Physiology Principles of Pharmacology

Primary - sequence of different amino acids of peptide or protein held together by covalent or peptide bonds

Secondary - α-helix & β-pleated sheets are the two main conformations further packing the protein tightly together and held by hydrogen bonds

Tertiary - 3D structure folded into a compact globule & held together by ionic bonds and disulfide bridges

Quaternary - larger assembly of several protein molecules or polypeptide chains stabalized by the same hydrophobic interactions and disulfide bonds as the tertiary structure

Active site

A receptor's conformation changes to improve the quality of the binding interaction.

e.x. altering shape of receptor can affect function, including enhancing affinity of drug for receptor

1) drug & receptor structure
2) chemical forces influencing drug-receptor interaction
3) drug solubility in H2O and the plasma membrane
4) function of receptor in its cellular environment

1) The more receptor selective a drug is the better it will be & less side effects
2) Cell-type specificity of receptors
3) Cell-type specificity of receptor-effector coupling (ea. cell having specific receptor-effector coupling will increase drug specificity)

1) Ion channels
2) G protein coupled
3) Enzymatic cytosolic domain
4) Intracellular

1) Ligand-gated (Direct binding)
Mech & Func: Binding of ligand to channel to alter ion conductance

2) Second messenger-regulated (Coupled binding)
Mech & Func: Binding of ligand to plasma membrane receptors linked to channel...2nd messenger regulates ion conductance of channel

3) Volatage-gated
Mech & Func: Change in transmembrane voltage gradient to alter ion conductance

4) Stretching cells also open channels (stretched blood vessel forces vasoconstriction)

1) Local anesthetics - block the conductance of Na+ through voltage-gated sodium channels in neurons that transmit pain info from periphery to CNS, thereby preventing action potentials and pain perception (nociception)

2) Benzodiazepines - inhibit neurotransmission in CNS by potentiating the ability of the neurotransmitter gamma-aminobutyric acid (GABA) to increase conductance of CL- across neuronal membranes, thereby driving membrane potential farther away from its threshold for activation

1) G-stimulatory (Gs) - subunit αs activates adenyl cyclase (drug is an agonist)

2) G-Inhibitory (Gi) - subunit αi inhibits adenyl cyclase (drug is still an agonist b/c it's producing a response)

3) Gq - subunit αq activates phospholipase C (PLC) (drug is an agonist)

Agonist binds to receptor which exchanges GTP-GDP. G-protein subunit αs-GTP activates adenyl cyclase which cleaves ATP to cAMP. cAMP then activates Protein Kinase A which increases protein phosphorylation & gene transcription

Agonist binds to receptor, GTP-GDP is exchanged and G-protein αi inhibits adenyl cyclase.

Agonist binds to receptor, GTP-GDP is exchanged and G-protein subunit αq binds to phospholipase C which cleaves phosphatidylinositol 4,5-biphosphate (PIP2) into IP3 & DAG. DAG activates Protein Kinase C which increases protein phosphorylation and gene transcription. IP3 releases Ca2+ from ER which activates CaM-Kinase and Protein Kinase C.

Transmembrane receptors that transduce an extracellular ligand-binding interaction into an intracellular action through the activation of a linked enzymatic domain

1) Receptor Tyrosine Kinases
2) Receptor Tyrosine Phosphatases
3) Tyrosine Kinase-Associated Receptors
4) Receptor Serine/Threonine Kinases
5) Receptor Guanylyl Cyclases

An extracellular molecule can diffuse through the plasma membrane and bind to intracellular transcription factor receptor which causes a conformational change and leads to the ligand-receptor complex transported into the nucleus where it binds to DNA and transcribed

ACE (angiotensin converting enzyme) & Acetylcholinesterase

ACE Inhibitors & Acetylcholinesterase Inhibitors (Anticholinesterases)

ACE & Kininase II

ACE - lower blood pressure by preventing angiotensin I being converted to the potent vasoconstrictor angiotensin II

Acetylcholinesterase inhibitors - enhance neurotransmission at cholinergic synapses by preventing neurotransmitter degradation

Amplification

Drugs that show diminishing effects over time

In pharmacologic terms the receptor and cell become desensitized to the action of the drug and can lead to tachyphylaxis or tolerance

The period of time required before a cell can again be activated

Prolonged receptor stimulation by ligand induces the cell to endocytose, sequestore or degrade the receptors in endocytic vesicles. This prevents receptors-ligand contact and thus cellular desensitization. Once stimulus whcih caused receptor sequestration subsides, the receptors can be recycled to the cell surface and rendered functional again

1) Osmotic diuretics - control fluid balance by altering the relative levels of H2O and ion absorption and secretion in the kidney

2) Antacids - absorb or chemically neutralize stomach acids

An increase in either the ligand or receptor will increase the drugs effect.

Kd is the dissociation constant, a type of equilibrium constant measuring propensity of larger object (drug-receptor) to seperate into smaller components (drug & receptor)...we use Kd50 which is 50% of ligand bound/dissociated.

Decreasing Kd would increase the affinity...[LR]=[L][R]/Kd

Linear Dose-Response

Linear Drug-Receptor

Semilogarithmic Dose-Response

Semilogarithmic Dose-Receptor

1) Maximum drug-receptor binding occurs when [LR]=Ro, or, [LR]/Ro]=1
2) Kd can be defined as the concentration of ligand at 50% of available receptors occupied

The concentration of receptors that are bound by the drug

Potency (EC50) is the concentration at which the drug elicits 50% of its maximal response

Efficacy (Emax) is the maximal response produced by the drug

Drug-receptor would be normal b/c it is still binding to the receptor

Dose-response would have a flat line as the drug doesn't elicit a response, rather prevents

False - potency is the concentration at which drug elicits 50% max response whereas efficacy is the maximal response which is commonly associated with all receptors occupied by drug

A drug capable of eliciting a maximal response when fewer than 100% of drug's receptors are occupied

Effective dose - dose at which 50% of subjects exhibit a therapeutic response
Toxic dose - dose at which 50% of subjects experience a toxic response
Lethal dose - dose at which 50% of subjects die

ED50 is a dose where 50% of subjects die whereas EC50 is the dose which elicits a half-maximal effect

A molecule that binds to a receptor and stabalizes the receptor in a particular conformation (usually the active conformation)

Antagonist is a molecule that inhibits the action of an agonist but has no effect in the absence of the agonist

Active site binding & Allosteric binding antagonists

Receptor and Nonreceptor antagonists

Reversible (Competitive) & Irreversible (Noncompetitive) active site antagonists

molecule that binds reversibly to the active site of a receptor

molecule that binds irreversibly to the active site of a receptor

Reversible and Irreversible - Both exhibit noncompetitive antagonism

The effect of an irreversible antagonist does not diminish when the free (unbound) drug is eliminated fromt the body, whereas the effect of a reversible antagonist can be "washed out" over time as it dissociates from the receptor.

Competitive antagonists reduce agonist potency, whereas noncompetitive antagonists reduce agonist efficacy

Aspirin is an example of a noncompetitive antagonist

Chemical antagonists inactivate the agonist by modifying or sequestering it, so that the agonist is no longer capable of binding to and activating the receptor (chemically inactivates)

Physiologic antagonist most commonly blocks a different receptor that mediates a response physiologically opposite to that of the receptor for agonist

Molecule that binds to a receptor at its active site but produces only a partial response, even when all the receptors are occupied (bound) by the agonist

False - even when all receptors are occupied by the agonist, partial agonists will only produce a partial response

Therapeutic window is the range of doses (concentrations) of a drug that elicits a therapeutic reponse w/o unacceptable adverse effects (toxicity)

Therapeutic index is: TI=TD50/ED50...TD50 is the toxic dose in 50% of the population and ED50 is the therapeutically effective level for 50% of population

TI quantifies the relative safety...large TI represents a large therapeutic window and thus a safe drug

Competitive antagonists effect agonist potency but not efficacy

Noncompetitive active site antagonists don't effect agonists potency but do effect efficacy

Noncompetitive allosteric antagonists don't effect agonists potency but do effect efficacy

Parmacokinetics affect the amount of free drug that ultimately reaches the target site (ADME)

Drugs are absorbed by exploiting or breaching the natural physiologic barriers

They are then distributed through various system of the body, including blood and lymph

It is then metabolized in which the body inactivates the drug through enzymatic degradation (primarily in liver)

Finally it is excreted (primarily by the kidneys and liver, and feces)

when it is bound to a protein

Membrane diffusion - rate of diffusion depends on concentration gradient of drug across the membrane, thickness, area & permiability of the membrane.
Fick's law of diffusion: Flux=(C2-C1)(Area X Permiability)/(Thickness)
C1 - intracellular conc.
C2 - extracellular conc.

pH Trapping - determined by the drugs acid dissociation constant (pKa) and pH gradient acorss the membrane

pKa - pH = log [HA]/[A-]

Bioavailability is the amount of a drug available to the target organ

Bioavailability=drug reaching circulation/drug administered

Enteral (mouth)
Parenteral (injection)
Mucous membrane
Transdermal (skin)

Adv: Simple, cheap, self-administered, low infection rate

Disadv: Passes through GIT (low pH), first pass metabolism (liver enzymes may inactivate portion of drug), relatively slow delivery

Adv: Rapid onset, high bioavailability

Disadv: Infection, skilled personnel, hurts, irreversible

Adv: Rapid delivery, painless, simple, convenient, low infection, direct delivery to affected organ

Disadv: Few drugs available

Adv: Simple, convenient, painless, excellent prolonged or continuous administration

Disadv: Requires highly lipophilic drug, slow delivery to site, may be irritating

1) Interstitial fluid - stores the most amount of drug

2) Intracellular - stores smaller than interstitial fluids

3) Fat

4) Bone & Teeth

*Any area of increased vascularity means increased drug storage

Volume of distribution is the amount of drug administered which stays in circulation

Vd = Dose/[Drug]plasma

↑Vd = ↑ concentration needed for therapeutic effect

Low

Protein bound drugs keep the Vd low.

The free drug will also be low.

As plasma concentrations decrease so does the elimination

The vessel-rich group is the first to see increased concentrations

Fat actually has the highest potential capacity and lowest blood flow resulting in a greater amount of drug capacity but at a slower rate that is commonly never reached b/c of metabolism and excretion.

Vascularization

Drugs may be (1) filtered at renal glomerulus, (2) secreted into the proximal tubule, (3) reabsorbed from tubular lumen & transported back into blood, (4) excreted in urine

↑blood flow, ↑glomerular filtration rate & ↓plasma protein binding all cause ↑drug excretion

↓renal function also ↓excretion

Drugs that are secreted into bile by the liver and then excreted.

Clearance is the amount of active drug cleared relative to amount in plasma

Clearance = metabolism+excretion/[drug]plasma

Amount of drug excreted is proportional to concentration in plasma

E=(Vmax X C)(Km + C)

↑ concentration(Km) = ↑ elimination

Clearance mechanisms are saturate and no longer see first order kinetics

Half-life is the time over which the drug concentration in the plasma decreases to one-half its original value

t1/2 = 0.693 X Vd/Clearance

Factors that increase half-life:

Decreasing clearance: Liver, kidney, cardiac failure, inhibition of cytochrome P450

Increasing Vd: Obesity, edema/ascites

Absorption, Distribution, Metabolism, Excretion

Csteady state = Bioavailability X Dose/ Dosing interval X Clearance

Absorption primarily determines route of drug administration & helps to determine optimal drug dose (**potency is the most important determinant of drug dose)

Elimination influences half-life which ultimately determines frequency of dose required for maintenance of therapeutic levels.

The loading dose gets you too the therapeutic range quickly. Takes Vd into account.

Loading dose = Vd X Csteady state
↑Vd = ↑Loading dose

Maintenance dose is the dose required to maintain drug concentrations within therapeutic range

Maintenance dose = Clearance X Csteady state
↑Clearance = ↑maintenance dose

Liver - Primary site of metab.
GI
Other organs

Basicly anywhere there's enzymes will break drugs down, but primarily in liver.

Oxidation/Reduction (Phase 1)
Conjugation/Hydrolysis (Phase 2)

Oxidation/Reduction rxn's

Membrane-associated enzymes, typically oxidases, expressed within ER of hepatocytes catalyze phase 1.

Heme protein mon-oxygenases of the CYP P450 antail the majority of these enzymes.

Drug-OH (oxidized/metabolised) drug which is more hydrophilic disolves in urine and is excreted

Conjugation/Hydrolysis

D-glucuronate
D-acetate
D-glycine
D-sulfate
D-glutathione
D-methyl

CYP P450 induction is an increase in the expression of the enzyme through increased transcription, increased translation, or decreased degradation.

Consequences of induction: 1) drug can increase its own metabolism, 2) drug can increase metabolism of co-administered drug, 3) can result in toxic metabolites of reactive drug

Inhibition is the decreased metabolism of drugs by the CYP P450 enzyme and can lead to toxic levels...such things as competitive antagonists & Irreversible antagonists will have such effects

Prodrugs - inactive compounds metabolized by our body into their active, therapeutic form.

Toxic metabolites - the intermediates or products of metabolism which have toxic effect

Pharmacogenomics
Race & Ethnicity
Age & Gender
Diet & Metabolism

1) Inhibition enzymes
2) Induction of enzymes that metabolize the drug itself can cause Pharmacokinetic tolerance - drug inducing own metabolism by increasing the amount of enzyme also reduces its efficacy over time
3) The same enzyme metabolizing two drugs will slow the metabolism and thus result in higher levels of drug in circulation

Innate tolerance - ea. person has own tolerance
Pharmacokinetic tolerance - drug induces body to produce more enzyme to break drug down
Pharmacodynamic tolerance - one sees desensitization, receptor down-regulation & tachyphylaxis
Learned - Substance abuse