Jameel Khan Pharmacology Review (3 rd Semester): MINI 1: Pharmacokinetics effects of body on drug Pharmacodynamics effects of drug on body Transfer/Permeation: 1) Bulk flow – intracellular pores; depends on P gradient (passive) 2) Aqueous diffusion – small molecules; aquaporins (<100 MW) 3) Lipid diffusion – uncharged molecules (**H-H principle**) pKa > pH = non ionized (lipid soluble) for W.A. (*THINK = ACID in more ACIDIC env. is uncharged) Differen ce >3 3 2 1 0.5 0 % ionized >99.9 99.9 99 90 76 50 pH stomach = 1.5 to 2; blood = 7.4; cell/cytoplasm = 7 (electroneutral) Ion trapping build-up within cell due to differences in pH/pKa; drugs with low pKa (i.e., aspirin) build-up in GI epithelium = gastric ulcers; can use to increase drug elimination by trapping in urine 4) Carrier transport – large / charged molecules; facilitated or active; saturable 5) Endocytosis – large / charged molecules; selective Administration: Parenteral = injection or infusion 1) Oral – 1 st pass effect; absorption in small intestine; gastric emptying can be hastened or delayed 2) IV – F = 1
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Jameel Khan
Pharmacology Review (3 rd Semester):
MINI 1:
Pharmacokinetics effects of body on drug
Pharmacodynamics effects of drug on body
Transfer/Permeation:
1) Bulk flow – intracellular pores; depends on P gradient (passive)2) Aqueous diffusion – small molecules; aquaporins (<100 MW)3) Lipid diffusion – uncharged molecules (**H-H principle**)
pKa > pH = non ionized (lipid soluble) for W.A. (*THINK = ACID in more ACIDIC env. is uncharged)
Ion trapping build-up within cell due to differences in pH/pKa; drugs with low pKa (i.e., aspirin) build-up in GI epithelium = gastric ulcers; can use to increase drug elimination by trapping in urine
4) Carrier transport – large / charged molecules; facilitated or active; saturable5) Endocytosis – large / charged molecules; selective
Administration:
Parenteral = injection or infusion
1) Oral – 1st pass effect; absorption in small intestine; gastric emptying can be hastened or delayed2) IV – F = 13) IM – fast absorption; NO anticoagulants (e.g., heparin)4) SC – slower than IM (bulk flow); heparin OK5) SL – NO 1st pass6) Rectal (suppository) – partial 1st pass avoidance; lower absorption7) Inhalation – inhalers or gases8) Topical – local effect9) Transdermal – systemic effect; slow; avoids 1st pass
Blood flow: higher = faster absorption; epinephrine with local anaesthetics (AVOID near end capillaries!)
Jameel Khan
Bioavailability (F) = AUC other / AUC iv (fraction of dose that reaches systemic circulation; CONSTANT for each drug)
Distribution:
Vd = D x F / Cp0
Can rearrange to solve for dose CONTSTANT, independent of dose! Cp0 can be obtained by extrapolating line to y-axis of Cp vs. time graph 3L = only in plasma (heparin); 13L = to ECF; 42L = TBW (ethanol); >42L = specific cells/tissues
Redistribution – IMPORTANT with lipid soluble anaesthetics in obese pts.
Protein binding – constant % bound = inactive, independent of dose; IMPORTANT with drugs with narrow T.I. (e.g., warfarin – 98% bound)
BBB – highly impermeable (intrathecal admin.); placenta is opposite
Placental crossing: slowed by ionization, protein binding, size (esp. >1500 MW)
Metabolism:
Biotransformation conversion to a metabolite is form of elimination (in SER of hepatocytes)o Phase I – CYP450; makes polaro Phase II – conjugations: glucoronidation & acetylation **fast/slow acetylators =
genetic Individual differences! (e.g., pseudocholinesterase deficiency prolonged duration of
succinylcholine) Prodrugs are inactive, metabolized to active form Liver consider damage/cirrhosis & CYP 450 effectors
o INDUCERS (barbiturates & rifampin) faster metab., therefore lower amt. of drugo INHIBITORS (cimetidine, macrolides, grapefruit juice) slower metab., therefore higher
amt. of drug
Elimination:
Not equal to EXCRETION! biliary, renal*, pulmonary (e.g., anaesthetics), others = saliva, sweat
First Order – constant proportion; exponential decrease; the norm for most drugs
Jameel Khan
Zero Order – constant amount; linear decrease; ethanol, phenytoin, toxic dose of aspirin
Compartment models: (use example Q)
One compartment – drug uniformly distributed; concentration of drug increases with constant proportion (single t1/2)
Two compartment – separate peripheral & central distribution; distribution phase & elimination phase (two distinct t1/2’s)
Clearance: CL(t) = CL(h) + CL(r) + CL(o)
CL(r) = Ud x V / Pd
GFR normally 125mL/min +/- 26; BUT if > 150 mL/min = secretion; <100 mL/min = reabsorption
**MUST adjust dose when elimination altered by disease based on fraction of drug eliminated by kidney & liver (do not consider CL(o))
Hepatic cirrhosis, disease or heart failure (reduced blood flow)
Renal impairment or heart failure (lowered CO); relate to creatinine CL & GFR
(provide question example)
Accumulation:
T1/2 = 0.693 (Vd/CL) CONSTANT for each drug!
Full elimination after 4 X t1/2
**Can determine from conc. vs time graph NOTE semilog scale (provide ex.)
**know how to determine based on Cp0 & Cp(after time)
Duration of action is proportional to t1/2 & administered dose
Continuous IV:
D / T = Css X CL
Css rate of infusion = rate of elimination; time to reach depends on t1/2; level depends on dose; reached after 4 x t1/2 (accumulation occurs provided that dosing interval is < 4 x t1/2)
1 x t1/2 50% Css2 x t1/2 75% Css3 x t1/2 87.5% Css
Jameel Khan
4 x t1/2 94% Css Therefore, if it takes 20 h to reach Css t1/2 = 5 h
**IMPORTANT for drugs with low T.I. smaller (lower D) & more frequent doses (lower T) decrease fluctuations at Css
Css = F x D / CL x T
Loading Dose = Vd x Cp / F (used in emergencies or with drugs with low T.I.)
Maintenance Dose / T = CL x Css / F
Dose-Effect Relationship: **IMPORTANT to relate these properties to their effect on the graph
Emax = maximal effect
EC50 = concentration where 50% receptors bound, or Kd
Intrinsic activity = ability of a drug to initiate changes (once bound) which lead to a biological response
Agonist full (max response); partial (below max response – acts as antagonist in presence of full agonist); inverse (decreases basal activity)
Antagonist intrinsic activity = 0
a) Chemical – combines & inactivatesb) Pharmacokinetic – prevents absorption or stimulates eliminationc) Physiological (functional) – binds different receptor causing opposite biological responsed) Pharmacological (receptor-block) – compete for same receptor,
Competitive / reversible bind agonist receptor site; Increases Kd; right shift on graph
Non-competitive / irreversible allosteric binding site; decreased Emax (# of effective receptors); lowers slope on graph
Threshold dose – min dose to produce any response
Potency – proportional to affinity (inverse to Kd); increase potency = lower dose for effect (more left on graph)
Efficacy – proportional to intrinsic activity/Emax; Emax increases on y-axis
Therapeutic Index = RATIO between harmful & effective dose (REMEMBER to calculate = lethal or toxic dose / effective dose) – digoxin (very low T.I. of 3-5)
Therapeutic Window = RANGE between min. therapeutic dose & min. toxic dose
Chronic activation densensitization & down-regulation = TACHYPHYLAXIS or TOLERANCE
Chronic inhibition up-regulation (supersensitivity) **DO NOT suddenly stop pt from B-blocker Tx
Interactions:
a) Addition 1 + 1 = 2b) Synergism 1 + 1 > 2c) Potentiation 0 + 1 > 1 ; drug with no effect enhances otherd) Antagonism 1 + 1 < 2 ; partial & full agonist.. OR... 0 + 1 < 1 ; antagonist & agonist
Placebo Effect = always present! MUST always consider
Pt compliance 15-95% non-compliant!
Adverse Effects: (not high yield on exams)
Majority are pharmacological (70-80%); can be cytotoxic (5-15%) or immunological (5-15%)
Mainly occur in first 10 days of Tx MUST reduce dosage or can switch to night time administration (e.g., sedation)
Jameel Khan
May be due to drug metabolite
Overdose toxicity most deaths in hospital; or idiosyncratic (e.g., genetically based)
Haptens = small molecule that elicits an immune response when attached to a larger protein (e.g., penicillin)
Allergy Types:
I) Immediate rxns IgEII) Ab-dep. cytotoxicity IgG or IgMIII) Immune complex-mediated IgG or IgM with complementIV) Delayed or cell-mediated T cell receptors
Pseudoallergic NO antibodies; anaphylactoid; dose-related
**IMPORTANCE of a detailed history
Teratogenesis – MW 800-1000 can cross placenta easily
Most sensitive stage = ORGANOGENESIS (17-80 days); before that is resistant
Most frequent mechanism is covalent bonds to DNA, RNA, enzymes, etc.
FDA Risk categories: (lowest) A, B, C, D, X (worst)
*AVOID all drugs unless deeply necessary in pregnancy
SNS from T1-L5 (short pre-) paravertebral chain ganglia (Ach @ Nn, then long post-) adrenergic transmission (catecholamines, NE/Ep) alpha/beta receptors on effector
*REMEMBER: Ach to sweat glands (M) & adrenal medulla (Nn) (which releases catecholamines)
PSNS from III, VII, IX, X & S2-4 (long pre-) ganglia (Ach @ Nn, usually near target oran) cholinergic transmission M receptors on target organ
Somatic voluntary motor nerve Ach to Nm on muscle
Adrenergic Transmission:
Jameel Khan
Tyrosine (tyrosine hydroxylase) DOPA dopamine (dopamine beta-decarboxylase) NE Ep
Termination:
1) Actively transported back into pre-synaptic cell (primary mechanism)2) Diluted & diffuse away3) Metabolized by MAO-A or B & COMT HVA and VMA (respectively)
Prostaglandins Ecosanoid Inhibitors*Alprostadil (PGE1)-Tx: erectile dysfunction (penile injection); maintains PDA until surgery (due to T of GVs)-AE: priaprism
AE: hepatotoxicity in OD or w alcohol (antidote is NAPQI)
*** DO NOT give aspirin to CHILDREN for FEVER (especially if due to viral illness) REYE’s SYNDROME = fatty liver, encephalopathy, kidney dz, hypoglycemia coma and even death!!!!
Acetaminophen OD n & v, diarrhea, appetite loss, sweating, irritability; may lead to liver failure (jaundice, dark urine, confusion, hypoglycaemia, bleeding)
Glucocorticoids: ALTER GENE EXPRESSION!
-inhibit Phospholipase A2
-Increase neutrophils; decrease lymphocytes, eosinophils, basophils and monocytes (immunosuppressive!)
*As a rule, estrogen-dependent tumors are Tx with estrogen antagonists or androgens; testosterone-dependent tumors are Tx with testosterone antagonists or estrogens.
Jameel Khan
***Major Toxicities (Toxicity Bear): MAJORITY OF TEST QUESTIONS! (along with MOA’s)
Drug Toxicity AntidoteCisplatin Ototoxic & nephrotoxic Amifostine
Azathioprine-antimetabolite (CCS)-prodrug of 6-MP inhibits PRPP synthetase & amidotransferase, therefore blocking purine synth. & salvage pathway NO clonal expansion of B & T cellsTx: prevents graft rejection; SLE; Crohn’s
**competes with allopurinol for metab. by xanthine oxidase (MUST reduce dose MP when using allopurinol for hyperuricemia)AE: myelosupp.; hepatotoxicity; infections; HS; carcinogenic!
ALG-antilymphocytic-binds T cells complement destruction-Ab’s raised in horsesTx: prophylaxis for GVHDAE: HS, serum sickness
Cyclosporine-binds to cyclophilin A1, inhibits calcineurin CAN’T enter nucleus to increase IL-2 prod’nTx: organ tx, GVHD, AI dz’sTox: nephrotoxic!
Etanercept-fusion protein“RECEPTS” / binds TNF-alpha-dimer of human TNF receptor fused to human IgGTx: RA, psoriasis, AS, added to MTX in cancer TxAE: injection site rxns
Infliximab-binds TNF-alpha preventing it from activating receptorTx: IBD (Crohn’s & ulcerative colitis), RA (w MTX), AS, psoriasisAE: HS, serum sickness, infectionCI: infections
Ig IV-polyclonal AB, most IgG, from donor poolTx: passive immunization; AI dz; etc.
Tacrolimus (FK506)-same as above, BUT binds to FKBP-12-more effective & less toxicTx: atopic dermatitis
Rho(D) Ig-RhoGAM (IgG)Tx: hemolytic dz of newborn -admin to Rho(D) neg. mom soon after birth to prevent Ab prod’n
Sirolimus-binds FKBP-12 & mTOR-inhibits IL-2 pathway, Ab prod’n & B cell prolif.Tx: stentsTox: hyperTGemia, hepatotox., diarrhea, myelosupp (non-nephro)
Daclizumab-binds IL-2 receptor on T cells, preventing activationTx: renal transplantAE: dyspnea, fever, GI distress
Muromonab-CD3-Ab to CD3 Ag on thymocytes, blocking T cell killing actionTx: acute renal allograft rejectionAE: HS, neuropsych., anaphylaxis
Mycophenylate mofetil-inhibits IMD (no de novo GTP synth)-suppresses B & T cellsTx: organ tx, GVHD, AI dz’sTox: GI, neutropeniaAsparginase
Jameel Khan
-see chemoTx CI: pregnancyGlucocorticoids: affect cellular immunity more than humoral decrease synthesis of prostaglandins, leukotrienes, cytokines, PAF, T cell proliferation, IgG levels; Tx for organ transplants, GVHD & hematologic cancers; Tox: adrenal suppression, growth inhibition, muscle wasting, osteoporosis, salt retention, glucose intolerance & behavioural changes.
Immunostimulants:
BCGTx: bladder CA (intravesicle admin); TB vaccine
- Inherited abnormality of Fe absorption- Frequent transfusions (eg., thalassemia major)
Tx: phlebotomy; Deferasirox or Deferoxamine (chronic admin.)
Vit B12 5 year reserve; essential for DNA synthesis (cofactor for formation of tetrahydrofolate, converts homocysteine to methionine & methylmalonyl CoA to succinyl CoA); megaloblastic anemia; neurologic defects (due to build up of methylmalonyl CoA)
- Folate supp’s will correct anemia, but NOT neurologic deficits, therefore MUST rule out B12 deficiency PRIOR to selecting Tx
Preps: Cyanocobalamin; Hydroxycobalamin (IV, longer t1/2, **used in Tx of pernicious anemia**)
*Schilling’s Test +ve result = pernicious anemia
Folate 1-6 month reserve; essential for DNA synthesis; megaloblastic anemia, neural tube defects
Preps: Folic acid (cofactor of DHFR, converts DHF to THF); Leucovorin (folinic acid; bypass DHFR; MTX rescue)
Jameel Khan
HEMATOPOIETIC GROWTH FACTORS
*All must be given IV (very low oral bioavailability proteins damaged by stomach acids)
1) Increased DA in limbic region (+)ve Sx’s = delusions, hallucinations, bizarre thoughts2) Decreased DA in prefrontal region, inhibition by 5-HT (-)ve Sx’s = blunted affect, apathy
Classical(D2 receptor affinity)
Atypicals(D2 & 5-HT receptor affinity)
Tx of (+)ve Sx’sM & a1 block dry mouth, blurred vision, orthostatic hypoTnhyperprolactinemia (galactorrhea & gynecomastia)Parkinsonian-like Sx’sEPS, tardive dyskinesia (enhanced by anti-muscarinics which help EPS) , akathisiaAll except Haloperidol = CARDIOTOXIC (increase QT interval)Still used because they are CHEAPER!
Tx of (+)ve & (-)ve Sx’sNo tardive dyskinesia, minimal EPSNo increase in prolactinMore expensive Higher death rate in elderly dementia pts
NMS (Neuroleptic Malignant Syndrome) high fever, severe muscle rigidity, altered consciousness, ANS instability, elevated CK, myoglobinemia (Tx with DANTROLENE!!!!)
DRUGS FOR BIPOLAR
Bipolar I HIGH & LOW mania & MDE (more equally manic to depressive)
Bipolar II MORE LOW hypomania & MDE (normal to depressive)
Increase intracellular Na depression; decreased intracellular Na mania
“Very Good & Calm”Valproic Acid-most effective DOC in acute illnessCan be used in combo w Li+AE: hepatic dysfn; GI distress; wt gain; alopecia; inhibition of drug metab.Gabapentin-use in pregnancy (no teratogenicity)
CarbamezapineTx: prophylaxis of depressive phaseAE: hematotoxicity; ataxia; diplopia; induces drug metab.LamotrigineAE: rash; nausea; dizziness; headache CI: liver problems*Valproate inhibits metab (dose must be halved)*Carbamezapine stimulates metab (dose must be doubled)
ANTI-DEPRESSANTS
TCA’s1st genInhibit 5HT & NE (increase BDNF) reuptake; plus M, H1 & alpha