PharmacologyCNS Flashcards
Some NT of CNS
Norepinephrine Epinephrine Dopamine Acetylcholine Serotonin Gamma amino butyric acid (GABA) Glutamate
Rank type of drugs from central sedative to central stimulative
- general anesthetics
- hypnotics
- sedatives* ,neuroleptics
- anxiolytics*
- antiepileptics/anticonvulsants
- antidepressives*
- Analeptics*
- psychoactives
What are less common CNS drugs
With medical indication 症状:
- central muscle relaxants, opiates and central α2-agonists
- Drugs against Parkinson
Without med. Indication
e.g. LSD, cannabinoids, (but med. indication CB-antagonists
Drugs with CNS side effect but are non-CNS drugs
antihistaminics, local anesthetics, antiarrhythmics, antihypertensive drugs
Pre-condition for central action
- passage BBB (lipophil, active transport)
- interaction with central structures like
- receptors (pre-, postsynaptic)
- transporter
- enzymes (e.g. delayed degradation of neurotransmitters)
- ion channels (Na+, K+, Ca++)
Type of NT and its % in CNS synapse
gamma amino butyric acid 30-40% (inhibitory)
glutamate 30-40% (excitatory)
acetylcholine ca. 10
dopamine ca. 1%
norepinephrine ca. 1%
serotonin (5-hydroxytryptamine= 5-HT) ca. 1%
CNS drugs are difficult because
- main effects and side effects are hard to differentiate
- BBB limits the drugs to be lipid soluble agents or drugs by specific transport systems
Understanding the effects of drugs on individual neurons
does not predict the effect on the whole organ
Projection of 5HT
everywhere
Projection of DA
mostly frontal lobe
Projection of Ach
everywhere except cerebellum
Projection of NA
everywhere
Benzodiazepines
main CNS drugs
BZD mess with…
GABA!
BDZ receptor linked to GABA-A receptor complex (bound to Cl channels).
GABA: an inhibitory neurotransmitter
BDZ increase the affinity of the receptor for GABA, and thus increase Cl- conductance and hyperpolarizing current
Therefore, BDZ are indirect GABA-agonists
Therapeutic use of BZD
Sedative-hypnotic Anxiolytic Muscle relaxants Anticonvulsants Alcohol withdrawal Premenstrual syndrome Psychoses (only supportive) Adjunct in mania of bipolar disorder
Patterns of use of BZD
45% of Use <30 days 80% of Use <4 months 15% of Use >12 months (7-18% Europe) Women, twice the rate as men <40% of Anxiety Diagnosis Treated >40% of Panic Disorder Treated
Sedative/Hypnotic effect of BZD
- Transient - lowest effective dose- time-limited
- Insignificant decrease in sleep latency-1 hour
- increase in sleep duration
- ? effect on sleep architecture ( REM, stages 3 and 4)
- Rebound insomnia - worsening of sleep - worse than before trying benzos.
- Daytime drowsiness, dizziness, lightheadedness
Anxiety effect of BZD
- benzos good for immediate symptom relief-faster than SSRI’s for panic.
- long-acting, low potency preferred (clonazepam or chlordiazepoxide)
- best used for exacerbations of anxiety-short term vs continuous use
Adverse Effects of BZD
-Sedation, CNS Depression worse if combined with EtOH -Behavioural Disinhibition irritability, excitement, aggression (<1%), rage -Psychomotor & Cognitive Impairment coordination, attention (driving) poor visual-spatial ability (not aware of it) ataxia, confusion -Overdose: Rare fatalities if BZD alone - Severe CNS & Respiratory Depression if combined with: alcohol barbiturates narcotics tricyclic antidepressants
Pharmacokinetics of BZD
Lipid-soluble:
fast cross blood-brain-barrier: rapid onset of action.
Persist longer in high fat-to-lean body mass (obese and elderly )
Abuse liability (Valium)
Biotransformation & Half-Life:
Hepatic oxidation: long-t1/2, active metabolites
Glucuronidation: short-t1/2, no active metab.
absorbtion distribution, metabolism and excretionof BZD
Well absorbed,
peak plasma concentrations approx. 1 hour
Several pharmacologically active intermediates
IG: Interactions of BZD with other drugs
- CNS Depressants
- p450 2C9 (TCAs, warfarin, phenytoin)
- p450 3A4 (triazolam, midazolam, alprazolam, CBZ, quinidine, terfenadine, erythromycin)
- Disulfiram & Cimetidine increaseBZD levels
Other sedative-hypnotics than BZD
-Barbiturates - pentobarbital,phenobarbital,
secobarbital, butalbital (Fiorinal)
-Barb-like: glutethimide, chloral hydrate, ethhchlorvynol (Placidyl), meprobamate (carisoprodol/Soma)
-Azapirone: buspirone (2-10 mg TID - max 60 mg/d)
-slow onset of action (1-3 wks)
-not abused, no withdrawal
-effective for anxiety disorders-not for acute
-does not block benzo withdrawal
-not sedating, anticonvulsant or mm relaxing
-no resp dep/ cognitive/psychomotor impair
IG: Non-Benzo Hypnotics
- Zolpidem (Ambien) imadozopyridine
- Zaleplon (Sonata) pyrazolopyrimidine
- Bind to specifically to BZ-1 sites
- Both rapid onset (1h-2.5 h) - short action/1/2 life
- Decrease sleep latency, increase REM sleep
- 5-20 mg dose range
- Safe in older adults, metab in liver, no active metabolites
- Potentiate ETOH impairment
- Both reinforcing, potentially abusable, and performance-impairing
Parkinson disease
a degenerative disorder of the CNS caused by death of neurons that produce the brain neurotransmitter dopamine @substantia nigra. It is the most common degenerative disease of the nerves
Parkinson’s disease is a disorder of the extrapyramidal system associated with disruption of neurotransmissions within the striatum; A disruption of neurotransmission within the striatum (proper function requires balance between dopamine and acetylcholine
Dyskinesias of Parkinson’s disease are
Tremor at rest Rigidity Postural instability Bradykinesia (slow movement) Akinesia (complete absence of movement)
Therapeutic goal of PD
- Improve Activity of Daily Living’s
- Restore balance between DA and ACH by activating DA receptors or blocking ACH receptors
- Drug selection and dosages are determined by activities of daily living performance
Classification of Drug Therapy for Parkinson’s Disease
Dopaminergic agents
- Promote activation of dopamine receptors
- Levodopa (Dopar)
Anticholinergic agents
- Prevent activation of cholinergic receptors
- Benztropine (Cogentin)
Mechanism of action for PD drugs
Dopaminergic Agents: Promotion of dopamine synthesis Prevention of dopamine degradation Promotion of dopamine release Direct activation of dopamine receptors (D2)
Anticholinergic Agents:
Blockade of muscarinic cholinergic receptors in the striatum
Drug Therapy for Parkinson’s Disease
May take a while for effect to show Levodopa Carbidopa Amantadine Bromocritine Pergolide Selegiline Benztropine
Epilepsy
Group of disorders characterized by excessive neuron stimulation within the central nervous system
Seizure types/epilepsy
Generalized seizures:
Convulsive (tonic-clonic)/Grand Mal
Nonconvulsive (absence)/Petite Mal
Partial (focal)Seizures:
Simple partial
Complex partial
Antiepilectic Drugs
Suppress neuronal discharge at the seizure’s focus and brain
Mechanism of action
-Suppression of sodium influx
-Suppression of calcium influx
Therapeutic Considerations for epilepsy
Treatment goal Diagnosis Drug Selection Plasma drug levels Compliance 服薬順守 Withdrawal
IG: Phenytoin
-Drug for Partial and tonic-clonic seizures
-Mechanism of action-selective inhibition of sodium channels
-Varied oral absorption
-Half-life 8-60 hours
-Adverse effects:
Nystagmus
Sedation
Ataxia
Diplopia
Cognitive Impairment
-Drug interactions:
Decreases effect of oral contraceptives, warfarin, glucocorticoids
Increases levels of diazepam,isoniazid,cimetidine,alcohol, valproic acid
IG: Phenobarbital
-Drug for Partial and generalized tonic-clonic seizures
-Promotes sleep and sedation
-Adverse Effects:
Physical dependence/porphyria
Nystagmus/Ataxia
CNS Depression
IG: Carbamazepine
-Drug for Partial and tonic-clonic seizures, Bipolar disorders, Trigeminal Neuralgias
-Adverse Effects:
CNS symptoms-nystagmus, ataxia
Anemia,leukopenia, thrombocytopenia
IG: Valproic Acid
-Uses: Absence seizures Other seizures Migraine -Adverse Effects: Hepatoxicity Teratogenic effects -potential use: neuroprotective, e.g. better rehabilitation after ischemic stroke (decreased excitation – more reserves?)
Migraine headaches
Migraine Headaches
-Inflammation and dilation of intracranial blood vessels
Types: With aura (classic migraine) Without aura (common migraine)
Drugs for Migraine headaches
To abort ongoing attack
- To eliminate headache pain
- Suppress nausea and vomiting
To prevent attacks
-Prophylaxis
To abort an attack
- Aspirin-like analgesics
- Opioid analgesics
- Ergot alkaloids: α-agonist vasoconstructive
- Serotonin agonists (Sumatriptan)
IG: Drugs for prophylaxis for Migraine headaches
予防薬 Beta blockers (atenolol) Calcium channel blockers (verapimil) Tricyclic antidepressant (amitryptyline)
Opioid (Narcotic) Analgesics
Opiod:
Drug similar to morphine
Derived from opium
Analgesic鎮痛剤:
Relieves pain without loss of consciousness
Opioid Receptors
Mu- Pure opioid agonists: activation cause analgesia, respiratory depression, euphoria, and sedation
Kappa: activation cause analgesia and sedation
Delta: activation does not interact with opioid
Increased activation of K+ channel causes
hyperpolarisation, excitation decrease
Decreased activation of v-gated Ca2+ channel causes
less ca influx leading to less NT release
endogenous opioids and their receptor preference
Endorphins: mu and delta
Dynorphins: delta over mu and kappa
Enkephalins: kappa over mu and delta
Nociceptin: ORL-1
Morphine
Used for relief of moderate and severe pain
Decreases sensation of pain
Decreases the emotional reaction to pain
Adverse effects of morphine
Respiratory depression Constipation Orthostatic 起立性のhypotension Urinary Retention Cough suppression Emesis嘔吐
What is tolerance
- Increasing doses to obtain same response
- Develops with analgesia, euphoria, sedation, respiratory depression
- Cross-tolerance to other opioid agonists
What is physical dependence
-Abstinence syndrome occurs if drug abruptly stopped
-Abstinence syndrome is dependent on:
Half life of drug
Degree of physical dependence
Opioid Overdose leads to
Classic Triad:
Coma
Respiratory depression
Pinpoint pupils
Can be treated by Ventilatory support and/or Opioid antagonist
What is Pain
- Unpleasant sensory and emotional experience associated with tissue damage
- Patient’s pain description is the cornerstone of pain assessment
What are the types of pain?
Nociceptive pain:
Results from injury to tissues
Called somatic or visceral pain
Neuropathic pain:
Results from injury to peripheral nerves
Responds poorly to opioids
Clinical Approach to Pain Management
A- Ask and assess B- Believe C- Choose D- Deliver E- Empower and enable
Assessment parameters of pain
Onset and temporal patterns Location Quality Intensity Modulating Factors Previous treatment Impact
WHO Analgesic Ladder
Step 1- Mild to moderate pain Nonopiod analgesic Step 2- More severe pain Add opioid analgesic Step 3- Severe pain Substitute opioid-morphine
Classes of Antidepressants
amines: amitriptyline imipramine doxepin clomipramine trimipramin desipramine
atypical: maprotiline (Ludiomil) trazodone (Desyrel) bupropion (Wellbutrin) venlafaxine (Effexor) nefazodone (Serzone) mirtazapine (Remeron)
Classes of Antidepressants (drug types)
SSRI/SNRI, MAOIs, psychostimulants
IG: SSRI
Antidepressants Specific serotonin reuptake inhibitors: fluoxetine (Prozac) sertraline (Zoloft) paroxetine (Paxil) fluvoxamine (Luvox) citalopram (Celexa)
IG: MAOIs
Antidepressants Monoamine oxidase inhibitors: phenelzine (Nardil) isocarboxazid (Marplan) tranylcypromine (Parnate) selegiline (Deprenyl)
IG: Psychostimulants
Antidepressants methylphenidate (Ritalin) dextro-amphetamine (Dexedrine) dex + amphetamine (Adderall) methamphetamine (Desoxyn) modafinil (Provigil)
The decision to treat a patient with antidepressants should be based on the following
- Severity of symptoms and ability to identify target symptoms
- Impairment of functioning
- Patient’s view of medication
- Not necessarily the specific diagnosis
Predictors of antidepressant response
- Acute onset
- Severe depressive symptoms
- Positive previous response to medication
- Patient’s willingness to accept medication as an aid to successful treatment
How to start antidepressants?
- Start low to assess tolerance of side effects
- Increase dosage rapidly as tolerated
- Maintain typical dose for at least 4 to 8 weeks
Most common reasons antidepressants fail
Dosage too low
Duration of trial to short
Poor compliance
Intolerable side effects
What is an adequate trial for antidepressants
Adequate dose:
5 mg/kg/d
Nortriptyline 100 to 150/d (therapeutic window)
Fluoxetine 20 mg/d
Adequate duration:
4 – 8 weeks
Indications for serum levels
Unequivocally useful for:
Patients who are not responding to usual doses
Patients who are at increased risk for toxicity, e.g. cardiac patients
May be useful for:
Patients where prompt response is critical
Determining compliance and metabolic availability
IG: Therapeutic Blood Levelsfor antidepressants
Known:
imipramine
desipramine
nortriptyline
Possibly known:
amitriptyline
Under assessment:
All other antidepressants
How Antidepressants Work
Most of the important clinical actions of antidepressant drugs cannot be fully accounted for on the basis of “synaptic pharmacology”.
There are two important observations that contribute to this rationale
Many drugs require long term administration to be effective;
Drugs of abuse require repeated administration to produce tolerance and physical dependence;
Clinical effects would appear to result from the slow onset adaptive changes that occur within neurons, not within the synapse. That is, activation of intraneuronal messenger pathway and regulation of neural gene expression play a central role. (drug-induced neural plasticity).
“Synaptic Pharmacology”of antidepressants
Acute:
Block reuptake or degradation of monoamines and post-synaptic alpha-1 receptor.
Chronic:
Down regulation of the post-synaptic receptors
Alteration of second messenger systems
Alteration of protein synthesis.
Pharmacokinetics of Antidepressants
Absorption is rapid Metabolism: extensive 1st pass Oxidation, hydroxylation, demethylation 5% = “slow acetylators” Protein bound: 90 – 95%
Cardiac Side-effectsof tricyclic antidepressants
Cardiac conduction delay
Anti-arrhythmic at therapeutic doses
Arrhythmigenic at toxic doses
Minimal effects on cardiac output
Monitoring EKG parameters:
QTc = 450 msec
PR = 210 msec
QRS - >30% above baseline
How to choose an antidepressant
Choose by side effects, not efficacy
The SSRIs, secondary amines, and atypical antidepressants, are generally better choices considering side effects
Norepinephrine uptake blockadePossible clinical consequences
Tremors and Tachycardia
Serotonin reuptake blockadePossible clinical consequences
Gastrointestinal disturbances
Anxiety (dose – dependent)
Sexual dysfunction
Dopaminergic uptake blockadePossible clinical consequences
Psychomotor activation
Antiparkinsonian effects
Psychoses
Increased attention/concentration
Histamine H1 blockadePossible clinical consequences
Sedation, drowsiness
Weight gain
hypotension
Muscarinic receptor blockadepossible clinical consequences
Blurred vision Dry mouth Sinus tachycardia Constipation Urinary retention Memory dysfunction
alpha – 1 receptor blockadepossible clinical consequences
Postural hypotension
Reflex tachycardia
Dizziness
Within the unclear CSN… depression, anxiety and schizo
Depression: noradrenaline (norepinephrine) and 5- HT
Anxiety: gammaamino butyric acid (GABA)
SCZ: hyperactivity in dopaminergic pathways???
chemical mediators within the brain can
- produce slow and long-lasting effects
- act rather diffusely, at a considerable distance from their site of release;
- can produce diverse effects, for example on transmitter synthesis and on the expression of neurotransmitter receptors, in addition to affecting the ionic conductance of the postsynaptic cells
A good example for “neuromodulator” dilemma
nitric oxide (NO) and arachidonic acid metabolites, which are not stored and released like conventional neurotransmitters and may come from non-neuronal cells as well as neurons
In general, neuromodulation relates to
synaptic plasticity, including short- term events, such as the regulation of presynaptic transmitter release or postsynaptic excitability, and longer-term events such as neuronal gene regulation
Neuromodulator vs neurotrophic factors
Neurotrophic factors act over even longer timescales to regulate the growth and morphology of neurons, as well as their functional properties
neuromodulators aka
neuromediators
Neuroactive drugs act on
four types of target protein, namely ion channels, receptors, enzymes and transport proteins
Current drugs are often designed for?
Of the four main receptor types — ionotropic receptors. Gproteincoupled receptors, kinase-linked receptors and nuclear receptors—current drugs target mainly the first two.
Complexity of drug action in CNS
Wiring diagram: glia cells
Secondary effects: can be counteracting and takes time to see the response of drugs
