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