Psychopharmacology
description
Transcript of Psychopharmacology
Psychopharmacology
General PrinciplesAyan Nayak
General plan of the session
• 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
• 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
• T1/2 & Tmax
• Cmax
• AUC• 1st order kinetics• Zero order kinetics• Steady state (enteric coated, longer T1/2)• Loading doses• Therapeutic index
Elemination
• 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
• 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
• H• Melatonin
DisorderAlzheimersF20, Parkinsonism, substance misuseAnx, depr, cognition, F20,HT, substance misuseHTDepr, anx,panic, hallu, OCD,Alzh,
migraine,eating disorders Arousal, cognitionSleep disorders
Neurotransmitters or neuromodulators
Amino acids• Glutamate• GABA
Other (Lipid NT)• Anandamide
DisorderNeurodegeneration (? →F20) Anx, Huntington’s, epilepsy, pain
Pain, F20, Eating disorders
Neurotransmitters or neuromodulators
Peptides• Enkephalin• Endorphin• Substance P/ tachykinins• Vassopressin• CCK• Neurotensin• TRH• Neuropeptide Y
DisorderPain, moodPain, moodHuntington, deprCognition, HTPain, anxietyPain, anxietyArousal, MNDEating disorders, BP Pain, F20, Eating disorders
Cotransmitter pairsCotransmission is the release of several types of neurotransmitters from a
single nerve terminal
• DA• DA• NA• NA• 5HT• 5HT• Ach• Ach• GABA
• 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) ↓ 3rd messenger kinase or phosphatase ↓ 4th, 5th or more-th messengers ↓activation or inactivation of phosphoprotein kinases↓ Biological response
Gene Expression
Activation of phosphoprotein kinase ↓
Activation of transcription factors ↓
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
• Cytoplasm → cytoplasmic vesicles• Energy intensive• Needs Na+ and Cl- ions• Nonspecific
Example: antidepressanats, cocaine, ADHD Rx, Amphetamines
Agonist, (silent) antagonist and inverse agonist
• 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
• 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 insufficiencyAntipsychotics
• Amisulpride and sulpiride• Haloperidol• Lower dose clozapine or
olanzapine, risperidone
• Avoid aripiprazole, quetiapine
Antidepressants
• Citalopram• Lower dose sertraline• Lower dose venlafaxine• Riboxetine• Lithium• Lorazepam, oxazepam
• Avoid TCAs, MAO inhibitors, valproate
Renal impairmentAntipsychotics
• Haloperidol• Olanzapine• Quetiapine
• Avoid sulpiride, amisulpride
Antidepressants
• 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