Psychopharmacology

1. Psychopharmacology General Principles AyanNayak

2. 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

3. Drugs responsible for depression • Steroids, steroidal contraceptives • Anticholinesterases • Alcohol • Β blockers, Ca channel blockers • Cimetidine • Antiretrovirals • T4 • Interferons (panic and anxiety) • Champix®

4. 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

5. 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.

6. P450 Induction or Inhibition Inducers Inhibitors Ranitidine Ciprofloxacin Erythromycin Valproate Fluoxetine, paroxetin TCAs Antipsychotics • Carbamazepine • Phenytoin • Burbiturates • Chronic EtOH • Cigarette smoking • Others such as Rifampicin, griseofulvin

7. 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

8. Definitions • T1/2 & Tmax • Cmax • AUC • 1st order kinetics • Zero order kinetics • Steady state (enteric coated, longer T1/2) • Loading doses • Therapeutic index

9. 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

10. PharmacodynamicsWhat drug does to the body • NTs • Receptors • Gene exression • Agonists • Antagonists • Partial agonists • Efficacy • Potency • Tolerance • Sensitisation • Ideosyncratic reaction

11. Neurotransmitter Types Inhibitory Excitatory Glutamate • Adr • NA • DA • Serotonin • Histamine • Ach • GABA

12. Neurotransmitters or neuromodulators Amines 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 Sleep disorders • Ach • Da • NA • Adr • 5HT • H • Melatonin

13. Neurotransmitters or neuromodulators Amino acids Disorder Neurodegeneration (? →F20) Anx, Huntington’s, epilepsy, pain Pain, F20, Eating disorders • Glutamate • GABA Other (Lipid NT) • Anandamide

14. Neurotransmitters or neuromodulators Peptides Disorder Pain, mood Pain, mood Huntington, depr Cognition, HT Pain, anxiety Pain, anxiety Arousal, MND Eating disorders, BP Pain, F20, Eating disorders • Enkephalin • Endorphin • Substance P/ tachykinins • Vassopressin • CCK • Neurotensin • TRH • Neuropeptide Y

15. 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

16. Receptors Types • Presynaptic : 5HT2A R blocks dopamine release • Postsynaptic • Autoreceptors: presynaptic α2

17. 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)

18. Implications • Initiation • How fast • Duration (related to other factors such as gene expression)

19. 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 phosphoproteinkinases ↓ Biological response

20. Gene Expression Activation of phosphoprotein kinase ↓ Activation of transcription factors ↓ Activation RNA polymerase ↓ Coding begins

21. 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

22. 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

23. 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

24. 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

25. Vesicular transporters • Cytoplasm → cytoplasmic vesicles • Energy intensive • Needs Na+ and Cl- ions • Nonspecific Example: antidepressanats, cocaine, ADHD Rx, Amphetamines

26. 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

27. Antagonism • Competitive (parallel shift to right) • Non-competitive (less height, not parallel) Different site • Uncompetitive: need agonist binding → then like non-competitive • See sketch

28. 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

29. 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: Exeggaratedrecurrance of the original condition upon stopping treatent

30. 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.

31. Hepatic insufficiency Antipsychotics Antidepressants Citalopram Lower dose sertraline Lower dose venlafaxine Riboxetine Lithium Lorazepam, oxazepam Avoid TCAs, MAO inhibitors, valproate • Amisulpride and sulpiride • Haloperidol • Lower dose clozapine or olanzapine, risperidone • Avoid aripiprazole, quetiapine

32. Renal impairment Antipsychotics Antidepressants Citalopram Sertraline Valproate lamotrigine lorazepam • Haloperidol • Olanzapine • Quetiapine • Avoid sulpiride, amisulpride

33. Pregnancy Antipsychotic Antidepressant Sertraline Nortriptylline Amitriptylline • Quetiapine is relatively safe and is used for BPAD also • Avoid mood stabilisers completely

34. Breast feeding Antipsychotics Antidepressant Sertraline Peroxetine Nortriptylline Lamotrigine with caution • Quetiapine