Psychopharmacology
General Principles
Ayan Nayak
General plan of the session
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Pharmacokinetics: Basics principles
Pharmacodynamics: Basic principles
Basic neuroanatomy: new developments
Basic neurochemistry
Illustrative selected pathways
Drug interactions and contraindications
Special cases: Pregnancy, breast feeding, liver and
renal failures
• Questions
Drugs responsible for depression
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Steroids, steroidal contraceptives
Anticholinesterases
Alcohol
Β blockers, Ca channel blockers
Cimetidine
Antiretrovirals
T4
Interferons (panic and anxiety)
Champix®
Pharmacokinetics
• What the body does to the drug
• Routes of administration: enteral (oral, rectal and SL)and
parenteral (IM, IV, intrathecal, peritoneal, inhalation, skin).
Advantages and disadvantages.
• Different routes =/≠ Different actions
• Bioavailability = the fraction of an administered dose of
unchanged drug that reaches the systemic circulation, one of
the principal pharmacokinetic properties of drugs. Depends on
absorption, distribution and elimination.
• Distribution: Free in blood, bound in blood(antidepressants),
BBB crossing → target tissue and other tissue.
• Volume of distribution,Vd=Q/CP
Metabolism
• Chemical transformation by the body: reducing lipid solubility
and altering biological activity. Eg: Diazepam→Oxazepam.
• By hepatomicrosomal and nonmicrosomal enzyme systems
and two phases: phase I and phase II
• Phase 1: Oxdn, redn, hydrolysis →may or may not be active
but shorter T1/2
• Phase 2: Combining with endogenous molecules, usually
glucoronides→ ↑H2O soluble.
• Now, if MW 300+ then through bile or otherwise → blood→
kidneys.
• Also in plasma, lung, kidney and skin.
P450 Induction or Inhibition
Inducers
• Carbamazepine
• Phenytoin
• Burbiturates
• Chronic EtOH
• Cigarette smoking
• Others such as Rifampicin,
griseofulvin
Inhibitors
• Ranitidine
• Ciprofloxacin
• Erythromycin
• Valproate
• Fluoxetine, paroxetin
• TCAs
• Antipsychotics
P450 subtypes
• 2D6: Conventional antipsychotics, TCAs,Fluoxetine,
Paroxetine
• 3A4: TCAs,BZD, Carbamazepine, Ca2+ Ch blockers
• 1A2: TCAs, HPL, Cloz
• 2C9: Phenytoin, warfarine, fluoxetine
Implications: Racial variation & drug interaction and changes to
Vd
Age
Sex
Definitions
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T1/2 & Tmax
Cmax
AUC
1st order kinetics
Zero order kinetics
Steady state (enteric coated, longer T1/2)
Loading doses
Therapeutic index
Elemination
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Excretion by kidneys most important
Li+: most important; What is the effect of Na+
Urinary pH: important for burbiturates
Age
Renal impairment
Also through bile or through skin
Pharmacodynamics
What drug does to the body
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NTs
Receptors
Gene exression
Agonists
Antagonists
Partial agonists
Efficacy
Potency
• Tolerance
• Sensitisation
• Ideosyncratic reaction
Neurotransmitter Types
Inhibitory
• Adr
• NA
• DA
• Serotonin
• Histamine
• Ach
• GABA
Excitatory
• Glutamate
Neurotransmitters or
neuromodulators
Amines
• Ach
• Da
• NA
• Adr
• 5HT
Disorder
Alzheimers
F20, Parkinsonism, substance misuse
Anx, depr, cognition, F20,HT, substance misuse
HT
Depr, anx,panic, hallu, OCD,Alzh,
migraine,eating disorders
Arousal, cognition
• H
• Melatonin Sleep disorders
Neurotransmitters or
neuromodulators
Amino acids
• Glutamate
• GABA
Disorder
Neurodegeneration (? →F20)
Anx, Huntington’s, epilepsy, pain
Other (Lipid NT)
• Anandamide Pain, F20, Eating disorders
Neurotransmitters or
neuromodulators
Peptides
• Enkephalin
• Endorphin
• Substance P/ tachykinins
• Vassopressin
• CCK
• Neurotensin
• TRH
• Neuropeptide Y
Disorder
Pain, mood
Pain, mood
Huntington, depr
Cognition, HT
Pain, anxiety
Pain, anxiety
Arousal, MND
Eating disorders, BP
Pain, F20, Eating disorders
Cotransmitter pairs
Cotransmission is the release of several types of
neurotransmitters from a single nerve terminal
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DA •
DA •
NA •
NA •
5HT •
5HT •
Ach •
Ach •
GABA
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Enkephalin
CCK
Enkephalin
Neurotensin
Enkephalin
Substance P
LHRH
Vasoactive intestinal peptide
Somatostatin
Receptors Types
• Presynaptic : 5HT2A R blocks dopamine
release
• Postsynaptic
• Autoreceptors: presynaptic α2
Receptors Types
• G protein linked (most common)
• Ion channel linked (ligand gated or voltage
gated). Voltage gated VSSC, VSCC
• Nuclear hormone receptors
• Receptor tyrosine kinases (NGFs)
Implications
• Initiation
• How fast
• Duration (related to other factors such as gene
expression)
How action happens: signal
tranduction
1st messenger , NT
↓
2nd messenger (Ca2+ or cAMP/cGMP or other)
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3rd messenger kinase or phosphatase
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4th, 5th or more-th messengers
↓
activation or inactivation of phosphoprotein kinases
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Biological response
Gene Expression
Activation of phosphoprotein kinase
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Activation of transcription factors
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Activation RNA polymerase
↓
Coding begins
Synaptic transporters
• These are transmembrane proteins facilitating
intercellular transfer of NTs (from synapse to
cytoplasm)
• Different transporters for different NTs
• Many different types have been identified
• NET, SERT, DAT etc
• Energy intensive
Gene Expression
• Early and late gene products
• So early gene products act as an nth messenger
system for a late gene product
• This is how most commonly used psychotropics work
• For hormones there is intracellular proteins which act
analogous to a membrane receptor
• For NGFs many different types of messenger systems
have been identified
• Concept of endophenotypes: ? Easier measurements
Ion channels
• Ligand gated
• Voltage gated (Voltage Sensitive SC,VSCC):
Ca ch blockers in HT
• Difference and clinical implication
• Examples: glutamate (AMPA and NMDA
receptors), GABA
R upregulation and downregulation
• Classical view ie., action of agonist and
antagonist. Well evidenced. By numbers.
• A different way: more common in
psychopharmacology by gene expression
• Microneuroanatomical change is visible. Plus
synaptic flexibility → like the end stage of a
river (draw) and appearence of interneuronal
scaffolding
Vesicular transporters
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Cytoplasm → cytoplasmic vesicles
Energy intensive
Needs Na+ and Cl- ions
Nonspecific
Example: antidepressanats, cocaine, ADHD Rx,
Amphetamines
Agonist, (silent) antagonist and
inverse agonist
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See picture
Intrinsic activity
Allosteric modulation
Constitutive activity → Draw sketch
Partial agonist: buprenorphine, aripiprazole
Clinical implications
Antagonism: Term used differently in clinical
practice
• Potency and efficacy
Antagonism
• Competitive (parallel shift to right)
• Non-competitive (less height, not parallel)
Different site
• Uncompetitive: need agonist binding → then
like non-competitive
• See sketch
Key definitions
• Abuse/misuse: culturally, politically disapproved
• Addiction: Compulsive abuse
• Dependance: neuroadaptation to chronic use necessiating
repeated administration to prevent withdrawal
• Reinforcement: The tendency of a pleasure producing drug to
lead to reapated self administration
• Tolerance: Same dose less intrinsic effect or more dose same
intrinsic effect
• Cross tolerance and cross dependance: Ability of one drug to
suppress withdrawal symptoms due to dependent state caused
by another drug
Key definitions
• Withdrawal: Abrupt cessation of a dependence
producing drug in a dependant individual
leading to psychological and physiological
reactions
• Relapse: Upon discontinuation of an effective
medical treatment restitution of the original
condition
• Rebound: Exeggarated recurrance of the
original condition upon stopping treatent
Tolerance
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Increased metabolism
Reduced receptor sensitivity or number
Behavioural tolerance to learn to cope
Sensitisation: One intrinsic effect facilitates a
greater occurence of the same intrinsic effect
through a synapse. Amphetamines, pain sx.
Hepatic insufficiency
Antipsychotics
Antidepressants
• Amisulpride and sulpiride
• Haloperidol
• Lower dose clozapine or
olanzapine, risperidone
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• Avoid aripiprazole,
quetiapine
Citalopram
Lower dose sertraline
Lower dose venlafaxine
Riboxetine
Lithium
Lorazepam, oxazepam
• Avoid TCAs, MAO
inhibitors, valproate
Renal impairment
Antipsychotics
Antidepressants
• Haloperidol
• Olanzapine
• Quetiapine
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• Avoid sulpiride, amisulpride
Citalopram
Sertraline
Valproate
lamotrigine
lorazepam
Pregnancy
Antipsychotic
• Quetiapine is relatively safe
and is used for BPAD also
• Avoid mood stabilisers
completely
Antidepressant
• Sertraline
• Nortriptylline
• Amitriptylline
Breast feeding
Antipsychotics
• Quetiapine
Antidepressant
• Sertraline
• Peroxetine
• Nortriptylline
• Lamotrigine with caution