Anxiolytics & Hypnotics PDF

ANXIOLYTICS & HYPNOTICS DR SARAH TRINDER Richard Hess [email protected] en.wikipedia.org OUTLINE WHAT IS ANXIETY AND COVER CLINICALLY RECOGNISED ANXIETY DISORDERS CHEMICAL MEDIATORS INVOLVED GABA 5-HT NA THERAPEUTICS USED THAT TARGET THOSE PATHWAYS INSOMNIA & THERAPEUTICS INVOLVED ANXIETY NORMA...

ANXIOLYTICS & HYPNOTICS DR SARAH TRINDER Richard Hess [email protected] en.wikipedia.org OUTLINE WHAT IS ANXIETY AND COVER CLINICALLY RECOGNISED ANXIETY DISORDERS CHEMICAL MEDIATORS INVOLVED GABA 5-HT NA THERAPEUTICS USED THAT TARGET THOSE PATHWAYS INSOMNIA & THERAPEUTICS INVOLVED ANXIETY NORMAL FEAR RESPONSE TO THREATENING STIMULI AUTONOMIC REFLEXES (RELEASE OF NA/A, ↑HR) ↑AROUSAL & ALERTNESS, DEFENSIVE BEHAVIOURS CORTICOSTEROID SECRETION NEGATIVE EMOTIONS PATHOLOGY – FEAR RESPONSE OCCURS IN ANTICIPATION, INDEPENDENT OF EXTERNAL EVENTS, TO THE POINT THAT SYMPTOMS INTERFERE WITH NORMAL PRODUCTIVE ACTIVITIES http://www.50symptomsgone.com/?p=4772 CLINICALLY RECOGNISED ANXIETY DISORDERS GENERALISED ANXIETY DISORDER (GAD) – LIFETIME PREVALENCE 4-7%, ♀ ˃ ♂ ‘THE PATIENT MUST HAVE EXCESSIVE AND DIFFICULT TO CONTROL ANXIETY ABOUT SEVERAL DIFFERENT EVENTS OR ACTIVITIES’ – DSM-IV WORRY, IRRITABILITY, INSOMNIA, MUSCLE TENSION + ANTICIPATING FUTURE HARM PLANNING/PREDICTING – PREFRONTAL CORTEX BASIC FEAR CIRCUIT – AMYGDALA GABA DYSFUNCTION CLINICALLY RECOGNISED ANXIETY DISORDERS POST TRAUMATIC STRESS DISORDER (PTSD) ANXIETY TRIGGERED BY RECALL OF PAST STRESSFUL EXPERIENCES RE-EXPERIENCE THE TRAUMA, HYPER-AROUSAL ↓ HIPPOCAMPUS ACTIVITY PANIC DISORDER - ♀ ˃ ♂ SUDDEN ATTACKS OF OVERWHELMING FEAR WITH SOMATIC SYMPTOMS SWEATING, TACHYCARDIA, HYPERVENTILATION CONDITIONED FEAR ‘FIGHT OR FLIGHT’ RESPONSE – AMYGDALA FEAR CONDITIONING – HIPPOCAMPUS OVERSENSITIVE TO 5-HT, NA & CORTISOL Roger et al. Nature Reviews Neuroscience 13, 769-787 CLINICALLY RECOGNISED ANXIETY DISORDERS OBSESSIVE COMPULSIVE DISORDER (OCD) – 1.2% UK, 50% CASES = SEVERE, ♀ = ♂ * OBSESSIONS – CONTINUALLY PREOCCUPIES MIND, ↑ ANXIETY COMPULSIONS – REPETITIVE BEHAVIOUR/RITUALS – ATTEMPT TO ↓ ANXIETY DECISION MAKING - CORTEX & BASAL GANGLIA PHOBIAS SPECIFIC/SIMPLE RELATES TO ONE THING COMPLEX PHOBIAS SOCIAL PHOBIA/ANXIETY – SPECIFIC SITUATION (PUBLIC SPEAKING) OR GENERAL SOCIALISING AGORAPHOBIA – SITUATIONS/PLACES * From OCD-UK BENZODIAZEPINES GABA ↓ GABAA FUNCTION IN BRAINS OF GAD PATIENTS THEORY GABAA DOWNREGULATED Glu GABA GABAergic neuron Inhibition Glu Glutaminase GlnT Gln BENZODIAZEPINES (BDZ) Glu GAD GAT1 GABA GABAergic neuron GABA BDZ α2 γ2 α2 β2 Clα2 β2 α2 γ2 β2 Cl- Cl Clβ2 GABA Cl γ2 α2 Cl- Cl - β2 ClCl- ClCl- β2 GABA + BDZ α2 α2 BDZ & GABAA Cl γ2 BDZ BINDS AT THE INTERFACE OF γ2 AND α1, α2, α3, OR α5 Anxiolytic Anti-convulsant Hypnotic Addictive Muscle relaxant Amnesia ClCl- ClCl- α2 α3 α4 GABA + BDZ α5 x x x x β2 β2 GABAA IS A PENTAMER – α1-6, β1-3, γ1-3 α1 Cl- Cl - x x x α6 α2 BENZODIAZEPINES (BDZ) α2 Cl TREAT ACUTE ANXIETY ↓ANXIETY & AGGRESSION γ2 Cl- Cl - β2 ClCl- ClCl- β2 ↓MUSCLE TONE HYPNOTIC ANTEROGRADE AMNESIA T1/2 VARIES 2-40H, MANY METABOLISED TO ACTIVE METABOLITES SIDE EFFECTS DROWSINESS CONFUSION & AMNESIA SUPRA-ADDITIVE EFFECTS WITH ALCOHOL (CV & RESPIRATORY DEPRESSION) GABA + BDZ α2 α2 BENZODIAZEPINES Cl γ2 Cl- Cl - β2 ClCl- ClCl- β2 OVERDOSE PROLONGED SLEEP IN COMBINATION CNS DEPRESSANTS (ALCOHOL) – POTENTIALLY LIFE THREATENING ‘ANTIDOTE’ FOR BENZODIAZEPINES TOLERANCE & DEPENDENCE TOLERANCE – DOSE ESCALATION TO PRODUCE REQUIRED EFFECT DEPENDENCE – ABRUPT WITHDRAWAL = ↑ANXIETY, TREMOR, INSOMNIA ABUSE MULTI-DRUG ABUSE GABA + BDZ α2 MODULATING 5HT OR NA IN ANXIETY 5-HT IMPLICATED IN ANXIETY, PANIC DISORDERS ETC. 5-HT CELL BODIES IN RAPHE NUCLEI PROJECT TO AREAS IMPLICATED IN ANXIETY: HIPPOCAMPUS, AMYGDALA & PREFRONTAL CORTEX ROLE OF 5-HT COMPLEX 5-HT HYPOFUNCTION ASSOCIATED WITH ENVIRONMENTAL HYPERSENSITIVITY ↓[5-HT] IN CSF OF GAD PATIENTS From Rang and Dale’s Pharmacology 5-HT Gi/o 5-HT1A THERAPIES SSRI INHIBITS 5-HT REUPTAKE BUSPIRONE Trp 5-HT1A PARTIAL AGONIST TH 5-HTP 5-HT D2 ANTAGONIST metabolites MAO 5-HT neuron Gi/o 5-HT1B/D SERT MECHANISM OF ACTION - SSRI 5-HT1A 5-HT1A 5-HT1A 5-HT1B/D 5-HT1B/D 5-HT 5-HT1B/D 5-HT1B/D 5-HT 5-HT 5-HT1B/D Health Anxiety SSRI Normalise postsynaptic Rs Desensitise/downregulate pre-synaptic Rs MECHANISM OF ACTION - BUSPIRONE 5-HT1A 5-HT1A 5-HT1A 5-HT1B/D 5-HT1B/D 5-HT 5-HT1B/D 5-HT1B/D 5-HT 5-HT 5-HT1B/D Health Anxiety Buspirone Normalise postsynaptic Rs Desensitise/downregulate pre-synaptic Rs ANXIOLYTICS – 5-HT PATHWAYS SSRI – EFFECTIVE IN GAD, PHOBIAS & PTSD LOWER SIDE EFFECT PROFILE THAN TCA OR MAOI SLOW ONSET, COMBINE WITH BDZ INITIALLY? BUSPIRONE – ONLY EFFECTIVE IN GAD BETTER SIDE EFFECT PROFILE THAN BZD DIZZINESS, NAUSEA, HEADACHE SLOW ONSET NORADRENALINE (NA) LOCUS COERULEUS-NA PATHWAY PHYSIOLOGICAL RESPONSE TO STRESS/PANIC TREMOR, PALPITATIONS, SWEATING VERY STRESS SENSITIVE & CAN BE CONDITIONED TO FEARFUL STIMULI β-ADRENOCEPTOR ANTAGONISTS (PROPRANOLOL) EFFECTIVE IN TREATING PHYSIOLOGICAL SYMPTOMS INSOMNIA INSOMNIA DIFFICULTY FALLING ASLEEP & STAYING ASLEEP TRANSIENT – SHIFT WORK, JET LAG SHORT TERM – ILLNESS, EMOTIONAL UPSET CHRONIC – UNDERLYING CAUSE? ANXIETY, DEPRESSION, PAIN, DRUG ABUSE Richard Hess SEDATIVE - ↓ACTIVITY, MODERATES EXCITEMENT & CALMS* HYPNOTIC – PRODUCES DROWSINESS, FACILITATES ONSET & MAINTENANCE OF STATE OF SLEEP THAT RESEMBLES NATURAL SLEEP* *Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 2011 SLEEP PSYCHOLOGICAL IMPORTANCE RAPID EYE MOVEMENT (REM) SLEEP DREAMING, LOW MUSCLE TONE LACK = IRRITABILITY & ANXIETY SLOW-WAVE SLEEP DEEPEST LEVEL OF SLEEP ↓METABOLIC RATE & CORTISOL, ↑GROWTH HORMONE MOST HYPNOTICS ↓ REM SLEEP BENZODIAZEPINES ↓ ONSET OF SLEEP ↑DURATION OF SLEEP IF GETTING