Pharmacology Flashcards
Pharmacology
Antiplatelet Classes
1) Cyclooxygenase inhibitors
2) ADP receptor antagonists
3) Glycoprotein IIb/IIIa receptor inhibitors
4) Phosphodiesterase III Inhibitor
Pharmacology
Antiplatelet Cyclooxygenase inhibitors
Aspirin
Pharmacology
ADP receptor antagonist
1) Clopidogrel
2) Prasugrel
3) Ticagrelor
4) Ticlopidine
Pharmacology
Glycoprotein IIb/IIIa receptor inhibitors
1) Abciximab
2) Eptifibatide
3) Tirofiban
Pharmacology
Phosphodiesterase III inhibitor
- Cilostazol
- Dipyridamole
Pharmacology
Anticoagulant drug classes
1) Direct anticoagulant
2) Indirect anticoagulant
Pharmacology
Heparin effect reversing drug
1) Protamine sulfate
Pharmacology
Direct anticoagulant
1) Heparin (antithrombin activator)
2) LMW heparin
- enoxaparin
3) Indirect inhibitors of factor Xa
- fondaparinux
4) Direct thrombin inhibitors
- dabigatran
- hirudin
- lepirudin
- argatroban
5) Direct factor Xa inhibitor
- Rivaroxaban
- Apixaban
Pharmacology
Indirect anticoagulant
1) Warfarin
Pharmacology
Warfarin effect reversing drug
1) Vitamin K1
Pharmacology
Thrombolytic drugs
1) Streptokinase
2) Anistreplase
3) Urokinase
4) Tissue plasminogen activators (Alteplase; tPA)
5) Reteplase (rPA)
6) Tenecteplase (TNK-tPA)
Pharmacology
Thrombolytics effect reversing agents
1) tranexamic acid
2) Fresh plasma/coagulation factor
Pharmacology
Fibrinolytic inhibitors
1) tranexamic acid
2) Aminocaproic acid
Pharmacology
Coagulants agents
1) Vitamin K1 and K2
Pharmacology
1st generation H1 receptor blocker
1) Chlorpheniramine
2) Diphenhydramine
3) Dimenhydrinate
4) Promethazine (promethazine theoclate)
5) Doxylamine
6) Hydroxyzine
Pharmacology
2nd generation H1 receptor blocker
1) fexofenadine
2) Loratadine
3) Cetirizine
Pharmacology
Antihistamine (H1) somnifacients / sedate
1) Diphenhydramine
2) Doxylamine
3) Promethazine
Pharmacology
Antihistamine (H1) antiemetics
1) Dimenhydrinate
2) hydroxyzine
3) Promethazine theoclate
Pharmacology
Immunosuppressive drug classes
1) Cytokine production inhibitors
2) Immunosuppressive antimetabolites
3) immunosuppresive antibodies
4) Adrenocorticoids
Pharmacology
Immunosuppresive Cytokine production inhibitors
1) Cyclosporine
2) Sirolimus
3) Tacrolimus (FK506)
Pharmacology
Immunosuppressive antimetabolites
1) Azathioprine2) Mycophenolate mofetil3) Cyclophosphamide4) MEthotrexate
Pharmacology
Immunosuppressive antibodies
1) Basiliximab2) Rho (D) immune globulin3) Muromonab (OKT3)4) Daclizumab
Pharmacology
Anti-CD25 antibodies (aka IL-2 receptor antagonist)
1) Basiliximab2) Daclizumab
Pharmacology
Immunosuppressive corticosteroids
1) methylprednisolone2) Prednisone
Pharmacology
Cytokine release syndrome prophylaxis drugs
1) methylprednisolone2) Diphenhydramine3) paracetamol
Pharmacology
Chemotherapy drug classes
I. Cell cycle-specific 1) Antimetabolites a) Folate antagonist b) Purine antagonist c) Pyramidine antagonist 2) Mitotic Inhibitors (Microtubule) a) Vinca Alkaloids b) Taxanes 3) Topoisomerase inhibitors a) Topoisomerase I inhibitor b) Topoisomerase II Inhibitor 4) Ribonucleotide reductase inhibitors a) HydroxyureasII. Cell-cycle Non-specific drugs 5) Alkylating agents a) Phosphoramide mustard precursor b) Nitrosureas c) Heavy metal platinum complex 6) Antibiotics a) Dactinomycin b) Bleomycin c) Anthracyclines 7) Glucocorticoids
Pharmacology
Cell cycle-specific Chemotherapy drug classes
1) Antimetabolites a) Folate antagonist b) Purine antagonist c) Pyramidine antagonist2) Mitotic Inhibitors (Microtubule) a) Vinca Alkaloids b) Taxanes3) Topoisomerase inhibitors a) Topoisomerase I inhibitor b) Topoisomerase II Inhibitor4) Ribonucleotide reductase inhibitors a) Hydroxyureas
Pharmacology
Cell cycle non-specific Chemotherapy drug classes
1) Alkylating agents a) Phosphoramide mustard precursor b) Nitrosureas c) Heavy metal platinum complex2) Antibiotics a) Dactinomycin b) Bleomycin c) Anthracyclines3) Glucocorticoids
Pharmacology
Targeted therapy drug classes
1) Hormone antagonist a) SERMs2) Monoclonal antibodies 3) Enzyme inhibitors
Pharmacology
Folate antagonist and mechanism
Methotrexate (MTX)
Mechanism:
- blocking the active site of dihydrofolate reductase, thus no reduced folate produced which is a co-enzyme for methylation in various metabolic processes
- MTX polyglutamated to be retained in the cell
Pharmacology
Purine antagonist
- Azathioprine- 6-mercaptopurine (6-MP)- 6-thioguanine (6-TG)
Pharmacology
Pyramidine antagonist
- 5-fluorouracil (5-FU)- Cytarabine (ara-c)
Pharmacology
Antimetabolites
a) Folate antagonist - Methotrexate (MTX)b) Purine antagonist - Azathioprine - 6-mercaptopurine (6-MP) - 6-thioguanine (6-TG)c) Pyramidine antagonist - 5-fluorouracil (5-FU) - Cytarabine (ara-c)
Pharmacology
Vinca Alkaloids
- Vincristine (VX)- Vinblastine (VBL)- Vinorelbine (VRB)
Pharmacology
Taxanes
- Paclitaxel- Docetaxel
Pharmacology
Mitotic Inhibitors
a) Vinca Alkaloids - Vincristine (VX) - Vinblastine (VBL) - Vinorelbine (VRB)b) Taxanes - Paclitaxel - Docetaxel
Pharmacology
Topoisomerase I inhibitor
- Irinotecan- Topotecan
Pharmacology
Topoisomerase II Inhibitor
- Etoposide (VP-16)- Teniposide (VM-26)
Pharmacology
Topoisomerase inhibitors
a) Topoisomerase I inhibitor - Irinotecan - Topotecanb) Topoisomerase II Inhibitor - Etoposide (VP-16) - Teniposide (VM-26)
Pharmacology
Ribonucleotide reductase inhibitors
Hydroxyureas
Pharmacology
Phosphoramide mustard precursor
- Cyclophosphamide- Ifosfamide
Pharmacology
Nitrosureas
- carmustin (BCNU)- Lomustin (CCNU)- Fotemustin- Semustin- Streptozocin
Pharmacology
Heavy metal platinum complex
- Cisplatin- Carboplatin
Pharmacology
Alkylating agents
a) Phosphoramide mustard precursor - Cyclophosphamide - Ifosfamideb) Nitrosureas - carmustin (BCNU) - Lomustin (CCNU) - Fotemustin - Semustin - Streptozocinc) Heavy metal platinum complex - Cisplatin - Carboplatin
Pharmacology
Antitumour Antibiotics
a) Dactinomycinb) Bleomycinc) Anthracyclines - Doxorubicin (DOX) - Daunorubicin (DNR) - Epirubicin - Idarubicin
Pharmacology
Anthracyclines
Doxorubicin (DOX)Daunorubicin (DNR)EpirubicinIdarubicin
Pharmacology
Antitumour Glucocorticoids
- Prednisone- Prednisolone
Pharmacology
SERMs
- Tamoxifen- Raloxifene
Pharmacology
Antitumour Monoclonal antibodies
Rituximab (CD20)
Cetuximab (EGFR)
Trastuzumab (HER-2 Breast Cancer)
Bevacizumab (VEGF)
Pharmacology
Antitumour Enzyme inhibitors
Imatinib DasatinibBosutinib(Imma das bossu) -> all for BCR-ABL tyrosine kinase blocking in CML
Pharmacology
Anti-tumour Drugs Overview
CHEMOTHERAPYI. Cell cycle-specific 1) Antimetabolites a) Folate antagonist - Methotrexate (MTX) b) Purine antagonist - Azathioprine - 6-mercaptopurine (6-MP) - 6-thioguanine (6-TG) c) Pyramidine antagonist - 5-fluorouracil (5-FU) - Cytarabine (ara-c) 2) Mitotic Inhibitors (Microtubule inhibitors) a) Vinca Alkaloids - Vincristine (VX) - Vinblastine (VBL) - Vinorelbine (VRB) b) Taxanes - Paclitaxel - Docetaxel 3) Topoisomerase inhibitors a) Topoisomerase I inhibitor - Irinotecan - Topotecan b) Topoisomerase II Inhibitor - Etoposide (VP-16) - Teniposide (VM-26) 4) Ribonucleotide reductase inhibitors a) HydroxyureasII. Cell-cycle Non-specific drugs 5) Alkylating agents a) Phosphoramide mustard precursor - Cyclophosphamide - Ifosfamide b) Nitrosureas - carmustin (BCNU) - Lomustin (CCNU) - Fotemustin - Semustin - Streptozocin c) Heavy metal platinum complex - Cisplatin - Carboplatin 6) Antibiotics a) Dactinomycin b) Bleomycin c) Anthracyclines - Doxorubicin (DOX) - Daunorubicin (DNR) - Epirubicin - Idarubicin 7) Glucocorticoids - Prednisone - Prednisolone——————TARGETED THERAPY 8) Hormone antagonist a) SERMs - Tamoxifen - Raloxifene 9) Monoclonal antibodies - Rituximab - Bevacizumab - Cetuximab - Trastuzumab 10) Enzyme inhibitors - Imatinib - Vemurafenib
Pharmacology
Doxorubicin cardiotoxicity reverse therapy
dexrazone (iron-chelator)
Pharmacology
rescue therapy for MTX toxicity; its mechanism
Leucovorin, an active form of folic acid to perform methylation in metabolic processes
Pharmacology
Cyclophosphamide andIfosfamide –> Hemorrhagic cystitis rescue drug
Mesna
Pharmacology
LMW heparin
enoxaparin
Pharmacology
Indirect inhibitors of factor Xa
Fondaparinux
Pharmacology
Direct thrombin inhibitors
- dabigatran - hirudin - lepirudin - argatroban
Pharmacology
Direct factor Xa inhibitor
- Rivaroxaban - Apixaban
Pharmacology
Drug-induced parkinsonisim
Reserpine (depleting dopamine store) Haloperidol (dopaminergic blocker)
Pharmacology
anti-parkinsonian drugs Classes
Dopaminergic acting:
1) Dopamine precursors, e.g. levodopa
2) peripheral DOPA decarboxylate inhibitor
3) dopamine agonists
4) MAO-B inhibitors
5) COMT inhibitors
6) Dopamine facilitator
Cholinergic acting;
7) central anticholinergics
Pharmacology
Counter indicated drugs with Levodopa
1) Nonselective MAO inhibitors
(Resulting in excess dopamine in the periphery, which could lead to a life-threatening hypertensive crisis)
2) Pyridoxine (Vitamin B6)
(Increasing peripheral breakdown of L-dopa)
3) Antipsychotics
(Blocking dopamine receptors and causing parkinsonian-like symptoms)
Pharmacology
Dopamine precursors drug (anti-parkinosonism)
levodopa
Pharmacology
Peripheral DOPA decarboxylase inhibitors (antiparkinosonism)
carbidopa, benserazide
Pharmacology
MADOPAR
levodopa + benserazide (4:1 ratio)
Pharmacology
Dopaminergic agonists (antiparkinsonism)
Ergot-derived:
- Bromocriptine (D2)
- Pergolide (D1,2)
Non-ergot:
Pramipexole (D2)
ropinirole (D2)
rotigotine (D2-like)
Bro Per-Plexed into Roping-role and got rot
Pharmacology
Ergot-derived dopaminergic D2 receptor agonist
Bromocriptine
Pharmacology
Ergot-derived dopaminergic D1&2 receptor agonist
Pergolide
Pharmacology
Non-ergot dopaminergic D2 receptor agonist
Pramipexole
ropinirole
Pharmacology
Non-ergot dopaminergic D2-like receptor agonist
rotigotine
Pharmacology
MAO-B inhibitors (antiparkinsonism)
Selegiline
Pharmacology
COMT inhibitors (antiparkinsonism)
Entacapone, tolcapone
Pharmacology
Dopamine facilitator (antiparkinsonism)
Amantadine
Pharmacology
Anticholinergic agents (antiparkinsonism)
Benztropine
Biperiden
Trihexyphenidyl
Benzhexol
Pharmacology
Huntington’s disease drug classes
1) Dopamine receptor antagonists - Haloperidol2) dopamine-depleting drug - Tetrabenazine3) depression and irritability drug - Fluoxetine
Pharmacology
Tourette’s syndrome drugs
ClonidineHaloperidol
Pharmacology
Alzheimer’s disease drugs
1) Anticholinesterases - Donepezil
Rivastigmine
Galantamine
(To increase the amount of ACh available for CNS functions such as memory)
2) NMDA receptor antagonists
Memantine
( improve cognitive ability by protecting CNS neurons from the excitotoxic effects of glutamate)
Pharmacology
Anticholinesterases (anti Alzheimer)
Donepezil
Rivastigmine
Galantamine
(To increase the amount of ACh available for CNS functions such as memory)
Pharmacology
NMDA receptor antagonist
Memantine
improve cognitive ability by protecting CNS neurons from the excitotoxic effects of glutamate
Pharmacology
Antidepressants drug classes
- Selective serotonin reuptake inhibitor
- Norepinephrine reuptake inhibitor
- Serotonin-Norepinephrine reuptake inhibitor
- Tricyclic antidepressants
- Serotonin antagonist-reuptake inhibition (SARI)
- α2 adrenoceptor antagonist
- Monoamine oxidase (MAO) inhibitors
Pharmacology
Serotonin selective reuptake inhibitor (Antidepressants)
Fluoxetine (Prozac)/CYP2D6
Paroxetine/CYP2D6
Fluvoxamine/CYP3A4
Citalopram
Escitalopram
Sertraline
Pharmacology
Noradrenaline reuptake inhibitor (Antidepressants)
Atomoxetine
Maprotiline
Reboxetine
Pharmacology
Serotonin-Norepinephrine Reuptake inhibitors (Antidepressants)
Venlafaxine Desvenlafaxine Duloxetine Bupropion Mirtazapine
Pharmacology
Tricyclic Antidepressants
Tertiary Amines:
- Amitriptyline
- Imipramine
Secondary Amines
- Desipramine
- Nortriptyline
Pharmacology
Serotonin antagonist-reuptake inhibition (SARI)(Antidepressants)
Trazodone
Pharmacology
α2 adrenoceptor antagonist (Antidepressants)
Mianserin
Pharmacology
Monoamine Oxidase Inhibitors (antidepressant)
Non-selective:
- Phenelzine
- Tranylcypromine
MAO-A selective:
- Moclobemide
Pharmacology
antipsychotics Classes
1) Typical (D2)
- Chlorpromazine
- Fluphenazine
- Haloperidol
- Thioridazine
- Trifluoperazine
2) Atypical (5-HT2) - Aripiprazole - Clozapine - Olanzapine - Quetiapine - Risperidone - Ziprasidone
Pharmacology
Typical antipsychotics
- Chlorpromazine
- Fluphenazine
- Haloperidol
- Thioridazine
- Trifluoperazine
Pharmacology
Atypical antipsychotics
- Aripiprazole
- Clozapine
- Olanzapine
- Quetiapine
- Risperidone
- Ziprasidone
Pharmacology
anxiolytic and hypnotic drugs classes
1) Benzodiazepines
2) Barbiturates
———•
Other anxiolytic drugs
– Buspirone/CYP3A4
– Hydroxyzine
– Antidepressants
• Other hypnotic agents – Zolpidem (GABA inhibit; P450) - Zaleplon – Ramelteon – Chloral hydrate – Antihistamines (diphenhydramine, doxylamine, promethazine) – Ethanol
Pharmacology
benzodiazepines by duration of acting
Cloned ox tempted Lora to Diarrhoea and flu
i) Short-acting (2 to 8 hr) Triazolam Oxazepam Midazolam Clonazepam
ii) Intermediate-acting (10 to 20 hr)
Temazepam
Lorazepam
Alprazolam
iii) Long-acting (1 to 3 days)
Chlordiazepoxide
Diazepam (Valium)
Flurazepam
Pharmacology
Benzodiazepine antagonist (rescue drug)
Flumazenil (GABAA receptor competitive inhibitor)
Pharmacology
barbiturates (by duration of acting)
i) Ultra-short-acting (10-20 min)
Thiopental
ii) Short-acting (2 to 8 hr)
Pentobarbital
Amobarbital
Secobarbital
iii) Long-acting (1 to 2 days)
Phenobarbital
Pharmacology
Anxiolytic benzodiazepine
– Alprazolam – Chlordiazepoxide – Clonazepam – Diazepam – Lorazepam
Pharmacology
Hypnotic benzodiazepine
– Triazolam
– Temazepam
– Flurazepam
Pharmacology
IV General anaesthetics
Thiopentone
Propofol
Ketamine
Etomidate
Pharmacology
Inhaled General Anaesthetics
- Desflurane
- Isoflurane (most potent)
- Sevoflurane
- nitrous oxide
- Xeon——
- Halothane
- Enflurane
Pharmacology
Endogenous analgesics
EnkephalinsBeta-endorphin
Pharmacology
Opioid analgesics classes (by structure)
- Morphine and related- Phenylpiperidine series - Methadone series- Mixed agonist-antagonist
Pharmacology
Morphine and related compounds (opioid analgesics)
Morphine (to morphine 6-beta glucuronide 6MG)CodeineHeroin
Pharmacology
Phenylpiperidine series (opioid analgesics)
Merperidine (pethidine)Fentanyl family - fentanyl - sufentanil - alfentanil - remifentanil
Pharmacology
Methadone family
Methadone (aka physeptone)Dextropropoxyphene
Pharmacology
Mixed agonist-antagonist
PentazocineBuprenorphineButorphanolTramadol
Pharmacology
Opioid analgesics by efficacy
Strong- morphine- pethidine - fentanyl familyMild- codeine- Dextropropoxyphene - mixed agonist-antagonist
Pharmacology
Opioid analgesics antagonist
Naloxone (narcan)
Pharmacology
Insulin preparations
Short acting
- regular human insulin (humulin, novolin)
Rapid onset and Ultrashort acting
- Lispro insulin (humalog)
- Aspart insulin (novolog)
Intermediate acting
- protamine (NPH) insulin
- Lente insulin
Long acting
- ultralente insulin
- glargine insulin
- detemir insulin
Pharmacology
Anti-diabetic agent classes
A) enhance insulin secretion
1) insulin secretagogues
- sulfonylurea
- meglitinide analogs
2) incretin mimetics
- GLP analog
3) dipeptidyl peptidase-4 (DPP-4) inhibitor
B) increases insulin action
1) insulin sensitizer
- biguanides
- thiazolidinediones
C) inhibits glucose uptake
1) alpha-glucosidase inhibitor
2) SGLT inhibitor
Pharmacology
Insulin secretagogues (diabetic drugs)
Sulfonylureas
- glipizide
- glimepiride
Meglitinide analogues
- repaglinide
- nateglinide
Pharmacology
Incretin mimetics (diabetic)
Glucagon-like peptide (GLP) analogs- exenatide- Liraglutide
Pharmacology
DDP-4 inhibitors (diabetic)
Sitagliptin phosphate
Vidagliptin
Pharmacology
Insulin sensitizer (diabetic)
A) biguanides
- metformin
B) thiazolidinediones
- rosiglitazone
- pioglitazone
Pharmacology
alpha-glucosidase inhibitor (diabetic)
Acarbose
Miglitone
Pharmacology
Short term treatment of hypertyroidism
Before surgery
Thyrotoxic crisis
Initial treatment for hyperthyroidism while waiting for effect of long term drugs
1) Beta blockers
- propanolol
2) Lugol’s solution
- 5% iodine + 10% potassium iodide
Pharmacology
Long term treatment of hyperthyroidism
1) Thionamides
- methimazole
- carbimazole
- propylthiouracil
2) Radioiodine
- iodine 131
3) Thyroidectomy
Pharmacology
Acute hypothyroidism drugs
T3 - Liothyronine
Due to quicker onset of effects
Pharmacology
Routine replacement therapy of hypothyroidism
Thyroxine (T4)
Due to longer half life
Pharmacology
B cell lymphoma medication
R-CHOP
Rituximab (anti-CD20)
Cyclophosphamide
Hydroxydaunarubicin
Vincristine
Prednisone
(purine analogue for low grade)
Thyroid Hormone replacement ADR
1) Thyrotoxicosis
2) worsening ischemic symptoms (caution in patients with cardiovascular disorder) due to beta-adrenoceptor and related vasoconstriction
3) Risk of acute adrenal crisis (because thyroxine ↑ metabolic clearance of adrenocortical hormones) -> hypoglycaemia and hypotension
THEREFORE MONITOR T4 AND TSH LEVELS
Propanolol use in hyperthyroidism
Beta blocker, for symptomatic relief:
1) Blocks beta 1 in heart, relieve palpitation
2) Blocks beta 1 in brain, relieve nevousness
3) Blocks beta 2 in skeletal muscles, relieve tremor
Mechanism of action of Lugol’s solution
1) By inhibition of H2O2 generation so thyroidal peroxidase cannot oxidise iodide to iodine
2) Decrease vascularity of thyroid
3) By inhibition of T3/T4 release
Angel dust effect
i.e. PCP, behaviour mimics schizophrenia
PCP binds to and inhibits NMDA glutamate receptor (block Na Ca entry)
Strategy for type 1 DM
Diet
Exercise
Insulin
DM type 2 treatment strategy
1) Diet, Exercise
2) add Anti-diabetic agents monotherapy
3) switch to combined therapy
4) add further Insulin injection
Gestational diabetes mellitus treatment strategy
Diet
Insulin
Anti diabetic agents
Criteria for basal insulin
- mimics normal pancreatic basal insulin secretion
- smooth peak less profile
- long lasting effect: 24 hours or more
- predictable or reproducible effects
Bolus insulin criteria
- rapid onset of action; usually given before meals
- short duration of action to avoid hypoglycaemia
- predictable and reproducible effects
Source of replacement insulin
Produced by recombinant DNA technology with E Coli or yeast
Regular insulin biochemistry and use
Self aggregate in antiparallel fashion to form dimers that stabilise around zinc ions to create hexamers –> delayed onset and prolonged time to peak actions
Useful for management of diabetic ketoacidosis (DMT1) or when insulin requirement is changing rapidly (post surgery and acute infection)
Not useful for bonus injection
Why is humulin not good for insulin bonus injection
1) slow onset of action due to self aggregation (hexameric insulin does not bind to insulin receptor)
- > inconvenient administration of 40 mins before meal
- > hypoglycaemic risk if meal delayed
- > mismatch with postprandial hyperglycemia peak
2) long duration of activity
- > potential for late postprandial hypoglycaemia
Lispro and Aspart insulin
Rapid onset and ultrashort acting insulin
- prevent hexameric formation so they break into monomer after SC injection
- closely mimics endogenous postprandial insulin secretion
- taken just before meal
- without risk of hypoglycaemia between meals
NPH insulin
Insulin mixed with protamine
- intermediate acting
- insulin bound to protamine -> slowly dissolve in body fluid
- facilitate control of glycemic over an extended period
Lente insulin
Mixture of 30% semilente and 70% ultralente insulin
- intermediate acting
- insulin bound to zinc -> slowly dissolve in body fluid
- facilitate control of glycemic over an extended period
Ultralente insulin
Long acting insulin, withdrawn from market due to unsafe
Entirely crystalline zinc -> slow onset, slow effect
Insulin glargine
Long acting insulin
- 2 arginine added to carboxyl terminal and substitution and glycine substituted for asparagine at A21 -> lower solubility and prolonged action
- ultra long acting, maximal effect maintained for 24 hours
- peakless activity, clear solution, no zinc in formula
- once daily at bedtime
Detemir insulin
Long acting insulin
- > added fatty acid moiety
- > when added to circulation, fatty acid cause it to bind to albumin -> slow release and extended circulating life
Insulin administration
1) Subcutaneous or intramuscular injection
2) Insulin pump
– experimental –
3) transdermal
4) oral
5) inhalation
6) pancreatic transplant and ST therapy
Insulin pump
Aka continuous subcutaneous insulin infusion device (CSII)
Major components:
1) pump
2) disposable reservoir for insulin inside the pump
3) disposable infusion set, including cannula for SC insertion, a tubing system to interface insulin reservoir to cannula
Insulin replacement therapy complications and solutions
1) hypoglycaemia (nausea, confusion, weakness, coma)
+ glucose administration
2) insulin allergy and immune resistance (rarely happen now with recombinant DNA production)
3) lipodystrophy at injection site
+ use multiple site injection
4) long term risk like DMT2, and lifelong dependency on exogenous insulin
SGLT2 inhibitors
Dapagliflozin
sulphonylureas mechanism
Anti diabetic (type 2) e.g. Glipizide, glibencalmide
Insulin secretagogue, long duration of action
Bind extracellularly to receptor on pancreatic beta cells to close K channel, which reduce K efflux, leading to depolarisation, Ca channel opening and Ca influx, then exocytosis of insulin
(ONLY USE IN CASES WITH INTACT beta cells! Primary and secondary failure)
Sulphonylureas ADRs
- stimulate appetite and weight gain
- hypoglycaemia (esp in hepatic or renal insufficients)
- GI upset (must give with food) and rashes
- cross placenta and deplete fetal pancreatic insulin
Meglitinide analogues mechanism
Anti diabetic (type 2) e.g. Repaglinide, nateglinide
Insulin secretagogue, rapid onset and short duration of action -> good for postprandial glucose control
Bind extracellularly to receptor on pancreatic beta cells to close K channel, which reduce K efflux, leading to depolarisation, Ca channel opening and Ca influx, then exocytosis of insulin
(ONLY USE IN CASES WITH INTACT beta cells!)
Meglitinide ADRs
- increase appetite and weight gain (rarely compared with sulphonylureas)
- hypoglycaemia (rarely compared with sulphonylureas)
Biguanides mechanism
Insulin sensitizer; Antidiabetic (type 2) eg metformin
Activating liver’s AMP-activated protein kinase (AMPK), which will:
- decrease glyconeogenic genes, decrease hepatic glucose production, thus reduce hyperglycemia
- decrease fatty acid synthesis and increase fatty acid oxidation, thus reduce hyperlipidemia
Metformin usage
Antidiabetic used for obese patients or patients with insulin resistance
- reduce CVS complications
- decrease incidence of diabetes related cancers
Metformin ADRs
- GI upset with nausea, diarrhoea and abdominal discomfort
- lactic acidosis, esp with glucocorticoid (because glucocorticoid cause steatosis and steatohepatitis that makes liver susceptible to metformin induced lactate production)
- Long term use -> Vit B12 deficiency
(Usage alone does not cause hypoglycaemia)
Metformin contraindications
Renal disease, hepatic disease, severe infection, alcoholism, glucocorticoids (lactic acidosis)
Thiazolidinediones mechanism
Insulin sensitizer: For prevention of type 2 DM
Acts on adipose tissue (liver and muscle too), by binding to the nuclear hormone receptor PPAR gamma (peroxisome proliferator-activated receptor) to decrease insulin resistance
Anti-inflammatory and improve lipid profile
Rosiglitazone ADRs
1) weight gain, fluid retention
2) increased risk of heart attack
Pioglitazone ADRs
- weight gain and fluid retention
- risk of bladder cancer
Alpha-glucosidase mechanism
DMT2, eg Acarbose, Miglitol
Inhibits small intestine’s alpha-glucosidase through competition with substrate, thus blocking postprandial digestion and absorption of starch and disaccharides -> lower blood glucose and insulin level after meals
WEAK antIdiabetic EFFECTS
Alpha-glucosidase inhibitor ADRs
Not absorbed into blood stream, therefore little systemic ADRs (no weight gain or hypoglycaemia)
- Flatulence
- diarrhoea
- abdominal pain
Exenatide mechanism
incretin mimetics, NEED INJECTION
- synthetic version of GLP-1 agonist, which acts to pancreatic cells to enhance insulin secretion and inhibit glucagon release
- only ~50% homology with GLP, therefore greater resistance to DPP-4 and have longer half life
- may decrease fatty liver too!
Examples of incretins
Gut derived hormones:
- glucagon like peptide 1 (GLP-1)
- glucose-dependent insulinotropic peptide (GIP)
Exenatide ADRs
1) GI disorder, acid stomach, belching, vomiting, diarrhoea
2) dizziness, headache
3) weight loss by slowing gastric emptying time
DPP-4 inhibitors mechanism
DMT2
Inhibits gut’s DPP-4 mediated degradation of GLP-1, thus increasing GLP-1 level, which acts in pancreatic alpha and beta cells to enhance insulin and reduce glucagon secretion
Long term blood glucose control
DPP-4 inhibitor ADRs
Upper respiratory tract infection
Sore throat
Diarrhoea
SGLT2 inhibitor (DM)
Blocks SGLT2 sodium glucose cotransporter in proximal tubule, thus reducing glucose reabsorption
SGLT2 inhibitor side effect
Genital infection
HSV drug
Acyclovir, valaciclovir
Foscarnet, cidofovir
CMV antiviral
Ganciclovir, valganciclovir
Foscarnet, Cidofovir
VZV antiviral
Acyclovir, valaciclovir
Foscarnet, Cidofovir
HIV antiviral overview
Entry inhibitor
1) fusion inhibitor Enfuvirtide (gp41)
2) binding inhibitor Maraviroc (CCR5 with gp120)
Reverse transcriptase inhibitor
1) Nucleoside: lamivudine, zidovudine, abacavir
2) nucleotide: tenofovir
3) non-nucleoside: nevirapine, efavirenz
Integrase inhibitor (HIV I integrase) 1) raltigravir
Protease inhibitor
1) ritonavir, atazanavir
Influenza antiviral
1) Amantadine, rimantadine (Viral uncoating inhibitor; blocks pore formation by M2 protein, thus prevent H+ influx to virus, prevent acidification of viral core, thus inhibits RNA transcriptase)
2) Oseltamivir, Zanamivir (Viral release inhibitor)
RSV antiviral
Ribavirin (IV for RSV in pre engraftment BM transplant)
Prophylaxis:
- Respigam (RSV-IVIg)
- palivizumab (anti RSV fusion protein)
Interferon alpha mechanism
Blocks viral RNA transcription, protein synthesis and augment immune response
(For HBV and HCV)
Peginterferon-α2a or 2b: interferon conjugated with polyethylene glycol, prolongs persistence of drug in blood.
Lugol’s solution ADRs
1) Allergy (rash, fever, angioedema, bronchitis, salivary gland pain)
2) Counterindicated for breastfeeding because will enter infant via milk; leads to hypothyroidism in baby, which will leads to feedback increase of TSH and thyroid hyperplasia (goitre)
Use of lugol’s solution
1) Improve acute thyroxic symptoms (in acute hyperthyroidism)
2) pre-operatively before thyroidectomy to decrease vascularity to Reduce bleeding risk during operation
3) NOT for long term use due to desensitisation
Thionamides mechanism
Anti-hyperthyroidism
Carbimazole converted to active Methimazole, which inhibits thyroidal peroxidase, thus preventing iodide conversion to iodine, and prevent organification of iodine with tyrosine and reduce formation of T3 T4
Propylthiouracil, apart from inhibiting thyroidal peroxidase, also block peripheral cell’s deiodinization of T4 to T3, thus preventing activation of thyroid hormone
Use of thionamides
1) Slow onset of action of 3-4 weeks (require depletion of T3, T4 store)
- long term therapy of 12-18 months
- higher dose initially, reduce when euthyroid reached
- if hypersensitive to carbimazole, then use propylthiouracil
- seldom curative, relapse common
Thionamides ADRs
1) Skin rash and pruritus (use antihistamine!)
2) Myelosuppression (thrombocytopenia, agranulolytosis)
3) Cross placenta and secreted in breast milk
- raised liver transaminase
- LOW risk of hypothyroidism
Iodine-131 mechanism against hyperthyroidism
Taken up by NI symport, and oxidised by thyroidal peroxidase into iodine and organified with tyrosine; emits beta radiation that damages the thyroid
Use of iodine-131
Oral administration as sodium iodide for:
1) Hyperthyroidism
- Preferred definitive treatment for Graves’ disease, toxic nodular goitre
- relapse of hyperthyroidism after thionamide therapy
2) Thyroid Tumour
- ablate well-differentiated thyroid cancer including papillary thyroid cancer and follicular thyroid cancer, especially after thyroidectomy
3) radioactive label for certain radiopharmaceuticals
Iodine-131 ADRs (in usual hyperthyroidism treatment)
- tolerable acute side effects (e.g. mild neck swelling, pain on swallowing -> use steroid)
- post-radiotherapy hypothyroidism (need lifelong TH replacement)
- Potential damage to thyroid glands of fetus and infants (via placenta and breast milk, therefore counter indicated)
- radioactive iodine may harm others
- Graves’ ophthalmopathy may develop or worsen after treatment
NO congenital defects or infertility
Counterindications for I-131
1) pregnancy and lactation (Potential damage to thyroid glands of fetus and infants via placenta and breast milk )
2) Children and adolescent
3) severe Graves’ ophthalmopathy (may develop or worsen after treatment)
I-125
nuclear imaging tracer and radioactive treatment for prostate cancer
I-123,I-124
nuclear imaging tracers for thyroid diseases
Use of thyroidectomy for hyperthyroidism
Usually total thyroidectomy with T4 replacement, uncommonly performed, used for:
- for multinodular/large goitre
- pregnant patients intolerant to antithyroid drugs
- suspected coexistent thyroid cancer
–> need to restore to uethyroidism before surgery
Complications of thyroidectomy
Hypothyroidism -> lifelong T4 replacement
Vocal cord paralysis (recurrent laryngeal nerve and external laryngeal nerves lies close)
Precautions before and after I-131 therapy
- 4 weeks of low iodine diet
- 4 weeks avoiding anti-thyroid medication
- Pregnancy test for patients with child-bearing potential
- symptomatic control of hyperthyroidism (e.g. propranolol for palpitation)
- No close contact with spouse/partner and children after for 2 weeks
- contraception for 6 months after, avoid pregnancy and breast feeding
Use of thyroidectomy for thyroid tumours
- ablate well-differentiated thyroid cancer including papillary thyroid cancer and follicular thyroid cancer, especially after thyroidectomy against residual microscopic tumour cells
- Destroys remaining normal thyroid tissue
- Makes serum thyroglobulin (Tg) a more specific tumor marker
- Facilitates future surveillance for relapse with I131- Whole Body Scan
- Reduces loco-regional recurrences
- Eradicates distant metastases
- Reduces relapse and improves overall survival
** Shorter effective half-life of I-131 due to: uptake via NIS is reduced, iodine organification is markedly reduced => therefore require larger dose
Iodine-131 ADRs (for tumours)
1) Sialadenitis, nausea/vomiting, epigastric discomfort, cystitis
LARGE DOSE:
- bone marrow suppression (very rare),
- aplastic anaemia (very rare)
- leukaemia (very rare)
- pulmonary fibrosis (lung metastasis)
- neurological complication (vertebral metastasis)
Pituitary dwarfism treatment
(deficiency of GH)
replacement therapy with somatropin
somatropin ADRs
1) Hypothyroidism (induce conversion of T4 to T3, depletes pool)
2) Peripheral edema (induces retention of sodium, potassium and phosphate)
3) Increase Intracranial hypertension -> Papilloedema (visual change) and headache
4) Impaired glucose tolerance
Hypopituitarism (gonadotrophin deficiency) treatment
Replacement therapy with
FOR FSH:
- Follitropin (recombinant FSH)
- HMG (Human menopausal gonadotrophin; contains both FSH and LH)
FOR LH:
- Lutropin α (recombinant LH)
- Choriogonadotropin α (recombinant HCG)
- Human chorionic gonadotrophin (HCG)
NOTE: FSH (follitropin α and β, HMG) must be used with LH (lutropin α, HCG, choriogonadotropin α)
FSH LH replacement therapy ADRs
FSH:
1) Ovarian hyperstimulation syndrome
- Ovarian enlargement
- Ascites
- Hydrothorax (difficult to breathe)
- Hypovolemia
2) Hemoperitoneum
3) Arterial thromboembolism (from hypovolemia)
4) Multiple birth
5) Gynaecomastia
LH:
1) Edema
2) Depression
3) Headache
4) Gynaecomastia
5) Precocious puberty
ACTH deficiency treatment
(Adrenal cortisol release is reduced but adolsterone release is regulated by renin-angiotensin system)
Corticosteroids with only glucocorticoid activity e.g. Hydrocortisone
- In replacement therapy, anti-inflammatory & immunosuppressive effects become unwanted side effects (e.g. increase chance of infection)
Primary hypoadrenalism (e.g. Addison’s disease)
Both cortisol and adolsterone release is reduced
Use corticosteroids with glucocorticoid & mineralocorticoid activity, e.g.:
1) Hydrocortisone
2) Cortisone
- In replacement therapy, anti-inflammatory & immunosuppressive effects become unwanted side effects (e.g. increase chance of infection)
Adverse effect of cortisol replacement therapy
Iatrogenic Cushing’s syndrome
hyperprolactinaemia treatment
Dopamine receptor agonists that acts on anterior pituitary:
1) Bromocriptine
2) cabergoline (longer t1/2 and higher selectivity for dopamine receptor)
Adverse effects of dopamine receptor agonists
1) Postural Hypotension, Arrhythmias
2) Constipation
3) Nausea & vomiting
- Bromoctiptine: Erythromelalgia i.e. swollen hand and feet
- Pergolide: urinary tract infection
- Pramipexole and ropinirole: dyskinesia, insomnia
- rotigotine: skin hypersensitivity cos transdermal patch
acromegaly and gigantism treatment
Somatostatin analogues:
1) Octreotide (inhibtits anterior pituitary and decrease tumour size)
2) Lanreotide (longer acting than octreotide; inhibtits anterior pituitary and decrease tumour size)
3) Pegvisomant (inhibits growth hormone’s action on liver and peripheral tissues)
4) Dopamine receptor agonists (causes a paradoxical decrease in growth hormone secretion)
ADR of Octreotide and Lanreotide
1) GI disturbance (as it inhibits the secretion of gastrointestinal peptides, VIP, PP, gastrin)
- Nausea & vomiting
- Abdominal cramps
- Flatulence
- Steatorrhoea
2) Gall stones (inhibition of gall bladder motility)
3) Impaired glucose tolerance (*somatostatin inhibits the
secretion of insulin from pancreas)
ADR of Pegvisomant
- Hepatotoxicity and Hepatitis (elevated LFT enzymes)
- Nausea & diarrhea
Cushing’s Syndrome treatment
- Metyrapone (inhibits 3-β-dehydrogenase)
- Trilostane (inhibits 11-β-hydroxylase)
Adverse effects of metyrapone and trilostane
- Hypotension
- Nausea & vomiting
- Headache
- Rash
Treatment of diabetes insipidus
ADH Replacement therapy with:
- Synthetic vasopressin
- Desmopressin (longer acting, less vasopressor
effect because it is more V2 selective)
ADR of ADH replacement therapy
1) Fluid retention
2) Dilutional Hyponatremia
3) Headache
4) Nausea
5) Allergy
- ——
6) Spasm of coronary artery => angina (unlikely in desmopressin)
7) Abdominal and uterine cramps (unlikely in desmopressin)
Treatment of hyperparathyroidism
Severe hypercalcemia corrected by rehydration via saline and loop diuretics, and calcitonin injection for short term
Long term:
- surgical removal of tumour (primary)
- treat underlying cause (secondary)
Hypoparathyroidism treatment
IV calcium infusion (for severe hypocalcemia)
Oral calcium with vit D
PTH replacement therapy
Mechanism of opioid analgesics
1) Peak plasma conc instantaneously, gradually decrease because Unionized form and lipid soluble crosses the BBB to reach effector site (delayed onset cos time required for penetrating BBB)
2) blocks the following pain receptors:
- μ receptor: Most of pain relief and ADRs
- δ and κ receptors: some of the pain relief, less important
=> analgesia
Context sensitive half life of opioid analgesic
The half life (1/2 conc) after a duration of steady infusion (context)
- context-sensitive drugs’s half life increases with longer duration of infusion; fixed half life for context-insensitive drugs e.g. remifentanil
Morphine metabolism
Converted to morphine 6-glucuronide, which is renal excreted
Penthidine metabolism
Converted to norpethidine
Strategy and Routes of administration for opioid analgesics
Patient Controlled Analgesia:
- After initial loading dose, patient press a button to activate IV infusion of drug
- hospital only
- closely control dosage to prevent ADRs
1) IV (PCA)
2) Transdermal (fentanyl)
3) Indwelling subcutaneous cannula (for paediatrics)
4) Epidural (so that effect localised in CNS)
5) Transmucosal (via oral mucosa -> lollipops! paediatrics)
Transdermal fentanyl pros and cons
PROS
- convenient
- can take home
CONS:
- so convenient overdose is common
- never multiple patches!
Acute opioid usage ADR
1) Sedation
2) Respiratory depression
3) Euphoria
4) Miosis
5) Nausea, vomit
** ED95 and LD05 may overlap -> individual titration
NOTE: for mixed agonist-antagonist, acute ADR only miosis, nausea, vomit
Chronic opioid usage ADR
1) Constipation
2) Tolerance/ dependence
3) Acute ADRs:
- Sedation
- Respiratory depression
- Euphoria -> addiction
- Miosis
- Nausea, vomit
NOTE: for mixed agonist-antagonist, chronic ADR only constipation, miosis, nausea, vomit
Opioid euphoria ranking
Pethidine > morphine > methadone
Drug Tolerance definition
a physiological state characterized by a decrease in the effects of a drug with chronic administration.
Drug dependence definition
1) Physical dependence
- physiological adaptation of the body to the presence of an opioid
- withdrawal symptoms when dose abruptly discontinued or reduced, or when antagonist or partial agonist added
- relieved by gradual withdrawal
2) Addiction
- compulsive use of drugs for non medical reasons
- Craving for mood altering effect not pain relief
- dysfunctional behavior e.g. lying, forgery of prescription, theft, etc
GA vs LA vs analgesics
GA: loss of all sensation, loss of consciousness
LA: loss of all sensation regionally
Analgesics: Loss of pain sensation
Modern Balanced Anaesthesia
1) Unconsciousness (GA)
2) Analgesia (analgesics)
3) Muscle relaxation (NMJ blocker)
Mechanism of GA action
1) Potentiate release of inhibitory neurotransmitter (GABA, glycine)
2) GABA binds to postsynaptic GABA receptor
3) Cl influx (and K efflux)
4) Hyperpolarization of cell -> reduced cell sensitivity and shut down brain
all GA’s potential dangers
Dangerous due to overlapping of ED95 and LD05
1) Airway obstruction
- consequence of deep sleep
- low tongue muscle tone, may slip back when lying (obstructive apnoea)
- protective airway reflex impaired
2) Aspiration
- reduced protective airway reflex
- entry of gastric acidic content when vomiting
Comparing pros cons of IV GAs (ADRs)
1) Thiopentone
- reduce BP and respiration (apnoea!)
- sulphur -> G6PD attacks
2) Propofol
- more reduced BP and respiration (apnoea! not for shock patient)
- Target controlled infusion needed to closely monitor
3) Ketamine
- no reduced BP, will increase BP
- may incease BP -> not used to coronary Heart disease
- CNS excitation! nightmare or move limbs
4) Etomidate
- no rise or drop in BP
- CNS excitation (less so)
inhaled GA compared with IV GA
- Inhaled has slower onset (30s) than IV (5s)
- IV used for adult first, then continue with inhaled; use inhaled directly on children
- inhaled not as precise and difficult to control amount
Inhaled GA administration instrument
Generic temperature-compensated Variable bypass vaporiser:
- incoming air into two streams, one bypass vaporising chamber, one mixes with vapour in vaporising chamber
- concentration of outgoing vapour controlled by mixing of two straws in different amount
Minimum alveolar concentration (definition, and level)
Indicator of GA potency -> smaller MAC means more potent
MAC lower in neonates and elderly
Definition: Minimum alveolar concentration of inhaled agent which prevents 50% subject’s response movement to standard painful stimulation
Oil:gas partition coefficient
Higher oil:gas partition coefficient -> higher potency of inhaled GA
Blood:gas partition coefficient
How easy a drug diffuse between blood and gas state, inverse with time of onset (lower means faster onset)
- quantified by wash-in = alveolar conc/ vaporiser conc
Affected by:
1) Nature of drug
2) Ventilation rate (high ventilation -> higher)
3) Cardiac output (higher CO -> lower)
Inhaled GA metabolism
Not important and negligible -> mainly leave through lungs
Inhaled GA ADRs
CVS effects:
- reduced systemic vascular resistance
- reduce mean arterial pressure
- reduce cardiac output
- increase heart rate
Parkinson’s disease treatment general mechanism
To re-establish the balance between dopamine and acetylcholine in the brain by:
1) Increasing dopamine in the nigrostriatal system
2) Reducing cholinergic inputs from striatum
Levodopa ADRs
1) conversion of L-dopa to dopamine in the periphery
- nausea, vomiting
- postural hypotension, Arrhythmias
- constipation
2) overstimulation of central dopamine receptors
- Dyskinesia
- Hallucinations
Carbidopa, Benserzide mechanism
does not cross BBB; peripheral DOPA decarboxylase inhibitor
Against PD by decreasing peripheral conversion of levodopa to dopamine, thus increasing availability of dopamine to CNS
Selegiline mechanism
Anti-PD, inhibits MAO-B
Against PD by decreasing peripheral metabolism of dopamine, thus increasing availability of dopamine to CNS
Selegiline ADRs
Hypertensive crisis if large dose
COMT inhibitor mechanism
Anti-PD, inhibits COMT, thus blocking the peripheral conversion of levodopa to 3-O- methyldopa
COMT inhibitor ADRs
- Postural hypotension
- Diarrhea
- Dyskinesias
- HEPATIC NECROSIS (Tolcapone only)
Amantadine anti-PD mechanism
- enhance the release of dopamine from surviving nigral neurons (with surviving neurons)
- inhibit the reuptake of dopamine at synapses
PD treatment regimens
1) Madopar (levodopa + benzerazide 4:1)
2) + Dopamine agonists (pramipexole, ropinirole)
3) + MAO-B or COMT inhibitor to reduce motor fluctuations in advanced disease
4) + Anticholinergics for tremor control
5) Apomorphine for rescue of “off episode”
When should we use antidepressants
The risk of untreated depression far outweigh those of antidepressant mediations
Better alternative to anti-depressants
TALK THERAPY
- Helps by teaching new ways of thinking & behaving.
- Changing habits that may be contributing to the depression.
Anti-depressant general ADR
black box warning:
- increases the risk of suicidality and suicidal ideas and gestures in patients under the age of 25
- after age of 65, no associated risk with suicidal.
Contraindicated drugs in SSRI
Fluoxetine, Paroxetine -> CYP2D6; cannot use with tricyclic antidepressants
Fluvoxamine ->CYP3A4; cannot use with diltiazem (Ca channel blocker), otherwise hypotension and bradycardia
SSRI ADRs
(suicidal under 25)
enhance serotonergic tone:
- nausea, GI upset, dairrhoea
- decreased libido
- Reducing serotonin-mediated platelet activation -> bleeding risk
- Vasoconstriction by inhibiting nitric oxide synthase (avoid in pregnancy with hypertension otherwise prematurity)
Selective NRI ADRs
(suicidal under 25)
Enhance noradrenergic tone:
- CNS activation (anxiety, agitation)
- Increase BP
- Heart rate
Serotonin-noradrenaline RI ADRs
(suicidal under 25)
1) enhance serotonergic tone:
- nausea, GI upset, dairrhoea
- decreased libido
- Reducing serotonin-mediated platelet activation -> bleeding risk
- Vasoconstriction by inhibiting nitric oxide synthase (avoid in pregnancy with hypertension otherwise prematurity)
2) Enhance noradrenergic tone:
- CNS activation (anxiety, agitation)
- Increase BP
- Heart rate
Tricyclic Antidepressants mechanism
secondary amine: predominantly NE reuptake inhibition, a bit shorter acting
Tertiary: NE and 5HT transporter for reuptake affected; strongly anticholinergic; long acting
Tricyclic ADRs
SERIOUS DRUG INTERACTION
Antihistamine:
- sedation
- weight gain
Anticholinergic (too much Fight or Flight!)
- Dry mouth
- constipation
- urinary retention
- blurred vision
Antiadrenergic (Comfy state!)
- Sedation
- sexual dysfunction
- postural hypotension
Trazodone mechanism
1) Mainly 5-HT2A receptor antagonism
2) Serotinin reuptake transporter (SERT) anatagonism
3) Converted to mCPP, which activates 5-HT1A receptor, leading to anti-depression effects
Mianserin mechanism
Anti-depression:
Blocks α2 presynatpic autoreceptor and enhances noradrenalin release.
Mianserin ADRs
Sedation
Dry mouth
Constipation
dizziness
MAO-A VS MAO-B
MAO A metabolises Dopamine, Tyramine, serotonin (5HT), Noradrenaline, adrenaline
MAO B metabolises Dopamine, Tyramine Phenylylaine
MAO inhbitor ADR
- Postural hypotension
- Weight gain
1) fatal interactions between MAOI and tyramine (e.g. in food like bananas, pineapple, eggplants):
- Increase blood pressure and heart rate
- Hypertensive crisis
- Stroke, heart attack, death
2) Serotonin syndrome when combines with serotonergic agent -> due to overstimulation of 5HT receptor
MAO-inhibitor usage guidelines
Serotonergic antidepressants should be discounted for at least 2 weeks before starting an MAOI (fluoxetine for 4-5 weeks due to long action)
MAOI should be discounted for at least 2 weeks before starting Serotonergic antidepressants
Antidepressant discontinuation solution and symptoms
Reduce doses gradually over at least a 4-week period
ABCDEF Agitation, anxiety Balance problems, bad dreams Concentration problems Dizziness, diarrhoea, vomiting Electric shock like sensation Flu like symptoms \+ psychosis, confusion, excitement
Anti-depressant application
- depression
- general anxiety disorder
- PTSD
- OCD
- smoking cessation
- bulimia
Psychosis treatment
1) Antipsychotics - symptom relief
2) Psychological therapies – help address the underlying cause of psychosis
3) Social support
4) Family therapy
5) Self-help groups
Side effects of typical antipsychotics
ADR due to blockade of D2 receptor at different sites other than mesolimbic-mesocortical pathways:
1) Extrapyramidal symptoms (nigrostrital)
- Acute dystonia
- tardive dyskinesia
- Parkinsonism
- Akathisia
2) Hyperprolactinemia (Tuberoinfundibular)
- gynaecomastia
- loss of libido
- low sperm count, infertility
- galactorrhoea
- Amenorrhoea
3) vomiting (Chemoreceptor trigger Zone)
4) Drowsiness
5**) Neuroleptic malignant syndrome - sudden fever to very high level
typical antipsychotics mechanism
Block D2 receptor at mesolimbic-mesocortical pathways, which controls memory, mood and motivation
Atypical antipsychotics mechanism
Blocks 5HT2 receptor
Atypical antipsychotics ADRs
Similar to tricyclics!
1) Antihistamine:
- sedation
- weight gain
2) Anticholinergic (too much Fight or Flight!)
- Dry mouth
- constipation
- urinary retention
- blurred vision
3) Antiadrenergic (Comfy state!)
- Sedation
- sexual dysfunction
- postural hypotension
+4) Metabolic effect
- hyperglycaemia
- Diabetes
- hyperlipidemia
5) Extrapyridmal symptoms
6) Hyperprolactinemia
7) Neuroleptic malignant syndrome
Anti-psychotic withdrawal symptoms
Nausea, vomiting, anxiety, insomnia
Super-sensitivity psychosis after withdrawal (due to up regulation of dopamine receptor number and sensitivity in response to blockade)
Chemotherapy strategies
1) Induction therapy - high dose to induce a complete response when initiating curative regimen
2) Adjuvant therapy - short course of high dose after radiotherapy or surgery to destroy residual tumour and prevent recurrence
3) Neoadjuvant therapy - short course before radiotherapy or surgery to reduce tumour burden
4) Maintenance - long term low dose for patient in complete remission, to prevent remission of residual tumour
5) Salvage therapy - potentially curative high‐dose when recurrent or when another regimen failed
(6? Consolidation therapy)
Advantages of drug combinations in chemotherapy
1) provide maximal cell killing within the range of tolerated toxicity
2) effective against a broader range of cell lines in the heterogeneous tumor population
3) delay or prevent the development of resistant cell lines
4) agents with similar dose‐limiting toxicities, such as myelosuppression, nephrotoxicity, or cardiotoxicity can be combined safely by reducing the doses of each
Methotrexate ADR
- excreted in the urine mostly as unchanged drug
- RENAL TOXICITY: High doses of MTX undergo hydroxylation to form 7‐ hyroxymethotrexate, which is less water soluble and may lead to crystalluria
(keep the urine alkaline and the patient well hydrated to avoid)
Purine analogue mechanism
Orally taken
INHIBITS DNA synthesis by blocking formation of normal purine nucleotides
- Azathioprine -> 6MP, converted to the nucleotide analog TIMP, then converted to 6-thioguanine
- TIMP inhibits de novo purine ring biosynthesis and blocks the formation of AMP and xanthinuric acid from inosinic acid
- RNA and DNA containing thioguanine monophosphate (TGMP) are not functional
6-MP ADRs
- Myelosuppression (especially in defected TPMT or ppl taking XO inhibitor e.g. allopurinol)
6-MP Pharmacokinetics
First pass in liver:
1) 6-MP converted to 6-methylmercaptopurine by TPMT Thiopurine S‐methyltransferase
2) 6-MP converted to 6-thiouric acid by XO xanthine oxidase
Pyramidine analogue mechanism
inhibit DNA synthesis both by blocking the formation of normal pyrimidine nucleotides via enzyme (thymidylate synthetase) inhibition and by interfering with DNA synthesis after incorporation into a growing DNA molecule:
—–DETAILS:
5-FU converted to fluorouridine monophosphate 5-FUMP
5‐FUMP is further metabolized to:
i) the triphosphate 5‐FUTP which is incorporated in
DNA/RNA
ii) 5‐fluorodeoxyuridine monophosphate = a strong inhibitor of thymidilate synthetase
5-FU ADRs
- Myelosuppression -> Anemia
- Pigmentation changes in the skin
Vinca alkaloids mechanism
Mitotic inhibitor
- GTP‐dependent binding to tubulin
- prevent polymerization to form microtubules
- dysfunctional spindle in metaphase, prevent chromosomal segregation and cell proliferation
Resistance to Vinca alkaloids
By enhanced efflux via P-glycoprotein
Vinca alkaloids ADRs
Vincristine: peripheral neuropathy, myelosuppression (milder)
Vinblastine: Myelosuppression (stronger)
Vinorelbine: granulocytopenia
Taxane mechanism
- bind reversibly to the tubulin subunit
- promote polymerization and stabilization
- accumulation of nonfunctional microtubules
- chromosomes cannot segregate
Paclitaxel ADRs
- neutropenia
- serious hypersensitivity
- myelusuppression
- alopecia
- neuropathy
- nausea, vomiting
Docetaxel ADRs
- neutropenia
- fluid retention (contraindicted in heart disease)
- skin (rash, desquamation of the hands and feet, palmar‐plantar erythrodysesthesia)
Drugs for Docetaxel
Post-regimen Corticosteroid to treat fluid retention
Taxane drug resistance
- Enhanced efflux by amplified P-glycoprotein
- Tubulin mutation
Drugs for Paclitaxel prophylaxis
To prevent serious hypersensitivity reaction, premedicate with:
1) Diphenhydramine and H1, H2 blocker
2) dexamethasone
Topoisomerase inhibitor ADRs
thrombocytopenia, neutropenia
Cyclophosphamide and Ifosfamide ADR
- Myelodepression
- hemorrhagic cystitis, which can lead to fibrosis of the bladder
- mutagenic and carcinogenic
Alkylating agent mechanism
- stop tumour growth by alkylating DNA, i.e. crosslinking guanine nucleobases in DNA double‐helix strands through covalent bonds
- makes the strands unable to uncoil and separate
- cells can no longer divide.
Cyclophosphamide and Ifosfamide activation
cytotoxic only after hydroxylation by cytochrome P450, to form phosphor amide mustard (Majorly in liver)
heavy metal platinum complex ADRs
nephrotoxicity and ototoxicity
- severe nausea and vomiting
Anthracyclin mechanism
1) Intercalating between base pairs of DNA/RNA
2) Inhibiting topoisomerase II enzyme and preventing the relaxation of supercoiled DNA
3) Interacting with oxygen, producing superoxide ions and hydrogen peroxide, which cause single‐strand breaks in DNA
Doxorubicin ADRs
cardiotoxicity (result of the generation of free radicals and lipid peroxidation)
Tamoxifen ADRs
- endometrial cancer
- thromboembolic events (stroke and pulmonary embolism),
- cataract formation.
Tamoxifen mechanism
SERM - for ER positive breast cancer
- binding to the estrogen receptors in the target cells, making the estrogen unavailable to the tumor
- producing estrogenic effects at various sites
Raloxifene use
Not for curing breast cancer; currently prescribed to prevent osteoporosis and breast cancer
exerts pro‐estrogen effects in the bone and heart. As a consequence lowered cholesterol and stronger bones appear to be common benefits of taking this drug.
Trastuzumab ADR
congestive heart failure
Trastuzumab mechanism
Monoclonal antibody (for HER2 positive breast cancer)
binds to extracellular domain of the HER‐2 growth receptor, and inhibits the proliferation of cells that overexpress the HER2 protein.
Topoisomerase I mechanism
(S‐phase specific.)
- bind to and stabilize topoisomerse I-DNA complex
- Prevent the religation of the single‐strand breaks created by the enzyme, which are converted to double‐strand breaks
- inhibiting DNA synthesis so that cells do not enter mitosis and prophase
Topoisomerase II mechanism
(premitotic, G2, and S phases)
- Bind to and stabilize topoisomerase II‐DNA complex
- Prevent the religation of the double‐strand breaks created by the enzyme
- inhibiting DNA synthesis so that cells do not enter mitosis and prophase
Potential sites of antiviral action and drugs example and disease
1) Attachment - Maraviroc - HIV
2) Penetration/fusion - Enfuvirtide - HIV
3) Uncoating - Amantadine - Influenza A
4) Protein synthesis - Ribavirin (HCV, RSV); Interferon (HBV, HCV)
5) Nucleuc acid synthesis - Acyclovir (HSV)
6) Virus assembly (i.e. protease) - Atazanavir
7) Virus release - oseltamivir (influenza)
acyclovir mechanism
e.g. HSV and VZV
viral thymidine kinase convert it to monophosphate form, where cell enzymes convert it to triphosphate form
Triphosphate form inhibits viral DNA polymerase
Resistance to acyclovir
Mutation of viral thymidine kinase to not add phosphate to acyclovir
Mutation of viral DNA polymerase to not be inhibited by acyclovir triphosphate
Valaciclovir mechanism
Increase bio-availability than acyclovir
Broken down to valine and acyclovir instantaneously in the blood
e.g. HSV and VZV
viral thymidine kinase convert it to monophosphate form, where cell enzymes convert it to triphosphate form
Triphosphate form inhibits viral DNA polymerase
Ganciclovir mechanism
In CMG
Phosphorylated by CMV enzyme UL97
Triphosphate form inhibits viral DNA polymerase
Ganciclovir resistance
UL97 or viral DNA polymerase mutation
zidovudine mechanism
Converted by cell enzyme into monophosphate and triphosphate, then selectively inhibit HIV RTase
(Some non-specific inhibition of cell polymerase)
Palivizumab mechanism
humanised anti-RSV fusion protein monoclonal antibody
Interferon α use
HBV HCV
aspirin adverse effects
Prolonged bleeding
GI irritation -> never use with peptic ulcer
Heparin usage and counterindicator, ADR
1) use for immediate anticoagulation
Counter indicated in haemophilia or bleedin
ADR: HIT
heparin induced thrombocytopenia -> use protamine sulphate and switch to direct thrombin inhibitor
Thrombolytic mechanism
Conversion of plasminogen to plasmin, which will break down fibrin and lyse the thrombus
Fibrinolytic inhibitor mechanism usage and ADRs
Competitive inhibitor of plasminogen activation
- > use for adjunctive therapy with clotting factor in haemophilia
- > uncontrolled bleeding eg fibronolytic overdose
ADRs: intravascular thrombosis
Haemophilia treatment
Clotting factor concentrate and Fibrinolytic inhibitor eg tranexemic acid
Benzodiazepines VS barbiturates
Benz is safer (drowsiness, anterograde annesia, respiratory depression with ethanol VS drowsiness, induction of P450, respiratory depression and coma)
Benz does not induce hepatic drug metabolising enzymes
Less marked dependence and withdrawal symptoms
Benzodiazepine antagonist available (Flumazenil)
Benzodiazepine mechanism
Increase affinity of GABA for its receptor
Selectively activates GABA-A receptor to increase chloride influx
-> decrease neuronal activity
Barbiturate action
Bonds to GABAa receptor, prolong chloride channel opening
Block excitatory glutamate receptors
