Amides: Metabolized by Hepatic microsomal enzymes.
• Excretion: In urine. Acidification of urine increases renal excretion.

• Block voltage-dependent Na+ channels, preventing Na+ influx and inhibiting nerve action potential propagation (nerve membrane stabilization).
• Reduces release of Acetylcholine (ganglion and neuromuscular blocker).
• Activity increases with intracellular pH (more acidic) and extracellular pH (more alkaline).
• Activity decreases with increased Ca2+ and increases with increased K+.
• Addition of Adrenaline: Causes vasoconstriction, decreases LA absorption, reduces systemic spread, increases duration and decreases toxicity and bleeding. (Contraindicated in fingers, toes, penis due to gangrene risk).

• On nerves: Inhibits impulse generation and propagation.
  • Sequence of anesthesia: Smaller fibers before larger; demyelinated before myelinated. Sympathetic & Pain > Temperature > Touch & Pressure > Motor fibers.
  • Recovery: Reverse direction.
• CNS actions: Stimulate CNS (restlessness, tremor). In toxic doses: convulsions, respiratory depression, coma, death. Cocaine is the most powerful stimulant.
• CVS actions: Myocardial depressant (decrease heart rate, myocardial contraction). Tend to reduce blood pressure (except cocaine raises BP).
• Smooth muscle: Spasmolytic effect (except cocaine).

• Surface, Infiltration, and Nerve block anesthesia.
• Spinal anesthesia.
• Systemic use in treatment of cardiac arrhythmias (Lidocaine).

A. Systemic Complications:

• LA toxicity: Due to increased LA level in blood (large dose, slow elimination, injection into blood vessel).
  • Mild toxicity: Irritability, slurred speech, sweating, nausea, vomiting, tinnitus, dizziness, visual disturbance.
  • Severe toxicity: Convulsions, hypotension, bradycardia, respiratory depression/failure, coma, death.
• Allergy: Especially PABA Esters. Ranges from mild to anaphylactic shock. Adrenaline (IM) is lifesaving for anaphylactic shock. Cross-allergy within the same group.

B. Local Complications:

• Syncope, infection, pain, soft tissue injury.
• LA and infections: Activity reduced in oral infections due to inflammatory cytokines antagonizing LA, vasodilation increasing LA removal, and acidic extracellular pH antagonizing LA action.

• Tachycardia, hypertension, angina, diabetes, thyrotoxicosis.

• With Adrenaline in LA:
  • With digitalis: Cardiac arrhythmias.
  • With beta-blockers (Propranolol): Severe hypertension.
• With LA:
  • PABA Esters: Antagonize antibacterial effect of Sulphonamides.
  • HME inducers (smoking, rifampicin): Decrease activity of amides LA.
  • HME inhibitors (ciprofloxacin, cimetidine, propranolol): Increase activity of amides LA.