Pharmacology - BDZ Flashcards
GABA
- main inhibitory neurotransmitter in CNS
- acts at 2 different receptor subtypes GABAa and GABAb
- Receptors - 5 subunits 2x alpha, beta, gamma, delta
GABAa
- Receptor is Ligand gated cl ion channel
- post synaptic ( not exclusively,) but widely disturbed throughout CNS
- 5 subunits arranged to form a central ion channel - GABA binds to and activates GABAa receptors increasing frequency of opening causing hyperpolarisation of neuronal membrane.
- CI ion conductance in potentiated by binding of BDZ to alpha subunit of activated complex.
GABAb
- Receptor is metabotropic ( acts via G proteins and 2nd messengers)
- when stimulated increases K conductance causing hyperpolarization
- Receptors are located
presynaptically - nerve terminals
post synaptically brain + spinal cord
Baclofen acts via GABAb to reduce spasticiity
Benzodiazepines
Uses
- sedation
- premedication
- anxiolytics
- hypnotics
- anticonvulsants
Benzodiazepines
Structure
At is core - BDZs have 2 rings
First is a benzene ring
Second diazepine ring ( has seven members - 5 carbon and 2 Nitrogen)
Also on ring one - benzene ring - has a halogen and another benzene ring
Ring 2 diazepine ring - carbonyl at postion 2
Midazolam
Presentation/ pH
water soluble imidazobenzodiazepine
presented as clear colourless solution of midazlolam hydrochloride 1/2/5 mg/ml. PH 3.5 - unique amongst BDZs as structure is dependent on surrounding pH.
At pH 3.5 diazepine ring is open resulting in an ionised molecule. Which is water soluble.
When surrounding pH is greater than 4 its diazpine ring structure closes so that it is no longer ionised and becomes lipid soluble. Its pKa is 6.5 so that at physiological PH 89% is present in an unionized form.
As is water soluble does not cause pain on injection.
Midazolam
effects
effects
CNS - hypnosis, sedation, anterograde amnesia. Cerebral o2 consumption and flow are decreased in a dose dependent manner.
CVS systolic BP decreases by 5%, decrease in SVR, increases in HR.
Resp - decrease in TV, offset by increase in RR( thus MV minimally changed) Impairs ventilatory response to hypercapnia.
Midazolam
ADME
Absorption - 40% PO, IM 80-100% Distribution -95% PB, short duration of action due to distribution. VD 1.0 l/kg Metabolism -virtually all metabolised in liver -metabolized by hydroxylation to active compound 1-alpha hydroxymidazolam which is conjugated with glucuronic acid prior to renal excretion. ( same enzyme CYP3A4 as alfentanil) Less than 5% is metabolised to oxepam
Diazepam
Doses
tablets 2/5/10mg a syrup 0.4mg/1mg/ml suppositories
clearwhite oil in water emulsion for inaction - 5mg/ml
doses
10-20mg, IV, 2-60mg PO
Diazepam
Effects
CNS -anxiolytic, decreases aggression, sedation, hypnosis, anterograde amnesia
CVS - transient decrease in BP slight decrease in CO, coronary flow is increased secondary to coronary artery vasodilatation
RESP - large doses cause respiratory depression
Diazpam
ADME
Absorption
- highly lipid soluble, well PO absorbed PO bioavailability - 86-100%
Distrubition
-95 PB to albumin, small VD
Metbolism
- metabolised in theliver by oxidation to desmethyl diazepam, oxepam and diazepam.
Does not induce enzymes
Excretion
Glucuronide derivatives are excreted in the urine.
Lorazepam
Hydroxybezodiazepine
1/2.5mg tablets, clear colourless solution for injection containing 4mg/ml (1-4mg per day)
metabolite are inactive
first line therapy for status
well absorbed PO and IM
highly plasma protein bound and conjugated with glucuronic acid producing metabolites.
Temazepam
Night time sedative Anxiolytic medication No uniques features within the BDZ family 75% PB, small VD, well absorbed from the GUT 80% is excreted unchanged in the urine, while glucurinidation occurs the liver. Only a very small amount is demthylated to oxazepam. Half life is 8 hours. Can have hang over effects
Diazapam
Kinetics
PB % -95 EL half life hours -20-45 VD l/kg 1-1.5 active metabolites yes CL ml/kg/min 0.2-0.5
Midazolam
Kinetics
PB % -95 EL half life hours -1-4 VD l/kg 1-1.5 active metabolites yes CL ml/kg/min 6-10
