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CP10 Clinical Pharmacology
Variability in Drug Response Toronto Notes 2019 Variability in Drug Response
recommendedpatientdosingisbasedonclinicalresearchandrepresentsmeanvaluesforaselect population, but each person may be unique in their dosing requirements possiblecausesofindividualvariabilityindrugresponseincludeproblemswith:
■ intake: patient adherence
■ PK
■ absorption: vomiting, diarrhea, or steatorrhea; first pass effect increased due to enzyme induction or
decreased due to liver disease
■ drug interactions (e.g. calcium carbonate complexes with iron, thyroxine, and fluoroquinolones) ■ distribution: very high or low percentage body fat; intact or disrupted BBB; patient is elderly or a
neonate, or has liver dysfunction
■ biotransformation and elimination: certain genetic polymorphisms or enzyme deficiencies related
to drug metabolism (e.g. acetylcholinesterase deficiency, CYP polymorphism); kidney or liver
dysfunction
■ PD: genetic variability in drug response (e.g. immune-mediated reactions); diseases that affect drug
PD; drug tolerance or cross-tolerance
Drug Interactions
concomitantprescriptions:onedrugalterstheeffectofanotherbychangingitsPKand/orPD PKinteractionsinvolvechangesindrugconcentration
■ absorption: alterations in gastrointestinal pH, gastric emptying, intestinal motility, gut transporters ■ metabolism: alterations in drug metabolizing enzymes (e.g. CYP)
■ excretion: alterations in renal elimination
PDinteractionsareduetotwodrugsthatexertsimilareffects(additive)oropposingeffects (subtractive) druginteractionscanalsoinvolveherbalmedications(e.g.St.John’swort)andfood(e.g.grapefruit juice)
Autonomic Pharmacology
• •
Examples of Clinically Relevant Drug Interactions
Interaction
Warfarin plus ciprofloxacin, clarithromycin, erythromycin, metronidazole, or trimethoprim- sulfamethoxazole
Warfarin plus acetaminophen
Oral contraceptive pills
plus rifampin Sildenafil plus nitrates
SSRI plus St. John’s wort, naratriptan, rizatriptan, sumatriptan, zolmitriptan
SSRI plus selegiline or non- selective MAO-I
Some HMG-CoA reductase inhibitors plus niacin, gemfibrozil, erythromycin or itraconazole
Sulfamethoxazole- Trimethoprim and ACEIs/ ARBs, beta-blockers, spironolactone
Potential Effect
Increased effect of warfarin
Acetaminophen (NAPQI) further increases INR
Decreased effectiveness of oral contraception
Hypotension Serotonin syndrome
Serotonin syndrome Possible rhabdomyolysis
Increased risk of hyperkalemia
• •
• •
Figure 10. Subdivisions of the peripheral nervous system
Peripheral Nervous System
Somatic
Autonomic (ANS)
Parasympathetic (PNS) Rest and Digest
Sympathetic (SNS) Fight or Flight
• mostorgansareinnervatedbybothsympatheticandparasympatheticnerves,whichhaveopposing effects (see Neurology, N8)
• AChandNEarethemainneurotransmittersoftheautonomicNS
• AChbindstocholinergicreceptors,whichincludenicotinicandmuscarinicreceptors
• NEbindstoadrenergicreceptors,whichprincipallyincludeβ1,β2,α1,andα2
• AChactionisterminatedbymetabolisminthesynapticcleftbyacetylcholinesteraseandintheplasma
by pseudocholinesterase
• acetylcholinesteraseinhibitors(pyridostigmine,donepezil,galantamine,rivastigmine)canbeusedto
increase ACh levels in conditions such as myasthenia gravis or Alzheimer’s disease
• NEactionisterminatedbyreuptakeatthepresynapticmembrane,diffusionfromthesynapticcleft,and
degradation at monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT)
Parasympathetic Nervous System
• bloodvessels,adrenals,sweatglands,spleencapsule,andadrenalmedulladoNOThave parasympathetic innervation
• parasympatheticpre-ganglionicfibresoriginateinthelowerbrainstemfromcranialnervesIII,VII, IX, X, and in the sacral spinal cord at levels S2-S4 and connect with post-ganglionic fibres via nicotinic receptors in ganglionic cells located near or within the target organ
• post-ganglionicfibresconnectwitheffectortissuesvia:
■ M1 muscarinic receptors located in the CNS
■ M2 muscarinic receptors located in smooth muscle, cardiac muscle, and glandular epithelium