Pharmacodynamics describes how drugs act on the body. Drugs can have full, partial, or no efficacy depending on their ability to produce a pharmacological response. Potency refers to the amount of drug needed for a desired effect. Affinity describes how tightly a drug binds to receptors. Genetics can impact variability in individual drug response. Pharmacokinetics describes what the body does to drugs, including absorption, distribution, metabolism, and excretion. Drugs are absorbed through various routes and distributed throughout the body, with factors like blood flow and protein binding affecting distribution. Drugs are metabolized and transformed by the liver and excreted primarily by the kidneys.
Pharmacodynamics describes how drugs act on the body. Drugs can have full, partial, or no efficacy depending on their ability to produce a pharmacological response. Potency refers to the amount of drug needed for a desired effect. Affinity describes how tightly a drug binds to receptors. Genetics can impact variability in individual drug response. Pharmacokinetics describes what the body does to drugs, including absorption, distribution, metabolism, and excretion. Drugs are absorbed through various routes and distributed throughout the body, with factors like blood flow and protein binding affecting distribution. Drugs are metabolized and transformed by the liver and excreted primarily by the kidneys.
Pharmacodynamics describes how drugs act on the body. Drugs can have full, partial, or no efficacy depending on their ability to produce a pharmacological response. Potency refers to the amount of drug needed for a desired effect. Affinity describes how tightly a drug binds to receptors. Genetics can impact variability in individual drug response. Pharmacokinetics describes what the body does to drugs, including absorption, distribution, metabolism, and excretion. Drugs are absorbed through various routes and distributed throughout the body, with factors like blood flow and protein binding affecting distribution. Drugs are metabolized and transformed by the liver and excreted primarily by the kidneys.
Efficacy How well Rx prod pharmaco resp|y Agn|full|partial|Antg|C|NC Relative|full Agn=1|Antg=0 Antg Rev|conf|effect|Endo Agn
Full Agn Partial Agn C Antg Reversible NC Antg Irreversible E/NE Pindolol Propranolol Pehnoxybenzamine
Potency Amt Rx needed for desired effect|y Affinity How tight Rx bind R|left=affinity Dose EC 50 |CAntg|NCAntg R# R max |NCAntg|y|spare R| Genetics Quantal DR curve|Cumulative Q-DR Variability|ED 50 |
Rx action EC 50 |R max |
Agn|CAntg EC 50 |R max |right shift CAntg|Agn Antg EC 50 dep on [Agn] NCAgtg EC 50 C|R max |R#
Spare R Saturate|limited by later step| Rmax reached before all R occupied Sm dose NC Antg Rmax
R Regulation Over|reg|mlc|R#|tachyphalaxis Prolong|reg|dose|rebound phenm pharmacodynamic tolerance
Quantal Normal curve % of pop need certain dose to respond Cum Q Sigmoid|% of pop responding to a dose Include those that resp to lower dose
Multi-effects Rx bind same R @ other tissue|potency Rx bind other R|completely selective R density|diff R isoforms expr
TI Rx safety|TD 50 /ED 50 |LD 50 /ED 50
Physicochemical properties Intracellular barrierlipid bilayer mem Rx specific carriers|not natural meta
PC PC=[Rx] fat /[Rx] H2O
PC=0|soluble in fat PC=|soluble in H 2 O
Rx N o |Weak A/B|Strong A/B Weak Ionized|Unionized|@equilibrium HA+BH + A - +B+H + |Ka
***Ionized Rx are trapped in urine & cleared*** Acidic AH|B + |Base excreted via urine Basic A - |BH|Acid excreted via urine Ka [B][H + ]/[HA]
HH Eq [A]/[B]=10 (pH-pKa)
Weak A Salicylic|ASA|0.01% N o |H2O insoluble Good PC in lipids Weak B Diphenhydramine|Benadryl|anti-his 1% N o |H2O insoluble|Good PC in lipids
Strong A|B Phophate|Sulfate|Poor PC| NH 4 + |always |poor PC Multiple weak A/B|act like strong Quaternary Ipratropium|inhale|analog of atropine COPD|deliberate poor PC| Strong A Heparin|lots SO 4 - & -OH|sugar Strong B AG|Tobra|multiple weak bases|NH 3
Sugar=low PC
Transportation
Diffusion Fav PC|N o |E|dissipate gradient| Rate=k1(C1-C2)|@Eq, C1=C2|trans wB conjAcross|N o B cross|[N o ] & PC wA conjBcross|N o A cross|[N o ] & PC
Diff pH Ion Trapping wB affect N o |ratio of B:A| accum in lower pH than blood wA affect N o |ratio of B:A| accum in higher pH than blood
Oral GI|exclude most Rx| Passive non-ionic diffusion| No|PC||wA/B|PC|pK|pH Fixed charge|poorly abs-but still does **Abs from GI complexed by the presence of Rx transporters & Rx meta enz in epithelial cells** Stomach designed for Abs|wBabs|wA may
Sm Int Lg SA|major abs site|GI & Liver meta P-gp|Rx back into lumen|HepPortal v 1 st pass |Rx uneffective
Bioavailability (f)fraction of Rx into Sys circ Rx w/f=0 still useful if metabolite is active agent Source of Rx interaction|more important for Rx with low f as interaction can f
Vein dmg|Aq soln|reverse IM capillary pore|lymphatic|BF|amt fat Ctrl abs rate|slow but sustained| use during anticoagulant Tx SubQ capillary pore|lymphatic|Aq soln~fast Insoluble Rx slow abs|sustained effect Solid pellets implant|abs for mo/yr use for Rx that irritate tissue Topical Local|minimize sys exposure|patches Potent & VERY fav PC|tolerance| Site of admin|scrotum best|sole worst BF|inflame Abs rate
Distribution [Rx] p
BF Heart|Liver|Kidney|Brain|min Muscle|Skin|Viscera|Fat|min/hr BloodECF [Rx] p =Rx admin /(V p +V EF )|pores|~rapid ECFCells V d =Vp+V EF +V IF |V d =V app |ICF|cell ***if Rx lipophilic, Distr limited to ECF*** BBB pores|Cap endo Rx transporter|P-gp Cap surr by glial cells,ECF| Very good PC|guarantee|P-gp Inflame vasc perm|meningitis|PCN BBB|ChemoR trigger zone|HTh Choroid plx Blood-CSF|3 rd & 4 th Lat Ventricles|CSF Tight Jxn|enter only thru passive dffsn 1/1000 SA of BBB|active trnsptr|enz Placenta pores|Lg or charged cross| Lipophilic crosses readily|simple dffsn P-gp|pH7-7.2|pH than mom| ***Fetus is exposed to some extent all Rx taken***
Testis/prost sertoli|tight Jxn|pore|limited distr Synovial pores|perm if inflamed Lungs large cap SA|Rx meta|*Dapto Blood from all organs pass thru lungs Bodily fluid passive non-ionic dffsn|ion trapping
Distr can be limited by prot binding Albumin|acidic Rx|1-gp|basic Rx Only free Rx can cross|enz meta|filter Reversible|buffering Rx interxn two Rx compete|transient [Rx]|elim ***Duration & significance of effect dep on t 1/2 ***
Storage prot bound=storage|accum in tissue Fat soluble|accum in adipose Affinity for Ca or |accum bn & teeth
Diseases plasma prot|Rx bound|free Rx in blood o synthesis|liver|albumin o prot excretion|renal neprhititis plasma prot|Rx bound|free Rx in blood o Acute phase response|prot syn o CA|arthritis|Crohns|MI
Elimination H 2 O soluble mlc|Kidneys MW|Prot bnd|Charge|PC
Glom Filtration|MW<50kDa|20%|bnd PT Active secretion|charged mlc|[bnd] Grad|dffsn|peritubular cap|alb bnd dev in babies|with age b/c GFR DT Reabsorption|N|wA/B|Fav PC pH dependent ***1% of filteredurine|2/3 reabsorbed***
Methylation Methyl|SAM|TPMT|O,N,S|Rx polarity Epinephrine syn|catecholCOMT| Azithioprine6-mercatopurinemeta () ***TPMT catalyze 6-MP to inactive metabolite; TPMT dfcn due to mutation=severe toxicity when taking 6- MP derived RxImmSupp|RA|IBD|chemotherapy***
LIVER HPV & HA to central v|GI Rx|HPV|Rest of body|HA Liver sinusoid extract Rx via transporters & passive dffsn Rx transported out of liver by 1. Into sys circ|kidney excretion 2. Bile canaliculus|GB|bile duct|Sm Int
Sinusoid mb (SLC) OAT|OATP|OCT Pm|Na/K pump Canaliculi mb(ABC) P-gp(MDR1)|MRP2|BRCP ATP hydrolysis Blood (ABC) via sinusoid mb|MRP1,3,4 ATP hydrolysis
Enterohepatic cycling
DDI due to t 1/2
Most Rx in the cycle ultimately elim by kidneys Rxcycle by reabst 1/2 |source of Rx interaction ABt that kill bacteria in GI Non-abs polymers|cholestyramine|fiber
Biliary Excretion Rx Poor PC Remain in GI Stool Fav PC Reabs via passive dffsn Back to liver (via blood) Liver Conj w/glucuronic Very bad PC Bact in colon rmv glucuronic Free Rx w/Fav PC Back to Liver Free Rx w/Bad PC Stool Rx Response Variation
Genetic variation Metabolism|Transporters
Rx Meta P450|UGT|NAT|Cholinestease|TPMT P450 2D6|4 phenotypes|/Rx metabolism Poor/P|intermed/IM|Extnsv/NL|ultrarpd/UP
Rx Trans ABC|SLC ABC P-gp|BCRP|MRP2 SLC OCT|OAT|MATE
CYP2D6 Affected Rx Tricyclic|-blocker|||tamoxifen| Tamoxifen by CYP|poor=poor resp to tamox
MEC & MTC but pts ability to metabolize codeine influence the effects of the Rx. For instance, P may not have enough active morphine in blood to reach MEC for analgesic effects whereas UR would have too much morphine surpassing MTC to prod toxic effects.
CYP3A4 2,7 Ccsn|16,18 Asn|low clnc signifc Dual pathway|3A5|diff meta rate
NAT2 2 pheno|rapid|slow|5A,6A,7A Affected Rx Hydralazine|INH|Carcinognc arylamine Hydralazine active Rx lvl|SLE-like Sx INH t1/2|1hr3hr|periph neuropathy CA arylamine CA risk after prolonged exposure
UGT1A1 glucuronidation|bilirubin| *6|20%|Jpn|Chn|neonatal jaundice Crigler-Najjar-I|CrNj-II|Gilberts CrNj-I conj bilirubin|early childhood death CrNj-II conj bilirubin|jaundice Gilberts promoter mutation|expr **GI & Bn tox to Colorectal CA Rx irinotecan (proRx|enterohepatic cycling) due to glucuronidation of active metabolite**
Rx Trans MRP2|BCRP|OAT
MRP2 ABC|Rx- out|hepatocytebile| Dfcn| transport from liverbile well GI tox of irinotecan|BM tox though BCRP Gln141Lys|activity|biliary excretion 30-60% Asn|5-10% Ccsn & AA Rosuvastatin HMG-CoA reductase|chol syn 90% bile CL|mutation effect & tox Asn|2xAUC|2xCmax|5mg|Ccsn20mg
OATP1B1 Rx- into| Simvastatin ProRx|N 0 lactone|fav PC|1 st pass Liver|H-lysis|acid|low PC|OAT Enterohepatic cycle|MRP2 OATP1B1|get in liver well|[Rx]p [simva acid] p |myopathy|efficacy
DDI Physiologic|Pharmacologic Pharm DDI Rx1 directly aff PharmDyn/Kin of Rx2
Abs pH|trapping|solub|trans|motility|bac meta
Rx that pH Rx affected by pH Antacid NaHCO 3
Mg(OH) 2
CaCO 3
H2 Antg|cimetidine H + pump |omep PCN G Ketoconazol|itraconazol|amp Fe supplement (FeSO 4 ) Bisacodyl coated laxative Digoxin (10% in f) Atazanavir (protease )
Trapping Rx that interact with another abs Non-abs Rx|bind other Rx|fiber Charged polymer|antacids multivalent Tetra|FQ|Cipro
Transporter P-gpabs & elim Cyclosporine|quinidine|clarith|itraco Cyclosporine Target T|immsupp Rx|prev renal rjct Sirolimus GI abs=limited by P-gp|CSA siro abs Admin 4hr apart to minize DDI
Elim Biotransformation|Excretion Biotrans biotrans|compete|Irrev|CYP3A4 Compete Rx meta by same pathway Irrev Cimetidine|irrev bnd CYP|Rx elim Wafarin|Diazepam|Chlordiazepoxide
3A4 Inhibitor Antifungal Ketoconazole Itraconazole Immunosuppressant Cyclosporine Antibiotics Erythromycin Clarithromycin HIV protease Inhibitor Ritonavir Indinavir Food/drink Grapefruit juice has furano-coumarins which intestinal CYP3A4proteolytic degradation
Transporter
INDUCTION ***the purpose of biotransformation is to protect the body against xenoBt and other foreign sub; when you are exposed to a large amount of xenoBt, its logical to induce biotransformation***
NR|TFprot syn|p450|RLS DDI|Low selectivity|induce meta of >1 Rx
Pharmacokinetic Tolerancewhen Rx induces its own metabolism Carbamazepine Antiepileptic|t1/2|36-8/12hr Bosentan Endothelin antg|Tx pulm HTN *even though t1/2 of rosentan is 5hr, it takes 3-5d to reach steady state when given 62.5mg twice daily*
Renal Excrtn Compete trans|pH u |passive reabs
2 nd Rx elim[1 st Rx] p 1 st Rx dose 2 nd Rx elim|reabs|Rx meta|[1s Rx] p D
Age pharmKin|body fat:H 2 O| BodFat:H2O with age|/ V d |Rx H 2 O or fat solub V d determines D load |t 1/2 |oscillation [Rx] p =X admin /V d |
Peds sens to Rx|immature organ dev clnc trial|unpredictable abs
Stom acid scrt Stom emptying & peristalsis Bile level Low @ birth |hrs/d/2yr Slower Irregular Slows abs| Amt Low bile abs or lipid soluble Rx
Biotrans P450 peak @ 2-6mo|faster than adults CYP1A2 peak @2yr|@puberty *P450 can be induced by mom taking phenobarbital* **Glucuronidation takes 3-4yr to reach adult lvl** ***Bilirubin accumulates in newborns***
Renal excretion in peds Low renal BF Neonate GFR=30-40% adult value 3wk GFR=50-60% 6-12mo GFR=100% GFR of kids continue to above adult values
Geriatrics >75yo|many Rx|SE/DDI|compliance Nutritional prob|limited $|diff Rx resp Rx sens|homeostatic mech less effcnt Diff resp Wt|muscle mass|H 2 O|fat renal fxn|CO|lung capacity Abs GI motility|t empty |stom scrt|GI BF Slower abs but extent unaffected Distr/Elim Alb|fat:H 2 O|/ V d dep on Rx solub live size|BF|CYP450|Rx t 1/2 Renal elim All : BF|GFR|PT secretion|#nephron Monitor renal fxn via creatinine CL Rule: use lower doses in geriatric pt
Diseases Impair: p450|Rx excretion|BF to liver
TOLERANCE Pharmacodynamic Rx resp|[Rx] p |tachyphylaxis Opioids DR right shift|dev rapidly Benzodiazepine antiepileptic -adr Agonists bronchodilator|asthma persistent -R in lungs|reg Shortterm PKA,-ARK,-arrestin Longterm R# -adr Antagonists HTN|Angina|Prolong|R# Rebound phenomenon| upon Rx w/d
Pharmacokinetic Metabolic|Dispositional [Rx] p due to cont admin
Toxicology
Toxicology is governed by the same principles as pharmacology. HOWEVER, overdose characteristics may be different from those of therapeutic doses.
Abs rate|extent|stom emptying|bezoar Distr BPrt saturate|free Rx|%bnd|Vd pH|distr wA & wB|Rx induced hypoperfusion|distr|delay elim Elim f|Rx meta enz saturate| Elim t 1/2 |1st order|pump saturate Dmg liver/kidn|blood pH|perfusion
General Tx Principles
1 st KEEP Pt ALIVE ABCD airway|breathing|circulation|dextrose
Consider WBI if Rx is: Slowly absorbed Fe tablet (Fe2+ not abs by charcoal) Poisons not adsorbed by charcoal Cocaine-filled condoms
Enhance Rate of Elimination
Forced diuresis Give large volume of IV diuretic (furosemide) to increase urine production. The procedure is obsolete.
Alkalization of urine|Weakly acid Rx Elimination of weakly acidic drugs by alkalinizing the urine. As salts and water are reabsorbed in the tubules, the concentration of drugs in urine increase to generate a favorable gradient for reabsorption. If Rx is uncharged and have a favorable PC, it will be reabsorbed passively. The rate of reabsorption dep on PC, pKa, and urine pH. Alkalination of the urine will resulting in ion trapping thus, inhibiting reabsorption and promoting excretion. NaHCO 3
o IV|pH7.5-8.5 o Nonionic reabsorption of CO 2
alkalinizes the urine o pH in blood relatively small due to greater volume & buffering power o Useful for ASA & Phenobarbital Other barbiturates are metabolized rapidly so Renal excretion play enough a role for this to be used ASA 138Da|80%bound|pKa=3.0|wA|active scrt Good PC|reabs| PhBbt CNS depressant|anticonvulsant|antiepileptic 232Da|50%bound|pKa=7.3|wA|active scrt Very fav PC|almost all uncharged @ urine pH Extensively & efficiently reabsorbed
Acidification of urine|Weakly basic Rx Same principle as alkalization for weakly acidic drugs. Note that this only works if there is significant non- ionic reabsorption of Rx in DT thus, significant amount of Rx must 1 st by filtered or actively secreted. NH 4 Cl|VitC o [NH 4 ] u & [NH 4 ] p |generate gradient o Nonionic reabsorption of NH3 acidify urine o Enhance elim of MDMA & PCP Urine is usually acidic anyways & further acidification can exacerbate renal complications of rhabdomyolysis often associated with amphetamine overdose. RARELY USED
Single Dose kinetics Dose
t max
t 1/2
C max
AUC TOA DOA OOA
CL
C max
t max
t 1/2
AUC DOA TOA
k abs
t 1/2 AUC
T max
OOA TOA C max
t max
Slow/Extended Release Rx
Combined Rapid and Slow Release Rx
ie. Zolpidem (Ambien)
Problem with these extended release Rx is if pt takes them via a faster absorption method (crushing it, IV) is toxicity of the Rx.