Prof Graeme Henderson Department of Pharmacology C32 Medical Sciences Building Anticholinergics Opioids Benzodiazepines and related agents Issues multiple agents and me too drugs receptor selectivity natural products and synthetic agents pharmacokinetics

Anticholinergic drugs/cholinergic antagonists Muscarinic antagonists (not nicotinic antagonists) Muscarinic receptor subtypes M1 – CNS M2 – heart M3 – smooth muscle and secretory glands M4 & M5 Most current drugs are not selective e.g. atropine pirenzepine M1/M3 benztropine M1 (less peripheral side effects)

Muscarinic antagonists Tertiary amines (CNS penetrant) atropine, scopolamine, benztropine, procyclidine Quaternary amines (not CNS penetrant) propantheline, ipratropium, dicyclomine (low absorption into blood stream after oral administration – use in GI spasticity disorders)

Use of muscarinic antagonists Smooth muscle relaxation (GI disorders - IBS) bronchodilation (exercise induced asthma, obstructive pulmonary disease) decrease secretions in surgery Parkinsons disease

Drugs exhibiting anticholinergic side effects tricyclic antidepressants (less with SSRIs) antipsychotics antihistamines (sedating) dopaminergics (e.g. amantidine)

Side effects of anticholinergics Constipation Transient bradycardia followed by tachycardia and increased BP Palpitations and arrythmias Decreased bronchial secretions Dry mouth and thirst Blurred vision, pupilary dilation, loss of accommodation Urinary urgency and retention Photophobia Confusion (elderly) Nausea and vomitting Giddiness

Opioid analgesics Receptors ORL1 (MOR)(DOR)(KOR)(NOR) euphoriadysphoria Partial agonist at receptor – buprenorphine Mixed agonist and antagonist – agonist and antagonist (pentazocine)

Major therapeutic effects Analgesia Sedation Euphoria Antitussive Constipation Unwanted effects Euphoria Constipation Nausea and vomitting Respiratory depression Decreased gastric acid secretion Histamine release (itch) Raised intracranial pressure hypotension Other effects Miosis – pin point pupils (no tolerance)

Contentious issues in pain therapy Is the patient receiving adequate pain relief? choice of drug, dose of drug Does tolerance occur? Does psychological dependence occur (craving)? Does physical dependence occur? Is respiration depressed?

Individual agents (>20 listed in BNF) Powerful agonists Morphine Heroin Fentanyl Tramadol Partial agonist Buprenorphine (bell shaped response curve) Weak agonists Codeine Pethidine Pentazocine Dextropopoxyphene Anti diarrhoeal Diphenoxylate (low CNS penetration) Antitussive Dextromethorphan Treatment of opioid dependence Methadone (orally active, long t 1/2 ) Antagonist Naloxone (short t 1/2 ) Naltrexone

Antianxiety, sedative and hypnotic agents BenzodiazepinesBZ receptor agonists Zopiclone/zolpidemBZ receptor agonists Buspirone5HT 1A receptor agonist

Role of pharmacokinetics in choice of drug Hypnotic Short t 1/2 - temazepam, nitrazepam, zopiclone Antianxiety Long t 1/2 - chlordiazepoxide, lorazepam, diazepam

Benzodiazepines Clinical Uses anti anxiety sedative hypnotic anticonvulsant muscle relaxant Side effects drowsiness confusion amnesia impaired motor coordination lack of depth perception reduced REM sleep

Benzodiazepines Tolerance greater to anxiolytic and anticonvulsant actions than to hypnotic actions Physical dependence withdrawal induces anxiety dizziness tremor sleep disturbances No Psychological dependence

Buspirone long t 1/2 Side effects (less than with benzodiazepines) nausea dizziness headache restlessness No reports of tolerance and physical dependence